Prognostic and predictive molecular markers for urologic cancers - Hartmann, Arndt; Schlomm, T.; Bertz, Simone; Heinzelmann, J.; Hoelters, S.; Simon, R.; Stoehr, R.; Junker, K. (Urologe, 2014)
Molecular prognostic factors and genetic alterations as predictive markers for cancer-specific targeted therapies are used today in the clinic for many malignancies. In recent years, many molecular markers for urogenital cancers have also been identified. However, these markers are not clinically used yet. In prostate cancer, novel next-generation sequencing methods revealed a detailed picture of the molecular changes. There is growing evidence that a combination of classical histopathological and validated molecular markers could lead to a more precise estimation of prognosis, thus, resulting in an increasing number of patients with active surveillance as a possible treatment option. In patients with urothelial carcinoma, histopathological factors but also the proliferation of the tumor, mutations in oncogenes leading to an increasing proliferation rate and changes in genes responsible for invasion and metastasis are important. In addition, gene expression profiles which could distinguish aggressive tumors with high risk of metastasis from nonmetastasizing tumors have been recently identified. In the future, this could potentially allow better selection of patients needing systemic perioperative treatment. In renal cell carcinoma, many molecular markers that are associated with metastasis and survival have been identified. Some of these markers were also validated as independent prognostic markers. Selection of patients with primarily organ-confined tumors and increased risk of metastasis for adjuvant systemic therapy could be clinically relevant in the future.
EVALuna2:6615

Prognostic and Predictive Potential of CCL5 Expression in Muscle-Invasive Bladder Cancer Patients - Smolka, Cedric; Eckstein, Markus; Jung, Rudolf; Lieb, Verena; Sikic, Danijel; Stöhr, Robert; Bahlinger, Veronika; Bertz, Simone; Kehlen, Astrid; Hartmann, Arndt; Wullich, Bernd; Taubert, Helge; et al. (International Journal of Molecular Sciences, 2024)
Bladder cancer (BC) is the 12th most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, prognostic and predictive markers for tumor cells and immune cells are still needed. Using a tissue microarray, we analyzed the expression of the chemokine CC motif ligand 5 (CCL5) by immunohistochemistry (IHC) in 175 muscle-invasive BC samples. The application of a single cutoff for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; positive vs. negative) revealed 75 patients (42.9%) and 123 patients (70.3%) with CCL5-positive TCs or ICs, respectively. IHC results were associated with prognostic and predictive data. Multivariate Cox regression analysis revealed that positive CCL5 staining in TCs was associated with significantly shorter disease-specific survival (DSS; RR = 1.51; p = 0.047), but CCL5-negative ICs were associated with significantly shorter overall survival (OS; RR = 1.66; p = 0.005), DSS (RR = 2.02; p = 0.001) and recurrence-free survival (RFS; RR = 1.94; p = 0.002). Adjuvant chemotherapy was favorable for patients with CCL5-negative ICs for OS (RR = 0.30; p = 0.006), DSS (RR = 0.36; p = 0.022) and RFS (RR = 0.41; p = 0.046) but not for patients with CCL5-positive ICs, except in the subgroup of N1 + N2 patients, where it was associated with better OS. We suggest that CCL5 expression can be a prognostic and predictive marker for muscle-invasive bladder cancer patients.
CRIS-Team Scopus Importer:2024-07-12
Keywords: CCL5; chemokine; chemotherapy; immune cells; muscle-invasive bladder cancer; prognosis; tumor cells

Prognostic and Predictive Value of Fibroblast Growth Factor Receptor Alterations in High-grade Non–muscle-invasive Bladder Cancer Treated with and Without Bacillus Calmette-Guérin Immunotherapy - Mayr, Roman; Eckstein, Markus; Wirtz, Ralph M.; Santiago-Walker, Ademi; Baig, Mahadi; Sundaram, Ramesh; Carcione, Jenna Cody; Stöhr, Robert; Hartmann, Arndt; Bolenz, Christian; Burger, Maximilian; Otto, Wolfgang; et al. (European Urology, 2022)
Background: Limited data are available on the prognostic and predictive value of fibroblast growth factor receptor alterations (FGFRa) relative to clinical outcomes in patients with non–muscle-invasive bladder cancer (NMIBC). Objective: To determine whether FGFRa may be clinically useful in stratifying for treatment response in a real-world cohort of patients with pT1 NMIBC treated and untreated with bacillus Calmette-Guérin (BCG) instillation therapy. Design, setting, and participants: A pooled dataset of matched clinical and genomic data (1992–2015) for pT1 NMIBC patients was assessed by the Bladder Cancer Research Initiative for Drug Targets in Germany consortium. Outcome measurements and statistical analysis: Key efficacy outcomes were recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS), which were estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model. Results and limitations: In this retrospective study of 263 patients with high-grade NMIBC, at a median follow-up of 63 mo, 32% showed recurrence and 15% progressed to muscle-invasive bladder cancer. FGFRa were found in 43% of patients, including 39% mutations and 5.7% fusions. FGFRa were associated with lower rates of concomitant carcinoma in situ. Among patients with or without FGFRa, there was no significant difference in PFS, RFS, and DSS in those who were BCG treated or BCG naive, or in the overall population. Limitations include the retrospective design from a single-center setting. Conclusions: In patients with high-risk NMIBC, FGFRa were frequently observed. Patients with FGFRa who often exhibit recurrence/relapse after BCG treatment have a high unmet need. Patient summary: Our retrospective study suggests that fibroblast growth factor receptor alterations (FGFRa) occur frequently in non–muscle-invasive bladder cancer (NMIBC). Outcomes were similar with or without FGFRa in patients with NMIBC, both overall and for standard bacillus Calmette-Guérin (BCG) treatment.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Bacillus Calmette-Guérin; Bladder cancer; FGFR alterations; Fibroblast growth factor receptor; Non–muscle-invasive bladder cancer

Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer - Fasching, Peter; Gaß, Paul; Häberle, Lothar; Volz, Bernhard; Hein, Alexander; Hack, Carolin; Lux, Michael P.; Jud, Sebastian; Hartmann, Arndt; Beckmann, Matthias; Slamon, Dennis J.; Erber, Ramona (Breast Cancer Research and Treatment, 2019)
Purpose: Several clinical trials have investigated the prognostic and predictive usefulness of molecular markers. With limited predictive value, molecular markers have mainly been used to identify prognostic subgroups in which the indication for chemotherapy is doubtful and the prognosis is favorable enough for chemotherapy to be avoided. However, limited information is available about which groups of patients may benefit from additional therapy. This study aimed to describe the prognostic effects of Ki-67 in several common subgroups of patients with early breast cancer. Methods: This retrospective study analyzed a single-center cohort of 3140 patients with HER2−, hormone receptor-positive breast cancer. Five-year disease-free survival (DFS) rates were calculated for low (< 10%), intermediate (10–19%), and high (≥ 20%) Ki-67 expression levels, as assessed by immunohistochemistry, and for subgroups relative to age, body mass index, disease stage, tumor grade, and (neo-)adjuvant chemotherapy. It was also investigated whether Ki-67 had different effects on DFS in these subgroups. Results: The 5-year DFS rates for patients with low, intermediate, and high levels of Ki-67 expression were 0.90, 0.89, and 0.77, respectively. Ki-67 was able to further differentiate patients with an intermediate prognosis into different prognostic groups relative to common clinical parameters. Patients with stage II breast cancer had 5-year DFS rates of 0.84, 0.88, and 0.79 for low, intermediate, and high levels of Ki-67 expression. Ki-67 had different prognostic effects in subgroups defined by age and tumor grade. Conclusions: Ki-67 may help identify patients in intermediate prognostic groups with an unfavorable prognosis who may benefit from further therapy.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Breast cancer; Ki-67; Molecular marker; Prognosis; Proliferation

Prognostic factors in clear cell sarcoma: an analysis of soft tissue sarcoma in 43 cases - Grothues, Janik; Hardes, Jendrik; Agaimy, Abbas; Collaud, Stephane; Podleska, Lars E.; Farzalyev, Farhad; Engel, Nina Myline; Hamacher, Rainer; Fletcher, Benjamin; Pöttgen, Christoph; Bertram, Stefanie; Schildhaus, Hans-Ulrich; et al. (Journal of Cancer Research and Clinical Oncology, 2024)
Purpose: Clear cell sarcoma (CCS) of tendons and aponeuroses and CCS-like malignant gastrointestinal neuroectodermal tumor/sarcoma (GINET) are characterized by frequent local and distant relapses, alongside with low efficacy of all systemic treatments. We aimed to collect a comprehensive dataset to identify prognostic factors and treatment outcomes. Methods: We performed a retrospective single center analysis for diagnosed CCS and GINET on demographic, tumor, treatment and survival data. Results: We identified 43 patients (w:25, m:18) with a median follow-up of 35mo and a 5y-OS-rate of 42%. At diagnosis the median age was 42yrs. Median tumor size was 3.6 cm (0.3–11.1 cm), and 24/26 (94%) tissues analyzed at our institute were EWSR1::ATF1-translocation-positive. Distant extremities (incl. knee or elbow) were affected in 72.5%. Of note, 79.5% received an excisional biopsy (benign histology suspected in 30.2%) leading to frequent incomplete resection. Final R0 status correlated significantly (p = 0.017) with longer survival rates compared to R + status in localized CCS (N0M0, 5-yr OS 0% vs 64%). Radiation and systemic treatment had limited antitumor effects while isolated limb perfusion was active in some patients. 18.6% of patients showed lymphatic spread and 20.9% distant metastases. Presence of initial M + was associated with a dismal survival of 1.4 years (M +) vs 7.1 years (M0; p <.001). Conclusion: We here present one of the largest clinical cohorts of patients with CCS/GINET. Our data underscores the exceptional risk of metastatic disease even in small tumors. As systemic treatment and radiation showed limited efficacy, complete resection was the most important treatment option.
CRIS-Team Scopus Importer:2024-11-29
Keywords: CCS; Clear cell sarcoma; EWSR1; Gastrointestinal sarcoma; Malignant melanoma of soft tissue; Prognostic factors

Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study - Dyrskjot, Lars; Reinert, Thomas; Algaba, Ferran; Christensen, Emil; Nieboer, Daan; Hermann, Gregers G.; Mogensen, Karin; Beukers, Willemien; Marquez, Mirari; Segersten, Ulrika; Hoyer, Soren; Ulhoi, Benedicte P.; et al. (European Urology, 2017)
BACKGROUND: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. RESULTS AND LIMITATIONS: The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.
EVALuna2:33571

Prognostic impact of molecular muscle-invasive bladder cancer subtyping approaches and correlations with variant histology in a population-based mono-institutional cystectomy cohort - Weyerer, Veronika; Stöhr, Robert; Bertz, Simone; Lange, Fabienne; Geppert, Carol-Immanuel; Wach, Sven; Taubert, Helge; Sikic, Danijel; Wullich, Bernd; Hartmann, Arndt; Eckstein, Markus (World Journal of Urology, 2021)
Purpose Recently discovered molecular classifications for urothelial bladder cancer appeared to be promising prognostic and predictive biomarkers. The present study was conducted to evaluate the prognostic impact of molecular subtypes assessed by two different methodologies (gene and protein expression), to compare these two approaches and to correlate molecular with histological subtypes in a consecutively collected, mono-institutional muscle-invasive bladder cancer (MIBC) cohort. Methods 193 MIBC were pathologically re-evaluated and molecular subtypes were assessed on mRNA (NanoString technology, modified 21-gene-containing MDACC approach) and protein levels (immuno-histochemical [IHC] analysis of CK5, CK14, CD44, CK20, GATA3 and FOXA1). Descriptive statistical methods and uni-/multi-variable survival models were employed to analyze derived data. Results Neither gene expression nor protein-based subtyping showed significant associations with disease-specific (DSS) or recurrence-free survival (RFS). Agreement between mRNA (reference) and protein-based subtyping amounted 68.6% for basal, 76.1% for luminal and 50.0% for double-negative tumors. Histological subtypes associated with RFS in uni-variable (P = 0.03), but not in multivariable survival analyses. Tumors with variant histology predominantly showed luminal subtypes (gene expression subtyping: 36/55 cases, 65.5%; protein subtyping: 44/55 cases, 80.0%). Squamous differentiation significantly associated with basal subtypes (gene expression subtyping: 44/45 squamous cases, 97.8%; protein subtyping: 36/45 cases, 80.0%). Conclusion In our consecutive cystectomy cohort, neither gene, protein expression-based subtyping, nor histological subtypes associated with DSS or RFS in multi-variably adjusted survival analyses. Application of a limited IHC subtyping marker panel showed high concordance of 83.9% with gene expression-based subtyping, thus underlining the utility for subtyping in pathological routine diagnostics. In addition, histological MIBC subtypes are strong indicators for intrinsic subtypes.
CRIS-Team WoS Importer:2021-07-23

Prognostic impact of PD-1 and its ligands in renal cell carcinoma - Erlmeier, Franziska; Weichert, Wilko; Schrader, Andres Jan; Autenrieth, Michael; Hartmann, Arndt; Steffens, Sandra; Ivanyi, Philipp (Medical Oncology, 2017)
Programmed death-1 receptor (PD-1) and programmed death-1 receptor-ligand (PD-L1) have been suggested to play a role as prognostic markers in clear cell renal cell carcinoma (ccRCC). The association between PD-L1 and prognosis seems to be more robust than for PD-1. Further, preliminary analyses suggest that neither PD-1 nor its ligands play a role as prognostic markers in non-clear cell RCC, while the prognostic role of PD-L2 in ccRCC as well as in non-clear cell RCC remains unclear.
EVALuna2:6874

Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy - Claps, Francesco; van de Kamp, Maaike W.; Mayr, Roman; Bostrom, Peter J.; Shariat, Shahrokh F.; Hippe, Katrin; Bertz, Simone; Neuzillet, Yann; Sanders, Joyce; Otto, Wolfgang; van der Heijden, Michiel S.; Jewett, Michael A.S.; et al. (Bju International, 2023)
Objectives: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). Materials and Methods: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox’ regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as ‘organ-confined’ (≤pT2N0), ‘locally advanced’ (pT3-4N0) and ‘node-positive’ (pTanyN1-3). Results: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. Conclusions: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.
CRIS-Team Scopus Importer:2023-03-03
Keywords: #BladderCancer; #blcsm; #uroonc; #utuc; bladder urothelial carcinoma; prognosis; radical cystectomy; survival; variant histology

Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients - Mertens, Laura S.; Claps, Francesco; Mayr, Roman; Bostrom, Peter J.; Shariat, Shahrokh F.; Zwarthoff, Ellen C.; Boormans, Joost L.; Abas, Cheno; van Leenders, Geert J.L.H.; Götz, Stefanie; Hippe, Katrin; Bertz, Simone; et al. (Urologic Oncology-Seminars and Original Investigations, 2022)
Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. Patients and methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). Results: pT-stage was
CRIS-Team Scopus Importer:2022-03-04
Keywords: Bladder; Cancer; Cystectomy; FGFR3; Immunohistochemistry; Ki-67; Mutation; p53; Urothelial carcinoma

Prognostic relevance of Ki-67 in the primary tumor for survival after a diagnosis of distant metastasis - Loehberg, Christian R.; Almstedt, Katrin; Jud, Sebastian; Haeberle, Lothar; Fasching, Peter; Hack, Carolin; Lux, Michael P.; Thiel, Falk; Schrauder, Michael G.; Brunner, Michaela; Bayer, Christian M.; Hein, Alexander; et al. (Breast Cancer Research and Treatment, 2013)
Prediction of the prognosis for metastatic breast cancer patients depends on molecular subtypes similar to those found in patients with primary breast cancer. Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) status determine the course of the disease and the prognosis. As Ki-67 helps to differentiate molecular subtypes in patients with primary breast cancer, the aim of this study was to assess the prognostic relevance of Ki-67 in the primary tumor in relation to its prognostic relevance for patients with metastatic breast cancer. A total of 467 patients with invasive breast cancer were identified in the database of a single breast cancer center, in whom Ki-67 had been assessed in tumor material from the breast at the time of the primary diagnosis and who had developed a metastasis at any time during the subsequent course. For these patients, tumor and patient characteristics were used to determine prognostic factors relative to overall survival after the diagnosis of distant metastases. Ki-67 was added to this model to investigate whether this might improve the prediction of overall survival. In the multivariate Cox model, age at diagnosis, body mass index, nodal status, tumor size, ER and PR status, and time from diagnosis to metastasis were identified as relevant prognostic factors. Adding Ki-67 to the model improved the prediction of overall survival. There was also a significant and relevant interaction with the PR status. In patients with a low-proliferation primary tumor, a high level of PR expression would indicate an extraordinarily good prognosis (HR 0.39; 95 % CI, 0.23-0.66). In patients with higher-proliferation primary tumors, PR status was not capable of differentiating prognostic groups. Ki-67 is useful in addition to known prognostic factors for breast cancer. It is able to indicate a group of women with a poorer prognosis, specifically in the group of patients with PR-positive breast cancer. © 2013 Springer Science+Business Media New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Ki-67; Metastatic breast cancer; Progesterone receptor; Prognosis; Proliferation

Prognostic Role of FGFR Alterations and FGFR mRNA Expression in Metastatic Urothelial Cancer Undergoing Checkpoint Inhibitor Therapy - Tully, Karl H.; Jütte, Hendrik; Wirtz, Ralph M.; Jarczyk, Jonas; Santiago-Walker, Ademi; Zengerling, Friedemann; Breyer, Johannes; Sikic, Danijel; Kriegmair, Maximilian C.; von Hardenberg, Jost; Wullich, Bernd; Taubert, Helge; et al. (Urology, 2021)
Objective: To examine the disease-specific survival(DSS) after checkpoint inhibitor(CPI) therapy based on FGFR alterations and FGFR mRNA expression levels in patients with metastatic urothelial cancer(mUCa) within a multi-center cohort. Methods: Within a cohort of 72 patients with mUCa from five academic centers in Germany FGFR alterations, as well as FGFR1-4 mRNA expression levels in tumor samples from the primary tumor or metastatic sites. Spearman rank correlations, logistic regression, as well as Kaplan-Meier survival analyses and univariate Cox proportional hazards regression models were employed to examine the impact of different FGFR patterns on the DSS after CPI treatment. Results: FGFR3 mutations or gene fusions (gene alterations) were detected in 16.9% of all samples. Patients with or without FGFR3 gene alterations did not show different oncological outcomes undergoing CPI treatment. Low expression of FGFR2 mRNA alone, as well as the combination of either low FGFR2mRNA expression and FGFR3 gene alteration or high FGFR3mRNA expression (P = 0.027), identified a subgroup of patients with unfavorable outcomes, comprising 40% of the total cohort. This trend was also observed in univariate Cox proportional hazards regression analysis(FGFR3 gene alteration: Hazard ratio(HR) 5.33, 95%Confidence interval(CI)1.76-15.0, P = 0.004; FGFR3mRNA expression:HR 3.04, 95%CI 1.40-7.13, P = 0.005). Conclusion: Assessment of FGFR mRNA expression identified a high-risk subgroup of patients with mUCa. These patients showing overexpression of FGFR3 mRNA were found to have unfavorable DSS after CPI treatment. Using this approach may be suitable for identifying a patient population with poor response to CPI treatment, which may benefit from early FGFR inhibition.
CRIS-Team Scopus Importer:2021-07-30

Prognostic role of FGFR Mutations and FGFR mRNA expression in metastatic urothelial cancer treated with anti-PD(L1) inhibitors in first and second-line setting - Roghmann, F.; Wirtz, R.; Jarczyk, J.; Kriegmair, M. C.; Worst, T. S.; Sikic, D.; Wach, S.; Taubert, Helge; Wullich, Bernd; Weyerer, Veronika; Stöhr, Robert; Zengerling, F.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Prognostic significance of PD-L2 expression in patients with oral squamous cell carcinoma-A comparison to the PD-L1 expression profile - Weber, Manuel; Wehrhan, Falk; Baran, Christoph; Agaimy, Abbas; Büttner-Herold, Maike; Kesting, Marco Rainer; Ries, Jutta (Cancer Medicine, 2019)
BACKGROUND: Despite the observed association of increased PD-L1 expression in peripheral blood of oral squamous cell carcinoma (OSCC) patients with histomorphologic parameters, the role of the PD1 ligands-PD-L1 and PD-L2-is insufficiently understood. Aim of the study was to investigate whether the alterations of PD-L1 and PD-L2 expression in blood are associated with survival and could serve as immune monitoring parameter. Moreover, it should be analyzed if PD-L2 is differentially expressed in tissue and blood samples of OSCC patients compared to healthy controls and if there is an association of PD-L2 expression with histomorphologic and prognostic tumor parameters. METHODS: PD-L2 mRNA expression was analyzed in tumors and healthy oral mucosa specimens and in corresponding peripheral blood samples of 48 OSCC patients and 26 healthy controls using RT-qPCR. A cutoff point (COP) was determined and a chi-square test (χ2 test) was carried out. Survival analysis of PD-L2 and previously reported PD-L1 expression data was performed using Kaplan-Meier analysis (Log-rank test). RESULTS: PD-L2 expression in tissue samples was significantly (P < 0.001) higher in OSCC patients compared to healthy controls. A significant association of PD-L2 expression above the COP (positive) with malignancy was ascertained (P < 0.001). A significant (P = 0.01) association of previously reported PD-L1 expression rates in peripheral blood with survival could be shown. CONCLUSION: Peripheral blood PD-L1 expression might be a prognostic marker for OSCC patients and a possible parameter to monitor immune dysfunction in malign diseases. In the peripheral blood, PD-L1 might be more relevant for immune tolerance than PD-L2. Local PD-L2 expression in tissue samples might be useful as a diagnostic parameter for malignancy and could contribute to the immunosuppressive local microenvironment in OSCC.
EVALuna2:35498

Prognostic subdivision of pT2 rectal carcinomas - Merkel, Susanne; Weber, Klaus; Brunner, Maximilian; Baecker, Justus; Agaimy, Abbas; Göhl, Jonas; Hohenberger, Werner; Schellerer, Vera; Grützmann, Robert (International Journal of Colorectal Disease, 2019)
Purpose The aim of the present study is to explore the prognostic impact of a subdivision of pT2 by the depth of invasion into the muscularis propria in rectal carcinomas.
CRIS-Team WoS Importer:2019-04-18

Prognostic subdivision of ypT3 rectal tumours according to extension beyond the muscularis propria - Merkel, Susanne; Weber, K.; Schellerer, Vera; Göhl, Jonas; Fietkau, Rainer; Agaimy, Abbas; Hohenberger, Werner; Hermanek, Peter (British Journal of Surgery, 2014)
The subdivision of T3 in rectal carcinoma according to the depth of invasion into perirectal fat has been recommended in the TNM Supplement since 1993. This study assessed the prognostic impact of this pathological staging in tumours removed after neoadjuvant chemoradiotherapy (ypT3).Data from patients with ypT3 rectal carcinoma (less than 12 cm from the anal verge) treated with neoadjuvant chemoradiation and total mesorectal excision were analysed. Tumour category ypT3 was subdivided into ypT3a (5 mm or less) and ypT3b (more than 5 mm), based on histological measurements of maximal tumour invasion beyond the outer border of the muscularis propria.Important differences between ypT3a (81 patients) and ypT3b (43) were found in 5-year rates of locoregional recurrence (7 versus 18 per cent; P = 0·049), distant metastasis (20 versus 41 per cent; P = 0·002), disease-free survival (73 versus 47 per cent; P = 0·001), overall survival (79 versus 74 per cent; P = 0·036) and cancer-related survival (81 versus 74 per cent; P = 0·007). In Cox regression analyses, the ypT3 subclassification was identified as an independent prognostic factor for disease-free (ypT3b: hazard ratio (HR) 2·13, 95 per cent confidence interval 1·16 to 3·89; P = 0·014), observed (ypT3b: HR 2·02, 1·05 to 3·87; P = 0·035) and cancer-related (ypT3b: HR 2·46, 1·20 to 5·04; P = 0·014) survival. Extramural venous invasion was found to be an additional prognostic factor, but the pathological node category after chemoradiotherapy (ypN) did not influence survival.In ypT3 rectal carcinomas, the proposed subclassification is superior to ypN in predicting prognosis.
EVALuna2:6571

Prognostic Value of Molecular Breast Cancer Subtypes based on Her2, ESR1, PGR and Ki67 mRNA-Expression in Muscle Invasive Bladder Cancer - Kriegmair, M. C.; Wirtz, R. M.; Worst, T. S.; Breyer, J.; Ritter, M.; Keck, Bastian; Boehmer, C.; Otto, W.; Eckstein, Markus; Weis, C. A.; Hartmann, Arndt; Bolenz, C.; et al. (Translational Oncology, 2018)
INTRODUCTION: Gene expression analyses have identified similarities between bladder and breast cancer, where clinical risk stratification is based on Her2, ESR1, PGR and Ki67 expression. The aim of the study was to assess the respective marker gene expression in patients treated with radical cystectomy for muscle-invasive bladder cancer (MIBC) and to evaluate the applicability of breast cancer subtypes for MIBC risk stratification. MATERIALS & METHODS: 102 patients treated with radical cystectomy for MIBC were assessed. Using routine FFPE tissue and an IVD validated kit, mRNA expression was measured by single step RT-qPCR. Partition test were employed to define cut-off values for high or low marker gene expression. Association of expression with outcome was assessed using Kaplan-Meier analysis and multivariate cox regression analysis. Finally, we performed validation of our results in the MD-Anderson cohort (n=57). RESULTS: Cancer specific survival (CSS) was impaired in patients with high gene expression of Her2 (P=0.0009) and ESR1 (P=0.04). In the multivariate regression model Her2 expression remained significant for the prediction of CSS (HR=2.11, CI 1.11-4.21, P=0.024). Furthermore, molecular stratification by breast cancer subgroups was significant (P=0.023) for CSS prediction. Especially the differentiation between Her2-positive and Luminal A (HR=4.41, CI 1.53-18.71, P=0.004) and Luminal B (HR=1.96, CI 0.99-4.08, P=0.053) respectively was an independent prognostic parameter for CSS. External validation resulted in comparable risk stratification with differences in fractional subgroups distribution. CONCLUSION: Gene expression of Her2, ESR1, PGR, Ki67 and corresponding breast cancer subtypes allow a risk-stratification in MIBC, whereby Her2 overexpressing tumors reveal a particularly poor prognosis.
EVALuna2:34058

Prognostic value of O-6-methylguanine-DNA methyltransferase loss in salivary gland carcinomas - Scesnaite, Asta; Jarmalaite, Sonata; Müller, Maximilian; Agaimy, Abbas; Zenk, Johannes; Hartmann, Arndt; Iro, Heinrich; Peters, Brigitte; Schwarz, Susanne; Schneider-Stock, Regine (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2014)
The purpose of this study was to determine the prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) inactivation in a group of 286 patients with salivary gland carcinoma and matched histologically normal tissues.MGMT promoter methylation was studied in 36 patients with salivary gland carcinoma and 19 histologically matched normal tissues by pyrosequencing. MGMT protein expression was examined in 286 patients with salivary gland carcinomas and histologically matched normal tissues by immunohistochemistry on tissue microarrays. The results were correlated to demographic, clinicopathologic parameters, and disease follow-up data.MGMT hypermethylation was significantly (p = .021) associated with the protein loss. MGMT loss was found in 39.2% of salivary gland carcinomas and was predominant in aggressive tumors (poorly differentiated, grade III, regional lymph node involved). MGMT loss significantly (p = .004) predicted poor clinical outcome of salivary gland carcinomas and defined high-risk subgroups in clinically favorable tumor groups.We suggest that immunohistochemical evaluation of nuclear MGMT protein might serve as a tool for the prediction of overall survival in patients with salivary gland carcinoma.
EVALuna2:6616

Prognostic value of β1 integrin expression in colorectal liver metastases. - Vassos, Nikolaos; Rau, Tilman; Merkel, Susanne; Feiersinger, Fabian; Geppert, Carol-Immanuel; Stürzl, Michael; Hohenberger, Werner; Croner, Roland S. (International Journal of Clinical and Experimental Pathology, 2014)
Integrins are cell surface adhesion molecules (CAM) that regulate via intercellular and cell-matrix signaling various cellular processes including wound healing, cell differentiation, division, growth, migration and metastatic dissemination. Although a correlation between carcinogenesis and changes in integrin expression, especially β1 integrin, has been reported, its role in colorectal liver metastases remains unclear. This study aimed to evaluate the expression of β1 integrin in colorectal liver metastases and to correlate the pattern of expression with clinicopathological features and to investigate the putative role of β1 integrin expression on survival of these patients. Formalin-fixed, paraffin-embedded (FFPE) tumor samples of 81 patients who were operated because of colorectal liver metastases without any neoadjuvant therapy were obtained and stained with hematoxylin and eosin (H & E). An immunohistochemical examination was performed using Dako, Peroxidase/DAB kit and a primary monoclonal β1 integrin (CD29, fibronectin receptor subunit beta; ab3167, Abcam plc). β1 integrin expression was evaluated according to the immunoreactive score of Remmele and Stegner and was related with clinicopathological features of prognostic significance and with disease-free and overall survival as well. Statistical analysis was performed using SPSS version 21.0. β1 integrin was overexpressed in tumor cells in 37 (48%) patients and in stromal cell in 27 (33%) patients. The β1 expression was not statistically correlated with clinicopathological features of the primary tumors but it was statistically correlated (p=0.03) with the histological grading of liver metastases. Kaplan-Meier survival analysis showed that there is a tendency but no statistically significant correlation in disease-free and overall survival. Considering that expression of β1 integrin in colorectal liver metastases remains controversial, specially its relation with survival of patients, we showed that the β1 expression represents a reliable prognostic factor regarding the grading of liver metastases of CRC and our findings imply that β1 integrin expression profiles may have further potential in identifying the stage of colorectal liver metastases and being a marker of prognosis in these patients. UNLABELLED METHODS RESULTS CONCLUSION

Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) expression in fumarate hydratase-deficient renal cell carcinoma - Alaghehbandan, Reza; Stehlik, Jan; Trpkov, Kiril; Magi-Galluzzi, Cristina; Mundo, Enric Condom; Foix, Maria Pane; Berney, Daniel; Sibony, Mathilde; Suster, Saul; Agaimy, Abbas; Montiel, Delia Perez; Pivovarcikova, Kristyna; et al. (Annals of Diagnostic Pathology, 2017)
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR. By IHC, PD-1 was negative in tumor cells in all 13 cases. PD-L1 was positive in tumor cells in 2/13 cases, weak positive in 7/13, and negative in 4/13 cases, respectively. In TILs, PD-1 was positive in 1/13, weak positive in 3/13, and negative in 9/13 cases. In TILs, PD-L1 was weak positive by IHC in 5/13, and negative in 8/13 cases, respectively. qPCR confirmed the result for 2 of 3 IHC weak positive PD-1 samples. Of 7 IHC weak positive samples (in tumor cells), PD-L1 mRNA was detected in all 7 tumors. The majority of FH-RCCs did not express PD-1/PD-L1 by IHC, which was confirmed by molecular analysis. PD-1/PD-L1 expression in FH-RCC is restricted to a proportion of cases which may benefit from targeted therapies.
EVALuna2:6888

Programmed death ligand 1 (PD-L1) in colon cancer and its interaction with budding and tumor-infiltrating lymphocytes (TILs) as tumor-host antagonists - Lang-Schwarz, Corinna; Melcher, Balint; Hartmann, Arndt; Bertz, Simone; Dregelies, Theresa; Lang-Schwarz, Klaus; Vieth, Michael; Sterlacci, William (International Journal of Colorectal Disease, 2021)
Purpose To analyze the role of programmed death ligand 1 (PD-L1) immunohistochemisty in the context of tumor microenvironment in colon cancer (CC) with focus on the interaction between tumor budding and tumor-infiltrating lymphocytes (TILs) and to elucidate its potential value for immunooncologic treatment decisions. Methods Three hundred forty seven patients with CC, stages I to IV, were enrolled. PD-L1 immunohistochemistry was performed using two different antibodies (clone 22C3 pharmDx, Agilent and clone QR1, Quartett). Tumor proportion score (TPS) as well as immune cell score (IC) was assessed. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and International TILs Working Group (ITWG). Correlation analyses as well as survival analyses were performed. Results PD-L1 positivity significantly correlated with TILs > 5% and MMR deficiency, and PD-L1-positive cases (overall and IC) showed significantly longer overall survival (OS) with both antibodies.The parameters "high grade," "right-sidedness," and "TILS > 5% regardless of MMR status" evolved as potential parameters for additional immunological treatment decisions. Additionally, TPS positivity correlated with low budding. More PD-L1-positive cases were seen in both high TIL groups. The low budding/high TIL group showed longer disease-free survival and longer OS in PD-L1-positive cases. Conclusion Overall, PD-L1 positivity correlated with markers of good prognosis. PD-L1 immunohistochemistry was able to identify parameters as additional potential candidates for immune therapy. Furthermore, it was able to stratify patients within the low budding/high TIL group with significant prognostic impact.
CRIS-Team WoS Importer:2021-07-16

Progranulin (GP88) is an independent prognostic factor for prostate cancer patients - Taubert, Helge; Abdulrahman, Amer; Eckstein, Markus; Jung, Rudolf; Guzman, Juan; Weigelt, Katrin; Serrero, Ginette; Yue, Binbin; Geppert, Carol-Immanuel; Stöhr, Robert; Hartmann, Arndt; Wullich, Bernd; et al. (CANCER RESEARCH, 2020)
CRIS-Team WoS Importer:2021-03-05

Progression-free survival and overall survival in patients with advanced her2-positive breast cancer treated with trastuzumab emtansine (T-dm1) after previous treatment with pertuzumab - Michel, Laura L.; Hartkopf, Andreas D.; Fasching, Peter; Kolberg, Hans Christian; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; Lüftner, Diana; Wallwiener, Markus; Müller, Volkmar; Beckmann, Matthias; et al. (Cancers, 2020)
The approval of trastuzumab emtansine (T-DM1) was conducted without pertuzumab as previous therapy. Efficacy data on T-DM1 following pertuzumab treatment are therefore limited. This study explores this issue in a real-world setting. Within the prospective PRAEGNANT (Prospective Academic Translational Research Network for the Optimization of the Oncological Health Care Quality in the Advanced Setting) metastatic breast cancer registry (NCT02338167), patients in all therapy lines receiving any kind of treatment were eligible for inclusion. This report describes patient characteristics and progression-free survival (PFS) in human epidermal growth factor receptor 2 (HER2)-positive patients receiving T-DM1 after pertuzumab treatment. Seventy-six patients were identified, 39 of whom received T-DM1 as second-line therapy, 25 as third-line, and 12 as fourth-line therapy or higher. Pertuzumab was mostly administered as a first-line treatment (n = 61; 80.3%). The median PFS in all patients was 3.5 months (95% CI: 2.8–7.8); in second-line treatment, 7.7 months (95% CI: 2.8–11.0); in third-line, 3.4 months (95% CI: 2.3–not reached (NR)); and in fourth-line therapy or higher, 2.7 months (95% CI: 1.2–NR). T-DM1 was mainly administered second-line after pertuzumab, but also in more heavily pretreated patients. The PFS in higher therapy lines appears to be shorter than in second-line.
CRIS-Team Scopus Importer:2020-10-30
Keywords: Advanced breast cancer; Chemotherapy; HER2 c-erbB2; HER2/neu; Metastatic; Pertuzumab; T-DM1; Trastuzumab

Prominent entrapment of respiratory epithelium in primary and metastatic intrapulmonary non-epithelial neoplasms: a frequent morphological pattern closely mimicking adenofibroma and other biphasic pulmonary lesions - Erber, Ramona; Haller, Florian; Hartmann, Arndt; Agaimy, Abbas (Virchows Archiv, 2020)
As one of the most common target organs for hematogenous spread from diverse cancers, biopsy interpretation of lung tumors is complicated by the challenging question of primary versus metastatic and by frequent entrapment of native respiratory glands. Nevertheless, the literature dealing with this issue is surprisingly sparse and no single study has been devoted to this topic. We reviewed 47 surgical lung specimens of non-epithelial neoplasms (38 metastases, mainly from sarcomas and 9 primary lesions) for frequency and pattern of intralesional epithelial entrapment. Respiratory epithelium entrapment was noted in 23/47 (49%) cases (diffuse in 15 and peripheral in 8). Entrapped glands frequently showed prominent regenerative and reactive changes mimicking neoplastic glands. Based on cellularity of the mesenchymal component and the extent, distribution and shape of entrapped respiratory glands, four morphological patterns were recognized: paucicellular sclerosing low-grade neoplasms containing leaflet-like glands indistinguishable from adenofibroma and fibroepithelial hamartomas (n = 11), and biphasic cellular lesions mimicking adenomyoepithelioma (n = 1), biphasic synovial sarcoma (n = 2), and pleuropulmonary blastoma (n = 1). Only a single genuine pulmonary adenofibroma was identified. This study highlights frequent respiratory epithelium entrapment in diverse non-epithelial lung tumors, both primary and metastatic. Recognition of this finding and use of adjunct IHC combined with clinical history should help to avoid misinterpretation as primary pulmonary biphasic neoplasm or as harmless adenofibroma. The vast majority of morphologically defined lung adenofibromas represent adenofibroma-like variants of histogenetically diverse entities so that a diagnosis of adenofibroma should be rendered only very restrictively and then as a diagnosis by exclusion.
CRIS-Team WoS Importer:2020-04-07

Proposal for a new M1 subclassification in colorectal carcinoma - Merkel, Susanne; Weber, K.; Croner, R.; Golcher, H.; Göhl, Jonas; Agaimy, Abbas; Semrau, S.; Wein, Axel; Hohenberger, Werner; Wittekind, C.; Siebler, Jürgen (2016)
EVALuna2:2176

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes. - Eckstein, Markus; Matek, Christian; Wagner, Paul; Erber, Ramona; Büttner-Herold, Maike; Wild, Peter J.; Taubert, Helge; Wach, Sven; Sikic, Danijel; Wullich, Bernd; Geppert, Carol-Immanuel; Compérat, Eva M.; et al. (European Urology Oncology, 2024)
BACKGROUND: Grading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. OBJECTIVE: To develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. DESIGN, SETTING, AND PARTICIPANTS: Tissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: GGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. RESULTS AND LIMITATIONS: Integration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. CONCLUSIONS: We propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. PATIENT SUMMARY: We developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.
EVALuna2:539845

Proposal of a T3 Subclassification for Colon Carcinoma. - Merkel, Susanne; Brunner, Maximilian; Geppert, Carol-Immanuel; Grützmann, Robert; Weber, Klaus; Agaimy, Abbas (Cancers, 2022)
The TNM classification system is one of the most important factors determining prognosis for cancer patients. In colorectal cancer, the T category reflects the depth of tumor invasion. T3 is defined by a tumor that invades through the muscularis propria into pericolorectal tissues. The data of 1047 patients with complete mesocolic excision were analyzed. The depth of invasion beyond the outer border of the muscularis propria into the subserosa or into nonperitonealized pericolic tissue was measured and categorized in 655 pT3 patients: pT3a (≤1 mm), pT3b,c (>1-15 mm) and pT3d (>15 mm). The prognosis of these categories was compared. Five-year distant metastasis increased significantly from pT3a (5.7%) over pT3b,c (17.7%) to pT3d (37.2%; p = 0.001). There was no difference between pT2 (5.3%) and pT3a or between pT3d and pT4a (42.1%) or pT4b (33.7%). The 5-year disease-free survival decreased significantly from pT3a (77.4%) over pT3b,c (65.4%) to pT3d (50.1%; p = 0.015). No significant difference was found between pT2 (80.5%) and pT3a or between pT3d and pT4a (43.9%; p = 0.296) or pT4b (53.4%). The prognostic inhomogeneity in pT3 colon carcinoma has been demonstrated. A three-level subdivision of T3 for colon carcinoma in the TNM system into T3a (≤1 mm), T3b (>1-15 mm), and T3c (>15 mm) is recommended.
EVALuna2:514502

Prospective randomized phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer - results of the SUNNIFORECAST trial - Bergmann, L.; Albiges, L.; Ahrens, M.; Gross-Goupil, M.; Boleti, E.; Gravis, G.; Fléchon, A.; Grimm, M. O.; Bedke, J.; Barthélémy, P.; Castellano, D.; Mellado, B.; et al. (Annals of Oncology, 2025)
Background: Non-clear cell renal cell cancers (nccRCCs) are a heterogeneous group of more than 20 different entities, but are rarely included in large, randomized trials. Tyrosine kinase inhibitors with or without immune checkpoint inhibition are considered as a standard of care (SOC), but optimal treatment is not yet defined. We designed the first prospective randomized trial comparing ipilimumab/nivolumab to SOC. Patients and methods: We randomized adult patients with previously untreated advanced or metastatic nccRCC 1:1 to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by fixed dose nivolumab of 240 mg every 2 weeks or 480 mg every 4 weeks or to SOC. Patients were stratified by histology and by IMDC risk score. Central pathology review was mandatory. The primary endpoint was the overall survival (OS) rate at 12 months, secondary endpoints included median OS, response rate, progression-free survival (PFS), safety and quality of life. Results: In total, 157 patients were assigned to receive ipilimumab/nivolumab, and 152 to SOC. The 12-month survival rate was 78% with ipilimumab/nivolumab [95% confidence interval (CI) 71-84%] compared to 68% with SOC (95% CI 60-75%, P = 0.026). Median OS was 33.2 months versus 25.2 months, P = 0.163 [HR 0.81 (0.61-1.099)]. PFS was similar in both arms [HR 0.99 (0.77-1.28)]. The ORR was 32.8% versus 19.3%. No major differences between papillary and non-papillary RCC subtypes were observed for any endpoint. Exploratory analysis showed a significant OS advantage [HR 0.56 (95% CI 0.37-0.86)] associated with a PD-L1 CPS score ≥1. Treatment discontinuation due to toxicity occurred in 27 patients (17%) with ipilimumab/nivolumab and 13 patients (9%) with SOC. Conclusions: Ipilimumab/nivolumab demonstrated a significantly longer OS at the 12-month milestone and an acceptable toxicity profile. Our results therefore underline a relevant clinical benefit of ipilimumab/nivolumab in previously untreated nccRCC entities compared to current SOC.
CRIS-Team Scopus Importer:2025-05-30
Keywords: checkpoint inhibitors; ipilimumab; nccRCC; nivolumab; non-clear cell renal cell carcinoma; tyrosine kinase inhibitors

Prostate Adenocarcinoma Grade Group 1: Rationale for Retaining a Cancer Label in the 2022 World Health Organization Classification - Netto, George J.; Amin, Mahul B.; Compérat, Eva M.; Gill, Anthony J.; Hartmann, Arndt; Moch, Holger; Menon, Santosh; Raspollini, Maria R.; Rubin, Mark A.; Srigley, John R.; Hoon Tan, Puay; Tickoo, Satish K.; et al. (European Urology, 2022)
CRIS-Team Scopus Importer:2022-11-25

Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status - Luedeke, Manuel; Rinckleb, Antje E.; Fitzgerald, Liesel M.; Geybels, Milan S.; Schleutker, Johanna; Eeles, Rosalind A.; Teixeira, Manuel R.; Cannon-Albright, Lisa; Ostrander, Elaine A.; Weikert, Steffen; Herkommer, Kathleen; Wahlfors, Tiina; et al. (Human Molecular Genetics, 2016)
Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.
EVALuna2:6909

Protein levels of Piwi-like 1 and-2 protein are prognostic factors for muscle invasive urothelial bladder cancer patients - Eckstein, Markus; Jung, Rudolf; Weigelt, Katrin; Sikic, Danijel; Stöhr, Robert; Geppert, Carol-Immanuel; Agaimy, Abbas; Lieb, Verena; Hartmann, Arndt; Wullich, Bernd; Wach, Sven; Taubert, Helge (CANCER RESEARCH, 2019)
CRIS-Team WoS Importer:2019-10-22

PRRX1–NCOA1-rearranged fibroblastic tumour: a clinicopathological, immunohistochemical and molecular genetic study of six cases of a potentially under-recognised, distinctive mesenchymal tumour - Dermawan, Josephine K.; Azzato, Elizabeth M.; Jebastin Thangaiah, Judith; Gjorgova-Gjeorgievski, Sandra; Rubin, Brian P.; Folpe, Andrew L.; Agaimy, Abbas; Fritchie, Karen J. (Histopathology, 2021)
Aims: PRRX1–NCOA1-rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis. Methods and results: The six cases were from three females and three males (age, 20–49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow-growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent-shaped or staghorn-like thin-walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA-sequencing revealed PRRX1–NCOA1 fusions in all cases. Of the four cases with limited follow-up (1.5–4 months), none recurred following local surgical excision. Conclusions: The morphological features of PRRX1–NCOA1-rearranged fibroblastic tumour overlap with those of RB1-deficient soft-tissue tumours, solitary fibrous tumour, and low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1–NCOA1-rearranged fibroblastic tumour appears to be quite favourable, although longer-term study of a larger number of cases is warranted.
CRIS-Team Scopus Importer:2021-09-10
Keywords: fibroblastic; NCOA1; PRRX1; RNA-sequencing; soft tissue

“PRRX1-rearranged mesenchymal tumors”: expanding the immunohistochemical profile and molecular spectrum of a recently described entity with the proposed revision of nomenclature - Warmke, Laura M.; Michal, Michael; Martínek, Petr; Agaimy, Abbas; Din, Nasir Ud; Perret, Raul; Hostein, Isabelle; Le Loarer, François; Voltaggio, Lysandra; Gross, John M. (Virchows Archiv, 2023)
Since the publication of the 2020 World Health Organization classification of soft tissue and bone tumors, the classification of “fibroblastic” tumors has expanded to include a novel subset of tumors characterized by PRRX1::NCOA1/2 gene fusions. These tumors defy conventional classification and are morphologically distinct, characterized by a multi-nodular growth of bland spindle cells suspended in a myxo-collagenous stroma with mild cytologic atypia, “staghorn-like” vessels, and variable perivascular hyalinization. Mitotic activity is rare, and necrosis is not identified. Herein, we present six additional cases of PRRX1-rearranged mesenchymal tumors, including five cases with PRRX1::NCOA1 fusion and one case with PRRX1::KMT2D fusion. Three cases (3/6, 50%) demonstrated focal co-expression of S100 protein and SOX10, thereby expanding the immunohistochemical profile of this emerging entity. Like prior reported cases, there was no evidence of malignant behavior on short-term follow-up. The novel fusion, PRRX1::KMT2D, further expands the molecular spectrum of this entity and leads to a proposed revision of the provisional nomenclature to “PRRX1-rearranged mesenchymal tumor” to both accommodate non-NCOA1/2 fusion partners and allow for the possibility of partial neural or neuroectodermal differentiation.
CRIS-Team Scopus Importer:2023-06-30
Keywords: KMT2D; Mesenchymal tumor; NCOA1; PRRX1; Soft tissue; Spindle cell

Pure large nested variant of urothelial carcinoma (Lnuc) is the prototype of an fgfr3 mutated aggressive urothelial carcinoma with luminal-papillary phenotype - Weyerer, Veronika; Eckstein, Markus; Compérat, Eva; Juette, Hendrik; Gaisa, Nadine T.; Allory, Yves; Stöhr, Robert; Wullich, Bernd; Rouprêt, Morgan; Hartmann, Arndt; Bertz, Simone (Cancers, 2020)
Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.
CRIS-Team Scopus Importer:2020-04-14
Keywords: FGFR3 mutation; Large nested variant; LNUC; Luminal subtype; Urothelial carcinoma

pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma - Ruf, Melanie; Mittmann, Christiane; Nowicka, Anna M.; Hartmann, Arndt; Hermanns, Thomas; Poyet, Cedric; Van Den Broek, Maries; Sulser, Tullio; Moch, Holger; Schraml, Peter (Clinical Cancer Research, 2015)
CD70, a member of the TNF ligand superfamily, has been shown frequently overexpressed in clear cell renal cell carcinoma (ccRCC). The mechanisms of CD70's upregulation and its role in ccRCC are unknown.CD70 expression was immunohistochemically analyzed in 667 RCCs and RCC metastases. Von Hippel-Lindau gene (VHL) mutations, expression patterns of VHL protein (pVHL), hypoxia-inducible factor (HIF) ?, and several HIF targets were studied in tissues and cell lines and correlated with CD70 overexpression. Gene promoter analysis was performed to confirm CD70 as HIF target gene. Consecutive tissue sections were immunostained to reveal the relation between CD70-expressing RCCs and tumor-infiltrating lymphocytes positive for the CD70 receptor (CD27). CD70-mediated release of soluble CD27 in RCC was assessed by coculture experiments and sera analysis of patients with RCC.Elevated CD70 expression was seen in 80% of primary tumors and metastases of ccRCC and correlated with dysregulation of the pVHL/HIF pathway. In vitro analyses demonstrated that CD70 upregulation is driven by HIF. Furthermore, CD27(+) lymphocytes preferentially infiltrate CD70-expressing ccRCCs. CD70-dependent release of soluble CD27 in cocultures may explain the high CD27 levels observed in sera of patients with CD70-expressing ccRCC. The combination of lymphocyte infiltration and CD70 expression in RCC was associated with worse patient outcome.Our findings demonstrate that in ccRCC, CD70 expression is regulated by HIF as a consequence of pVHL inactivation. Increased serum levels of CD27 suggest the existence of CD70-expressing ccRCC, thus representing a potential serum marker for patients suffering from this disease.
EVALuna2:6795

Quality-Assured Analysis of PIK3CA Mutations in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer Tissue: A Story About the Need for Proficiency Testing for High-Quality Molecular Biomarker Reporting in Precision Medicine - Schmidt, Carolin; Stöhr, Robert; Dimitrova, Lora; Beckmann, Matthias; Rübner, Matthias; Fasching, Peter; Denkert, Carsten; Lehmann, Ulrich; Vollbrecht, Claudia; Haller, Florian; Hartmann, Arndt; Erber, Ramona (Journal of Molecular Diagnostics, 2024)
In precision oncology, reliable testing of predictive molecular biomarkers is a prerequisite for optimal patient treatment. Interlaboratory comparisons are a crucial tool to verify diagnostic performance and reproducibility of one's approach. Herein is described the design and results of the first recurrent, internationally performed PIK3CA (phosphatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit α) breast cancer tissue external quality assessment (EQA), organized by German Quality in Pathology GmbH and started in 2021. After the internal pretesting phase performed by the (lead) panel institutes, in both 2021 and 2022, each EQA test set comprised n = 10 tissue samples of hormone receptor–positive, human epidermal growth factor receptor 2–negative invasive breast cancer that had to be analyzed and reported by the participants. In 2021, the results were evaluated separately for German-speaking countries (part 1) and international laboratories (part 2). In 2022, the EQA was performed across the European Union. The EQA success rates were 84.6% (n = 11/13), 88.6% (n = 39/44), and 87.9% (n = 29/33) for EQA 2021 part 1, part 2, and EQA 2022, respectively. The most commonly used methods were next-generation sequencing and mutation-/allele-specific qualitative PCR-based assays. In summary, this recurrent PIK3CA EQA proved to be a suitable approach to obtain an international overview of methods used for PIK3CA mutation analysis, to evaluate them qualitatively, and identify the strengths and weaknesses of individual methods.
CRIS-Team Scopus Importer:2024-05-31

Quantification of translocation-specific ctDNA provides an integrating parameter for early assessment of treatment response and risk stratification in ewing sarcoma - Krumbholz, Manuela; Eiblwieser, Johanna; Ranft, Andreas; Zierk, Jakob; Schmidkonz, Christian; Stuetz, Adrian M.; Peneder, Peter; Tomazou, Eleni M.; Agaimy, Abbas; Bäuerle, Tobias; Hartmann, Wolfgang; Dirksen, Uta; et al. (Clinical Cancer Research, 2021)
Purpose: We evaluated the predictive and prognostic value of circulating tumor DNA (ctDNA) in patients with Ewing sarcoma (EWS) treated in the EWING2008 trial. Experimental Design: Plasma samples from 102 patients with EWS enrolled in the EWING2008 trial were obtained before and during induction chemotherapy. Genomic EWSR1 fusion sequence spanning primers and probes were used for highly specific and sensitive quantification of the levels of ctDNA by digital droplet PCR. ctDNA levels were correlated to established clinical risk factors and outcome parameters. Results: Pretreatment ctDNA copy numbers were correlated with event-free and overall survival. The reduction in ctDNA levels below the detection limit was observed in most cases after only two blocks of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy. The persistence of ctDNA after two VIDE blocks was a strong predictor of poor outcomes. ctDNA levels correlated well with most established clinical risk factors; an inverse correlation was found only for the histologic response to induction therapy. ctDNA levels did not provide simple representations of tumor volume, but integrated information from various tumor characteristics represented an independent EWS tumor marker with predictive and prognostic value. Conclusions: ctDNA copy number in the plasma of patients with EWS is a quantifiable parameter for early risk stratification and can be used as a dynamic noninvasive biomarker for early prediction of treatment response and outcome of patients.
CRIS-Team Scopus Importer:2021-11-26

Quantitative proteome profiling of lymph node-positive vs. -negative colorectal carcinomas pinpoints MX1 as a marker for lymph node metastasis - Croner, Roland S.; Stürzl, Michael; Rau, Tilman; Metodieva, Gergana; Geppert, Carol-Immanuel; Naschberger, Elisabeth; Lausen, Berthold; Metodiev, Metodi V. (International Journal of Cancer, 2014)
We used high-resolution mass spectrometry to measure the abundance of more than 9,000 proteins in 19 individually dissected colorectal tumors representing lymph node metastatic (n = 10) and nonmetastatic (n = 9) phenotypes. Statistical analysis identified MX1 and several other proteins as overexpressed in lymph node-positive tumors. MX1, IGF1-R and IRF2BP1 showed significantly different expression in immunohistochemical validation (Wilcoxon test p = 0.007 for IGF1-R, p = 0.04 for IRF2BP1 and p = 0.02 for MX1 at the invasion front) in the validation cohort. Knockout of MX1 by siRNA in cell cultures and wound healing assays provided additional evidence for the involvement of this protein in tumor invasion. The collection of identified and quantified proteins to our knowledge is the largest tumor proteome dataset available at the present. The identified proteins can give insights into the mechanisms of lymphatic metastasis in colorectal carcinoma and may act as prognostic markers and therapeutic targets after further prospective validation.
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Radiostereometric migration analysis of the Cerafit femoral stem: 28 patients followed for 2 years - Tschunko, Franz; Wagner, Benedikt; Hong, Yutong; Söder, Stephan; Wölfel, Rainer; Müller, Lutz Arne; Forst, Raimund; Sesselmann, Stefan (Biomedizinische Technik, 2015)
Radiostereometric analysis (RSA) is the gold standard evaluating micromovements after total hip arthroplasty. The aim of this study was to investigate the migratory pattern of an uncemented femoral stem during the first 2 years after surgery. We followed 28 patients with a mean age of 57 (SD 13) years for the first two postoperative years. Radiostereometric analysis was used to measure the translation and rotation of the femoral component. The Harris hip score (HHS) was determined to evaluate the clinical outcome. No stem had to be revised. The mean HHS advanced from 35 (SD 11) preoperative to 89 (SD 10) 1 year after surgery. At the end of the observation period, mean subsidence of the stem was 0.26 mm (SD 0.82). Maximum total point motion (MTPM) was 1.23 mm (SD 1.22). The main distal migration took place up to 6 weeks after surgery with nearly no further subsidence up to 2 years postoperatively. All the measured migrations of the hip stem were very small. Results of the HHS demonstrate good clinical outcome. Long-term RSA is necessary to assess possible late migration of the Cerafit standard femoral stem.
EVALuna2:10856

Raman difference spectroscopy: a non-invasive method for identification of oral squamous cell carcinoma: publisher's note - Knipfer, Christian; Motz, Johanna; Adler, Werner; Brunner, Kathrin; Gebrekidan, Medhanie; Hankel, Robert; Agaimy, Abbas; Will, Stefan; Bräuer, Andreas; Neukam, Friedrich Wilhelm; Stelzle, Florian (Biomedical Optics Express, 2015)
The author list appeared incorrectly in [Biomed. Opt. Express 5(9), 3252-3265 (2014)]. The author names were corrected online as of January 17, 2015: https://www.osapublishing.org/boe/abstract.cfm?uri=boe-5-9-3252.[This corrects the article on p. 3252 in vol. 5, PMID: 25401036.].

Raman Differenz-Spektroskopie für die nicht-invasive optische Biopsie des oralen Plattenepithelkarzinomes - Knipfer, Christian; Motz, Johanna; Adler, Werner; Brunner, Kristin; Gebrekidan, Medhanie; Hankel, Robert; Agaimy, Abbas; Bräuer, Andreas; Neukam, Friedrich Wilhelm; Stelzle, Florian; Will, Stefan (66. Kongress der Deutschen Gesellschaft für Mund-, Kiefer- und Gesichtschirurgie, 2016)

RANK and RANKL Expression in Tumors of Patients with Early Breast Cancer - Behrens, Annika; Wurmthaler, Lena; Heindl, Felix; Gaß, Paul; Häberle, Lothar; Volz, Bernhard; Hack, Carolin; Emons, Julius; Erber, Ramona; Hartmann, Arndt; Beckmann, Matthias; Rübner, Matthias; et al. (Geburtshilfe und Frauenheilkunde, 2023)
Introduction The receptor activator of nuclear factor-κB (RANK) pathway was associated with the pathogenesis of breast cancer. Several studies attempted to link the RANK/RANKL pathway to prognosis; however, with inconsistent outcomes. We aimed to further contribute to the knowledge about RANK/RANKL as prognostic factors in breast cancer. Within this study, protein expression of RANK and its ligand, RANKL, in the tumor tissue was analyzed in association with disease-free survival (DFS) and overall survival (OS) in a study cohort of patients with early breast cancer. Patients and Methods 607 samples of female primary and early breast cancer patients from the Bavarian Breast Cancer Cases and Controls Study were analyzed to correlate the RANK and RANKL expression with DFS and OS. Therefore, expression was quantified using immunohistochemical staining of a tissue microarray. H-scores were determined with the cut-off value of 8.5 for RANK and 0 for RANKL expression, respectively. Results RANK and RANKL immunohistochemistry were assessed by H-score. Both biomarkers did not correlate (ρ = -0.04). According to molecular subtypes, triple-negative tumors and HER2-positive tumors showed a higher number of RANK-positive tumors (H-score ≥ 8.5), however, no subtype-specific expression of RANKL could be detected. Higher RANKL expression tended to correlate with a better prognosis. However, RANK and RANKL expression could not be identified as statistically significant prognostic factors within the study cohort. Conclusions Tumor-specific RANK and RANKL expressions are not applicable as prognostic factors for DFS and OS, but might be associated with subtype-specific breast cancer progression.
CRIS-Team Scopus Importer:2023-12-22
Keywords: breast cancer; immunohistochemistry; prognosis; RANK; RANKL

Rapid Evolution of Metastases in Patients with Treated G3 Neuroendocrine Tumors Associated with NEC-Like Transformation and TP53 Mutation - Kasajima, Atsuko; Pfarr, Nicole; Mayr, Eva Maria; Ura, Ayako; Moser, Elisa; von Werder, Alexander; Agaimy, Abbas; Pavel, Marianne Ellen; Klöppel, Günter (Endocrine Pathology, 2024)
Little is known about the morphomolecular features of G3 neuroendocrine tumors (G3NETs) under prolonged systemic treatments, although rapid progression is increasingly observed. This longitudinal study aims to elucidate the course and morphomolecular features of metastasized G3NETs with high-grade transformation. Clinical and histological findings in 40 patients with metastasized and treated G3NETs, which were histologically examined at least twice with an interval time of more than 6 months (median 27), were reviewed and the morphomolecular changes recorded and assigned to treatment. Neuroendocrine carcinoma (NEC)-like histology defined by high-grade atypia, diffuse growth pattern, and/or necrosis was identified in nine (22%) G3NETs (seven pancreatic, two rectal) patients. All NEC-like tumors showed a significantly higher Ki67 increase and longer interval time between first and last examination than non-NEC-like G3NETs (53 vs. 19% and 60 vs. 24 months, respectively). Moreover, all NEC-like G3NETs had TP53 (100%), but rarely RB1 (12%) mutations, and retained NET-typical mutations such as MEN1 or DAXX (five of the pancreatic NETs). The last treatments received prior to the NEC-like transformation included PRRT (n = 3), somatostatin analog, everolimus, sunitinib (n = 1 each), and alkylating agents (n = 2). Abrupt clinical progression in patients with metastasized G3NETs is associated with a significant increase in Ki67, accelerated growth, and NEC-like histology. These findings are most likely attributable to the novel TP53 mutation, which was detected in all nine cases at the last evaluation. However, none of the cases exhibited a complete transformation to a typical NEC, as the tumors retained partial histological and genetic features of NETs.
CRIS-Team Scopus Importer:2024-10-18
Keywords: NEC-like NET G3; Neuroendocrine tumors; Progression; Transformation

Rapidly fatal SMARCA4-deficient undifferentiated sarcoma originating from hybrid hemosiderotic fibrolipomatous tumor/pleomorphic hyalinizing angiectatic tumor of the foot - Agaimy, Abbas; Meidenbauer, Norbert; Sukov, William R.; Stöhr, Robert; Vieth, Michael; Roemer, Frank; Grützmann, Robert; Folpe, Andrew L. (Virchows Archiv, 2021)
Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient's death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT.
CRIS-Team WoS Importer:2021-08-27

Rapidly growing cardiac myxoma diagnosed within 1 year after unremarkable prior cardiac imaging - Strecker, Thomas; Nooh, Ehab; Agaimy, Abbas; Marwan, Mohamed (Journal of Cardiac Surgery, 2019)
CRIS-Team Scopus Importer:2019-11-26
Keywords: cardiac surgery; cardiac tumors; computed tomography; echocardiography; myxoma; pathology

Rapid single-cell physical phenotyping of mechanically dissociated tissue biopsies - Soteriou, Despina; Kubankova, Marketa; Schweitzer, Christine; Lopez Posadas, Rocío; Pradhan, Rashmita; Thoma, Oana-Maria; Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Waldner, Maximilian; Distler, Jörg; Scheuermann, Stefan; Langejuergen, Jens; et al. (Nature Biomedical Engineering, 2023)
A method for the sequential assessment of the physical phenotypes of suspended cells singularized from tissue biopsies by mechanical dissociation allows for rapid diagnoses.
CRIS-Team WoS Importer:2023-05-05

Rare Case Report: Left Atrial Sarcoma Obstructing the Left Ventricular Inflow - Kaemmerer, Ann-Sophie; Suleiman, Mathieu; Agaimy, Abbas; Harig, Frank; Weyand, Michael; Tandler, Rene (Journal of Clinical Medicine, 2023)
Malignant cardiac tumors of the heart are extremely rare and may present tremendous diagnostic and therapeutic challenges. These tumors are able to infiltrate the heart and metastasize systemically. Early detection is often elusive as the clinical presentation is highly variable, posing significant diagnostic and therapeutic difficulties. Despite a multidisciplinary approach, the prognosis for patients with malignant cardiac tumors remains guarded. Early diagnosis and a multidisciplinary approach involving cardiac surgeons, oncologists and critical care specialists are crucial in the management of this disease. Further research is needed to better understand the pathomechanisms of tumor-related complications and to develop effective treatment strategies to improve patient outcomes. The rare case of a 78-year-old woman with left atrial tumor requiring emergency surgery for acutely developing mitral valve obstruction is presented. Pathology confirmed an undifferentiated pleomorphic sarcoma. This patient tragically did not survive, highlighting the difficulties of managing such a rare and deceptive heart disease.
CRIS-Team Scopus Importer:2023-11-10
Keywords: cardiac sarcoma; cardiac surgery; left atrial tumor; malignant cardiac tumor; undifferentiated pleomorphic cardiac sarcoma

Rare Case Report - Mucoepidermoid Carcinoma (MEC) of the Vulva - Dietl, Anna; Stübs, Frederik; Schulmeyer, Carla; Behrens, Annika; Hartmann, Arndt; Agaimy, Abbas; Beckmann, Matthias; Gaß, Paul (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Rare manifestation of non-Hodgkin lymphoma of the head & neck following cochlear implant surgery - Gehrking, Mika; Miksch, Malin; Agaimy, Abbas; Iro, Heinrich; Sievert, Matti (Otolaryngology Case Reports, 2024)
Background: Lymphomas are the second most common malignant neoplasm in the head & neck region (H&N). This report describes a rare cutaneous manifestation of non-Hodgkin lymphoma (NHL) after cochlear implant (CI) surgery. Case presentation: A 71-year-old female presented to the university hospital with an ulcerative retroauricular lesion. The lesion had developed over a week at the site of prior incision for CI surgery 5 years ago and revision surgery due to device failure 16 months ago. The patient's history is notable for NHL with cervical lymphadenopathy and tonsillar manifestation treated with Ibrutinib. A delayed infection after CI surgery is suspected. Histopathologic examination shows infiltration of NHL cells. Conclusion: Lymphomas display variable clinical presentation in the head & neck. A history of trauma may delay the diagnosis. A locus minoris resistentiae may be created at those sites and allow lymphoma cells to accumulate. Thorough analysis of the patient's medical history is therefore crucial. Suspicious findings in the head and neck should be biopsied timely and a histopathologic examination should be conducted.
CRIS-Team Scopus Importer:2024-11-08
Keywords: CLL; Cochlear implant; Head & neck; Non-hodgkin lymphoma

Reappraisal of Morphologic Differences Between Renal Medullary Carcinoma, Collecting Duct Carcinoma, and Fumarate Hydratase-deficient Renal Cell Carcinoma - Ohe, Chisato; Smith, Steven C.; Sirohi, Deepika; Divatia, Mukul; De Peralta-Venturina, Mariza; Paner, Gladell P.; Agaimy, Abbas; Amin, Mitual B.; Argani, Pedram; Chen, Ying-Bei; Cheng, Liang; Colecchia, Maurizio; et al. (American Journal of Surgical Pathology, 2018)
Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.
EVALuna2:205475

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016 - Lugli, Alessandro; Kirsch, Richard; Ajioka, Yoichi; Bosman, Fred; Cathomas, Gieri; Dawson, Heather; El Zimaity, Hala; Flejou, Jean-Francois; Hansen, Tine Plato; Hartmann, Arndt; Kakar, Sanjay; Langner, Cord; et al. (Modern Pathology, 2017)
Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.
EVALuna2:34254

Recording of the regional Origin Areas of Patients from the Molecular Tumor Board to Identify the "white Spots" in the Service Area - A joint Initiative of the Bavarian CCC WERA Alliance - Lueke, F.; Haller, F.; Utpatel, K.; Krebs, M.; Meidenbauer, Norbert; Scheiter, A.; Spörl, Silvia; Heudobler, D.; Keil, F.; Schubart, Christoph; Tögel, Lars; Einhell, S.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Recurrent EWSR1::COLCA2 Fusions Define a Novel Sarcoma With Spindle/Round Cell Morphology and Strong Predilection for the Sinonasal Tract. - Agaimy, Abbas; Baněčková, Martina; De Almeida, John; Dickson, Brendan C.; Dimmler, Arno; Hartmann, Wolfgang; Laé, Marick; Pablik, Jessica; Schubart, Christoph; Skálová, Alena; Stöhr, Robert; Trautmann, Marcel; et al. (American Journal of Surgical Pathology, 2023)
The last 2 decades have attended a dynamic evolution in the nosology of poorly differentiated sinonasal tract malignancies, with several new molecularly defined entities having been described in addition to delineation of the genetic driver/s of some established older entities. These discoveries, however, mostly concerned epithelial-derived neoplasms (carcinomas). Adamantinoma-like Ewing sarcoma and biphenotypic sinonasal sarcoma are the major representatives of the newly defined mesenchymal categories. The colorectal cancer associated 2 (COLCA2) has been discovered recently as a colorectal cancer risk gene locus, but fusions involving this gene have not been well characterized. We, herein, describe clinicopathologic and molecular features of a novel sinonasal sarcoma characterized by undifferentiated spindle/round cell morphology and defined by recurrent EWSR1::COLCA2 fusions. All patients (n=5) were adults (3 female and 2 male) with a median age of 46 years (range, 23 to 60 y). The tumors originated in different subsites of the sinonasal tract with frequent multisite involvement. Original diagnoses were undifferentiated or unclassified round cell/spindle cell neoplasm/sarcoma (n=4) and neuroendocrine carcinoma (n=1). Surgery with or without adjuvant chemoradiation was the treatment in all cases. At the last follow-up, 1 patient developed multiple local recurrences over 21 years and another developed local recurrence and distant metastasis to bone 27 months after diagnosis. A third patient developed local recurrence 11 months later. Two patients were disease-free at 23, and 24 months. Histology showed nondescript highly cellular neoplasms with an admixture of spindled and round cells disposed into solid sheets and fascicles with brisk mitotic activity. Immunohistochemistry was negative for all lineage-specific markers with only limited focal membranous CD99 (4 of 5 cases) and weak pankeratin (1 of 5 cases) expression. Targeted RNA sequencing revealed an EWSR1::COLCA2 fusion, verified by EWSR1 fluorescence in situ hybridization, in all cases. This series identifies a novel member in the undifferentiated spindle/round cell sarcoma category with strong predilection for the sinonasal tract. None of >10,000 epithelial and mesenchymal neoplasms tested at the authors' centers during the same period showed this fusion, highlighting rarity of tumors carrying this gene fusion. Accordingly, molecular testing of unclassified sinonasal malignancies/sarcomas showing round and spindle cell morphology is recommended to enhance the identification and further characterization of this entity.
EVALuna2:518253

Recurrent Fusions Between YAP1 and KMT2A in Morphologically Distinct Neoplasms Within the Spectrum of Low-grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma - Puls, Florian; Agaimy, Abbas; Flucke, Uta; Mentzel, Thomas; Sumathi, Vaiyapuri P.; Ploegmakers, Marieke; Stoehr, Robert; Kindblom, Lars Gunnar; Hansson, Magnus; Sydow, Saskia; Arbajian, Elsa; Mertens, Fredrik (American Journal of Surgical Pathology, 2020)
Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These "hybrid" tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene expression profiling, YAP1 and KMT2A/PRRX1 and KMT2D tumors were distinct from LGFMS/SEF. The patients were 4 female individuals and 4 male individuals aged 11 to 91 years. Tumors with known locations were in the lower extremity (5), trunk (2), and upper extremity (1); 3 originated in acral locations. Tumor size ranged from 2.5 to 13 cm. Proportions of SEF-like and LGFMS-like areas varied considerably among tumors. All tumors that showed infiltrative growth and mitotic figures per 10 HPFs ranged from 0 to 18. Tumor necrosis was present in 1 case. Follow-up was available for 5 patients (11 to 321 mo), 2 of whom developed local recurrences, and 1 died of metastatic disease. The clinical behavior of these soft tissue sarcomas remains to be further delineated in larger series with extended follow-up; however, our limited clinical data indicate that they are potentially aggressive.
CRIS-Team Scopus Importer:2020-04-28

Recurrent IDH2 Mutations in Salivary Gland Striated Duct Adenoma Define an Expanded Histologic Spectrum Distinct From Canalicular Adenoma - Rooper, Lisa M.; Agaimy, Abbas; Assaad, Adel; Bal, Munita; Eugene, Henrietta; Gagan, Jeffrey; Nonogaki, Hiro; Palsgrove, Doreen N.; Shah, Akeesha; Stelow, Edward; Stöhr, Robert; Thompson, Lester D. R.; et al. (American Journal of Surgical Pathology, 2023)
Striated duct adenoma (SDA) is a rare salivary gland neoplasm defined by histologic similarity to normal striated ducts. However, doubt persists about whether SDA represents a genuine entity distinct from canalicular adenoma and if a malignant counterpart exists. This study aims to evaluate the molecular underpinnings of SDA to clarify its pathogenesis and classification. We identified 10 SDA and 2 tumors called low-grade adenocarcinoma not otherwise specified that were retrospectively recognized to resemble SDA. All cases showed recurrent histologic features including (1) discrete monophasic tubules, (2) tall columnar eosinophilic cells, (3) monotonous oval nuclei, and (4) scant fibrous stroma, and most were positive for S100 protein (91%), SOX10 (80%), and CK7 (80%). Although 1 case was previously called adenocarcinoma based on interdigitation with normal acini, this pattern was also seen in some SDA, and likely does not indicate malignancy; the significance of growth surrounding nerve in 1 other case is less clear. Targeted sequencing identified IDH2 R172X mutations in all 8 cases with sufficient tissue, with positivity for IDH1/2 mutation-specific immunohistochemistry in 9 cases stained. In contrast, 5 canalicular adenomas lacked IDH2 mutations or other oncogenic alterations. Overall, IDH2 R172X mutations are a defining feature of SDA that, in combination with its recognizable pathologic profile, confirm it is a unique entity separate from canalicular adenoma. IDH1/2 mutation-specific immunohistochemistry may provide a convenient tool to facilitate diagnosis. Both morphology and IDH2 mutations raise parallels between SDA and breast tall cell carcinoma with reverse polarity.
CRIS-Team WoS Importer:2023-03-17

Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma. - Agaimy, Abbas; Clarke, Blaise A.; Kolin, David L.; Lee, Cheng-Han; Lee, Jen-Chieh; Mccluggage, W. Glenn; Pöschke, Patrik; Stöhr, Robert; Swanson, David; Turashvili, Gulisa; Beckmann, Matthias; Hartmann, Arndt; et al. (American Journal of Surgical Pathology, 2022)
With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1 fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1 (n=11) and KAT6A::KANSL1 (n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1 fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor.
EVALuna2:504168

Recurrent Loss of SMARCA4 in Sinonasal Teratocarcinosarcoma - Rooper, Lisa M.; Uddin, Nasir; Gagan, Jeffrey; Brosens, Lodewijk A.A.; Magliocca, Kelly R.; Edgar, Mark A.; Thompson, Lester D.R.; Agaimy, Abbas; Bishop, Justin A. (American Journal of Surgical Pathology, 2020)
Molecular analysis has reshaped the landscape of high grade sinonasal tumors by defining novel entities and identifying recurrent mutations in established tumor types. However, sinonasal teratocarcinosarcoma (TCS), a rare and aggressive tumor with intermixed teratomatous, carcinomatous, and sarcomatous elements, remains poorly understood. The multiphenotypic differentiation of TCS has engendered persistent controversy about its histogenesis and leads to diagnostic overlap with several other malignancies. In this study, we evaluated the molecular underpinnings of TCS to clarify its pathogenesis and diagnosis. We performed SMARCA4 immunohistochemistry (IHC) on 22 TCS and 153 other sinonasal tumors. We identified loss of SMARCA4 expression in 18 TCS (82%), including 15 (68%) with complete loss and 3 (14%) with partial loss. Although we also identified partial SMARCA4 loss in 1 of 8 SMARCB1-deficient sinonasal carcinomas (13%), SMARCA4 was intact in all other sinonasal carcinomas and neuroendocrine tumors. We then selected 3 TCS with complete SMARCA4 loss by IHC for a targeted next-generation sequencing panel that included 1425 cancer-related genes. We confirmed biallelic somatic inactivation of SMARCA4 without other known oncogenic mutations in these 3 cases. Overall, these findings suggest that SMARCA4 inactivation may be the dominant genetic event in TCS, expanding understanding of this gene's role in sinonasal tumorigenesis. They also raise the possibility that TCS is on a diagnostic spectrum with the newly described SMARCA4-deficient sinonasal carcinoma, blurring the lines between established and emerging sinonasal entities. In addition, SMARCA4 IHC may provide a useful adjunct for confirming a diagnosis of TCS in limited material.
CRIS-Team Scopus Importer:2020-06-19
Keywords: BRG1; immunohistochemistry; malignant teratocarcinosarcoma; molecular diagnostics; nasal cancers; nasal neoplasms; SMARCA4

Recurrent Mutations within the Amino-Terminal Region of ?-Catenin Are Probable Key Molecular Driver Events in Sinonasal Hemangiopericytoma - Haller, Florian; Bieg, Matthias; Moskalev, Evgeny; Barthelmeß, Sarah; Geddert, Helene; Boltze, Carsten; Diessl, Nicolle; Braumandl, Karin; Brors, Benedikt; Iro, Heinrich; Hartmann, Arndt; Wiemann, Stefan; et al. (American Journal of Pathology, 2015)
Sinonasal hemangiopericytoma (SN-HPC) is an uncommon, site-specific, low-grade mesenchymal neoplasm of probable perivascular myoid cell origin. In contrast to solitary fibrous tumors of soft tissue and sinonasal tract origin, SN-HPCs were recently shown to lack recurrent NAB2-STAT6 fusion variants. Other molecular alterations known to occur in some of soft tissue perivascular myoid cell neoplasms were also absent in SN-HPC; thus, the molecular pathogenesis of SN-HPCs remained unknown. Guided by whole-genome sequencing combined with RNA sequencing of an index case, we analyzed a total of six SN-HPCs for mutations within the amino-terminal region of the gene CTNNB1 (cadherin-associated protein), ? 1, 88 kDa, encoding ?-catenin. All six cases showed missense mutations, with amino acid substitutions clustering at positions 33 to 45, corresponding to the recognition site of the ?-catenin destruction complex. Similar CTNNB1 mutations have been described in a variety of epithelial and mesenchymal neoplasms. These mutations prevent ?-catenin phosphorylation and proteasomal degradation but promote its nuclear accumulation and subsequent increased transcription of Wingless-related integration site target genes. Consistent with these molecular findings, ?-catenin IHC showed consistent diffuse and strong nuclear staining of the tumor cells in all six SN-HPCs. Our results highlight, for the first time, CTNNB1 mutations as the likely initiating molecular events driving SN-HPC tumorigenesis, which places SN-HPC among the growing family of ?-catenin-driven mesenchymal neoplasms.
EVALuna2:6646

Recurrent novel HMGA2-NCOR2 fusions characterize a subset of keratin-positive giant cell-rich soft tissue tumors - Agaimy, Abbas; Michal, Michael; Stoehr, Robert; Ferrazzi, Fulvia; Fabian, Pavel; Michal, Michal; Franchi, Alessandro; Haller, Florian; Folpe, Andrew L.; Kosemehmetoglu, Kemal (Modern Pathology, 2021)
Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14-60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14-168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.
CRIS-Team WoS Importer:2021-03-26

Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas - Agaimy, Abbas; Bieg, Matthias; Michal, Michael; Geddert, Helene; Maerkl, Bruno; Seitz, Jan; Moskalev, Evgeny; Schlesner, Matthias; Metzler, Markus; Hartmann, Arndt; Wiemann, Stefan; Michal, Michal; et al. (American Journal of Surgical Pathology, 2017)
Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions.
EVALuna2:6839

Recurrent VGLL3 fusions define a distinctive subset of spindle cell rhabdomyosarcoma with an indolent clinical course and striking predilection for the head and neck - Agaimy, Abbas; Dermawan, Josephine K.; Leong, Iona; Stöhr, Robert; Swanson, David; Weinreb, Ilan; Zhang, Lingxin; Antonescu, Cristina R.; Dickson, Brendan C. (Genes Chromosomes & Cancer, 2022)
The mammalian Vestigial-like (VGLL) transcriptional cofactor family of proteins VGLL1-4 has recently emerged as an important player in the tumorigenesis of diverse neoplasms. The role of VGLL3 in soft tissue tumors is exemplified by its amplification in myxoinflammatory fibroblastic sarcoma and its rearrangement (fused to CHD7, CHD9, or MAMLD1) in hybrid schwannoma-perineurioma. This study characterizes a distinctive low-grade myogenic neoplasm with a striking predilection for the head and neck, characterized by VGLL3 fusions. The study includes five males and one female patient, aged 30–71 years (median, 56). Three tumors originated in the tongue, with one case each in the nasopharynx, oral cavity, and oropharynx. The VGLL3 fusion partners included TCF12 (n = 3), EP300 (n = 2), and PPARGC1A (n = 1). The tumor size range was 0.8–1.6 cm (all, but one, was <1 cm). Histologically, all tumors displayed bland spindle to ovoid cells arranged into vague fascicular and diffuse patterns. Mitotic activity ranged from 1 to 7 per 10 HPFs. Five tumors were muscle-centered and infiltrative, and one was centered beneath nasopharyngeal mucosa. Immunohistochemistry revealed consistent expression of desmin (diffuse in four and patchy in two cases) associated with patchy smooth muscle actin expression (4/6), and focal reactivity for myogenin (5/6) and myoD1 (1/3). All patients were managed surgically; one patient each received adjuvant radio- or chemotherapy. Three patients with follow-up were without disease at 8, 19, and 60 months and one was alive with unknown disease status at 24 months. All VGLL3 fusions were in-frame and involved exon 2, fused with either TCF12 exon 16, EP300 exon 31, or PPARGC1A exon 5, respectively. This series characterizes a distinctive subset of spindle cell rhabdomyosarcoma (RMS) with a predilection for the head and neck in adults, defined by VGLL3 fusions, likely indolent behavior and limited rhabdomyoblastic differentiation. Further delineation of this entity and differentiation from more aggressive molecular subtypes of spindle cell RMS is mandatory to define the most appropriate therapeutic strategy and avoid overtreatment.
CRIS-Team Scopus Importer:2022-08-12
Keywords: EP300; gene fusion; head and neck; PPARGC1A; sarcoma; spindle cell rhabdomyosarcoma; TCF12; VGLL3

Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma - Rooper, Lisa M.; Agaimy, Abbas; Bell, Diana; Gagan, Jeffrey; Gallia, Gary L.; Jo, Vickie Y.; Lewis, James S.; London, Nyall R.; Nishino, Michiya; Stöhr, Robert; Thompson, Lester D.R.; Din, Nasir Ud; et al. (Modern Pathology, 2024)
Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term “olfactory carcinoma” to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.
CRIS-Team Scopus Importer:2024-03-29
Keywords: adenocarcinoma; immunohistochemistry; molecular diagnostics; nasal neoplasms; neuroendocrine carcinoma; olfactory carcinoma; olfactory neuroblastoma; teratocarcinosarcoma

Recurrent YAP1-TFE3 Gene Fusions in Clear Cell Stromal Tumor of the Lung - Agaimy, Abbas; Stöhr, Robert; Michal, Michael; Christopoulos, Petros; Winter, Hauke; Zhang, Lei; Stenzinger, Albrecht; Michal, Michal; Mechtersheimer, Gunhild; Antonescu, Cristina R. (American Journal of Surgical Pathology, 2021)
Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCST-L) is a recently described distinctive rare pulmonary neoplasm of unknown histogenesis and molecular pathogenesis. Only 7 cases have been reported in 2 recent studies, although additional cases might have been reported under the heading of extraneural pulmonary hemangioblastoma. We herein describe 4 CCST-L cases, 3 of them harboring a YAP1-TFE3 fusion. The fusion-positive tumors occurred in 3 women, aged 29, 56, and 69 years. All presented with solitary lung nodules measuring 2.3 to 9.5 cm. Histologically, all tumors showed similar features being composed of relatively uniform medium-sized epithelioid to ovoid cells with clear cytoplasm and small round monomorphic nuclei. Scattered larger cells with enlarged hyperchromatic nuclei and marked pleomorphism were noted in 2 cases. The tumors were associated with a hypervascularized stroma with variable but essentially subtle resemblance to capillary hemangioblastoma and perivascular epithelioid cell tumor (PEComa). Immunohistochemistry was negative for all lineage-specific markers. Targeted RNA sequencing showed a YAP1-TFE3 fusion in 3 of 4 cases. All 3 tumors showed homogeneous nuclear TFE3 immunoreactivity. Two patients were disease free at 36 and 12 months. The third patient had biopsy-proven synchronous renal and hepatic metastases, but extended follow-up is not available (recent case). The fourth case lacking the fusion affected a 66-year-old woman and showed subtle histologic differences from the fusion-positive cases, but had comparable TFE3 immunoreactivity. CCST-L represents a distinctive entity unrelated to hemangioblastoma and likely driven by recurrent YAP1-TFE3 fusions in most cases. The relationship of our cases to the recently reported "hemangioblastoma-like" CCST-L remains to be determined. Analysis of larger series is paramount to delineate the morphologic spectrum and biological behavior of this poorly characterized entity.
CRIS-Team WoS Importer:2021-10-29

Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11 - Drayton, Ross M.; Dudziec, Ewa; Peter, Stefan; Bertz, Simone; Hartmann, Arndt; Bryant, Helen E.; Catto, James W. F. (Clinical Cancer Research, 2014)
Resistance to cisplatin-based chemotherapy is a major obstacle to bladder cancer treatment. We aimed to identify microRNAs (miRNA) that are dysregulated in cisplatin-resistant disease, ascertain how these contribute to a drug-resistant phenotype, and how this resistance might be overcome.miRNA expression in paired cisplatin-resistant and -sensitive cell lines was measured. Dysregulated miRNAs were further studied for their ability to mediate resistance. The nature of the cisplatin-resistant phenotype was established by measurement of cisplatin/DNA adducts and intracellular glutathione (GSH). Candidate miRNAs were examined for their ability to (i) mediate resistance and (ii) alter the expression of a candidate target protein (SLC7A11); direct regulation of SLC7A11 was confirmed using a luciferase assay. SLC7A11 protein and mRNA, and miRNA-27a were quantified in patient tumor material.A panel of miRNAs were found to be dysregulated in cisplatin-resistant cells. miRNA-27a was found to target the cystine/glutamate exchanger SLC7A11 and to contribute to cisplatin resistance through modulation of GSH biosynthesis. In patients, SLC7A11 expression was inversely related to miRNA-27a expression, and those tumors with high mRNA expression or high membrane staining for SLC7A11 experienced poorer clinical outcomes. Resistant cell lines were resensitized by restoring miRNA-27a expression or reducing SLC7A11 activity with siRNA or with sulfasalazine.Our findings indicate that miRNA-27a negatively regulates SLC7A11 in cisplatin-resistant bladder cancer, and shows promise as a marker for patients likely to benefit from cisplatin-based chemotherapy. SLC7A11 inhibition with sulfasalazine may be a promising therapeutic approach to the treatment of cisplatin-resistant disease.
EVALuna2:6614

Reduced Recurrence Rates Are Associated with Photodynamic Diagnostics Compared to White Light after Extended Transurethral Resection of Bladder Tumors - Marquardt, Alexander; Richterstetter, Mario; Taubert, Helge; Hartmann, Arndt; Wullich, Bernd; Lieb, Verena; Bellut, Laura; Wach, Sven; Apel, Hendrik (Life, 2022)
One pillar in treating non-muscle-invasive bladder cancer (NMIBC) is the complete and high-quality transurethral resection of the primary tumor (TURBT). However, even after a high-quality primary resection, the residual tumor risk is considerable, thus requiring a re-TURBT. Resections performed with the aid of a photodynamic diagnostics report improved recurrence-free survival rates and increased detection rates of carcinoma in situ (CIS). This monocentric retrospective study reports on patients treated with an extended TURBT procedure using conventional white-light cystoscopy or photodynamic diagnostics (PDD). Only patients undergoing a TURBT resection for their primary tumor were included in the statistical analysis. Recurrence-free survival and overall survival were the clinical endpoints. Mann-Whitney U tests and chi-squared tests were used for descriptive intergroup comparisons. The associations with overall survival and recurrence-free survival were determined by univariate and multivariate analyses. The test results were considered significant when p was < 0.05. In comparison to conventional white-light cystoscopy, PDD increased the detection rates of CIS (p = 0.004) and tumor multifocality (p = 0.005) and led to reduced residual tumor incidence at the primary resection site (p < 0.001). Likewise, tumor recurrence rates were reduced in the PDD cohort (p < 0.001). Patient age and the presence of residual tumor at the primary resection site were identified as independent predictors of overall survival. For recurrence-free survival, only the PDD resection method was an independent predictor (HR = 0.43; p < 0.001). In summary, we demonstrated that the utilization of PDD techniques was associated with improved detection rates of CIS and multifocal tumors and with reduced recurrence rates. The extended resection protocol allowed us to determine that PDD resections lead to a reduced residual tumor rate at the initial resection site. This residual tumor state at the resection site, determined by extended TURBT, became an independent predictor of long-term survival. On the other hand, the PDD technique was confirmed as the only independent predictor of recurrence-free survival.
CRIS-Team WoS Importer:2022-06-10

Refinement of the surgical indication and increasing expertise are associated with a better quality of pathology specimen in pleomorphic adenomas - Mantsopoulos, Konstantinos; Iro, Ann Kristin; Sievert, Matti; Müller, Sarina Katrin; Agaimy, Abbas; Koch, Michael; Iro, Heinrich (Acta Oto-Laryngologica, 2021)
Background: Traditional surgical philosophy condemns extracapsular dissection for pleomorphic adenoma as a euphemism for the enucleation of this lesion. Objectives: The aims of the study were to trace the development of surgical treatment by pleomorphic adenomas of the parotid gland over the last 15 years and explore its effects on the histopathology specimen. Materials and Methods: The medical records of all cases with pleomorphic adenomas of the parotid gland between 2006 and 2020 were examined for information on age, gender, and type of surgery. An experienced head and neck pathologist re-evaluated the histology slides from all the cases. Results: The study included 844 patients. Our analysis showed an increase in the performance of extracapsular dissection from 52.8% (2006) to 63.3% (2020), and an increase in histopathology specimens with tumours completely covered by healthy tissue from 27.7% (2006) to 50% (2020). Conclusions: Our decision-making process reached its peak in the last study years, in terms of reduced surgical invasiveness and quality of the pathology specimen. Significance: Extracapsular dissection has gained a firm hold as an indispensable tool for the experienced parotid surgeon. Proper indication is based on careful selection of cases and the correct interpretation of preoperative features on palpation and imaging.
CRIS-Team Scopus Importer:2021-01-29
Keywords: capsule; extracapsular dissection; facial nerve; Parotid gland; pathology; pleomorphic adenoma; pleomorphic adenoma

Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma - Valletta, Daniela; Czech, Barbara; Spruss, Thilo; Ikenberg, Kristian; Wild, Peter; Hartmann, Arndt; Weiss, Thomas S.; Oefner, Peter J.; Mueller, Martina; Hellerbrand, Claus; Bosserhoff, Anja Katrin (Carcinogenesis, 2014)
In human cancers, giant cadherin FAT1 may function both, as an oncogene and a tumor suppressor. Here, we investigated the expression and function of FAT1 in hepatocellular carcinoma (HCC). FAT1 expression was increased in human HCC cell lines and tissues compared with primary human hepatocytes and non-tumorous liver tissue as assessed by quantitative PCR and western blot analysis. Combined immunohistochemical and tissue microarray analysis showed a significant correlation of FAT1 expression with tumor stage and proliferation. Suppression of FAT1 expression by short hairpin RNA impaired proliferation and migration as well as apoptosis resistance of HCC cells in vitro. In nude mice, tumors formed by FAT1-suppressed HCC cells showed a delayed onset and more apoptosis compared with tumors of control cells. Both hepatocyte growth factor and hypoxia-mediated hypoxia-inducible factor 1 alpha activation were identified as strong inducers of FAT1 in HCC. Moreover, demethylating agents induced FAT1 expression in HCC cells. Hypoxia lead to reduced levels of the methyl group donor S-adenosyl-L-methionine (SAM) and hypoxia-induced FAT1 expression was inhibited by SAM supplementation in HCC cells. Together, these findings indicate that FAT1 expression in HCC is regulated via promotor methylation. FAT1 appears as relevant mediator of hypoxia and growth receptor signaling to critical tumorigenic pathways in HCC. This knowledge may facilitate the rational design of novel therapeutics against this highly aggressive malignancy.
EVALuna2:6668

Regulation of uptake of 18F-FDG by a follicular human thyroid cancer cell line with mutation-activated K-ras - Prante, Olaf; Maschauer, Simone; Fremont, Valerie; Reinfelder, Julia; Stöhr, Robert; Szkudlinski, Mariusz; Weintraub, Bruce; Hartmann, Arndt; Kuwert, Torsten (Journal of Nuclear Medicine, 2009)

Regulatory T cells and cytotoxic T cells close to the epithelial–stromal interface are associated with a favorable prognosis - Rudolf, Julian; Büttner-Herold, Maike; Erlenbach-Wuensch, Katharina; Posselt, Rebecca; Jeßberger, Jonas; Haderlein, Marlen; Hecht, Markus; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (OncoImmunology, 2020)
Cytotoxic T cells and regulatory T cells play a crucial role in the outcome of cancer patients. Besides the density of these cells, it was shown recently that the spatial distribution is equally important. Here, we specifically analyzed the spatial distribution of these T cell subtypes at the epithelial–stromal interface in a rectal cancer cohort and its relevance for prognosis. We studied a cohort of 191 patients with advanced rectal cancer treated by radiochemotherapy (RCT). Tissue microarrays were immunohistochemical double-stained by FoxP3+ and CD+. Cell densities were analyzed in the stromal and epithelial compartment. Additionally, an image analysis software calculated the distances of lymphocytes to the epithelial–stromal interface (ESI). CD8+ and FoxP3+ cell counts decreased clearly after RCT with the decrease of FoxP3+ being more pronounced than of CD8+ cells. In the invasive front, short distances of the ESI to CD8+ and to FoxP3+ cells were associated with improved overall survival. Cell counts in the stromal compartment had no influence on prognosis. No correlation between stromal and epithelial lymphocyte densities was observed. The distance of epithelial–stromal interface to CD8+ and FoxP3+ cells was more accurate in predicting prognosis in the stromal compartment of rectal cancer patients than mere cell counts and could thereby be means of better stratifying patients for therapy. This observation will have to be validated in future prospective studies with regard to other tumor entities and its implications for the responsiveness of tumors to new therapeutic modalities.
CRIS-Team Scopus Importer:2020-04-28
Keywords: epithelial–stromal interface; rectal cancer; regulatory T cells; spatial distribution; ﻿cytotoxic T cells

Renal Cell Carcinoma with "Gonadal Sex-cord Stromal tumor-like" Features: Analysis of 5 Cases of Novel Renal Entity - Wang, Gang; Amin, Mahul; Grossmann, Petr; Hayes, Malcolm; Hartmann, Arndt; Agaimy, Abbas; Lopez, Jose; Hes, Ondrej (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Renal cell tumor with sex-cord/gonadoblastoma-like features: analysis of 6 cases - Wang, Gang; Amin, Mahul B.; Grossmann, Petr; Ptakova, Nikola; Hayes, Malcolm; Hartmann, Arndt; Agaimy, Abbas; Lopez, Jose; Michal, Michal; Hes, Ondrej (Virchows Archiv, 2021)
Renal tumors are one of the most diverse groups of tumors in pathology. Many emerging and important entities have been described recently. Here, we describe a series of renal tumors occurring in adult patients, with distinct histologic features, and with a striking resemblance to gonadal sex cord-stromal tumors. Patients were three males and three females aged 39–82 years; tumor size ranged from 0.9 to 3.6 cm. Five tumors were organ-confined, while one case had a focal perinephric invasion. No aggressive behavior was noted. Microscopically, all the tumors were composed of loose or compact tubular structures with elongated or angulated shapes. The tumor cells were cylindrical or cuboidal, with pale eosinophilic cytoplasm, irregular nuclear membranes, and ISUP/WHO grade 2–3 nuclei. The stroma showed focal or prominent collagen deposition with prominent basement membrane–like material. In all cases, the tumor cells were positive for PAX8, CD10, and vimentin and retained positivity for FH and SDHB. Cathepsin K and AMACR were variably positive. Tumors were negative for HMB45, Melan A, TFE3, SF1, inhibin, calretinin, ER, PR, CD117, OCT3/4, SALL4, ALK, and WT1. Molecular studies showed no abnormalities in TFEB, TFE3, or FH genes. In 3/4 tested cases, mutation of the NF2 gene was present. In all the tested male cases, loss of the Y chromosome was found. In the relatively short follow-up, these tumors appear to have indolent behavior. This study expands the clinicopathologic diversity of renal cell tumors by describing a series of potentially novel tumors morphologically resembling gonadal sex-stromal tumors, with negativity for sex cord-stromal markers. Potential relationship to recently described biphasic hyalinizing psammomatous renal cell carcinoma is discussed.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Biphasic hyalinizing psammomatous renal cell carcinoma; Gonadoblastoma-like; Kidney; NF2 mutation; Renal cell carcinoma; Sex cord-stromal tumor-like

Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in mucin 1 or uromodulin - Ekici, Arif Bülent; Hackenbeck, Thomas; Moriniere, Vincent; Panness, Andrea; Büttner, Maike; Uebe, Steffen; Janka, Rolf Matthias; Wiesener, Antje; Hermann, Ingo; Grupp, Sina; Hornberger, Martin; Huber, Tobias B.; et al. (Kidney International, 2014)
For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis. In contrast to what the frequently used term 'Medullary Cystic Kidney Disease' implies, development of (medullary) cysts is neither an early nor a typical feature, as determined by MRI. In addition to Sanger and gene panel sequencing of the four genes, we established SNaPshot minisequencing for the predescribed cytosine duplication within a distinct repeat region of MUC1 causing a frameshift. A mutation was found in 7 of 9 families (3 in UMOD and 4 in MUC1), with one indeterminate (UMOD p.T62P). On the basis of clinical and pathological characteristics we propose the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' as an improved terminology. This should enhance recognition and correct diagnosis of affected individuals, facilitate genetic counseling, and stimulate research into the underlying pathophysiology.
EVALuna2:3695

Renal neuroendocrine tumors: clinical and molecular pathology with an emphasis on frequent association with ectopic Cushing syndrome - Kasajima, Atsuko; Pfarr, Nicole; von Werder, Alexander; Schwamborn, Kristina; Gschwend, Jürgen; Din, Nasir Ud; Esposito, Irene; Weichert, Wilko; Pavel, Marianne Ellen; Agaimy, Abbas; Klöppel, Günter (Virchows Archiv, 2023)
Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7.6 cm) included 2 patients with Cushing syndrome (CS). WHO grade (23% G1, 54% G2, and 23% G3) and tumor progression did not correlate. CS-associated RenNETs (CS-RenNETs) showed a solid and eosinophilic histology and stained for ACTH, while the remaining non-functioning tumors had a trabecular pattern and expressed variably hormones somatostatin (91%), pancreatic polypeptide (63%), glucagon (54%), and serotonin (18%). The transcription factors ISL1 and SATB2 were expressed in all non-functioning, but not in CS-RenNETs. NGS revealed no pathogenic alterations or gene fusions. In the literature review (N = 194), 15 (8%) of the patients had hormonal syndromes, in which CS being the most frequent (7/15). Large tumor size and presence of metastasis were associated with shorter patients’ survival (p < 0.01). RenNETs present as large tumors with metastases. CS-RenNETs differ through ACTH production and solid-eosinophilic histology from the non-functioning trabecular RenNETs that produce pancreas-related hormones and express ISL1 and SATB2. MEN1 or DAXX/ARTX abnormalities and fusion genes are not detected in RenNETs, indicating a distinct yet unknown molecular pathogenesis.
CRIS-Team Scopus Importer:2023-07-21
Keywords: Hormone; ISL1; Kidney; Neuroendocrine neoplasms; SATB2

Renal rupture - Not what it seems - Pichler, Renate; Heidegger, Isabel; Schachtner, Gert; Stuehmeier, Jannik; Agaimy, Abbas; Maier, Hans; Glodny, Bernhard; Rehder, Peter (Urology Case Reports, 2018)
EVALuna2:34890

Repetitive Maturation of Oocytes From Non-Stimulated Xenografted Ovarian Tissue From a Prepubertal Patient Indicating the Independence of Human Ovarian Tissue - Raffel, Nathalie; Lotz, Laura; Hoffmann, Inge; Liebenthron, Jana; Söder, Stephan; Beckmann, Matthias; Dittrich, Ralf (Geburtshilfe und Frauenheilkunde, 2017)
Introduction: Modern anti-cancer strategies have distinctly increased survival rates; nevertheless, often accompanied by sterility. Currently, the only option for preserving fertility in prepubertal females is to cryopreserve ovarian tissue and re-transplant frozen-thawed tissue to restore fertility after treatment. Our aim was to report the occurrence of repetitive antral follicle formation and oocyte maturation in a prepubescent ovarian tissue xenograft without exogenous hormone stimulation. Material and Methods: Frozen-thawed ovarian tissue from a 6-year-old patient suffering from nephroblastoma was xenotransplanted in oophorectomized severe combined immunodeficiency (SCID) mice to evaluate follicle development. Ergebnisse: Repetitive follicle development to the antral stage occurred in the same xenograft of prepubertal ovarian tissue without exogenous hormone administration; 37 days after retrieving a maturing oocyte (this first retrieval has been previously published), another, completely mature oocyte was harvested from the xenograft. Subsequent histological evaluation of the grafted tissue showed primordial follicles, nearly all stages of developing follicles, as well as large atretic ones. Many clusters with dormant primordial follicles were also present. Conclusion: Xenotransplanted prepubertal ovarian tissue has the potential for repetitive oocyte retrieval cycles without administering exogenous hormones. The results indicate that the human ovarian tissue might be able to synchronize the hypothalamus-hypophysis-axes of the mouse to the physiological human cycle; this should be investigated in future studies.
EVALuna2:34929

Reply: Intra-patient heterogeneity of BRAF mutation status: fact or fiction? - Heinzerling, Lucie; Schuler, Gerold; Hartmann, Arndt; Schneider-Stock, Regine (British Journal of Cancer, 2014)
EVALuna2:6657

Reply to Jérôme Verine, Christophe Leboeuf and Philippe Ratajczak's letter to the editor re: Jimsgene Sanjmyatav, Sven Hauke, Mieczyslaw Gajda, et al. Establishment of a multicolour fluorescence in situ hybridisation-based assay for subtyping of renal cel - Sanjmyatav, Jimsgene; Hartmann, Arndt; Moch, Holger; Hauke, Sven; Gajda, Mieczyslaw; Meyer, Britta; Pryalukhin, Alexey; Grimm, Marc-Oliver; Junker, Kerstin (European Urology, 2014)
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Reply To Kenneth B. Yatai, Mark J. Dunning, Dennis Wang. Consensus Genomic Subtypes of Muscle-invasive Bladder Cancer: A Step in the Right Direction but Still a Long Way To Go. Eur Urol. In press - Kamoun, Aurélie; de Reyniès, Aurélien; Allory, Yves; Sjödahl, Gottfrid; Robertson, A. Gordon; Seiler, Roland; Hoadley, Katherine A.; Groeneveld, Clarice S.; Al-Ahmadie, Hikmat; Choi, Woonyoung; Castro, Mauro A.A.; Fontugne, Jacqueline; et al. (European Urology, 2020)
CRIS-Team Scopus Importer:2020-02-14

Reply to Yongbao Wei, Haijian Huang, and Liefu Ye's Letter to the Editor re: George J. Netto, Mahul B. Amin, Daniel M. Berney, et al. The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs—Part B: Prostate and Urinary Tract Tumors. Eur Urol. 2022;82:469–82. - Rubin, Mark A.; Amin, Mahul B.; Compérat, Eva; Gill, Anthony; Hartmann, Arndt; Menon, Santosh; Raspollini, Maria; Srigley, John; Tan, Puay Hoon; Ticktoo, Satish; Tsuzuki, Toyonori; Turajlic, Samra; et al. (European Urology, 2023)
CRIS-Team Scopus Importer:2022-12-23

Report from the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer: Progress and Challenges - Warrick, Joshua I.; Knowles, Margaret A.; Yves, Allory; Van Der Kwast, Theo; Grignon, David J.; Kristiansen, Glen; Egevad, Lars; Hartmann, Arndt; Cheng, Liang (American Journal of Surgical Pathology, 2020)
During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into "molecular subtypes," based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended. Mutations in the TERT promoter are present in the majority of bladder cancers, including the noninvasive stage of tumor evolution, but not in reactive conditions. Mutational analysis of the TERT promoter thus distinguishes histologically deceptive cancers from their benign mimics in some cases. A minority of pathologists employ this test. FGFR3 mutations are common in bladder cancer, and metastatic urothelial carcinoma (UC) with such mutations frequently responds to erdafitinib, an FGFR inhibitor. Testing for FGFR3 alterations is required before using this drug. Metastatic UC responds to immune-oncology (IO) agents in 20% of cases. These are approved as first and second-line treatments in metastatic UC. Several biological parameters associate with response to IO agents, including tumor mutational burden, molecular subtype, and infiltration by programmed death-ligand 1-positive lymphocytes, detected by immunohistochemistry. Programmed death-ligand 1 immunohistochemistry is mandatory before administering IO agents in the first-line setting. In conclusion, much has been learned about the biology of bladder cancer, and this understanding has improved the care of patients with the disease.
CRIS-Team Scopus Importer:2020-03-10
Keywords: bladder cancer; FGFR3 mutation; immune-oncology; molecular subtypes; PD-L1 immunohistochemistry; TERT promoter

Report From the International Society of Urological Pathology (ISUP) Consultation Conference On Molecular Pathology Of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer: Progress and Challenges. - Warrick, Joshua; Knowles, Margaret A.; Yves, Allory; van der Kwast, Theodorus H.; Grignon, David J.; Kristiansen, Glen; Egevad, Lars; Hartmann, Arndt; Cheng, Liang (American Journal of Surgical Pathology, 2020)
During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into "molecular subtypes," based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended. Mutations in the TERT promoter are present in the majority of bladder cancers, including the noninvasive stage of tumor evolution, but not in reactive conditions. Mutational analysis of the TERT promoter thus distinguishes histologically deceptive cancers from their benign mimics in some cases. A minority of pathologists employ this test. FGFR3 mutations are common in bladder cancer, and metastatic urothelial carcinoma (UC) with such mutations frequently responds to erdafitinib, an FGFR inhibitor. Testing for FGFR3 alterations is required before using this drug. Metastatic UC responds to immune-oncology (IO) agents in 20% of cases. These are approved as first and second-line treatments in metastatic UC. Several biological parameters associate with response to IO agents, including tumor mutational burden, molecular subtype, and infiltration by programmed death-ligand 1-positive lymphocytes, detected by immunohistochemistry. Programmed death-ligand 1 immunohistochemistry is mandatory before administering IO agents in the first-line setting. In conclusion, much has been learned about the biology of bladder cancer, and this understanding has improved the care of patients with the disease.
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Report of the Chairman of the Working Group for Head and Neck Pathology of the German Society for Pathology Annual Activities 2016/2017 - Agaimy, Abbas (Pathologe, 2017)
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Report of the meeting of the working group on uropathology 2014 - Hartmann, Arndt; Knüchel-Clarke, R. (Pathologe, 2014)
EVALuna2:6698

Report of the working group on molecular pathology Bericht der Arbeitsgemeinschaft Molekularpathologie - Haller, Florian; Lassmann, S.; Siebolts, U. (Pathologe, 2019)
CRIS-Team Scopus Importer:2019-11-26

Report of the working group on uropathology of the German Society of Pathology 2015 - Knuechel-Clarke, R.; Hartmann, Arndt (Pathologe, 2015)
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Report on the session of the Head and Neck Pathology Working Group on 24 May 2018 at the 102nd annual meeting of the DGP in Berlin - Agaimy, Abbas (Pathologe, 2018)
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Reproducibility of histopathologic tumor grading in penile cancer–results of a European project - Kakies, Ch.; Lopez-Beltran, A.; Comperat, E.; Erbersdobler, A.; Grobholz, R.; Hakenberg, O. W.; Hartmann, Arndt; Horn, L. -C.; Hoehn, A. K.; Koellermann, J.; Kristiansen, G.; Montironi, R.; et al. (Virchows Archiv, 2014)
Since reliable molecular prognostic parameters for inguinal lymph metastases in penile cancer are not available, tumor grading is often used as a surrogate prognostic tool for the indication of inguinal lymphadenctomy and has been integrated into the current TNM classification for penile cancer. The reliability of tumor grading is under discussion. We examined interobserver grading variability in 90 primary penile carcinomas, assessed by 12 different uropathologists from five European countries. Tumor grading, following the CAP scheme, was compared, and interobserver variability was calculated using kappa statistics. The interobserver variability was high as reflected by an overall low kappa coefficient (mean k = 0.34) and reached a moderate level only in 26.4 % of the cases (range 0.02-0.67). The percentage of G1 tumors assigned ranged from 8.6 to 52.5 %, G2 tumors from 27.1 to 72.6 % and G3 tumors from 11.7 to 48.7 %. Only some observers assigned G4 with a range of 0.6-21.9 %. Subdivision into low and high grade according to UICC and EAU classifications differed significantly (P < 0.001). Low reproducibility of grading in penile carcinomas with the favored method does not allow a reliable prognostication of tumor aggressiveness. Inclusion of histological grading into the TNM classification currently seems not to be a benefit.
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Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer-A Europe-Wide External Quality Assessment - Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Rübner, Matthias; Stöhr, Robert; Beckmann, Matthias; Zentgraf, Miriam; Popp, Verena; Weidler, Jodi; Simon, Iris; Becker, Steffi; Hübner, Hanna; et al. (Cancers, 2021)
Simple Summary Four biomarkers [estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2], are used to stratify breast cancer (BC) into subtypes predictive of therapy response. In a Europe-wide external quality assessment, we compared performance of an mRNA-based method [Xpert(R) Breast Cancer STRAT4 (CE-IVD)] for determining ESR1, PGR, ERBB2, and MKI67 expression against the gold standard [immunohistochemistry (IHC)/HER2 in situ hybridization (ISH)]. The coordinating center (CC) and five European laboratories tested ten breast cancer samples. STRAT4 binary (positive or negative) results of each marker were compared with the gold standard. ESR1 and ERBB2 mRNA results were concordant with IHC/ISH in all single analyses. In contrast, PGR and MKI67 results were discordant in a few cases, which had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. STRAT4 assay may be a reproducible method. However, cases with expression values close to cut-offs should be carefully reviewed. Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert(R) Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed.
CRIS-Team WoS Importer:2021-10-08

Restoration of an academic historical gross pathology collection-refreshed impact on current medical teaching? - Eichhorn, Philip; Andraschke, Udo; Dross, Fritz; Geppert, Carol-Immanuel; Hartmann, Arndt; Rau, Tilman (Virchows Archiv, 2018)
The declaration of Leiden pronounces the demand to conserve pathological-anatomical collections as cultural heritage. Likewise, the Institute of Pathology of the Friedrich-Alexander-University Erlangen-Nuremberg owns macroscopic pathological-anatomical specimens reaching back over 150 years. The purpose of this work is to examine the impact, meaning, and perception of such historical preparations during the current medical curriculum. Additionally, the experiences from the renovation process can be used as a template for other institutes. All preparations were documented, photographed, and catalogued in an electronic database. During a restoration period, a series of didactically suitable specimens were professionally restored. Hereby, the help of a special course of interested students was admitted. In a second step, the specimens were integrated into the regular teaching of students in macroscopic pathology. An evaluation was carried out on two student cohorts with and without historical specimens by means of a questionnaire with 23 items and two free text fields. In total, 1261 specimens were registered covering diseases from almost the complete human body with a strong representation of the cardiovascular, urinary, gastrointestinal, and central nervous systems. Hereby, exceptional rare and untreated cases with medical relevance could be found and stepwise implemented into the curriculum. The student evaluation positively addressed that the courses became livelier and interactive. Furthermore, a more comprehensive overview and a better understanding of the macroscopic pathology were appreciated. However, more self-study time with the specimen was demanded. The authenticity of historical specimens contrasts with the tendency to carry out virtual "online" didactic methods. The stereoscopic view on often untreated and, therefore, unbiased cases enhances a skill-oriented deeper understanding of diseases. In conclusion, historical specimens regain interest and even didactic value, especially in an era of declining autopsy rates.
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Results of the first prototypical Ring Trial of QuIP for PD-L1 Expression in Urothelial Carcinomas - Sommer, Ulrich; Baretton, Gustavo; Hartmann, Arndt; Eckstein, Markus; Schwamborn, Kristina; Weichert, Wilko; Kristiansen, Glen; Wild, Peter; Knuechel-Clarke, Ruth; Schirmacher, Peter; Dietel, Manfred; Joehrens, Korinna (Pathologe, 2020)
CRIS-Team WoS Importer:2020-07-17

Re: Svetlana Avulova, John C. Cheville, Christine M. Lohse, et al. Grading Chromophobe Renal Cell Carcinoma: Evidence for a Four-tiered Classification Incorporating Coagulative Tumor Necrosis. Eur Urol 2021;79:225-31: Two-, Three-, or Four-tiered Grading of Chromophobe Renal Cancer: That's the Question! - Ohashi, Riuko; Hartmann, Arndt; Martignoni, Guido; Moch, Holger (European Urology, 2021)
CRIS-Team Scopus Importer:2021-07-02

Retrospective histological evaluation of orchiectomy specimens following testicular torsion reveals a 10% incidence of reversible injury. Is it time for a change of strategy? - Marcou, Marios; Hartmann, Arndt; Wullich, Bernd; Apel, Hendrik; Hirsch-Koch, Karin (Andrology, 2022)
BackgroundAccording to standard medical practice, immediate orchiectomy is advised in the case of a non-viable testis following testicular torsion. Because of the lack of objective criteria in the evaluation of testicular viability, the fate of the testis solely depends on the discretion and experience of the surgeon. ObjectiveIn this study, we retrospectively reassess the management of patients with testicular torsion in our center, and we ask the question, from a retrospective point of view, of whether the decision to perform orchiectomy has always been correct. Materials and methodsWe retrospectively reviewed all cases of patients with testicular torsion who underwent surgery in our center between 2001 and 2021. All orchiectomy specimens were reevaluated and graded by an experienced pathologist using the Mikuz grading system. ResultsImmediate orchiectomy was performed in 48 of the 136 patients (35%). Five (10.4%) of the 48 orchiectomy specimens were categorized as "grade 1," and 17 (35.4%) were categorized as "grade 2." The time between the onset of symptoms and surgical exploration exceeded 12 h in three of the five patients with a "grade 1" testicular injury, and in one case, it even exceeded 24 h. Discussion"Grade 1" testicular injury is potentially reversible, whereas the fate of a testis with a "grade 2" testicular injury remains unknown. Whether and to what extent partial testicular tissue salvage in a "grade 2" injury is still possible remain unclear. ConclusionsOur results indicate that at least 10% of the testicles removed in our center could, from a retrospective point of view, have been salvaged. Our study further demonstrated that the duration of symptoms is not an absolute indicator of testicular damage and that the decision of whether orchiectomy should be performed, based simply on the subjective macroscopic image of the affected testis, is not always correct.
CRIS-Team WoS Importer:2023-01-20

Review of renal anastomosing hemangioma with focus on clinical and pathological aspects - Kuroda, Naoto; Ohe, Chisato; Deepika, Sirohi; Yorita, Kenji; Mikami, Shuji; Furuya, Mitsuko; Nagashima, Yoji; Hes, Ondrej; Agaimy, Abbas; Michal, Michal; Amin, Mahul B. (Polish Journal of Pathology, 2016)
Renal anastomosing hemangiomas (RAH) has been recently proposed as a new entity. In this article, we summarize the clinicopathologic features of this tumor. RAH usually develops on a background of end-stage renal disease. Macroscopically, tumors are well-defined and their cut surface shows mahogany brown spongy tissue with epicenter in the renal medulla. Tumors are usually small, but larger lesions are reported. On microscopic examination, the tumor consists of sinusoid-like vascular channels lined by cuboidal endothelial cells with occasional hobnail-like appearance of endothelial cells closely mimicking splenic sinusoids. Eosinophilic hyaline globules may be present in the cytoplasm of neoplastic endothelial cells. Extramedullary hematopoiesis containing erythroid precursor and megakaryocytes may be present in the vascular lumens. Immunohistochemically, endothelial cells are positive for CD31 and CD34, but negative for D2-40, GLUT-1 and HHV8. The surrounding stroma around endothelial cells demonstrates positivity for ? smooth muscle action. To date, there are no studies on molecular genetic aspects of RAH. This tumor is indolent based on site and size of the lesion, partial or nephrectomy is sufficient as a therapeutic modality.
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Revised histopathological consensus classification of joint implant related pathology - Krenn, V.; Morawietz, L.; Perino, G.; Kienapfel, H.; Ascherl, R.; Hassenpflug, G. J.; Thomsen, M.; Thomas, P.; Huber, M.; Kendoff, D.; Baumhoer, D.; Krukemeyer, M. G.; et al. (Pathology Research and Practice, 2014)
This extended classification of joint implant related pathology is a practical histopathologic classification based on defined morphological criteria covering the complete spectrum of pathohistologic changes in periprosthetic tissues. These changes may occur as a consequence of endoprosthetic replacement of large joints and may lead to a reduction in the prosthesis survival rate. We describe the established consensus classification of the periprosthetic membrane, in which aseptic and septic prosthetic loosening can be subdivided into four histological types, as well as histopathological criteria for additional significant pathologies including endoprosthetic-associated arthrofibrosis, particle-induced immunological, inflammatory and toxic mechanisms (adverse reactions), and bone tissue pathologies. These characteristic tissue alterations and their relationships are summarized in the extended classification. Since particle heterogeneity in periprosthetic tissue is high and particle identification is a necessary part of diagnosis, the identification of different types of particles is described in the histopathological particle algorithm. The morphological qualities of prosthetic material particles and the demarcation between abrasion and non-abrasion endogenous particles are also summarized. This feasible classification which is based on low cost standard tissue processing and examination and on well-defined diagnostic criteria is a solid platform for the histological diagnosis of implant associated pathologies providing a stable and reproducible tool for the surgical pathologist. Since this classification is suitable for standardized histopathological diagnostics, it might also provide a useful data set for joint arthroplasty registers, particularly for registers based on so-called routine data.
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Rhabdoid and Undifferentiated Phenotype in Renal Cell Carcinoma: Analysis of 32 Cases Indicating a Distinctive Common Pathway of Dedifferentiation Frequently Associated With SWI/SNF Complex Deficiency - Agaimy, Abbas; Cheng, Liang; Egevad, Lars; Feyerabend, Bernd; Hes, Ondrej; Keck, Bastian; Pizzolitto, Stefano; Sioletic, Stefano; Wullich, Bernd; Hartmann, Arndt (American Journal of Surgical Pathology, 2017)
Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with >=pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.
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Risk and timing of biochemical recurrence in pT3aN0/Nx prostate cancer with positive surgical margin - A multicenter study - Karl, Alexander; Buchner, Alexander; Tympner, Christiane; Kirchner, Thomas; Ganswindt, Ute; Belka, Claus; Ganzer, Roman; Wieland, Wolf; Eder, Fabian; Hofstaedter, Ferdinand; Schilling, David; Sievert, Karl-Dietrich; et al. (Radiotherapy and Oncology, 2015)
Positive surgical margins (PSM) after radical prostatectomy have been shown to be associated with impaired outcome. In pT3pN0 patients with PSM either immediate radiotherapy or clinical and biological monitoring followed by salvage radiotherapy is recommended by the latest guidelines of the European Association of Urology.A retrospective, multicenter study of eight urological centers was conducted on 536 prostatectomy patients with pT3aN0/NxR1 tumors and no neoadjuvant/adjuvant therapy. A pathological re-review of all prostate specimens was performed. Association of clinical and pathological features with biochemical recurrence (BCR) was analyzed using univariate and multivariate analysis.With 48months median follow-up, BCR occurred in 39.7%. Preoperative PSA value, performance of pelvic lymph node dissection and Gleason score were significantly associated with BCR. In multivariate analysis, Gleason score was the only independent prognostic factor (p<0.001) for BCR. Five-year BCR-free survival rates were 74%, 70%, 38%, and 51% with Gleason score 6, 3+4=7a, 4+3=7b, and 8-10, respectively.In pT3aN0/NxR1 patients with no adjuvant/neoadjuvant treatment, Gleason Score permits independent prediction of the risk for BCR. These findings could help to estimate and discuss the individual risk for BCR with our patients on an individual basis.
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Risk Assessment after Neoadjuvant Chemotherapy in Luminal Breast Cancer Using a Clinicomolecular Predictor - Loibl, Sibylle; Weber, Karsten; Huober, Jens; Krappmann, Kristin; Marme, Frederik; Schem, Christian; Engels, Knut; Pfitzner, Berit Maria; Kuemmel, Sherko; Furlanetto, Jenny; Hartmann, Arndt; Darb-Esfahani, Silvia; et al. (Clinical Cancer Research, 2018)
Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathologic tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen receptor (ER)-positive/HER2-negative breast cancer. We also compared the prognostic power of the mEPclin with that of the CPS-EG score.Experimental Design: A total of 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cut-off values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS).Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse [HR, 2.16; 95% confidence interval (CI), 1.86-2.51; P < 0.001] and death (HR, 2.28; 95% CI, 1.90-2.75; P < 0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer DFS and overall survival compared with those at low risk. In contrast with CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR, 2.13; 95% CI, 1.73-2.63; P < 0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; P < 0.001).Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies. Clin Cancer Res; 24(14); 3358-65. ©2018 AACR.
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Risk factors associated with positive surgical margins’ location at radical cystectomy and their impact on bladder cancer survival - Claps, Francesco; Van De Kamp, Maaike W.; Mayr, Roman; Bostrom, Peter J.; Boormans, Joost L.; Eckstein, Markus; Mertens, Laura S.; Boeve, Egbert R.; Neuzillet, Yann; Burger, Maximilian; Pouessel, Damien; Trombetta, Carlo; et al. (World Journal of Urology, 2021)
Purpose: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). Methods: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan–Meier method was used to estimate DSS stratified by margins’ status and location. Log-rank statistics and Cox’ regression models were used to determine significance. Results: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). Conclusions: PSMs’ location represents distinct risk factors’ patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.
CRIS-Team Scopus Importer:2021-07-16
Keywords: Bladder; Cancer; Cystectomy; Margin; Soft tissue; Ureter; Urethra; Urothelial carcinoma

Risk of penile tumor development in Caucasian individuals is independent of the coding variant rs7208422 in the TMC8 (EVER2) gene - Stöhr, Robert; Wendler, Olaf Dietrich; Giedl, Josef; Richter, Georg; Campean, Valentina; Burger, Maximilian; Bertz, Simone; Hartmann, Arndt; Gaisa, Nadine T.; Wullich, Bernd (Molecular and Clinical Oncology, 2021)
Genetic variation in the transmembrane channel-like (TMC)6/TMC8 region has been linked to beta-type human papillomavirus (HPV) infection and squamous cell carcinoma (SCC) of the skin and the head and neck, alpha-type HPV persistence and progression to cervical cancer. The functional variant rs7208422 of the TMC8 gene was suggested to have a high impact on susceptibility to beta-papillomaviruses and their oncogenic potential and to also have an influence on alpha-type HPV-related disease. The aim of the present study was to evaluate a possible influence of rs7208422 on penile cancer risk, a known alpha-type HPV-related malignancy. Therefore, the distribution of rs7208422 was determined by direct Sanger sequencing of 104 Caucasian penile SCC cases and compared to data of 3,810 controls taken from the literature. HPV detection was performed by usage of GP5+/6+ primers and subtype-specific PCR. It was observed that the distribution of rs7208422 followed the Hardy Weinberg equilibrium in both cases and controls. HPV DNA was detected in 39% of the penile SCC cases. Overall, there was no significant difference in the distribution of rs7208422 neither between cases and controls (P=0.726) nor between HPV-positive and-negative penile SCC cases (P=0.747). There was also no association between rs7208422 genotypes and age of disease onset (P=0.740). In conclusion, the present data argue against a significant impact of rs7208422 on the risk for the development of penile SCC in Caucasians. Even in combination with the HPV status, the SNP appears not to influence the risk of penile SCC in HPV-positive cases.
CRIS-Team WoS Importer:2021-11-26

Risk of postmenopausal hormone therapy and patient history factors for the survival rate in women with endometrial carcinoma - Hein, Alexander; Schneider, Michael; Renner, Stefan; Fasching, Peter; Fießler, Cornelia; Titz, Susanna; Hartmann, Arndt; Beckmann, Matthias; Thiel, Falk C. (Archives of Gynecology and Obstetrics, 2019)
Purpose: Postmenopausal hormone therapy (HT) is known to affect the development of hormone-dependent endometrial carcinoma (type I EC). Several studies on breast and ovarian carcinoma have shown that HT influences the molecular profile and prognostic behavior of these tumors. This study aimed to investigate the influence of prior HT and other risk factors on the prognosis in a cohort of patients with invasive endometrial carcinoma (EC). Methods: Among 525 patients diagnosed with EC between 1987 and 2010, 426 postmenopausal patients were identified. Information regarding HT was available in 287 of these patients, 78 of whom had a history of HT and 209 of whom did not. Both overall survival (OS) and progression-free survival (PFS) were analyzed. In addition to OS and PFS, risk factors such as age at diagnosis, postmenopausal HT, body mass index (BMI), diabetes mellitus, tumor stage, EC type (I or II), and recurrences were analyzed. Results: Relative to HT alone, women with EC and a history of HT had a longer survival than those with no HT. However, the Cox proportional hazards model showed that it was not HT itself, but rather other characteristics in the HT group that were causally associated with longer survival. Conclusions: Age (the older, the worse) and tumor stage (the higher, the worse) were significant influences on overall survival. Patients with HT also had lower BMIs, less diabetes, more type I EC, and fewer recurrences in comparison with the non-HT group. With regard to the PFS, it made no difference whether the patient was receiving HT.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Endometrial carcinoma; Estrogen; Hormone replacement therapy; Hormone therapy; Overall survival; Progesterone; Prognosis; Risk factors

Risk, Prediction and Prevention of Hereditary Breast Cancer - Large-Scale Genomic Studies in Times of Big and Smart Data - Wunderle, Marius; Olmes, Gregor; Nabieva, Naiba; Häberle, Lothar; Jud, Sebastian; Hein, Alexander; Rauh, Claudia; Hack, Carolin; Erber, Ramona; Ekici, Arif Bülent; Hoyer, Juliane; Vasileiou, Georgia; et al. (Geburtshilfe und Frauenheilkunde, 2018)
Over the last two decades genetic testing for mutations in BRCA1 and BRCA2 has become standard of care for women and men who are at familial risk for breast or ovarian cancer. Currently, genetic testing more often also includes so-called panel genes, which are assumed to be moderate-risk genes for breast cancer. Recently, new large-scale studies provided more information about the risk estimation of those genes. The utilization of information on panel genes with regard to their association with the individual breast cancer risk might become part of future clinical practice. Furthermore, large efforts have been made to understand the influence of common genetic variants with a low impact on breast cancer risk. For this purpose, almost 450 000 individuals have been genotyped for almost 500 000 genetic variants in the OncoArray project. Based on first results it can be assumed that - together with previously identified common variants - more than 170 breast cancer risk single nucleotide polymorphisms can explain up to 18% of familial breast cancer risk. The knowledge about genetic and non-genetic risk factors and its implementation in clinical practice could especially be of use for individualized prevention. This includes an individualized risk prediction as well as the individualized selection of screening methods regarding imaging and possible lifestyle interventions. The aim of this review is to summarize the most recent developments in this area and to provide an overview on breast cancer risk genes, risk prediction models and their utilization for the individual patient.
EVALuna2:34612

RNA sequencing of collecting duct renal cell carcinoma suggests an interaction between miRNA and target genes and a predominance of deregulated solute carrier genes - Wach, Sven; Taubert, Helge; Weigelt, Katrin; Hase, Nora; Köhn, Marcel; Misiak, Danny; Hüttelmaier, Stefan; Stöhr, Christine G.; Kahlmeyer, Andreas; Haller, Florian; Vera, Julio; Hartmann, Arndt; et al. (Cancers, 2020)
Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight normal tissues of renal cell carcinoma patients. At a threshold of |log2fold-change| ≥ 1, 3349 genes were upregulated and 1947 genes were downregulated in CDCs compared to the normal samples. Pathway analysis of the deregulated genes revealed that cancer pathways and cell cycle pathways were most prominent in CDCs. The most upregulated gene was keratin 17, and the most downregulated gene was cubilin. Among the most downregulated genes were four solute carrier genes (SLC3A1, SLC9A3, SLC26A7, and SLC47A1). The strongest negative correlations between miRNAs and mRNAs were found between the downregulated miR-374b-5p and its upregulated target genes HIST1H3B, HK2, and SLC7A11 and between upregulated miR-26b-5p and its downregulated target genes PPARGC1A, ALDH6A1, and MARC2. An upregulation of HK2 and a downregulation of PPARGC1A, ALDH6A1, and MARC2 were observed at the protein level. Survival analysis of the cancer genome atlas (TCGA) dataset showed for the first time that low gene expression of MARC2, cubilin, and SLC47A1 and high gene expression of KRT17 are associated with poor overall survival in clear cell renal cell carcinoma patients. Altogether, we identified dysregulated protein-coding genes, potential miRNA-target interactions, and prognostic markers that could be associated with CDC.
CRIS-Team Scopus Importer:2020-01-10
Keywords: Collecting duct carcinoma; RNA sequencing; Solute carrier proteins

RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions - Klubickova, Natalie; Agaimy, Abbas; Hajkova, Veronika; Ptakova, Nikola; Grossmann, Petr; Steiner, Petr; Michal, Michal; Michal, Michael (Virchows Archiv, 2022)
Myxoinflammatory fibroblastic sarcoma (MIFS) has been shown to harbor various recurrent molecular aberrations; most of which, however, seem to be present in only a minority of cases. In order to better characterize the molecular underpinnings of MIFS, fourteen cases were analyzed by targeted RNA-sequencing (RNA-seq), VGLL3 enumeration FISH probe, and BRAF break-apart and enumeration probes. Neither t(1;10)(p22;q24) nor BRAF gene amplifications were found. However, VGLL3 gene amplification was detected in 5 cases by FISH which corresponded with an increase in VGLL3 expression detected by RNA-seq. In 1 of these cases, RNA-seq additionally revealed a novel SND1::BRAF fusion. Two of the 9 cases lacking VGLL3 amplification harbored either a SEC23IP::VGLL3 or a TEAD1::MRTFB rearrangement by RNA-seq, both confirmed by RT-PCR and Sanger sequencing. The detected molecular aberrations have a potential to either activate the expression of genes regulated by the transcription factors of the TEAD family, which are involved in tumor initiation and progression, or switch on the MEK/ERK signaling cascade, which plays an important role in cell cycle progression. Our results broaden the molecular genetic spectrum of MIFS and point toward the importance of the VGLL3-TEAD interaction, as well as the deregulation of the MEK/ERK pathway in the pathogenesis of MIFS, and may represent a potential target for therapy of recurrent or advanced disease.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Myxoinflammatory fibroblastic sarcoma; SEC23IP::VGLL3; SND1::BRAF; TEAD transcription factors; TEAD1::MRTFB fusion; VGLL3 amplification

Robust Colon Tissue Cartography with Semi-Supervision - Dexl, Jakob; Benz, Michaela; Kuritcyn, Petr; Wittenberg, Thomas; Bruns, Volker; Geppert, Carol-Immanuel; Hartmann, Arndt; Bischl, Bernd; Goschenhofer, Jann (Current Directions in Biomedical Engineering, 2022)
We explore the task of tissue classification for colon cancer histology in a low label regime comparing a semi-supervised and a supervised learning strategy in a series of experiments. Further, we investigate the model robustness w.r.t. distribution shifts in the unlabeled data and domain shifts across different scanners to prove their practicality in a histology context. By utilizing unlabeled data in addition to nl = 1000 labeled tiles per class, we yield a substantial increase in accuracy from 89.9% to 91.4%.
CRIS-Team Scopus Importer:2022-09-30
Keywords: Colon Cancer; Computational Pathology; Model Robustness; Semi-Supervised Learning

Robust Slide Cartography in Colon Cancer Histology: Evaluation on a Multi-scanner Database - Kuritcyn, Petr; Geppert, Carol-Immanuel; Eckstein, Markus; Hartmann, Arndt; Wittenberg, Thomas; Dexl, Jakob; Baghdadlian, Serop; Hartmann, David; Perrin, Dominik; Bruns, Volker; Benz, Michaela (Informatik aktuell, 2021)
CRIS-Team Scopus Importer:2021-04-19

Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer - Zhang, Shuman; Yun, Duo; Yang, Hao; Eckstein, Markus; Elbait, Gihan Daw; Zhou, Yaxing; Lu, Yanxi; Yang, Hai; Zhang, Jinping; Dörflein, Isabella; Britzen-Laurent, Nathalie; Pfeffer, Susanne; et al. (Cell Death Discovery, 2024)
Pancreatic cancer is a malignant tumor of the digestive system. It is highly aggressive, easily metastasizes, and extremely difficult to treat. This study aimed to analyze the genes that might regulate pancreatic cancer migration to provide an essential basis for the prognostic assessment of pancreatic cancer and individualized treatment. A CRISPR knockout library directed against 915 murine genes was transfected into TB 32047 cell line to screen which gene loss promoted cell migration. Next-generation sequencing and PinAPL.py- analysis was performed to identify candidate genes. We then assessed the effect of serine/threonine kinase 11 (STK11) knockout on pancreatic cancer by wound-healing assay, chick agnosia (CAM) assay, and orthotopic mouse pancreatic cancer model. We performed RNA sequence and Western blotting for mechanistic studies to identify and verify the pathways. After accelerated Transwell migration screening, STK11 was identified as one of the top candidate genes. Further experiments showed that targeted knockout of STK11 promoted the cell migration and increased liver metastasis in mice. Mechanistic analyses revealed that STK11 knockout influences blood vessel morphogenesis and is closely associated with the enhanced expression of phosphodiesterases (PDEs), especially PDE4D, PDE4B, and PDE10A. PDE4 inhibitor Roflumilast inhibited STK11-KO cell migration and tumor size, further demonstrating that PDEs are essential for STK11-deficient cell migration. Our findings support the adoption of therapeutic strategies, including Roflumilast, for patients with STK11-mutated pancreatic cancer in order to improve treatment efficacy and ultimately prolong survival.
CRIS-Team Scopus Importer:2024-04-12

Role of Fibroblast Growth Factors in the Crosstalk of Hepatic Stellate Cells and Uveal Melanoma Cells in the Liver Metastatic Niche - Seitz, Tatjana; John, Nora; Sommer, Judith; Dietrich, Peter; Thasler, Wolfgang E.; Hartmann, Arndt; Evert, Katja; Lang, Sven A.; Boßerhoff, Anja Katrin; Hellerbrand, Claus (International Journal of Molecular Sciences, 2022)
Hepatic metastasis is the critical factor determining tumor-associated mortality in different types of cancer. This is particularly true for uveal melanoma (UM), which almost exclusively metastasizes to the liver. Hepatic stellate cells (HSCs) are the precursors of tumor-associated fibroblasts and support the growth of metastases. However, the underlying mechanisms are widely unknown. Fibroblast growth factor (FGF) signaling is dysregulated in many types of cancer. The aim of this study was to analyze the pro-tumorigenic effects of HSCs on UM cells and the role of FGFs in this crosstalk. Conditioned medium (CM) from activated human HSCs significantly induced proliferation together with enhanced ERK and JNK activation in UM cells. An in silico database analysis revealed that there are almost no mutations of FGF receptors (FGFR) in UM. However, a high FGFR expression was found to be associated with poor survival for UM patients. In vitro, the pro-tumorigenic effects of HSC-CM on UM cells were abrogated by a pharmacological inhibitor (BGJ398) of FGFR1/2/3. The expression analysis revealed that the majority of paracrine FGFs are expressed by HSCs, but not by UM cells, including FGF9. Furthermore, the immunofluorescence analysis indicated HSCs as a cellular source of FGF9 in hepatic metastases of UM patients. Treatment with recombinant FGF9 significantly enhanced the proliferation of UM cells, and this effect was efficiently blocked by the FGFR1/2/3 inhibitor BGJ398. Our study indicates that FGF9 released by HSCs promotes the tumorigenicity of UM cells, and thus suggests FGF9 as a promising therapeutic target in hepatic metastasis.
CRIS-Team Scopus Importer:2022-10-28
Keywords: fibroblast growth factor 9; fibroblast growth factors; hepatic metastasis; hepatic stellate cells; uveal melanoma

Role of Surgical Pathologist for Detection of Predictive Immuno-oncological Factors in Breast Cancer. - Berner, Mandy; Hartmann, Arndt; Erber, Ramona (Advances in Anatomic Pathology, 2023)
Immune checkpoint inhibitors (ICIs) have changed therapy strategies in breast cancer (BC) patients suffering from triple-negative breast cancer (TNBC). For example, in Europe the anti-programmed cell death 1 ligand 1 (PD-L1) ICI Azetolizumab is approved for adult patients with locally advanced or metastasized TNBC (mTNBC), depending on the immunohistochemical (IHC) PD-L1 expression of immune cells in the tumor area [immune cell (IC) score ≥1%); the anti-programmed cell death 1 (PD-1) ICI pembrolizumab is approved for mTNBC if PD-L1 Combined Positive Score (CPS), that is PD-L1 expression on tumor and/or immune cells, is ≥10. For early TNBC, in contrast, neoadjuvant use of pembrolizumab is approved in the United States and Europe independent from PD-L1 IHC expression. The determination of PD-L1 expression in tumor tissue to predict response to ICI therapy requires sensitive immunostaining with appropriate primary antibodies and staining protocols and a standardized and meticulous assessment of PD-L1 IHC stained breast cancer tissue slides. For the selection of the test material and continuous quality control of the dyeing, high standards must be applied. The evaluation is carried out according to various evaluation algorithms (scores). Here, the role of PD-L1 in BC and the currently most relevant PD-L1 assays and scores for TNBC will be explained. Furthermore, other tissue-based biomarkers potentially predictive for ICI therapy response in BC, for example, tumor mutational burden (TMB), will be presented in this review.
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Role of the human ErbB family receptors in urothelial carcinoma of the bladder: mRNA expression status and prognostic relevance - Erben, Philipp; Wezel, Felix; Wirtz, Ralph; Martini, Thomas; Stein, Doron; Weis, Cleo-Aaron; Hartmann, Arndt; Bolenz, Christian (Aktuelle Urologie, 2017)
Background Altered expression of epidermal growth factor (EGF) family (ErbB) receptors in urothelial carcinoma of the urinary bladder (UCB) has been associated with adverse outcomes. Given the limited treatment options in UCB, EGFR and HER2 (ERBB2) represent established therapeutic targets in other entities. We assessed the expression of ErbB family receptors (ERBB1 - 4) on mRNA levels in correlation with histopathological and clinical parameters in patients treated with radical cystectomy (RC). Methods 94 patients (female = 22; male = 72; median age: 66.5 years [range 39 - 88]) with UCB (pT1 - 4) treated with RC were included. Median follow-up was 28.2 months (range 0.6 - 139). ErbB mRNA expression levels were determined after extraction from formalin-fixed, paraffin-embedded tissue. Univariate and multivariate Cox proportional hazard models were performed to assess recurrence-free survival (RFS) and cancer-specific survival (CSS). Results Overexpression was observed in 18 % (ERBB3), 39 % (EGFR), 34 % (HER2, ERBB2) and 30 % (ERBB4) of patients, respectively. Higher pathological stage (p = 0.012), a positive nodal status (p = 0.0002), high ERBB4 (p = 0.012) and high HER2 (ERBB2) levels (p = 0.014) were significantly associated with reduced RFS. A negative lymph node status (p = 0.0003) and low HER2 (ERBB2) (p = 0.042) levels had a favourable prognostic impact on CSS. In multivariate analysis, positive pN stage (p = 0.0011) and high ERBB4 (p = 0.0073) expression were independent predictors of reduced RFS. Higher pN stage (p = 0.0016) was an independent predictor of reduced CSS. Conclusions Higher HER2 (ERBB2) expression is associated with an unfavourable prognosis in patients with UCB. However, it is not an independent predictor when measured on mRNA levels. Further analyses need to clarify which patients may still benefit from HER2 (ERBB2) targeted drugs.
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Role of two single nucleotide polymorphisms in secreted frizzled related protein 1 and bladder cancer risk - Rogler, Anja; Hoja, Sabine; Socher, Eileen; Nolte, Elke; Wach, Sven; Wieland, Wolf; Hofstädter, Ferdinand; Goebell, Peter; Wullich, Bernd; Hartmann, Arndt; Stoehr, Robert (International Journal of Clinical and Experimental Pathology, 2013)
In this study, we determined the genotype distribution of two single nucleotide polymorphisms (SNPs) in secreted frizzled related protein 1 (SFRP1), rs3242 and rs921142, in a Caucasian bladder cancer case-control study. Allelic variants of the SNPs were determined using restriction fragment length polymorphism (RFLP) analysis and partly verified by sequencing analysis. Overall, DNA from 188 consecutive and 215 early-onset bladder cancer patients (≤45 years) as well as from 332 controls was investigated. Potential microRNA binding sites were determined for rs3242, and microRNA expression was analysed in cell lines and tumour specimens. We observed a remarkable distribution difference in rs3242 between bladder cancer patients and healthy controls (p=0.05). Additionally, we found a significant difference in genotype distribution (p=0.032), resulting from the difference of early-onset patients and the control group (p=0.007). The risk allele T showed increased frequency in the early-onset patient group (p=0.002). Genotype-dependent differences of microRNA binding capacity were predicted in SFRP1 mRNA for two microRNAs. Hsa-miR-3646 showed strong expression in cell lines and tumour tissue, whereas hsa-miR-603 exhibited weak expression. The rs921142 SNP showed no significant association with bladder cancer risk. This is the first study to describe an association of the SFRP1 SNP rs3242 and bladder cancer risk as well as the influence of rs3242 on genotype-dependent microRNA capacity on SFRP1 mRNA. The onset of bladder seems to be associated with the increased occurrence of the T-allele in rs3242.
Keywords: Bladder cancer; Microrna; Sfrp1; Snp; Wnt signalling pathway

RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasms: A series of five cases expanding their anatomic distribution and highlighting significant morphological and phenotypic diversity - Agaimy, Abbas; Din, Nasir Ud; Dermawan, Josephine K.; Haller, Florian; Melzer, Katja; Denz, Axel; Baumhoer, Daniel; Stöhr, Robert; Grützmann, Robert; Antonescu, Cristina R. (Genes Chromosomes & Cancer, 2022)
The RREB1::MRTFB (former RREB1::MKL2) fusion characterizes ectomesenchymal chondromyxoid tumors (EMCMT) of the tongue. Only five molecularly confirmed extra-glossal EMCMT cases have been reported recently; all occurring at head and neck or mediastinal sites. We herein describe five new cases including the first two extracranial/extrathoracic cases. The tumors occurred in three male and two female patients with an age ranging from 18 to 61 years (median, 28). Three tumors were located in the head and neck (jaw, parapharyngeal space, and nasopharyngeal wall) and two in the soft tissue (inguinal and presacral). The tumor size ranged from 3.3 to 20 cm (median, 7). Treatment was surgical without adjuvant treatment in all cases. Two cases were disease-free at 5 and 17 months; other cases were lost to follow-up. Histologically, the soft tissue cases shared a predominant fibromyxoid appearance, but with variable cytoarchitectural pattern (cellular perineurioma-like whorls and storiform pattern in one case and large polygonal granular cells embedded within a chondromyxoid stroma in the other). Two tumors (inguinal and parapharyngeal) showed spindled to ovoid and round cells with a moderately to highly cellular nondescript pattern. One sinonasal tumor closely mimicked nasal chondromesenchymal hamartoma (NCMH). Mitotic activity was low (0-5 mitoses/10 hpfs). Immunohistochemical findings were heterogeneous with variable expression of S100 (2/5), EMA (2/3), CD34 (1/4), desmin (1/4), and GFAP (1/3). Targeted RNA sequencing revealed the same RREB1::MRTFB fusion in all cases, with exon 8 of RREB1 being fused to exon 11 of MRTFB. This study expands the topographic spectrum of RREB1::MRTFB fusion-positive mesenchymal neoplasms, highlighting a significant morphological and phenotypic diversity. Overall, RREB1::MRTFB-rearranged neoplasms seem to fall into two subcategories: tumors with lobulated, chondroid, or myxochondroid epithelioid morphology (Cases 2 and 3) and those with more undifferentiated hypercellular spindle cell phenotype (Cases 1, 4, and 5). Involvement of extracranial/extrathoracic sites and the NCMH-like pattern are novel. The biology of these likely indolent or benign tumors remains to be verified in the future.
CRIS-Team WoS Importer:2022-07-29

Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity - Groß, Miriam; Speckmann, Carsten; May, Annette; Gajardo-Carrasco, Tania; Wustrau, Katharina; Maier, Sarah Lena; Panning, Marcus; Huzly, Daniela; Agaimy, Abbas; Bryceson, Yenan T.; Choo, Sharon; Chow, C. W.; et al. (Journal of Allergy and Clinical Immunology, 2021)
Background: Rubella virus–induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas. Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays. Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses. Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Cytotoxicity; granuloma; Griscelli syndrome type 2; hemophagocytic lymphohistiocytosis; live vaccine; primary immunodeficiency; rubella virus

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8 - Hecht, Markus; Gostian, Antoniu Oreste; Eckstein, Markus; Rutzner, Sandra; von der Grün, Jens; Illmer, Thomas; Hautmann, Matthias Günther; Klautke, Gunther; Laban, Simon; Brunner, Thomas; Hinke, Axel; Becker, Ina; et al. (Journal for ImmunoTherapy of Cancer, 2020)
BACKGROUND: To determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer. METHODS: Patients received a single cycle of cisplatin 30 mg/m² on days 1-3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy. RESULTS: A total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3-4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3-4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR. CONCLUSIONS: Single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.
CRIS-Team Scopus Importer:2020-10-23
Keywords: CD8-Positive T-lymphocytes; clinical trials; combined modality therapy; head and neck neoplasms; Phase II as topic; radioimmunotherapy

Salivary carcinosarcoma: insight into multistep pathogenesis indicates uniform origin as sarcomatoid variant of carcinoma ex pleomorphic adenoma with frequent heterologous elements - Ihrler, Stephan; Stiefel, David; Jurmeister, Philipp; Sandison, Ann; Chaston, Nicola; Laco, Jan; Zidar, Nina; Brcic, Luka; Stöhr, Robert; Agaimy, Abbas (Histopathology, 2022)
Aims: The formal pathogenesis of salivary carcinosarcoma (SCS) remained unclear, both with respect to the hypothetical development from either preexisting pleomorphic adenoma (PA) or de novo and the clonal relationship between highly heterogeneous carcinomatous and sarcomatous components. Methods and results: We performed clinicopathological and molecular (targeted RNA sequencing) analyses on a large series of 16 cases and combined this with a comprehensive literature search (111 cases). Extensive sampling (average 11.6 blocks), combined with immunohistochemistry and molecular studies (PA-specific translocations including PLAG1 or HMGA2 proven in 6/16 cases), enabled the morphogenetic identification of PA in 15/16 cases (93.8%), by far surpassing a reported rate of 49.6%. Furthermore, we demonstrated a multistep (intraductal/intracapsular/extracapsular) adenoma-carcinoma-sarcoma-progression, based on two alternative histogenetic pathways (intraductal, 56.3%, versus myoepithelial pathway, 37.5%). Thereby, early intracapsular stages are identical to conventional carcinoma ex PA, while later extracapsular stages are dominated by secondary, frequently heterologous sarcomatous transformation with often large tumour size (>60 mm). Conclusion: Our findings strongly indicate that SCS (almost) always develops from PA, with a complex multistep adenoma-carcinoma-sarcoma-sequence, based on two alternative histogenetic pathways. The findings from this novel approach strongly suggest that SCS pathogenetically is a rare (3–6%), unique, and aggressive variant of carcinoma ex PA with secondary sarcomatous overgrowth. In analogy to changes of terminology in other organs, the term “sarcomatoid carcinoma ex PA with/without heterologous elements” might be more appropriate.
CRIS-Team Scopus Importer:2022-12-16
Keywords: carcinosarcoma; gene fusion; HMGA2; molecular testing; PLAG1; pleomorphic adenoma; salivary glands; true malignant mixed tumour

Salivary duct carcinoma of the sinonasal cavity: A case report and review of the literature - Müller, Sandra; Mantsopoulos, Konstantinos; Iro, Heinrich; Agaimy, Abbas (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2016)
Salivary duct carcinoma is a rare, aggressive tumor entity first described by Kleinsasser et al in 1968, as a group of malignant salivary gland tumors characterized by duct formation and central necrosis. A case with an unusual localization in the nasal cavity and maxillary sinus is being described in our report.A 60-year-old patient presented with difficulty of nasal breathing and recurrent episodes of epistaxis from the left nasal cavity over the previous 3 months. On endoscopy, a vulnerable lesion in the left inferior nasal meatus could be seen. Biopsy showed salivary duct carcinoma. Treatment consisted of tumor resection by means of a combined endoscopic-osteoplastic surgical approach to the maxillary sinus, bilateral neck dissection, partial parotidectomy, and adjuvant radiochemotherapy.The patient is 6 months after completion of treatment and is free of disease.As salivary duct carcinoma of the sinonasal tract is extremely rare, no therapeutic standards have been developed and treatment essentially is based upon experience with ductal adenocarcinoma of the salivary glands. Surgery therapy should be radical, aiming at eradicating locoregional disease with the role of adjuvant radiotherapy lying in the management of cases with negative prognostic factors. © 2016 Wiley Periodicals, Inc. Head Neck 38:E2464-E2466, 2016.
EVALuna2:6924

Salivary Gland Carcinoma in Children and Adolescents: The Expert/Partner Diagnosis and Treatment Recommendations - Bisogno, G.; Schneider, D.; Ferrari, A.; Stachowicz-Stencel, T.; Rascon, J.; Synakiewicz, A.; Agaimy, Abbas; Martinova, K.; Kachanov, D.; Roganovic, J.; Bien, E.; Bisogno, G.; et al. (PEDIATRIC BLOOD & CANCER, 2021)
CRIS-Team WoS Importer:2021-12-03

Salivary gland carcinoma in children and adolescents: The EXPeRT/PARTNER diagnosis and treatment recommendations - Surun, Aurore; Schneider, Dominik T.; Ferrari, Andrea; Stachowicz-Stencel, Teresa; Rascon, Jelena; Synakiewicz, Anna; Agaimy, Abbas; Martinova, Kata; Kachanov, Denis; Roganovic, Jelena; Bien, Ewa; Bisogno, Gianni; et al. (Pediatric Blood & Cancer, 2021)
Salivary gland carcinomas (SGCs) are rare during childhood and adolescence. Consequently, no standardized recommendations for the diagnosis and therapeutic management of pediatric SGC are available, and pediatric oncologists and surgeons generally follow adult guidelines. Complete surgical resection with adequate margins constitutes the cornerstone of treatment. However, the indications and modalities of adjuvant therapy remain controversial and may be challenging in view of the potential long-term toxicities in the pediatric population. This paper presents the consensus recommendations for the diagnosis and treatment of children and adolescents with SGCs, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER project (Paediatric Rare Tumours Network - European Registry).
CRIS-Team WoS Importer:2021-07-09

Salivary gland carcinoma (SGC) with perineural spread and/or positive resection margin - High locoregional control rates after photon (chemo) radiotherapy - Experience from a monocentric analysis - Haderlein, Marlen; Scherl, Claudia; Semrau, Sabine; Lettmaier, Sebastian; Hecht, Markus; Putz, Florian; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer (Radiation Oncology, 2019)
Background: The aim was to evaluate the outcome, especially locoregional control of patients with locally advanced salivary gland carcinoma (SGC) with perineural spread (Pn1) and/or positive resection margins (R1/2) after postoperative photon (chemo) radiotherapy in a single centre. Methods: We retrospectively reviewed data of 65 patients with newly diagnosed locally advanced SGC without distant metastases who underwent radio (chemo) therapy in the department of radiation oncology of the university hospital of Erlangen from January 2000 until April 2017. Kaplan Meier method was used to calculate survival and recurrence rates. In univariate analysis the log-rank test was used to correlate patient-/tumor- and treatment-related parameters to survival and recurrence rates. Results: Median follow-up was 45 months (range: 6; 215). After 1, 3, 5 years cumulative incidence of local and locoregional failure was 3.1, 7.0, 7.0% and 3.1, 9.7, 12.9%, whereas cumulative incidence of distant metastases (DM) was 15.6, 36.0, 44.0%. After 1,3, 5 years cumulative Overall (OS) and Disease-free survival (DFS) was 90.5, 74.9, 63.9% and 83.0, 54.8, 49.4%. The only significant predictor for decreased local and locoregional control was a macroscopic resection margin(R2) (p = 0.002 and p = 0.04). High-grade histology (p = 0.006), lymph node metastases with extracapsular spread (p = 0.044) and an advanced T-stage (p = 0.031) were associated with an increased rate of DM. High-grade histology was the only factor predicting for a decreased DFS (p = 0.014). Conclusion: Photon radiotherapy leads to high local and locoregional control rates in a high-risk patient population with SGC with microscopically positive resection margins and/or perineural spread. The most common site of disease recurrence was distant metastases. Therefore the real challenge for the future should be to prevent distant metastases.
CRIS-Team Scopus Importer:2019-05-03
Keywords: Locoregional control; Perineural spread; Photon radiotherapy; Positive resection margin; Salivary gland cancer

Salivary Gland Secretory Carcinoma: Clinicopathologic and Genetic Characteristics of 215 Cases and Proposal for a Grading System - Baněčková, Martina; Thompson, Lester D.R.; Hyrcza, Martin D.; Vaněček, Tomáš; Agaimy, Abbas; Laco, Jan; Simpson, Roderick H.W.; Di Palma, Silvana; Stevens, Todd M.; Brcic, Luka; Etebarian, Arghavan; Dimnik, Katarina; et al. (American Journal of Surgical Pathology, 2023)
Salivary gland secretory carcinoma (SC), previously mammary analog SC, is a low-grade malignancy characterized by well-defined morphology and an immunohistochemical and genetic profile identical to SC of the breast. Translocation t(12;15)(p13;q25) resulting in the ETV6::NTRK3 gene fusion is a characteristic feature of SC along with S100 protein and mammaglobin immunopositivity. The spectrum of genetic alterations for SC continues to evolve. The aim of this retrospective study was to collect data of salivary gland SCs and to correlate their histologic, immunohistochemical, and molecular genetic data with clinical behavior and long-term follow-up. In this large retrospective study, we aimed to establish a histologic grading scheme and scoring system. A total of 215 cases of salivary gland SCs diagnosed between 1994 and 2021 were obtained from the tumor registries of the authors. Eighty cases were originally diagnosed as something other than SC, most frequently acinic cell carcinoma. Lymph node metastases were identified in 17.1% (20/117 cases with available data), with distant metastasis in 5.1% (6/117). Disease recurrence was seen in 15% (n=17/113 cases with available data). The molecular genetic profile showed ETV6::NTRK3 gene fusion in 95.4%, including 1 case with a dual fusion of ETV6::NTRK3 and MYB::SMR3B. Less frequent fusion transcripts included ETV6::RET (n=12) and VIM::RET (n=1). A 3-tiered grading scheme using 6 pathologic parameters (prevailing architecture, pleomorphism, tumor necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), and mitotic count and/or Ki-67 labeling index) was applied. Grade 1 histology was observed in 44.7% (n=96), grade 2 in 41.9% (n=90), and grade 3 in 13.5% (n=29) of cases. Compared with low-grade and intermediate-grade SC, high-grade tumors were associated with a solid architecture, more prominent hyalinization, infiltrative tumor borders, nuclear pleomorphism, presence of PNI and/or LVI, and Ki-67 proliferative index >30%. High-grade transformation, a subset of grade 2 or 3 tumors, seen in 8.8% (n=19), was defined as an abrupt transformation of conventional SC into high-grade morphology, sheet-like growth, and a tumor lacking distinctive features of SC. Both overall survival and disease-free survival (5 and 10 y) were negatively affected by tumor grade, stage, and TNM status (each P<0.0001). SC is a low-grade malignancy with predominantly solid-microcystic growth patterns, driven by a gene fusion, most commonly ETV6::NTRK3. There is a low risk for local recurrence and a good overall long-term survival, with a low risk for distant metastasis but a higher risk for locoregional lymph node metastasis. The presence of tumor necrosis, hyalinization, PNI and/or LVI, and positive resection margins correlate with higher tumor grade, less favorable prognosis, and increased mortality. The statistical results allowed us to design a 3-tiered grading system for salivary SC.
CRIS-Team Scopus Importer:2023-06-02
Keywords: disease-free survival; ETV6:: NTRK3; grading; hazard ratio; overall survival; salivary gland; secretory carcinoma

SATB2 is frequently expressed in ossifying and non-ossifying peripheral oral fibroma of the gingival region but not in reactive fibromatous lesions from other intraoral sites - Baněčková, Martina; Agaimy, Abbas (Annals of Diagnostic Pathology, 2020)
Ossifying and non-ossifying peripheral oral fibromas (POF) of the gingival and alveolar mucosa are localized, cellular, small fibrous nodular lesions likely resulting from diverse external/ internal physical and chemical irritation or injuries. A central nidus of metaplastic woven bone characterizes and defines the ossifying variant. The inherent tendency of these lesions to ossify remains elusive. We herein analyze SATB2 expression as osteoblastic transcription and differentiation factor in 28 gingival POFs (10 of them ossifying) and compare them to 28 fibrous lesions from different non-gingival intraoral sites. Strong to moderate diffuse nuclear SATB2 immunoreactivity was detected in all ossifying (10/10; 100%) and in 8/18 (44%) non-ossifying gingival POFs, but in only 1/28 (3%) non-gingival oral reactive nodular fibrous lesions. This study illustrates for the first-time consistent expression of the osteoblastic marker SATB2 in ossifying and most of non-ossifying POFs of the gingival area but lack of this marker in reactive fibrous lesions from other oral cavity sites. This finding is in line with the proposed origin of gingival POFs from periodontal ligaments and may explain the frequent ossification observed in them. It is mandatory to consider this finding when assessing biopsies from SATB2-positive oral cavity neoplasms to avoid misinterpretation.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Fibrous epulis; Jaw tumors; Non-ossifying fibroma; Oral cavity; Ossifying fibroma; Peripheral oral fibroma; SATB2

Satellite nodules in pleomorphic adenomas of the parotid gland: A nightmare for less invasive parotid surgery? - Iro, Ann Kristin; Agaimy, Abbas; Müller, Sarina Katrin; Sievert, Matti; Iro, Heinrich; Mantsopoulos, Konstantinos (Oral Oncology, 2021)
Objectives: The aim of this study was to thoroughly investigate the incidence of satellite nodules (SN) and some of their characteristics (number, distance to main lesion) in a large series of pleomorphic adenomas (PA) and to compare several surgical modalities regarding their efficacy in addressing this critical morphological feature. Materials and methods: The records of all patients treated for primary PA of the parotid gland between 2006 and 2020 were studied retrospectively. All the histological slides of all tumours were critically re-evaluated for this study by an experienced head and neck pathologist. Results: 845 cases made up our initial study sample. SNs were detected in 68/845 cases (8%). No statistically significant difference could be detected in the incidence of SNs in the surgical specimens between the patient groups managed by extracapsular dissection (46/577, 7.9%) and facial nerve dissecting surgery (22/268, 8.2%, p = 0.502). In the group of cases with SNs, no recurrences were detected (mean follow-up time: 71.4 months). The mean distance from the main lesion to the most distant SN was 1.1 mm (0.08–6.3 mm). The mean size of the SN was 1.9 mm (0.1–9.7 mm). Altogether, the mean distance from the main lesion to the outer periphery of the most distant SN was 3.1 mm (0.4–10.5 mm). Conclusion: Our analysis could not award SNs the title of an “extracapsular dissection's nightmare”. In the majority of cases, their favourable histological patterns offer the ideal circumstances for their surgical inclusion in a tumour specimen.
CRIS-Team Scopus Importer:2021-04-09
Keywords: Capsule; Extracapsular dissection; Parotidectomy; Pleomorphic adenoma; Satellite nodule

Sclerosing epithelioid fibrosarcoma of the kidney: clinicopathologic and molecular study of a rare neoplasm at a novel location - Ohlmann, Carsten-Henning; Brecht, Ines B.; Junker, Kerstin; Van Der Zee, Jill A.; Nistor, Adriana; Bohle, Rainer M.; Stöckle, Michael; Metzler, Markus; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2015)
Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site.
EVALuna2:6701

Sclerosing Microcystic Adenocarcinoma of the Head and Neck Mucosa: A Neoplasm Closely Resembling Microcystic Adnexal Carcinoma - Mills, Anne M.; Policarpio-Nicholas, Maria Luisa C.; Agaimy, Abbas; Wick, Mark R.; Mills, Stacey E. (Head and Neck Pathology, 2016)
Microcystic adnexal carcinoma (MAC) occurs predominantly in the centrofacial skin and has been only rarely reported in mucosal surfaces. We here present a 5 case series of tumors closely resembling MAC occurring in the mucosal surfaces of the head and neck, which we have termed sclerosing microcystic adenocarcinomas. These tumors showed a predilection for women (4:1) with an average patient age of 52.6 years (range 41-73 years). Location included the tongue (n = 2), the floor of the mouth (n = 2), and the nasopharynx/clivus (n = 1). One occurred after radiation therapy and another occurred in the setting of immune compromise. Immunohistochemistry highlighted a dual cell population with luminal cells showing positivity for high and low-molecular weight keratins and surrounding myoepithelial cells showing S100 and smooth muscle actin staining. No cases had nodal involvement, and the single patient with clinical follow-up was alive and free of disease 34 months after diagnosis and definitive radiochemotherapy. Differential diagnoses for all cases diverged from those provoked by MAC in the skin and included a variety of salivary gland neoplasms such as adenoid cystic carcinoma, polymorphous low grade adenocarcinoma, and mucoepidermoid carcinoma. Recognition of sclerosing microcystic adenocarcinoma in the head and neck mucosa is critical given its bland appearance and subtle infiltration pattern, infrequency of nodal involvement, and behavioral differences from the other entities on the differential.
EVALuna2:6925

Sclerosing mucoepidermoid carcinoma of salivary glands - Othman, Bacem Khalele; Bradová, Martina; Simpson, Roderick H.W.; Laco, Jan; Agaimy, Abbas; Rito, Miguel; Ihrler, Stephan; Steiner, Petr; Grossmann, Petr; Hájková, Veronika; de Rezende, Gisele; Goma, Montse; et al. (Virchows Archiv, 2024)
Sclerosing mucoepidermoid carcinoma (SMEC) of the salivary glands is a rare variant of low-grade mucoepidermoid carcinoma with scanty cellular atypia characterized by marked fibrosis/sclerosis and a rich inflammatory infiltrate. Herein, we report 25 unpublished cases of SMEC, two of them with prominent eosinophilia (2/25; 8%) and three with abundant IgG4-positive plasma cells (3/25; 12%). In our series of salivary SMEC, molecular analysis using fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) provided evidence of MAML2 gene rearrangement in 18 cases of the 21 analyzable cases tested (86%), while this gene locus was intact in 3 cases (14%). This study focuses on the diagnostic criteria of salivary SMEC given its challenge of abundant collagenous stroma, minimal residual neoplastic areas, and inconspicuous mucous cells. Follow-up data of our cases indicate that salivary SMECs have favorable outcomes. Molecular analysis for MAML2 gene rearrangement suggests that SMECs of salivary glands represent a rare variant of conventional low-grade MECs of salivary glands. In contrast, SMECs of the thyroid gland are genetically distinct from salivary-type thyroid MECs.
CRIS-Team Scopus Importer:2024-11-22
Keywords: IgG4; Keloid-like stromal fibrosis; MAML2 rearrangement; Salivary gland; Sclerosing mucoepidermoid carcinoma; Sclerosis; SMEC; Tissue eosinophilia

Sclerosing Polycystic Adenoma of Salivary Glands A Novel Neoplasm Characterized by PI3K-AKT Pathway Alterations-New Insights Into a Challenging Entity - Skalova, Alena; Baneckova, Martina; Laco, Jan; Di Palma, Silvana; Agaimy, Abbas; Ptakova, Nikola; Costes-Martineau, Valerie; Petersson, Bengt F.; Van Den Hout, Mari F. C. M.; De Rezende, Gisele; Klubickova, Natalie; Koblizek, Miroslav; et al. (American Journal of Surgical Pathology, 2022)
Sclerosing polycystic adenoma (SPA) is a rare salivary gland neoplasm originally thought to represent a non-neoplastic lesion. Recently we have encountered an index case of apocrine intraductal carcinoma of parotid gland of 62-year-old man with invasive salivary duct carcinoma component arising from SPA, a combination of tumor entities that has never been published so far. Here, we further explore the nature of SPA by evaluating 36 cases that were identified from the authors' consultation files. The patients were 25 females and 11 males aged 11 to 79 years (mean, 47.8 y). All tumors originated from the parotid gland. Their size ranged from 11 to 70 mm (mean, 28 mm). Histologically, all cases revealed characteristic features of SPA, such as lobulated well-circumscribed growth, focal hyalinized sclerosis, presence of large acinar cells with abundant brightly eosinophilic intracytoplasmic granules, and ductal components with variable cytomorphologic characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. In all cases, there were foci of intraluminal solid and cribriform intercalated duct-like epithelial proliferations with variable dysplasia which were positive for S100 protein and SOX10, and fully enveloped by an intact layer of myoepithelial cells. In addition, 14/36 cases (39%) had focal intraductal cribriform and micropapillary apocrine-type dysplastic epithelial structures composed of cells positive for androgen receptors and negative for S100/SOX10. The intraductal proliferations of both types showed focal mild to severe dysplasia in 17 cases (17/36; 47%). Two cases showed overt malignant morphology ranging from high-grade intraductal carcinoma to invasive carcinoma with an apocrine ductal phenotype. Next generation sequencing using ArcherDX panel targeting RNA of 36 pan-cancer-related genes and/or a TruSight Oncology 170/500 Kit targeting a selection of DNA from 523 genes and RNA from 55 genes was performed. Tumor tissue was available for molecular analysis in 11 cases, and 9 (9/11; 82%) of them harbored genetic alterations in the PI3K pathway. Targeted sequencing revealed HRAS mutations c.37G>C, p.(Gly13Arg) (2 cases) and c.182A>G, p.(Gln61Arg) (2 cases), and PIK3CA mutations c.3140A>G, p.(His1047Arg) (3 cases), c.1633G>A, p.(Glu545Lys) (1 case), and c.1624G>A, p.(Glu542Lys) (1 case). Moreover, mutations in AKT1 c.49G>A, p.(Glu17Lys) and c.51dup, p.(Tyr18ValfsTer15); c.49_50delinsAG, p.(Glu17Arg) (as a double hit) were found (2 cases). In addition, germinal and somatic mutation of PTEN c.1003C>T, p.(Arg335Ter); c.445C>T, p.(Gln149Ter), respectively, were detected. Gene fusions were absent in all cases. These prevalent molecular alterations converging on one major cancer-related pathway support the notion that SPA is a true neoplasm with a significant potential to develop intraluminal epithelial proliferation with apocrine and/or intercalated duct-like phenotype. The name SPA more correctly reflects the true neoplastic nature of this enigmatic lesion.
CRIS-Team WoS Importer:2022-01-21

Scoring PD-L1 Expression in Urothelial Carcinoma: An International Multi-Institutional Study on Comparison of Manual and Artificial Intelligence Measurement Model (AIM-PD-L1) Pathology Assessments - Rüschoff, Josef; Kumar, George; Badve, Sunil; Jasani, Bharat; Krause, Emma; Rioux-Leclercq, Nathalie; Rojo, Federico; Martini, Maurizio; Cheng, Liang; Tretiakova, Maria; Mitchell, Catherine; Anders, Robert A.; et al. (Virchows Archiv, 2024)
Assessing programmed death ligand 1 (PD-L1) expression on tumor cells (TCs) using Food and Drug Administration-approved, validated immunoassays can guide the use of immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, substantial interobserver variability has been reported using these immunoassays. Artificial intelligence (AI) has the potential to accurately measure biomarker expression in tissue samples, but its reliability and comparability to standard manual scoring remain to be evaluated. This multinational study sought to compare the %TC scoring of PD-L1 expression in advanced urothelial carcinoma, assessed by either an AI Measurement Model (AIM-PD-L1) or expert pathologists. The concordance among pathologists and between pathologists and AIM-PD-L1 was determined. The positivity rate of ≥ 1%TC PD-L1 was between 20–30% for 8/10 pathologists, and the degree of agreement and scoring distribution for among pathologists and between pathologists and AIM-PD-L1 was similar both scored as a continuous variable or using the pre-defined cutoff. Numerically higher score variation was observed with the 22C3 assay than with the 28–8 assay. A 2-h training module on the 28–8 assay did not significantly impact manual assessment. Cases exhibiting significantly higher variability in the assessment of PD-L1 expression (mean absolute deviation > 10) were found to have patterns of PD-L1 staining that were more challenging to interpret. An improved understanding of sources of manual scoring variability can be applied to PD-L1 expression analysis in the clinical setting. In the future, the application of AI algorithms could serve as a valuable reference guide for pathologists while scoring PD-L1.
CRIS-Team Scopus Importer:2024-04-12
Keywords: Artificial intelligence; Bladder cancer; Pathology; PD-L1

Sebaceous breast carcinoma: report of a rare histological special subtype - Wachter, David; Rauh, C.; Wenkel, Evelyn; Fasching, Peter; Beckmann, Matthias; Hartmann, Arndt (Pathologe, 2014)
We report on a case of sebaceous carcinoma of the breast as a rare histological special subtype of breast cancer. Because these tumors are uncommon, differential diagnostic considerations and the exclusion of Muir-Torre syndrome are emphasized. Finally possible mechanisms of development and therapeutic strategies for this carcinoma are discussed.
EVALuna2:6578

Second-Line Treatment of Advanced Urothelial Cancer with Paclitaxel and Everolimus in a German Phase II Trial (AUO Trial AB 35/09) - Niegisch, Guenter; Retz, Margitta; Thalgott, Mark; Balabanov, Stefan; Honecker, Friedemann; Ohlmann, Carsten Henning; Stoeckle, Michael; Boegemann, Martin; Vom Dorp, Frank; Gschwend, Juergen; Hartmann, Arndt; Ohmann, Christian; et al. (Oncology, 2015)
The efficacy of second-line treatment after failure of platinum-based chemotherapy in patients with advanced urothelial cancer is limited. Based on encouraging preclinical and clinical phase I data, we evaluated the safety and efficacy of the combination of paclitaxel and everolimus in these patients.In this trial, patients having failed to respond to prior platinum-based combination treatment of urothelial cancer were treated with paclitaxel (175 mg/m(2) i.v., 3-weekly) and the mTOR-inhibitor everolimus (10 mg p.o., once daily). The patients were treated until tumor progression or until a maximum of 6 cycles was completed. A one-stage design was used to evaluate the objective response rate (ORR) as the primary endpoint.A total of 27 patients (67% male; median age 63 years) were enrolled. The most frequent grade III/IV toxicities were anemia (28%), peripheral neuropathy (28%), and fatigue (24%). No treatment-related deaths were reported. Complete and partial remissions were observed in 0/24 and 3/24 patients eligible for efficacy analysis, respectively (ORR 13%). Progression-free survival was 2.9 months [95% confidence interval (95% CI) 1.9-4.2], and the median overall survival was 5.6 months (95% CI 4.8-10.2).The combination of paclitaxel and everolimus has not achieved the expected efficacy in second-line treatment of urothelial cancer and should not be further explored.
EVALuna2:6790

Seizure-induced neuronal apoptosis is related to dysregulation of the RNA-edited GluR2 subunit in the developing mouse brain - Jung, Susan; Ballheimer, Yili Elisabeth; Brackmann, Florian; Zoglauer, Daniel; Geppert, Carol-Immanuel; Hartmann, Arndt; Trollmann, Regina (Brain Research, 2020)
Ca2+-permeable AMPA receptors (AMPAR) which crucially modify maturational programs of the developing brain are involved in seizure-induced glutamate excitotoxicity and apoptosis. Regulatory effects on AMPAR subunit composition and RNA-editing in the developing brain and their significance as therapeutic targets are not well understood. Here, we analyzed acute effects of recurrent pilocarpine-induced neonatal seizures on age- and region-specific expression of AMPAR subunits and adenosine deaminases (ADAR) in the developing mouse brain (P10). After recurrent seizure activity and regeneration periods of 6–72 h cerebral mRNA levels of GluR (glutamate receptor subunit) 1, GluR2, GluR3, and GluR4 were unaffected compared to controls. However, ratio of GluR2 and GluR4 to pooled GluR1-4 mRNA concentration significantly decreased in seizure-exposed brains in comparison to controls. After a regeneration period of 24–72 h ADAR1 and ADAR2 mRNA expression was significantly lower in seizure-exposed brains than in those of controls. This was confirmed at the protein level in the hippocampal CA3 region. We observed a regionally increased apoptosis (TUNEL+ and CC3+ cells) in the hippocampus, parietal cortex and subventricular zone of seizure-exposed brains in comparison to controls. Together, present in vivo data demonstrate the maturational age-specific, functional role of RNA-edited GluR2 in seizure-induced excitotoxicity in the developing mouse brain. In response to recurrent seizure activity, we observed reduced expression of GluR2 and the GluR2 mRNA-editing enzymes ADAR1 and ADAR2 accompanied by increased apoptosis in a region-specific manner. Thus, AMPA receptor subtype-specific mRNA editing is assessed as a promising target of novel neuroprotective treatment strategies in consideration of age-related developmental mechanisms.
CRIS-Team Scopus Importer:2020-03-17
Keywords: ADAR; Adenosine deaminases; Apoptosis; Brain injury; Experimental seizure model; Neonatal brain; Neurodegeneration; Neuroprotection; Pilocarpine; RNA editing

Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells - Hatscher, Lukas; Lehmann, Christian; Purbojo, Ariawan; Onderka, Constantin; Liang, Chunguang; Hartmann, Arndt; Cesnjevar, Robert; Bruns, Heiko; Gross, Olaf; Nimmerjahn, Falk; Burmazovic, Ivana Ivanovic; Kunz, Meik; et al. (Science Signaling, 2021)
The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1 is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1. These cytokines induced prominent T helper type 1 (TH1) and TH17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.
CRIS-Team Scopus Importer:2021-05-14
Keywords: Dendritic cells; cDC2; CD1c; inflammasome; hyperactivation; L18-MDP; T cell differentiation

Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells - Heger, Lukas; Hatscher, Lukas; Lehmann, Christian; Purbojo, Ariawan; Onderka, Constantin; Liang, C.; Hartmann, Arndt; Cesnjevar, Robert; Bruns, Heiko; Gross, O.; Nimmerjahn, Falk; Ivanovic-Burmazovic, I.; et al. (EXPERIMENTAL DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-03-04

Sellar Region Atypical Teratoid/Rhabdoid Tumors (ATRT) in Adults Display DNA Methylation Profiles of the ATRT-MYC Subgroup - Johann, Pascal D.; Bens, Susanne; Oyen, Florian; Wagener, Rabea; Giannini, Caterina; Perry, Arie; Raisanen, Jack M.; Reis, Gerald F.; Nobusawa, Sumihito; Arita, Kazunori; Felsberg, Joerg; Reifenberger, Guido; et al. (American Journal of Surgical Pathology, 2018)
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.
EVALuna2:34888

Sensitive allele-specific real-time PCR test for mutations in BRAF codon V600 in skin melanoma - Pisareva, Ekaterina; Gutkina, Nadezhda; Kovalenko, Sergei; Kuehnapfel, Sarah; Hartmann, Arndt; Heinzerling, Lucie; Schneider-Stock, Regine; Lyubchenko, Lyudmila; Shamanin, Vladimir A. (Melanoma Research, 2014)
Mutations at BRAF codon V600 are used as predictive biomarkers for targeted therapy of skin melanoma. Here, a simple sensitive test to detect mutations of BRAF-V600 was developed using real-time PCR with allele-specific primers and TaqMan probes. Two versions of the test using sense and antisense allele-specific primers were designed and evaluated. The test detected 1% mutant allele V600E/K in 10 ng DNA standard made from wild-type human DNA spiked with BRAF-V600E or the V600K plasmid. The test was validated on clinical formalin-fixed paraffin-embedded samples of skin melanoma using pyrosequencing as a reference method. In the clinical samples, we detected the common mutation V600E, as well as the rare mutations V600K, V600E2 (codon GAA), V600E2 K601del, V600D-K601del, and V600R. In comparison with pyrosequencing, both versions of the test had 100% specificity with sensitivities of 97 and 86% for sense and antisense allele-specific primers, respectively. Using the PCR test with sense allele-specific primers, mutations in V600 were found in 33 of 51 Russian patients (64.7%) with cutaneous melanoma. This closed-tube real-time PCR test can be used as a simple and sensitive assay for mutations of BRAF-V600 in cutaneous melanoma.
EVALuna2:6621

Sensitive and specific detection of EML4-ALK rearrangements in non-small cell lung cancer (NSCLC) specimens by multiplex amplicon RNA massive parallel sequencing - Moskalev, Evgeny; Frohnauer, Judith; Merkelbach-Bruse, Sabine; Schildhaus, Hans-Ulrich; Dimmler, Arno; Schubert, Thomas; Boltze, Carsten; Koenig, Helmut; Fuchs, Florian; Sirbu, Horia; Rieker, Ralf J.; Agaimy, Abbas; et al. (Lung Cancer, 2014)
Recurrent gene fusions of anaplastic lymphoma receptor tyrosine kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) have been recently identified in 5% of non-small cell lung cancers (NSCLCs) and are targets for selective tyrosine kinase inhibitors. While fluorescent in situ hybridization (FISH) is the current gold standard for detection of EML4-ALK rearrangements, several limitations exist including high costs, time-consuming evaluation and somewhat equivocal interpretation of results. In contrast, targeted massive parallel sequencing has been introduced as a powerful method for simultaneous and sensitive detection of multiple somatic mutations even in limited biopsies, and is currently evolving as the method of choice for molecular diagnostic work-up of NSCLCs.We developed a novel approach for indirect detection of EML4-ALK rearrangements based on 454 massive parallel sequencing after reverse transcription and subsequent multiplex amplification (multiplex ALK RNA-seq) which takes advantage of unbalanced expression of the 5' and 3' ALK mRNA regions. Two lung cancer cell lines and a selected series of 32 NSCLC samples including 11 cases with EML4-ALK rearrangement were analyzed with this novel approach in comparison to ALK FISH, ALK qRT-PCR and EML4-ALK RT-PCR.The H2228 cell line with known EML4-ALK rearrangement showed 171 and 729 reads for 5' and 3' ALK regions, respectively, demonstrating a clearly unbalanced expression pattern. In contrast, the H1299 cell line with ALK wildtype status displayed no reads for both ALK regions. Considering a threshold of 100 reads for 3' ALK region as indirect indicator of EML4-ALK rearrangement, there was 100% concordance between the novel multiplex ALK RNA-seq approach and ALK FISH among all 32 NSCLC samples.Multiplex ALK RNA-seq is a sensitive and specific method for indirect detection of EML4-ALK rearrangements, and can be easily implemented in panel based molecular diagnostic work-up of NSCLCs by massive parallel sequencing.
EVALuna2:1847

Serrated epithelial colorectal polyps (hyperplastic polyps, sessile serrated adenomas) with perineurial stroma: Clinicopathological and molecular analysis of a new series - Erlenbach-Wuenscha, Katharina; Bihl, Michel; Hartmann, Arndt; Groisman, Gabriel M.; Agaimy, Abbas; Vieth, Michael (Annals of Diagnostic Pathology, 2018)
Serrated colorectal fibroblastic polyps (FPs) are rare benign mucosal lesions composed of serrated epithelial crypts separated and distorted by intimately associated bland spindle cell proliferations with perineurial-like phenotype. We herein describe 21 new FPs affecting 10 females and 9 males aged 45 to 80 yrs. (mean, 62 yrs). Lesions originated in the sigmoid colon/rectosigmoid junction (n = 16), rectum (n = 2), and other parts of the colon (n = 3). Most patients had additional synchronous or metachronous polyps: classical adenomas (12 patients), sessile serrated adenoma/SSA (1 patient), hyperplastic polyps/HPs (7 patients), both HPs and adenomas (6 patients) and colorectal cancer (2 patients). Size of the lesions varied from 1 to 6 mm (mean: 3 mm). Histologically, all lesions were composed of serrated epithelial crypts that were separated and distorted by spindle cell stromal proliferations (consistently EMA+, claudin-1+ and GLUT-1+). The epithelial component displayed features of HPs (n = 17) and SSA (n = 4). Laser-microdissection-guided molecular testing was successful for 13 epithelial and 9 stromal components (9 paired samples). The BRAF V600E mutation was detected in 54% of the epithelial but in none of the stromal components. In conclusion, colorectal FPs represent genuine serrated epithelial polyps corresponding either to HP or (less frequently) SSA and should be better classified as such with a note on the presence of the stromal component. A more concise terminology reflecting their epithelial nature is needed to fulfill the requirements for colorectal cancer risk assessment and hence adopt appropriate follow-up strategies.
EVALuna2:34303

Serum miRNAs Support the Indication for MRI-Ultrasound Fusion-Guided Biopsy of the Prostate in Patients with Low-PI-RADS Lesions - Keck, Bastian; Borkowetz, Angelika; Pöllmann, Julia; Jansen, Thilo; Fischer, Moritz; Fuessel, Susanne; Kahlmeyer, Andreas; Wirth, Manfred; Huber, Johannes; Cavallaro, Alexander Josef; Hammon, Matthias; Platzek, Ivan; et al. (Cells, 2021)
Multiparametric MRI (mpMRI) and targeted biopsy of the prostate enhance the tumor detection rate. However, the prediction of clinically significant prostate cancer (PCa) is still limited. Our study tested the additional value of serum levels of selected miRNAs in combination with clinical and mpMRI information for PCa prediction and classification. A total of 289 patients underwent targeted mpMRI-ultrasound fusion-guided prostate biopsy complemented by systematic biopsy. Serum miRNA levels of miRNAs (miR-141, miR-375, miR-21-5p, miR-320b, miR-210-3p, let-7c, and miR-486) were determined by quantitative PCR. Detection of any PCa and of significant PCa were the outcome variables. The patient age, pre-biopsy PSA level, previous biopsy procedure, PI-RADS score, and serum miRNA levels were covariates for regularized binary logistic regression models. The addition of miRNA expression of miR-486 and let-7c to the baseline model, containing only clinical parameters, increased the predictive accuracy. Particularly in patients with PI-RADS ≤3, we determined a sensitivity for detecting significant PCa (Gleason score ≥ 7a corresponding to Grade group ≥2) of 95.2%, and an NPV for absence of significant PCa of 97.1%. This accuracy could be useful to support patient counseling in selected cases.
CRIS-Team Scopus Importer:2021-06-18
Keywords: diagnosis; microRNA; miRNA; mpMRI; PI-RADS; prostate biopsy; prostate cancer

Serum vitamin D level, sun-exposed area, dietary factors, and physical activity as predictors of invasive breast cancer risk among Sudanese women: A case-control study - Husain, Nazik Elmalaika; Suliman, Ahmed A.; Abdelrahman, Ismail; Bedri, Shahinaz A.; Musa, Rasha M.; Osman, Hind E.; Mustafa, Ayda H.; Gafer, Nahla; Farah, Ehab; Satir, Ali Abdel; Ahmed, Mohamed H.; Osman, Mugtaba; et al. (Journal of Family Medicine and Primary Care, 2019)
Background: The role of vitamin D in the development, progression, and prognosis of breast cancer, though widely studied worldwide, has been inconclusive. This study intended to assess the role of some factors (including serum vitamin D level, sun-exposed area, dietary factors, and physical activity) as predictors of the development of invasive breast cancer (IBC) among Sudanese women. Methods: A case-control study was conducted on 200 Sudanese women (100 with newly diagnosed IBC and 100 matched healthy females). Serum 25-hydroxyvitamin D was measured through a competitive electrochemiluminescence immunoassay. Matching analysis was adopted by R version 3.4.1 making use of the "MatchIt" package for calculating propensity scores to build a confounder-adjusted, multiple generalized, linear logistic regression model. Results: Participants' age ranged from 28 to 85 years with a mean [+/- standard deviation (SD)] of 48.10 (+/- 12.11) years. The mean (+/- SD) serum vitamin D level was 12.97 (+/- 8.60) and 13.79 (+/- 6.79) ng/mL in breast cancer and noncancer Sudanese women, respectively [P = 0.013; odds ratio (OR) 0.862; 95% confidence interval (CI) 0.766-0.969; beta = 0.149)]. Sun-exposed area (P = 0.038; OR 0.013; 95% CI 0.000-0.782; beta = 4.339) is significantly and negatively associated with breast cancer development. While moderate physical activity (P = 0.0008; OR 2625.430; 95% CI 26.647-258673.001; beta = 7.873) is significantly and positively associated with IBC risk. Occasional consumption of milk, dairy products, eggs, and fish reduces the risk of developing IBC by 78.1%, 75.0%, 78.4%, and 76.4%, respectively. Conclusion: The higher the plasma vitamin D level by one unit, the lower the risk of breast cancer by 13.84%. Sedentary lifestyle, reduced sun-exposed skin area, and low serum vitamin D levels can be considered as predictors of IBC. Encouraging moderate physical activity and consumption of certain foods may, in part, decrease the precipitating risks of breast cancer. More studies and research are needed to confirm these findings.
CRIS-Team WoS Importer:2021-10-18

Shift in prevalence of HPV types in cervical cytology specimens in the era of HPV vaccination - Fischer, Sonja; Bettstetter, Marcus; Becher, Andrea; Lessel, Marlene; Bank, Cyril; Krams, Matthias; Becker, Ingrid; Hartmann, Arndt; Jagla, Wolfgang; Gaumann, Andreas (Oncology Letters, 2016)
The aim of the present population-based cohort study was to analyze the association between the prevalence of 32 types of human papilloma virus (HPV) in 615 female patients with abnormal cervical cytopathology findings. In total, 32 HPV types were screened by DNA array technology. HPV infection was detected in 470 women (76.42%), 419 of whom (89.15%) were infected with >=1 high-risk (HR)-HPV type. HPV16, which is recognized as the main HR-HPV type responsible for the development of cervical cancer, was observed in 32.98% of HPV+ participants, followed by HPV42 (18.09%), HPV31 (17.66%), HPV51 (13.83%), HPV56 (10.00%), HPV53 (8.72%) and HPV66 (8.72%). The prevalence of HR-HPV types, which may be suppressed directly (in the case of HPV16 and 18), or possibly via cross-protection (in the case of HPV31) following vaccination, was considerably lower in participants <=22 years of age (HPV16, 28.57%; HPV18, 2.04%; HPV31, 6.12%), compared with participants 23-29 years of age (HPV16, 45.71%; HPV18, 7.86%; HPV31, 22.86%), who were less likely to be vaccinated. Consequently, the present study hypothesizes that there may be a continuous shift in the prevalence of HPV types as a result of vaccination. Furthermore, the percentage of non-vaccine HR-HPV types was higher than expected, considering that eight HPV types formerly classified as 'low-risk' or 'probably high-risk' are in fact HR-HPV types. Therefore, it may be important to monitor non-vaccine HPV types in future studies, and an investigation concerning several HR-HPV types as risk factors for the development of cervical cancer is required.
EVALuna2:6918

Shifts in Macrophage as a prognostic Biomarker in Patients with luminal Breast Cancer - A Confirmatory Study - Schnellhardt, Sören; Segelhorst, Sarah; Erber, Ramona; Daniel, Christoph; Hartmann, Arndt; Fasching, Peter; Beckmann, Matthias; Fietkau, Rainer; Distel, Luitpold; Rübner, Matthias (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Signal decomposition for X-ray dark-field imaging - Käppler, Sebastian; Bayer, Florian; Weber, Thomas; Maier, Andreas; Anton, Gisela; Hornegger, Joachim; Beckmann, Matthias; Fasching, Peter; Hartmann, Arndt; Heindl, Felix; Michel, Thilo; Oezguel, Gueluemser; et al. (MICCAI 2014, 2014)
Grating-based X-ray dark-field imaging is a new imaging modality. It allows the visualization of structures at micrometer scale due to small-angle scattering of the X-ray beam. However, reading darkfield images is challenging as absorption and edge-diffraction effects also contribute to the dark-field signal, without adding diagnostic value. In this paper, we present a novel–and to our knowledge the first–algorithm for isolating small-angle scattering in dark-field images, which greatly improves their interpretability. To this end, our algorithm utilizes the information available from the absorption and differential phase images to identify clinically irrelevant contributions to the dark-field image. Experimental results on phantom and ex-vivo breast data promise a greatly enhanced diagnostic value of dark-field image
EVALuna2:6632

Significance of altered PD-L1 expression in tumor tissue of oral squamous cell carcinomas - Weber, Manuel; Wehrhan, Falk; Baran, Christoph; Agaimy, Abbas; Buettner-Herold, M.; Preidl, Raimund; Neukam, Friedrich Wilhelm; Ries, Jutta (2018)
EVALuna2:34231

Simultaneous juvenile polyposis syndrome and neurofibromatosis type 1-Response to Letter to the Editor - Agaimy, Abbas; Vieth, Michael (Histopathology, 2016)
EVALuna2:6769

Single cycle induction treatment with cisplatin/docetaxel plus durvalumab/tremelimumab in stage III-IVB head and neck squamous cell cancer (CheckRad-CD8 trial) - Hecht, Markus; Gostian, A-O.; Eckstein, Markus; Rutzner, Sandra; Von Der Gruen, J.; Illmer, T.; Hautmann, M. G.; Brunner, T.; Laban, S.; Klautke, G.; Tamaskovics, B.; Frey, Benjamin; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Single nucleotide polymorphism D1853N of the ATM gene may alter the risk for breast cancer - Schrauder, M.; Frank, S.; Strissel, Pamela; Lux, Michael P.; Bani, Mayada; Rauh, C.; Sieber, Cornel; Heusinger, K.; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Strick, Reiner; Beckmann, Matthias; et al. (Journal of Cancer Research and Clinical Oncology, 2008)
Purpose Various ATM (ataxia telangiectasia-mutated) mutations and polymorphisms have been reported to be associated with an increased breast cancer risk. Recent studies have produced contradictory results regarding the association between ATM genetic variants and breast cancer risk.Materials and methods The common ATM polymorphism 5557G > A (p.D1853N) (rs1801516), previously suggested to be associated with bilateral breast cancer, was analyzed using real-time PCR in 514 unselected patients with breast cancer and 511 age-matched healthy control individuals. DNA was obtained from peripheral blood draw.Results The ATM genotype was weakly associated with the risk for breast cancer (P = 0.04 for the overall test). The odds ratio for women with a heterozygous genotype was 0.70 (95% CI, 0.52-0.94) and for the homozygous variant 0.63 (95% CI, 0.27-1.49). Disease-free survival and overall survival showed no significant association with specific genotypes.Conclusions The results of this study might suggest a minor association between polymorphism 5557G > A and a reduced risk of breast cancer.
Keywords: TM gene variants; polymorphism; breast cancer; DNA damage; epidemiology; association

Sinonasal Leiomyosarcoma: Clinicopathological Analysis of Nine Cases with Emphasis on Common Association with Other Malignancies and Late Distant Metastasis - Agaimy, Abbas; Semrau, Sabine; Koch, Michael; Thompson, Lester D.R. (Head and Neck Pathology, 2018)
Sinonasal tract (SNT) leiomyosarcoma (LMS) is exceedingly rare with < 100 cases reported. Their relationship to retinoblastoma and other malignancies, along with previous irradiation has not been clarified. Routine and consultation cases were reviewed for histologically and immunohistochemically proven SNT LMS. The tumors were tested with antibodies against α-smooth muscle actin, desmin, h-caldesmon, HMB45, S100 protein, Rb1, MDM2, CDK4 and EBV (EBER-ISH). Nine tumors affecting 5 males and 4 females aged 26 to 77 years (median: 48 years) were identified in the maxillary sinus (n = 4), nasal cavity (n = 3) and combined SNT (n = 2). Three patients had previous irradiation (2 for retinoblastoma, 1 for fibrous dysplasia) and 1 patient had chemotherapy and stem cell transplantation for Hodgkin lymphoma. One patient had prostatic adenocarcinoma (prior) and rectal adenocarcinoma (post) to the LMS. All patients with follow-up developed either local recurrences and/or metastases, principally to lung (time to metastasis: 16-156 months, mean 62 months). Histologically, 6 tumors were conventional high-grade LMS, two had glycogen-rich clear cell (PEComa-like) morphology and one was spindle cell low-grade. The latter showed grade 2 in the recurrence and grade 3 in the lung metastases. Two cases showed dedifferentiation to anaplastic pleomorphic (inflammatory MFH-like) phenotype. Immunohistochemistry revealed diffuse expression of at least 2 smooth muscle markers in 8 and only actin in one case/s. All other markers were negative. RB1 loss was observed in 6/8 cases tested. Sinonasal tract leiomyosarcomas are rare aggressive sarcomas that frequently develop in a background of previous cancer therapy (4/9), most frequently irradiation. Their varied morphology underlines the wide differential diagnostic considerations. Long-term survival may be achieved with aggressive multimodal therapy.
EVALuna2:34895

Sinonasal mixed transitional epithelial-seromucinous papillary glandular neoplasms with BRAF p.V600E mutations — sinonasal analogues to the sialadenoma papilliferum family tumors - Patel, Simmi; Snyderman, Carl H.; Müller, Sarina Katrin; Agaimy, Abbas; Seethala, Raja R. (Virchows Archiv, 2022)
Sinonasal non-intestinal type adenocarcinoma (non-ITAC) is a heterogeneous category that may benefit from improved taxonomy. With the recognition that most non-ITAC are phenotypically seromucinous, stratification may be improved by applying salivary type morphologic criteria and molecular findings. We report two cases of papillary seromucinous adenocarcinoma with sinonasal papilloma-like surface components that show histologic and molecular features analogous to the salivary sialadenoma papilliferum family of tumors. Case 1 concerns a 50-year-old female who presented with a left anterior nasoethmoid polyp, while case 2 is that of a 74 year old female with nasal polyposis. Histologically, both cases demonstrated a surface transitional sinonasal papilloma-like component (more prominent in case 2) with a deeper bilayered glandular component showing papillary and tufted micropapillary growth of monomorphic columnar to cuboidal cells with eosinophilic cytoplasm. Case 1 also showed a deep cribriform/microcystic component. Immunostains showed a delimiting p63/p40 positive basal layer around the SOX-10 positive glandular elements, while the transitional sinonasal papilloma-like components were diffusely p63/p40 positive. Like sialadenoma papilliferum and related tumors, both cases demonstrated BRAF p.V600E mutations in both components and no other alterations. The patients remain disease free at 9 and 19 months respectively. Our cases illustrate a novel sinonasal lesion and suggest that improved morphologic and molecular categorization may refine and reduce the category of non-ITAC.
CRIS-Team Scopus Importer:2022-07-01
Keywords: BRAF p.V600E; Non-intestinal type sinonasal adenocarcinoma; Non-salivary type sinonasal adenocarcinoma; Salivary type-adenocarcinoma; Sinonasal papilloma

Sinonasal papillomas: A single centre experience on 137 cases with emphasis on malignant transformation and EGFR/KRAS status in “carcinoma ex papilloma” - Maisch, Saskia; Müller, Sarina Katrin; Traxdorf, Maximilian; Weyerer, Veronika; Stoehr, Robert; Iro, Heinrich; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2020)
Among the three major histological subtypes of sinonasal papillomas, inverted (ISP) and oncocytic (OSP) sinonasal papillomas tend to undergo malignant transformation to carcinoma. However, criteria determining risk of recurrence and malignant progression have not been established. Recently, EGFR and KRAS mutations were detected to be characteristic for ISP and OSP, respectively. In this study, we analyzed 137 sinonasal papilloma cases (132 ISP and 5 OSP) for clinicopathological characteristics, frequency of recurrences/malignant transformation, and histological types and genetic features of carcinoma ex Schneiderian papilloma. OSP presented at a higher age than ISP (median, 75 vs. 57 years) and affected predominantly females. Overall frequency of recurrences and malignant transformation was 23.1% and 9.5%, respectively. Rates of recurrence (33.3% vs. 22.0%) and malignant transformation (33.3% vs. 8.8%) were higher in OSP compared to ISP, respectively. Carcinomas (n = 10) occurred mostly synchronously, more frequently in females and mainly associated with ISP (n = 9). Squamous cell carcinoma (SCC) was the most frequently associated malignancy. Concordant EGFR (in ISP/associated carcinoma) and KRAS (in the OSP/associated carcinoma) mutations were detected in all successfully analyzed matching papilloma/carcinoma pairs, confirming their shared clonal origin. Results of this large study are in line with recent studies showing frequent EGFR and KRAS mutations in sinonasal carcinoma ex Schneiderian papilloma. As the papilloma component might on occasion be missed on biopsy of synchronous carcinoma ex papilloma, EGFR and KRAS mutation testing represents a promising molecular surrogate for sinonasal “carcinoma ex papilloma”, at the same time offering an opportunity for targeting mutant EGFR in this rare cancer type.
CRIS-Team Scopus Importer:2020-03-27
Keywords: Carcinoma ex papilloma; EGFR; Inverted papilloma; KRAS; Oncocytic papilloma; Schneiderian papilloma; Sinonasal papilloma; Squamous cell carcinoma

Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults: A Clinicopathologic and Immunophenotypic Study of Fifty-Two Cases with Emphasis on Epithelial Immunoreactivity - Thompson, Lester D. R.; Jo, Vickie Y.; Agaimy, Abbas; Llombart-Bosch, Antonio; Morales, Gema Nieto; Machado, Isidro; Flucke, Uta; Wakely, Paul E.; Miettinen, Markku; Bishop, Justin A. (Head and Neck Pathology, 2018)
Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (≥18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18-72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4-286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance.
EVALuna2:207217

Sinonasal tumors : News from the WHO with special reference to mesenchymal entities - Agaimy, Abbas; Haller, F.; Hartmann, Arndt (Pathologe, 2018)
The last two decades have seen significant advances in the pathology of sinonasal tract neoplasms. This was the consequence of the availability of several innovative diagnostic tools, which resulted in a dynamic evolution of entities and splitting of newly defined or conceptualized entities and subtypes that have been included in the spectrum of old heterogeneous diseases. Most of these new tumor subtypes have distinctive demographic, clinicopathologic, and biological characteristics with prognostic and therapeutic implications for individual patients. NUT carcinoma (NUT midline carcinoma) was separated from the spectrum of sinonasal undifferentiated carcinoma (SNUC) and is defined by specific recurrent translocation. On the other hand, the recently described SMARCB1-deficient carcinoma (while probably representing a distinctive clinicopathologic entity) remained as a variant in the SNUC spectrum. A new neoplasm in the spectrum of non-keratinizing carcinomas is the human papillomavirus(HPV)-related adenoid-cystic-like sinonasal carcinoma with its distinctive, albeit diverse, morphology. In the group of small round-cell malignancies, adamantinoma-like Ewing sarcoma has been delineated as an important diagnostic pitfall given its prominent epithelial differentiation. Inclusion of the biphenotypic (myoneural) sinonasal sarcoma (BSS) as a low-grade malignancy defined by recurrent PAX3/MAML3-translocation represents an important feature of the new WHO classification given the distinctive biological behavior of this low-grade non-metastasizing rare entity, which has been uniformly misclassified as a peripheral nerve sheath tumor or leiomyosarcoma in the past. Recognition of CTNNB1 mutations and STAT6/NAB2 gene fusions as defining genetic markers for sinonasal hemangio‑/glomangiopericytoma and solitary fibrous tumors, respectively, represents another important achievement in recent years. This review summarizes the new aspects in the WHO classification and also addresses recently described entities that have not been included in the WHO classification.
EVALuna2:34102

Sinonasal Undifferentiated Carcinoma (SNUC): From an Entity to Morphologic Pattern and Back Again-A Historical Perspective - Agaimy, Abbas; Franchi, Alessandro; Lund, Valerie J.; Skalova, Alena; Bishop, Justin A.; Triantafyllou, Asterios; Andreasen, Simon; Gnepp, Douglas R.; Hellquist, Henrik; Thompson, Lester D. R.; Rinaldo, Alessandra; Ferlito, Alfio (Advances in Anatomic Pathology, 2020)
Plasmablastic neoplasms encompass several entities including plasmablastic lymphoma, plasmablastic plasmacytoma/multiple myeloma, primary effusion lymphoma and its extracavitary variant, anaplastic lymphoma kinase-positive large B-cell lymphoma, and Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified. Morphologically, the tumor cells are large with eccentrically located nuclei, prominent nucleoli, and basophilic/amphophilic cytoplasm. Immunophenotypically, the tumor cells express plasma cell-related antigens including CD38, CD138, interferon regulatory factor-4 (IRF4)/MUM1, PR domain zinc finger protein-1 (PRDM1), and/or X-box binding protein-1 (XBP1), with frequent loss of CD20. These tumors are diagnostically challenging for general pathologists due to their overlapping morphology and immunophenotype, and due to their rarity, and particularly so when clinical and radiologic information is insufficient. We also discuss HHV8-negative effusion-based lymphoma due to its overlapping features with primary effusion lymphoma. In this review, we focus on the useful diagnostic markers and pertinent molecular findings in these distinct entities and propose a practical diagnostic algorithm using anaplastic lymphoma kinase, HHV8, in situ hybridization for Epstein-Barr virus-encoded small RNA, immunoglobulin M, light chain stains, and clinicoradiologic criteria to avoid misdiagnosis. At the molecular level, MYC protein overexpression with or without MYC rearrangement and PRDM1-inactivating mutations or deletions are noted in a subset of such tumors, especially in plasmablastic lymphoma. Prognosis in these entities is dismal with conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Therefore, novel target therapies, such as anti-CD30 agents, and/or immune blockade therapy, are potential treatment options in the future.
CRIS-Team Scopus Importer:2020-02-28
Keywords: ALK-positive large B-cell lymphoma; effusion-based lymphoma; Epstein-Barr virus; HHV8-positive diffuse large B-cell lymphoma; human herpesvirus 8; MYC; plasmablastic lymphoma; plasmablastic plasmacytoma/multiple myeloma; PRDM1; Primary effusion lymphoma

Sinunasale Neoplasien: Neues aus der WHO 2022 - Agaimy, Abbas (Die Pathologie, 2023)
The pathology of poorly differentiated sinonasal malignancies has undergone a dynamic evolution during the last decade, resulting in a refined, mostly genetically or etiologically oriented classification of neoplasms in the historical spectrum of sinonasal undifferentiated carcinoma (NUT carcinoma, SWI-/SNF-deficient carcinomas, and others). Moreover, some new entities have been established, while others could be further delineated and better characterized. A highlight of the new classification is the inclusion of SWI/SNF (SMARCB1 or SMARCA4)-deficient carcinomas into a separate category. In addition, carcinomas with DEK::AFF2 fusions have been included as a provisional entity in the spectrum of nonkeratinizing squamous cell carcinoma. This review addresses the major changes in the classification of sinonasal tract neoplasms in the new WHO classification.
CRIS-Team Scopus Importer:2023-07-21
Keywords: Gene fusion; Paranasal sinuses; Sinonasal undifferentiated carcinoma; Squamous cell carcinoma; Tumour staging

SIRT1 regulates Mxd1 during malignant melanoma progression - Meliso, Fabiana M.; Micali, Danilo; Silva, Camila T.; Sabedot, Thais S.; Coetzee, Simon G.; Koch, Anna Maria; Fahlbusch, Fabian B.; Noushmehr, Houtan; Schneider-Stock, Regine; Jasiulionis, Miriam G. (Oncotarget, 2017)
In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.
EVALuna2:33949

Small cell neuroendocrine carcinoma and poorly differentiated rhabdomyosarcomas of the urinary bladder in adults—A comparative analysis in favor of a common histogenesis - Bahlinger, Veronika; Stöhr, Robert; Hartmann, Arndt; Hes, Ondřej; Agaimy, Abbas (Virchows Archiv, 2024)
Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related other genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.
CRIS-Team Scopus Importer:2024-06-14
Keywords: FOXO1 gene fusions; Rhabdomyosarcoma; Small cell neuroendocrine carcinoma; TERT promoter mutations; Urinary bladder

Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages - An immunohistochemical analysis - Weber, Manuel; Büttner, Maike; Hyckel, Peter; Moebius, Patrick; Distel, Luitpold; Ries, Jutta; Amann, Kerstin Ute; Neukam, Friedrich Wilhelm; Wehrhan, Falk (Journal of Cranio-Maxillofacial Surgery, 2014)
In solid malignancies the influence of immunological parameters - especially of macrophages - on invasiveness, metastatic potential and prognosis has been shown. There are no studies quantitatively analysing the macrophage polarization in oral squamous cell carcinoma (oscc). The aim of this study was to correlate macrophage polarization in the epithelial and stromal compartment of oscc with histopathologic parameters.T1 and T2 oscc samples (n = 34) were used. Automated immunohistochemical staining detected CD68, CD11c, CD163 and MRC1 positive cells. All samples were completely digitalized using whole slide imaging and the number of stained cells per area was assessed quantitatively.Primary tumours with lymphogenic metastasis (N+) showed a significantly (p < 0.05) increased count of CD68, CD11c, CD163 and MRC1 positive cells in the epithelial fraction compared to N0 tumours. The ratio of CD163 positive cells (M2 macrophages) to CD68 positive cells (M1 and M2 macrophages) was significantly (p < 0.05) increased in N+ tumours.An increased macrophage infiltration and an increased M2 polarization in primary oral squamous cell carcinomas with lymphogenic metastasis was shown. Macrophages that migrated into the epithelial tumour fraction seem to be of special biological importance. The results indicate a central role of macrophages in the progression of oscc.
EVALuna2:18151

Small renal cell carcinomas–how dangerous are they really? Results of a large multicenter study - Steffens, Sandra; Junker, Kerstin; Roos, Frederik C.; Janssen, Martin; Becker, Frank; Henn, Daniela; Wegener, Gerd; Siemer, Stefan; Hofmann, Rainer; Schrader, Mark; Stoeckle, Michael; Thueroff, Joachim W.; et al. (European Journal of Cancer, 2014)
Modern diagnostic ultrasound and cross-sectional imaging has enabled the detection of increasing numbers of renal tumours. The aim of this study was to investigate the tumour- and patient-specific characteristics and prognosis of small renal cell carcinomas (RCCs) after surgical resection.The study included 2197 patients who underwent surgical resection of histologically confirmed RCC ? 4 cm between 1990 and 2011. Median (mean) follow-up was 56.2 (65.5) months.At the time of surgery, tumours were staged as pT ? 3a in 175 (8.0%) cases, 134 (6.2%) were poorly differentiated and 75 (3.5%) were metastasised. The larger the tumour size, the higher was the risk of presenting with stage pT ? 3a (p<0.001), poor tumour differentiation (p = 0.004), microscopic vascular involvement (p = 0.001) and collecting system invasion (p = 0.03). The 5-year cancer-specific survival (CSS) rate was 93.8% for stage pT1a versus 79.4% for stage pT ? 3a (p<0.001), and it was 93.7% for G1-2 versus 76.8% for G3-4 differentiation (p<0.001). Multivariate analysis identified age in years (hazard ratio (HR) 1.04, p<0.001), metastatic disease (HR 12.5, p < 0.001), tumour differentiation (HR 2.8, p<0.001) and non-clear cell histology (HR 0.51, p = 0.02) as independent prognosticators for CSS in patients with small RCC. Interestingly, the 5-year cancer-specific mortality rate for pT1a N/M0 patients was 5.8%.This large multicenter study has clearly shown that, though most small RCC have a low pathological stage and a good prognosis, there is also a small but significant subgroup of these tumours that are already locally advanced or poorly differentiated.
EVALuna2:6670

SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens - Herpel, Esther; Rieker, Ralf J.; Dienemann, Hendrik; Muley, Thomas; Meister, Michael; Hartmann, Arndt; Warth, Arne; Agaimy, Abbas (Annals of Diagnostic Pathology, 2017)
The chromatin remodeling switch sucrose nonfermentable (SWI/SNF) complex has been increasingly implicated in the pathogenesis and dedifferentiation of neoplasms from several organs with prognostic and potential therapeutic implications. We herein investigated the expression of the SWI/SNF complex catalytic subunits SMARCA4 (BRG1) and SMARCA2 (BRM) in 316 consecutive non-small cell lung cancer (NSCLC) specimens on tissue microarrays (171 adenocarcinomas [ADCAs], 130 squamous cell carcinomas [SCCs], 9 adenosquamous carcinomas, and 6 large cell carcinomas) excluding undifferentiated/giant cell or rhabdoid carcinomas. Complete loss of SMARCA4 was observed in 8 (5.5%) of 146 evaluable pulmonary ADCAs and 6 (5.2%) of 115 evaluable pulmonary SCCs, whereas 9 (6.4%) of 140 ADCAs and 2 (1.7%) of 117 SCCs showed SMARCA2 loss. Two of 6 large cell carcinomas were SMARCA2 deficient. Concurrent loss of both markers was observed in 4 cases (2 ADCAs and 2 SCCs). Of 15 ADCAs with loss of either or both markers, 12 (80%) were TTF1 negative. In conclusion, SMARCA4 and SMARCA2 deficiency is observed in 5.1% and 4.8% of NSCLC, respectively. SMARCB1 expression was intact in all cases. The presence of differentiated histology (glandular or squamous) is a novel aspect among SWI/SNF-deficient carcinomas which in other organs generally are associated with undifferentiated/rhabdoid morphology. The predominance of TTF1 negativity among SWI/SNF-deficient pulmonary ADCA (80%) underlines the need to include these 2 markers in the evaluation of TTF1-negative ADCA of putative pulmonary origin. Given the recently documented potential of SMARCA4 loss as a predictor of chemosensitivity to platinum-based chemotherapy in NSCLC, recognition of the clinicopathological features of SMARCA4-deficient NSCLC in routine surgical pathology practice is recommended.
EVALuna2:6837

SMARCA4-Deficient Carcinoma of Unknown Primary Presenting with Fatal Paraneoplastic Hypercalcemia in a Heart Transplant Recipient: First Report in a Male Patient - Agaimy, Abbas; Strobel, Deike; Strecker, Thomas (Case Reports in Pathology, 2017)
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare SMARCA4-driven aggressive malignancy of young age characteristically associated with paraneoplastic hypercalcemia. Comparable neoplasms/presentations have not been reported in males. A 39-year-old male heart transplant recipient (HTX 40 months previously) presented with multiple liver nodules and hypercalcemic crisis. The serum parathyroid hormone-related protein (PTHrp) was significantly elevated (241 pg/ml; reference value < 57). Liver biopsy showed poorly differentiated partially rhabdoid neoplasm expressing pancytokeratin, CK20, and focally GATA3, SATB2, p63, and SALL4. The tumor cells showed dual loss of SMARCA4 and SMARCA2. He died of irreversible multiorgan failure one week after admission. To our knowledge, this is the first report highlighting the rare occurrence of paraneoplastic hypercalcemia associated with SMARCA4-deficient malignancies in males. Although the immunophenotype suggests urothelial or upper gastrointestinal tract origin, the exact primary tumor site could not be ascertained due to rapid death of the patient. SMARCA4 immunohistochemistry should be included in the workup of neoplasms associated with hypercalcemia irrespective of gender and site.
EVALuna2:34894

SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype - Agaimy, Abbas; Fuchs, Florian; Moskalev, Evgeny; Sirbu, Horia; Hartmann, Arndt; Haller, Florian (Virchows Archiv, 2017)
Alterations in SMARCA4, a member of the chromatin remodeling Switch Sucrose Non-Fermentable (SWI/SNF) complex, characterize a subset of non-small cell lung cancer (NSCLC), but detailed morphological and immunophenotypic description of this tumor type is lacking. We describe 20 NSCLC cases found on routine screening not to express SMARCA4 by immunohistochemistry (IHC). These tumors were stained for CK7, TTF1, SMARCA2, SMARCA4, SMARCB1, and HepPar-1 and analyzed for molecular alterations, using a 160 cancer-related gene panel including the full coding sequence of SMARCA4. Patients were eight females and 12 males aged 41 to 76 (median, 60). Of 18 tumors with detailed data, 14 presented with synchronous distant metastases (M1). Histological examination showed predominantly solid adenocarcinoma (n = 15), frankly rhabdoid (n = 3) and mucinous (n = 2) patterns. Except for the rhabdoid cases, all tumors showed at least focal unequivocal glands and lacked squamous differentiation, justifying a diagnosis of adenocarcinoma. IHC showed a distinctive uniform immunophenotype (CK7+/HepPar-1+/TTF1-) in 18/20 cases. Only 2/16 cases showed limited weak expression of neuroendocrine markers. EGFR mutations and EML4-ALK and ROS1 gene rearrangements were not found in any of the examined cases. Next-generation sequencing, using a 160 cancer-related gene panel, revealed concurrent SMARCA4 and TP53 mutations in nine of the 12 (75%) successfully tested cases. Our study highlights (1) the morphological diversity of SMARCA4-deficient lung adenocarcinoma, (2) the consistent absence of expression of TTF1 in the presence of expression of HepPar-1, (3) absence of EGFR driver mutations, and (4) frequent inactivating SMARCA4 mutations as underlying mechanism of the observed SMARCA4 protein loss. SMARCA4-deficient pulmonary adenocarcinoma is emerging as a distinctive, albeit phenotypically heterogeneous molecular subgroup of TTF1-negative NSCLC. Uniform HepPar-1 expression in this subset of NSCLC may represent a diagnostic pitfall and merits further studies to explore the mechanisms involved.
EVALuna2:34083

SMARCA4-deficient Sinonasal Carcinoma: A Series of 10 Cases Expanding the Genetic Spectrum of SWI/SNF-driven Sinonasal Malignancies - Agaimy, Abbas; Jain, Deepali; Uddin, Nasir; Rooper, Lisa M.; Bishop, Justin A. (American Journal of Surgical Pathology, 2020)
The molecular pathogenesis of poorly differentiated sinonasal carcinoma received significant attention in recent years. As a consequence, several unclassified carcinomas in the morphologic spectrum of sinonasal undifferentiated carcinoma have been reclassified as distinctive genetically defined variants or entities. Among the latter are NUT-rearranged carcinoma and SMARCB1-deficient carcinomas. In this study, we further characterize a rare variant of sinonasal undifferentiated carcinoma-like tumors characterized by inactivation of the SWItch/Sucrose Nonfermentable chromatin remodeler SMARCA4 (BRG1) detectable by immunohistochemistry. Patients were 7 males and 3 females aged 20 to 67 years (median, 44). Tumors originated in the nasal cavity (6), nose and sinuses (2), or at unspecified site (2). Six tumors were initially misdiagnosed as small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC). Histologically, the tumors were composed of small basaloid (3 cases) or large epithelioid (7) cells disposed into nests and solid sheets with extensive areas of necrosis. No glands or other differentiating features were noted. Abortive rosettes were seen in 1 case. Immunohistochemistry showed consistent expression of pankeratin and absence of CK5, p63, p16, and NUT in all tumors tested. Other tested markers were variably positive: CK7 (2/6), synaptophysin (9/10; mostly focal and weak), chromogranin-A (4/10; focal), and CD56 (3/5; focal). All tumors showed total loss of SMARCA4 and retained expression of SMARCB1/INI1. Co-loss of SMARCA2 was seen in 1 of 8 cases. Limited data were available on treatment and follow-up. Two patients received surgery (1 also radiotherapy) and 3 received chemotherapy. Metastases (cervical nodes, liver, bone, and lung/mediastinal) were detected in 3 patients; 2 were alive under palliative chemotherapy at 8 and 9 months while 1 died of progressive lung disease at 7 months. Three patients (1 with brain invasion) died soon after diagnosis (1 to 3 mo). In total, 4 of 6 patients (66%) with follow-up died of disease (median, 3 mo). This series characterizes SMARCA4-deficient sinonasal carcinoma as a genetically distinct aggressive entity in the spectrum of undifferentiated sinonasal carcinomas. These variants add to the spectrum of SWItch/Sucrose Nonfermentable-deficient sinonasal carcinomas, at the same time expanding the topographic distribution of SMARCA4-related malignancies.
CRIS-Team Scopus Importer:2020-02-04
Keywords: large cell; neuroendocrine carcinoma; NUT midline carcinoma; sinonasal; small cell carcinoma; SMARCA4; SMARCB1; SNUC; SWI/SNF complex

SMARCA4-deficient Sinonasal Carcinoma - Agaimy, Abbas; Weichert, Wilko (Head and Neck Pathology, 2017)
The term "sinonasal undifferentiated carcinoma (SNUC)" has been coined in 1986 for a highly aggressive sinonasal tract epithelial neoplasm showing distinctive morphology, but lacking any specific line of differentiation. Recent developments resulted in a dynamic splitting of new entities traditionally included in the spectrum of SNUC. Sinonasal NUT-midline carcinoma, adamantinoma-like Ewing family tumors and most recently, SMARCB1(INI1)-deficient sinonasal carcinoma are the main entities defined by specific genetic aberrations. To our knowledge, involvement of subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex other than SMARCB1 has not been implicated in the pathogenesis of SNUC-like neoplasms. We herein describe a 40-year-old woman who presented with a large infiltrative mass involving the right nasal cavity and the sinuses with extension into the skull base and periorbital tissue (cT4N2M0). Biopsies were interpreted initially as poorly differentiated neuroendocrine carcinoma followed by surgical resection and radiochemotherapy. No other extra-nasal tumor was detected on imaging. The patient was alive with disease at last follow-up (9 months from initial diagnosis). Histological evaluation showed poorly differentiated small round blue cell neoplasm with diffuse expression of pancytokeratin but not high molecular weight cytokeratin subsets, CK7, p63, S100, desmin or NUT. Neuroendocrine markers showed limited focal weak reactivity. SMARCB1, SMARCA2 and ARID1A were intact in the tumor cells but SMARCA4 was completely lost. This case highlights the rare occurrence of SMARCA4-deficiency in poorly differentiated sinonasal carcinomas and points to the importance of including other SWI/SNF complex subunits in the evaluation of SMARCB1-intact sinonasal malignancies.
EVALuna2:6928

SMARCA4-deficient undifferentiated carcinoma of the ovary (small cell carcinoma, hypercalcemic type): clinicopathologic and immunohistochemical study of 3 cases - Agaimy, Abbas; Thiel, Falk; Hartmann, Arndt; Fukunaga, Masaharu (Annals of Diagnostic Pathology, 2015)
Small cell carcinoma of the ovary, hypercalcemic type is a very rare aggressive neoplasm of unknown histogenesis, affecting mainly girls and young women. Recently, inactivating mutations in SMARCA4 (BRG1), a member of the switch/sucrose nonfermenting chromatin remodeling complex, has been identified as driver events in most cases. We herein describe 3 cases in 34, 34, and 37-year-old women. Symptoms were mainly abdominal pain and mass. One patient was normocalcemic, and the other 2 had no preoperative serum calcium values available. All patients received radical hysterectomy with salpingo-oophorectomy, lymphadenectomy, and variable multimodality therapy. Two developed abdominal recurrences/metastases and died of disease at 4 and 12 months. One patient was alive without disease 17 months after surgery and radiochemotherapy. Histologic examination showed undifferentiated neoplasms composed of diffuse sheets, nests and cords of noncohesive monomorphic small blue/basaloid cells (classic variant, 1 case), and large undifferentiated/rhabdoid cells with abundant cytoplasm (large cell/rhabdoid variant, 2 case) admixed with minor small cell areas. One case contained rare isolated goblet cells, but true glandular component was absent. All tumors expressed vimentin and variably pancytokeratin and WT1. Nuclear SMARCB1 was intact in all cases (1 case showed small foci with mosaic loss). All tumors showed complete loss of SMARCA4. In conclusion, SMARCA4 immunohistochemistry represents a highly valuable emerging tool in identifying small cell carcinoma of the ovary, hypercalcemic type in routine practice. Distinguishing this aggressive neoplasm from juvenile granulosa cell tumor and other undifferentiated ovarian cancers is mandatory in selecting appropriate chemotherapeutic regimens and would allow better characterization of this entity, for which targeted molecular therapy still remains to be established.
EVALuna2:6715

SMARCB1-deficient sinonasal adenocarcinoma: a rare variant of SWI/SNF-deficient malignancy often misclassified as high-grade non-intestinal-type sinonasal adenocarcinoma or myoepithelial carcinoma - Skálová, Alena; Taheri, Touraj; Bradová, Martina; Vaněček, Tomáš; Franchi, Alessandro; Slouka, David; Kostlivý, Tomáš; de Rezende, Gisele; Michálek, Jaroslav; Klubíčková, Natálie; Ptáková, Nicola; Nemcová, Antónia; et al. (Virchows Archiv, 2023)
SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival.
CRIS-Team Scopus Importer:2023-12-22
Keywords: Head and neck; Next-generation sequencing; Rhabdoid; Sinonasal; SMARCB1-deficient adenocarcinoma; SWI/SNF complex; Yolk sac-like

SMARCB1 (INI-1)-Deficient Adenocarcinoma of the Sinonasal Tract: A Potentially Under-Recognized form of Sinonasal Adenocarcinoma with Occasional Yolk Sac Tumor-Like Features - Shah, Akeesha A.; Jain, Deepali; Ababneh, Emad; Agaimy, Abbas; Hoschar, Aaron P.; Griffith, Christopher C.; Magliocca, Kelly R.; Wenig, Bruce M.; Rooper, Lisa M.; Bishop, Justin A. (Head and Neck Pathology, 2019)
The classification of sinonasal adenocarcinoma (SNAC) is complex. The high-grade, non-intestinal SNAC group is particularly heterogeneous, with tumors showing widely variable morphology. SMARCB1 (INI-1)-deficient sinonasal carcinoma is a newly described, aggressive tumor that usually resembles sinonasal undifferentiated carcinoma (SNUC) or non-keratinizing squamous cell carcinoma; however, glandular differentiation has been rarely reported and this feature may be under-recognized. We present a dedicated series of 12 SMARCB1-deficient SNACs. All tumors had an oncocytoid/plasmacytoid cytomorphology with variable degrees of glandular differentiation consisting of tubules and cribriform structures with foci of intracellular or intraluminal mucin. Three of 12 tumors exhibited foci of yolk sac tumor-like histologic features. The tumors were uniformly high-grade, with nuclear pleomorphism, elevated mitotic rates and frequent necrosis. By immunohistochemistry, all tumors were entirely SMARCB1-deficient, and 10 of 12 were CK7-positive. Occasional expression of CDX2 (4 of 12), CK20 (3 of 12), and p40 (3 of 10) was seen. Expression of yolk sac markers was variably present in tumors that harbored yolk sac-like areas but also tumors that did not: glypican-3 (10 of 11), SALL4 (6 of 11), HepPar-1 (4 of 11), PLAP (1 of 10), and AFP (1 of 11). SMARCB1-deficient sinonasal carcinoma, particularly the oncocytoid/plasmacytoid form, can demonstrate variable degrees of glandular differentiation. This unexpected morphology combined with variable immunohistochemical results may lead to misdiagnoses of high-grade intestinal or non-intestinal SNAC, myoepithelial carcinoma, or even yolk sac tumor or metastatic hepatocellular carcinoma.
CRIS-Team Scopus Importer:2019-10-22
Keywords: Adenocarcinoma; INI-1; Sinonasal; SMARCB1; SMARCB1-deficient sinonasal carcinoma; Yolk sac tumor

SMARCB1(INI1)-deficient renal cell carcinoma: medullary and beyond Evolving concepts - Agaimy, Abbas; Hartmann, Arndt (Pathologe, 2021)
During the last decades, the SWI/SNF chromatin-remodeling complex has received enormous recognition as a major player in the molecular pathogenesis of diverse neoplasms. Accordingly, SWI/SNF defects affecting different subunits of the complex became defining genetic features in the nosology of different neoplastic entities. In the kidney, loss of SMARCB1(INI1) as a major component of the SWI/SNF complex has emerged as the defining genetic marker for renal medullary carcinoma and pediatric malignant rhabdoid tumor. Diagnosis of these two rare entities is based on a set of defined demographic, clinicopathological, immunophenotypic, and genetic (SMARCB1 loss) criteria. Moreover, the sickle cell trait is considered a prerequisite for renal medullary carcinoma. Current knowledge illustrates that SMARCB1 loss is encountered in three major tumor categories in the kidney: (1) histologically defined neoplasms that are primarily driven by de novo SMARCB1 loss (renal medullary carcinoma and malignant rhabdoid tumor); (2) SMRACB1-deficient renal cell carcinoma (RCC) with variable non-specific histology ranging from collecting duct-like, papillary high-grade (papillary type 2), or medullary-like (lacking sickle cell trait), to fully undifferentiated; and (3) biphasic (dedifferentiated) RCC showing a variable SMARCB1-deficient undifferentiated component. The latter variant most frequently originates from pre-existing clear cell RCC but may rarely superimpose on papillary or chromophobe RCC. This review summarizes the major defining features of the emerging SMARCB1-deficient renal neoplasms. All SMARCB1-deficient carcinomas have a poor prognosis in common. Therefore, exact diagnosis of these tumors is a prerequisite for studies investigating new therapies.
CRIS-Team WoS Importer:2021-10-15

SMARCB1(INI1)-deficient sinonasal basaloid carcinoma: a novel member of the expanding family of SMARCB1-deficient neoplasms - Agaimy, Abbas; Koch, Michael; Lell, Michael; Semrau, Sabine; Dudek, Wojciech; Wachter, David; Knöll, Antje; Iro, Heinrich; Haller, Florian; Hartmann, Arndt (American Journal of Surgical Pathology, 2014)
Poorly differentiated sinonasal carcinomas are a heterogenous group of aggressive neoplasms that encompasses squamous cell carcinoma including basaloid variant, lymphoepithelial carcinoma, sinonasal undifferentiated carcinoma, and neuroendocrine-type small cell carcinoma. We herein describe 3 cases of a hitherto unreported variant combining features of basaloid carcinoma with variable intermingled rhabdoid cells. Patients were 2 women (aged 28 and 35) and a man (52 y) who presented with sinonasal masses. All had advanced local disease with bone involvement (pT4). None had a history of irradiation or a family history of rhabdoid tumors. Treatment was surgery and adjuvant chemoradiation. One patient developed liver, lung, pleural, and pericardial metastases (63 mo) and is currently (70 mo) alive under palliative treatment. Another developed recurrent cervical lymph node metastases and died of disease 8.5 years later. The youngest patient was disease-free at last follow-up 7 years later. Histologic features were very similar in all 3 cases and showed intimate admixture of compact basaloid cell nests with peripheral palisading, perivascular pseudorosettes, and a few scattered rhabdoid cells. Rhabdoid cells were more extensive in the metastasis in 1 case but formed a minor inconspicuous component in the primary tumors in all cases. Striking features common to all cases were (1) basaloid "blue" appearance at low power, (2) papilloma-like exophytic component, (3) extensive pagetoid surface growth with prominent denuding features, and (4) replacement of underlying mucous glands mimicking an inverted papilloma. Clear-cut origin from benign papilloma and overt squamous differentiation were lacking. Diffuse (2) or partial (1) p16 expression was noted, but all cases lacked human papillomavirus DNA by molecular tests. In situ hybridization was negative for Epstein-Barr virus. Immunohistochemistry showed diffuse expression of pancytokeratin. CK5 and vimentin showed intermingling of CK5/vimentin basaloid and CK5/vimentin rhabdoid cells. Complete loss of nuclear SMARCB1 expression was seen in all cases including also the denuding carcinoma in situ-like surface lesions. To our knowledge, this variant of sinonasal carcinoma has not been reported before. The identical features in all 3 cases suggest a specific disease rather than a nonspecific dedifferentiated phenotype. Awareness of this rare variant and thus reporting of additional cases is necessary for defining its full morphologic and biological spectrum.
EVALuna2:6600

SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity - Agaimy, Abbas; Hartmann, Arndt; Antonescu, Cristina R.; Chiosea, Simion I.; El-Mofty, Samir K.; Geddert, Helene; Iro, Heinrich; Lewis, James S.; Markl, Bruno; Mills, Stacey E.; Riener, Marc-Oliver; Robertson, Thomas; et al. (American Journal of Surgical Pathology, 2017)
To more fully characterize the clinical and pathologic spectrum of a recently described tumor entity of the sinonasal tract characterized by loss of nuclear expression of SMARCB1 (INI1), we analyzed 39 SMARCB1-deficient sinonasal carcinomas collected from multiple medical centers. The tumors affected 23 males and 16 females with an age range of 19 to 89 years (median, 52). All patients presented with locally advanced disease (T3, n=5; T4, n=27) involving the sinuses (mainly ethmoid) with variable involvement of the nasal cavity. Thirty patients received surgery and/or radiochemotherapy with curative intent. At last follow-up, 56% of patients died of disease 0 to 102 months after diagnosis (median, 15), 2 were alive with disease, and 1 died of an unrelated cause. Only 9 patients (30%) were alive without disease at last follow-up (range, 11 to 115 mo; median, 26). The original diagnosis of retrospectively identified cases was most often sinonasal undifferentiated carcinoma (n=14) and nonkeratinizing/basaloid squamous cell carcinoma (n=5). Histologically, most tumors displayed either a predominantly basaloid (61%) or plasmacytoid/rhabdoid morphology (36%). The plasmacytoid/rhabdoid form consisted of sheets of tumor cells with abundant, eccentrically placed eosinophilic cytoplasm, whereas similar cells were typically rare and singly distributed in the basaloid variant. Glandular differentiation was seen in a few tumors. None of the cases showed squamous differentiation or surface dysplasia. By immunohistochemistry, the tumors were positive for pancytokeratin (97%), CK5 (64%), p63 (55%), and CK7 (48%); and they were negative for NUT (0%). Epstein-Barr virus and high-risk human papillomavirus was not detected by in situ hybridization. Immunohistochemical loss of SMARCB1 (INI1) expression was confirmed for all 39 tumors. Investigation of other proteins in the SWI/SNF complex revealed co-loss of SMARCA2 in 4 cases, but none were SMARCA4 deficient or ARID1A deficient. Of 27 tumors with SMARCB1 fluorescence in situ hybridization analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions. SMARCB1-deficient sinonasal carcinoma represents an emerging poorly differentiated/undifferentiated sinonasal carcinoma that (1) cannot be better classified as another specific tumor type, (2) has consistent histopathologic findings (albeit with some variability) with varying proportions of plasmacytoid/rhabdoid cells, and (3) demonstrates an aggressive clinical course. This entity should be considered in any difficult-to-classify sinonasal carcinoma, as correct diagnosis will be mandatory for optimizing therapy and for further delineation of this likely underdiagnosed disease.
EVALuna2:6856

SMARCB1 (INI1)-negative rhabdoid carcinomas of the gastrointestinal tract: clinicopathologic and molecular study of a highly aggressive variant with literature review - Agaimy, Abbas; Rau, Tilman; Hartmann, Arndt; Stoehr, Robert (American Journal of Surgical Pathology, 2014)
Gastrointestinal (GI) neoplasms with rhabdoid features have been reported since 1989 under diverse names (giant cell carcinoma, pleomorphic carcinoma, malignant rhabdoid tumor, adenocarcinoma with rhabdoid features/phenotype, anaplastic carcinoma, etc.), but their clinicopathologic spectrum, SMARCB1 (INI1) status and relationship to common GI carcinomas have not been clarified yet. We describe 2 carcinomas from the stomach and the cecum with exclusive rhabdoid morphology. The patients died of disease at 6 and 10 months, respectively. The tumors coexpressed vimentin, pancytokeratin, and EMA. Both showed complete loss of nuclear SMARCB1/INI1. Molecular analysis (KRAS, EGFR, BRAF, PIK3CA, and microsatellite studies) revealed a CpG-island methylator phenotype in the cecal tumor (CIMP(+)/MLH1(-)/BRAF(V600E)/MSI-H), confirming epithelial origin. The gastric tumor showed poorly differentiated adenocarcinoma in regional nodes, again confirming epithelial derivation. Other genes tested were wild type in both cases. Review of reported cases (total: 39) revealed a glandular component in 33%. Affected sites are: stomach (13), colon (11), small bowel (10), and distal esophagus (5). Of the 34 patients with follow-up >=12 months, 29 (85%) died within 1 year (mean: 4 mo). Molecular tests were performed in 8/39 cases. A CIMP(+)/BRAF(V600E)/MLH1(-) phenotype was found in 3/4 right colon tumors. Loss of nuclear SMARCB1 protein was noted in 3/6 cases tested. This study highlights the heterogeneity of rhabdoid GI neoplasms and supports their epithelial derivation. Rhabdoid phenotype likely represents a common pathway of dedifferentiation with frequent loss of SMARCB1 and highly aggressive course. The CIMP phenotype represents a novel subset of rhabdoid GI carcinomas. This rare variant should be distinguished from proximal-type epithelioid sarcoma and other SMARCB1-deficient mimics.
EVALuna2:6589

Smoking status and PD-L1 mRNA-expression as a predictor of response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer - Reike, Moritz; Juette, Hendrik; Wirtz, Ralph; Erben, Philipp; Tully, Karl; Eckstein, Markus; Weyerer, Veronika; Hartmann, Arndt; Kriegmair, Maximilian; Wezel, Felix; Bolenz, Christian; Tannapfel, Andrea; et al. (JOURNAL OF CLINICAL ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-05-22

Soft tissue tumors in hereditary tumor syndromes - Agaimy, Abbas (Pathologe, 2017)
Benign and malignant soft tissue tumors usually develop de novo without identifiable risk factors or predisposing conditions. However, in recent decades, soft tissue tumors have been increasingly recognized to be associated with diverse hereditary tumor syndromes as a consequence of germline mutations involving mainly tumor suppressor genes, but rarely also affecting proto-oncogenes. This is mainly the consequence of increasing application of modern genetic analysis tools, such as next-generation sequencing (NGS) and whole genome analyses. Syndrome-associated soft tissue tumors frequently show distinctive clinicopathological features and peculiarities that facilitate and potentially enhance their recognition and identification during routine surgical pathology practice. As it is not uncommon that pathologists are the first medical specialists to recognize a potential hereditary etiology of neoplastic diseases on the basis of specific pathological features, it is mandatory that pathologists be familiar with the main features that characterize those soft tissue tumors with inherited etiology, at least the most common and important of them. This review summarizes the main syndromes and their associated soft tissue tumors and discusses their characteristic pathological features that help in the recognition of hereditary syndromes.
EVALuna2:6862

Solid pseudopapillary neoplasms of the pancreas in childhood and adolescence—an analysis of the German Registry for Rare Pediatric Tumors (STEP) - Jentzsch, Christian; Fuchs, Jörg; Agaimy, Abbas; Vokuhl, Christian; Escherich, Gabriele; Blattmann, Claudia; Warmann, Steven W.; Schmidt, Andreas; Schäfer, Jürgen; Brecht, Ines B.; Schneider, Dominik T.; Abele, Michael (European Journal of Pediatrics, 2023)
Solid pseudopapillary neoplasms (SPNs) are the most common entity among pediatric pancreatic tumors. Still, these are rare tumors with an annual incidence of 0.1–0.2/1,000,000, and little is known about their optimal treatment. This analysis aimed to increase knowledge about the occurrence and treatment strategies of SPN in childhood. Data regarding diagnostics, treatment, and outcome of children aged 0–18 years with SPN recorded in the German Registry for Rare Pediatric Tumors (STEP) were analyzed. Thirty-eight patients were identified with a median age of 14.5 years at diagnosis (range: 8–18) and a female preponderance (81.6%). The most frequent location of the tumor was the pancreatic tail. In histopathological and immunohistochemical examination, pseudopapillary, solid, and cystic lesions as well as expression of beta-catenin, progesterone receptors, and cyclin D1 were the most common findings. All patients underwent surgical resection. Most patients underwent open resection, predominantly tail resection for tumors in the tail region and pylorus-preserving pancreaticoduodenectomy for tumors in the head region. The main postoperative sequela was exogenous pancreatic insufficiency (23.7%), especially with SPN in the pancreatic head. No recurrence occurred during follow-up, although two patients underwent resection with microscopic residue. Conclusion: SPN of the pancreas in childhood are low-grade malignancies with usually favorable treatment outcomes. However, therapy can lead to relevant long-term sequelae. To prevent recurrence, complete surgical resection is recommended, sparing as much healthy pancreatic tissue as possible. Interdisciplinary collaboration between specialists is essential to optimize treatment. Molecular genetic analysis of these tumors could improve understanding of their genesis. What is Known: • Solid pseudopapillary neoplasms (SPNs) of the pancreas are very rare tumors in childhood. • Little is known about tumorigenesis, and there are no specific guidelines for treatment and follow-up in pediatric patients. What is New: • Characteristics, treatment, and outcome were comprehensively assessed in a large cohort of pediatric patients with SPN. • We propose recommendations for diagnosis, treatment, and follow-up of children with SPN, based on our analysis and considering published experience.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Children; Rare tumor; Solid pseudopapillary neoplasm; SPN; STEP

Solitary Fibrous Tumor: Natural History and Prognosis in Accordance with the WHO 2021 Classification of CNS Tumors - Eschbacher, Kathryn; Jenkins, Sarah; Fritchie, Karen; Jensch, Kassandra; Moskalev, Evgeny; Caron, Alissa; Link, Michael; Brown, Paul; Guajardo, Andrew; Brat, Daniel; Wu, Ashley; Santagata, Sandro; et al. (JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Solitary fibrous tumors/hemangiopericytomas with different variants of the NAB2-STAT6 gene fusion are characterized by specific histomorphology and distinct clinicopathological features - Barthelmeß, Sarah; Geddert, Helene; Boltze, Carsten; Moskalev, Evgeny; Bieg, Matthias; Sirbu, Horia; Brors, Benedikt; Wiemann, Stefan; Hartmann, Arndt; Agaimy, Abbas; Haller, Florian (American Journal of Pathology, 2014)
Recurrent somatic fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been recently identified to be presumable tumor-initiating events in solitary fibrous tumors (SFT). Herein, we evaluated a cohort of 52 SFTs/hemangiopericytomas (HPCs) by whole-exome sequencing (one case) and multiplex RT-PCR (all 52 cases), and identified 12 different NAB2-STAT6 fusion variants in 48 cases (92%). All 52 cases showed strong and diffuse nuclear positivity for STAT6 by IHC. We categorized the fusion variants according to their potential functional effects within the predicted fusion protein and found strong correlations with relevant clinicopathological features. Tumors with the most common fusion variant, NAB2ex4-STAT6ex2/3, corresponded to classic pleuropulmonary SFTs with diffuse fibrosis and mostly benign behavior and occurred in older patients (median age, 69 years). In contrast, tumors with the second most common fusion variant, NAB2ex6-STAT6ex16/17, were found in much younger patients (median age, 47 years) and represented typical HPCs from deep soft tissue with a more aggressive phenotype and clinical behavior. In summary, these molecular genetic findings support the concept that classic pleuropulmonary SFT and deep-seated HPC are separate entities that share common features but correlate to different clinical outcome.
EVALuna2:6577

Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20 - Konukiewitz, Bjoern; Schlitter, Anna Melissa; Jesinghaus, Moritz; Pfister, Dominik; Steiger, Katja; Segler, Angela; Agaimy, Abbas; Sipos, Bence; Zamboni, Giuseppe; Weichert, Wilko; Esposito, Irene; Pfarr, Nicole; et al. (Modern Pathology, 2017)
Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.
EVALuna2:6860

Spatial distribution of FoxP3+ and CD8+ tumour infiltrating T cells reflects their functional activity - Posselt, Rebecca; Erlenbach-Wuensch, Katharina; Haas, Matthias; Jeßberger, Jonas; Buettner-Herold, Maike; Haderlein, Marlen; Hecht, Markus; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (Oncotarget, 2016)
Regulatory and cytotoxic T cells are key players in the host's anticancer immune response. We studied the spatial distribution of FoxP+ and CD8+ cells to identify potential interactions.In 202 patients 103 pre-radiochemotherapy biopsies and 153 post-radiochemotherapy tumour specimens of advanced rectal cancer were available and an immunohistochemical double staining of FoxP3+ and CD8+ tumour-infiltrating lymphocytes was performed to investigate cell density and cell-to-cell distances.FoxP3+ cells decreased after radiochemotherapy by a factor of 3 while CD8+ cells remained nearly unchanged. High epithelial (p=0.033) and stromal (p=0.009) FoxP3+ cell density was associated with an improved overall survival. Cell-to-cell distances of randomly distributed cells were simulated and compared to observed cell-to-cell distances. Observed distances shorter than the simulated, random distances were hypothesized to represent FoxP3+ cells actively interacting with CD8+ cells. Epithelial short distances were associated with a favourable prognosis while the opposite was true for the stromal compartment.The analysis of cell-to-cell distances may offer a tool to predict outcome, maybe by identifying functionally active, interacting infiltrating inflammatory cells in different tumour compartments.
EVALuna2:6815

Spatial expression of claudin 18.2 in matched primaries and metastases of tubo-ovarian carcinoma of all subtypes - Wagner, Paul; Gaß, Paul; Pöschke, Patrik; Eckstein, Markus; Gloßner, Laura; Hartmann, Arndt; Beckmann, Matthias; Fasching, Peter; Rübner, Matthias; Emons, Julius; Erber, Ramona (Virchows Archiv, 2024)
Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases. Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining. Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype. In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.
CRIS-Team Scopus Importer:2024-02-16
Keywords: CLDN18.2; Immunohistochemistry; Mucinous tubo-ovarian carcinoma; Targeted therapy; Tubo-ovarian cancer

Spatial Immunephenotypes of Distant Metastases but not Matched Primary Urothelial Carcinomas Predict Response to Immune Checkpoint Inhibition - Erlmeier, Franziska; Klümper, Niklas; Landgraf, Laura; Strissel, Pamela; Strick, Reiner; Sikic, Danijel; Taubert, Helge; Wach, Sven; Geppert, Carol-Immanuel; Bahlinger, Veronika; Breyer, Johannes; Ritter, Manuel; et al. (European Urology, 2022)
Background: The value of programmed cell death ligand-1 (PD-L1) to predict durable responses to immune checkpoint inhibitors (ICIs) in metastatic urothelial carcinoma (mUC) is inconsistent. We hypothesize that the use of archived primary tumor material (PRIM) for PD-L1 testing in clinical trials not properly reflecting the metastatic disease status (MET) contributes to this clinical issue. Objective: To analyze the predictive and prognostic value of PD-L1, spatial immunephenotypes, and major histocompatibility complex class I (MHC-I) determined in patient-matched PRIM/MET. Design, setting, and participants: PD-L1, spatial immunephenotypes, and MHC-I were examined in 154 mUC patients with at least one available pretreatment MET (138 patient-matched PRIM/MET pairs). Outcome measurements and statistical analysis: PD-L1, spatial immunephenotype, and MHC-I status of (patient-matched PRIM and) pretreatment MET were correlated with chemotherapy and ICI response and outcomes. Results and limitations: Discordance rates in patient-matched PRIM/MET were 25/30%, 36%, and 49% for PD-L1 (CPS10/IC5%), immunephenotypes, and MHC-I (loss vs preserved), respectively. Correlations with chemotherapy and ICI responses were observed for immunephenotypes and MHC-I status determined in MET (not for PD-L1 alone), but not in PRIM. In case of ICIs, patients with cytotoxic tumor immune microenvironment (TIME) showed durable responses with disease control rates of 90% and a hazard ratio for disease progression/death of 0.05 (95% confidence interval: 0.01–0.65) versus patients with immunedepleted MET (disease control rate 29%). MET MHC-I status added an incremental value to predict durable ICI responses. Limitations include the partly retrospective design and the lack of MET multisampling on individual patient level. Conclusions: The TIME is subject to substantial dynamics during metastatic evolution. MET immunephenotypes and MHC-I statuses show promising potential to predict chemotherapy and durable ICI responses, while the PRIM TIME does not. Thus, future clinical trials should rather rely on pretreatment MET biopsies reflecting the current immunological disease state than on PRIM. Patient summary: Prediction of chemotherapy and responses to immune checkpoint inhibitors might be possible using representative pretreatment metastatic biopsies.
CRIS-Team Scopus Importer:2022-11-25
Keywords: Immune microenvironment; Immune therapy; Metastatic urothelial cancer; Subtypes; Urothelial cancer

Special mesenchymal neoplasms of the head and neck: Update from the 2022 WHO Spezielle mesenchymale Tumoren der Kopf-Hals-Region: Neues aus der WHO 2022 - Agaimy, Abbas; Franchi, Alessandro (Die Pathologie, 2023)
Similar to the approach adopted in the classification of tumors in other organs, a new feature of the current Word Health Organization (WHO) classification of the head and neck tumors is the exclusion of soft tissue tumors from single organs and their inclusion in a separate chapter devoted to them. This applies to tumors that are principally ubiquitous but show a predilection for the head and neck sites. The only exception to this rule represents those entities that are almost restricted to a specific head and neck site/organ (such as nasopharyngeal angiofibroma, sinonasal glomangiopericytoma, and biphenotypic sinonasal sarcoma), which remain in their respective organ chapters. Included among soft tissue tumors are some old but still underrecognized entities, such as phosphaturic mesenchymal tumors, and newly defined entities, such as GLI1-altered tumors. The aim of including these entities is to enhance recognition of these uncommon but likely under-recognized entities to better characterize them in the future. This review summarizes the main features of these rare entities and discusses their differential diagnoses.
CRIS-Team Scopus Importer:2023-07-21
Keywords: Angiofibroma; Gene amplification; Gene fusion; Glioma-associated oncogene GLI1; Paranasal sinus neoplasms

Species-, organ- and cell-type-dependent expression of SPARCL1 in human and mouse tissues. - Klingler, Anika; Regensburger, Daniela; Tenkerian, Clara; Britzen-Laurent, Nathalie; Hartmann, Arndt; Stürzl, Michael; Naschberger, Elisabeth (PLoS ONE, 2020)
SPARCL1 is a matricellular protein with anti-adhesive, anti-proliferative and anti-tumorigenic functions and is frequently downregulated in tumors such as colorectal carcinoma or non-small cell lung cancer. Studies have identified SPARCL1 as an angiocrine tumor suppressor secreted by tumor vessel endothelial cells, thereby exerting inhibitory activity on angiogenesis and tumor growth, in colorectal carcinoma. It is unknown whether SPARCL1 may exert these homeostatic functions in all organs and in other species. Therefore, SPARCL1 expression was comparatively analysed between humans and mice in a systematic manner. Murine Sparcl1 (mSparcl1) is most strongly expressed in the lung; expressed at an intermediate level in most organs, including the large intestine; and absent in the liver. In human tissues, SPARCL1 (hSPARCL1) was detected in all organs, with the strongest expression in the stomach, large intestine and lung, mostly consistent with the murine expression pattern. A striking difference between human and murine tissues was the absence of mSparcl1 expression in murine livers, while human livers showed moderate expression. Furthermore, mSparcl1 was predominantly associated with mural cells, whereas hSPARCL1 was detected in both mural and endothelial cells. Human SPARCL1 expression was downregulated in different carcinomas, including lung and colon cancers. In conclusion, this study revealed species-, organ- and cell-type-dependent expression of SPARCL1, suggesting that its function may not be similar between humans and mice.

Specific types of bladder cancer - Bertz, Simone; Hartmann, Arndt; Knuechel-Clarke, R.; Gaisa, N. T. (Pathologe, 2016)
Bladder cancer shows rare variants and special subtypes with diverse prognostic importance and therefore may necessitate different therapeutic approaches. For pathologists it is important to histologically diagnose and specify such variants. Nested variants of urothelial carcinoma with inconspicuous, well-formed tumor cell nests present with an aggressive course. The plasmacytoid variant, which morphologically resembles plasma cells is associated with a shorter survival time and a high frequency of peritoneal metastasis. Micropapillary urothelial carcinoma with small papillary tumor cell islands within artificial tissue retraction spaces and frequent lymphovascular invasion also has a poor prognosis. Other important rare differential variants listed in the World Health Organization (WHO) classification are microcystic, lymphoepithelioma-like, sarcomatoid, giant cell and undifferentiated urothelial carcinomas. Additionally, there are three special types of bladder cancer: squamous cell carcinoma, adenocarcinoma and small cell neuroendocrine carcinoma of the bladder. These tumors are characterized by pure squamous cell or glandular differentiation and are sometimes less responsive to adjuvant (chemo)therapy. Small cell carcinoma of the bladder mimics the neuroendocrine features of its pulmonary counterpart, shows an aggressive course but is sensitive to (neo-)adjuvant chemotherapy. The morphology and histology of the most important variants and special types are discussed in this review.
EVALuna2:6786

Sporadic endolymphatic sac tumor–a diagnostic and therapeutic challenge - Kuenzel, Julian; Agaimy, Abbas; Hornung, Joachim; Lell, Michael; Ganslandt, Oliver Thomas; Semrau, Sabine; Zenk, Johannes (International Journal of Clinical and Experimental Pathology, 2014)
Endolymphatic sac tumor (ELST) is a rare low-grade locally aggressive neoplasm of the inner ear that may occur sporadically or in the setting of von Hippel-Lindau syndrome. We herein present a case of sporadic ELST in a 39-year-old man, treated using an interdisciplinary approach (surgery+radiotherapy), with a 10-year follow-up. The patient presented with hearing loss of sudden onset. The treatment of choice for ELST is radical tumor resection, which is associated with a good long-term prognosis. Remission may last for years, but there may be local recurrences, probably as a result of incomplete resection. Adjuvant radiotherapy is an option in case of recurrence and could be discussed after incomplete resection. The purpose of this report is to call attention to ELSTs, which are difficult to diagnose due to their rarity and variety of presentations.
EVALuna2:6593

Spread through Air Spaces (STAS) in Solitary Pulmonary Metastases from Colorectal Cancer (CRC) - Haj Khalaf, Mohamed; Sirbu, Horia; Hartmann, Arndt; Agaimy, Abbas; Dudek, Wojciech; Higaze, Mostafa; Rieker, Ralf (Thoracic and Cardiovascular Surgeon, 2022)
Background Spread through air spaces (STAS) is a recently described route of tumor invasion associated with poor prognosis in primary lung cancer. Aim of this study was to investigate the presence of STAS and to assess its prognostic significance in patients undergoing pulmonary metastasectomy (PM) for solitary metastases from colorectal cancer (CRC). Materials and Methods All 49 CRC patients (30 male and 19 female, median age 66 years) who underwent PM between January 2008 and December 2015 were retrospectively analyzed. Results STAS was identified in 26.5% ( n = 13) of resected specimens. Location of pulmonary lesions (central vs. peripheral) was assessed based on the available computed tomography imaging ( n = 47, 96%). STAS was detected in all five patients with central metastases (100%) versus 7 of 42 (17%) with peripheral metastases ( p = 0.0001). Locoregional recurrence occurred in STAS-positive patients ( n = 4 of 13 vs. n = 0 of 36), all STAS-negative patients remained recurrence-free ( p = 0.003). Median number of alveoli with STAS involvement was four (range from 2 to 9). There was statistically positive relationship between the number of alveoli invaded with STAS and locoregional recurrence of metastases ( p = 0.0001). The presence of STAS is not a factor affecting the 5-year overall survival rate ( p = 0.6651). Conclusion We identified STAS as a frequent finding in resected CRC lung metastases and found insignificant association with outcome.
CRIS-Team WoS Importer:2022-10-28

SST gene hypermethylation acts as a pan-cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood-based diagnosis - Manoochehri, Mehdi; Wu, Yenan; Giese, Nathalia A.; Strobel, Oliver; Kutschmann, Stefanie; Haller, Florian; Hoheisel, Joerg D.; Moskalev, Evgeny; Hackert, Thilo; Bauer, Andrea S. (Molecular Oncology, 2020)
Aberrant DNA methylation is often involved in carcinogenesis. Our initial goal was to identify DNA methylation biomarkers associated with pancreatic cancer. A genomewide methylation study was performed on DNA from pancreatic ductal adenocarcinoma (PDAC) and endocrine pancreas tumors. Validation of DNA methylation patterns and concomitant alterations in expression of gene candidates was performed on patient samples and pancreatic cancer cell lines. Furthermore, validation was done on independent data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Finally, droplet digital PCR was employed to detect DNA methylation marks in cell-free (cf) DNA isolated from plasma samples of PDAC patients and cancer-free blood donors. Hypermethylation of the SST gene (encoding somatostatin) and concomitant downregulation of its expression were discovered in PDAC and endocrine tumor tissues while not being present in chronic pancreatitis (inflamed) tissues and normal pancreas. Fittingly, treatment with a somatostatin agonist (octreotide) reduced cell proliferation and migration of pancreatic cancer cells. Diagnostic performance of SST methylation in a receiver operating characteristic curve analysis was 100% and 89% for tissue and plasma samples, respectively. A large body of TCGA and GEO data confirmed SST hypermethylation and downregulation in PDAC and showed a similar effect in a broad spectrum of other tumor entities. SST promoter methylation represents a sensitive and promising molecular, pan-cancer biomarker detectable in tumor tissue, and liquid biopsy samples.
CRIS-Team WoS Importer:2020-04-24

Standardized 18F-FDG PET/CT radiomic features provide information on PD-L1 expression status in treatment-naive patients with non-small cell lung cancer - Zhang, Ruiyun; Hohenforst-Schmidt, Wolfgang; Steppert, Claus; Sziklavari, Zsolt; Schmidkonz, Christian; Atzinger, Armin; Kuwert, Torsten; Klink, Thorsten; Sterlacci, William; Hartmann, Arndt; Vieth, Michael; Foerster, Stefan (Nuklearmedizin-Nuclear Medicine, 2022)
Purpose To study the relationship between standardized 18F-FDG PET/CT radiomic features and clinicopathological variables and programmed death ligand-1 (PD-L1) expression status in non-small cell lung cancer (NSCLC) patients. Methods 58 NSCLC patients with preoperative 18F-FDG PET/CT scans and postoperative results of PD-L1 expression were retrospectively analysed. A standardized, open-source software was used to extract 86 radiomic features from PET and low-dose CT images. Univariate analysis and multivariate logistic regression were used to find independent predictors of PD-L1 expression. The Area Under the Curve (AUC) of receiver operating characteristic (ROC) curve was used to compare the ability of variables and their combination in predicting PD-L1 expression. Results Multivariate logistic regression resulted in the PET radiomic feature GLRLM_LGRE (Odds Rate (OR): 0.300 vs 0.114, 95% confidence interval (CI): 0.096-0.931 vs 0.021-0.616, in NSCLC and adenocarcinoma respectively) and the CT radiomic feature GLZLM_SZE (OR: 3.338 vs 7.504, 95%CI: 1.074-10.375 vs 1.382-40.755, in NSCLC and adenocarcinoma respectively), being independent predictors of PD-L1 status. In NSCLC group, after adjusting for gender and histology, the PET radiomic feature GLRLM_LGRE (OR: 0.282, 95%CI: 0.085-0.936) remained an independent predictor for PD-L1 status. In the adenocarcinoma group, when adjusting for gender the PET radiomic feature GLRLM_LGRE (OR: 0.115, 95%CI: 0.021-0.631) and the CT radiomic feature GLZLM_SZE (OR: 7.343, 95%CI: 1.285-41.965) remained associated with PD-L1 expression. Conclusion NSCLC and adenocarcinoma with PD-L1 expression show higher tumour heterogeneity. Heterogeneity-related 18F-FDG PET and CT radiomic features showed good ability to non-invasively predict PD-L1 expression.
CRIS-Team WoS Importer:2022-07-29

Standardized Procedures for Patients with Dysplasia and Other Diseases of the Cervix, Vulva, and Vagina at a Certified Dysplasia Unit Prior to the Introduction of the Organized Cervical Cancer Screening Program. - Schulmeyer, Carla; Koch, Martin C.; Dietl, Anna; Stübs, Frederik; Behrens, Annika; Renner, Simone K.; Mehlhorn, Grit; Geppert, Carol-Immanuel; Hartmann, Arndt; Beckmann, Matthias; Gaß, Paul (Geburtshilfe und Frauenheilkunde, 2023)
Introduction Gynecologic dysplasia units and dysplasia consultations are obliged to offer diagnosis and treatment in accordance with the guidelines. The organization of the consultation process, management of patient appointments, diagnosis, and treatment algorithms are heterogeneous. The legislation arising from the new Federal Joint Committee decision, dated 22 November 2018, concerning the organized cervical cancer screening program has been in force since 1 January 2020. In this article we provide an overview of the existing structures and interdisciplinary cooperation of specialized dysplasia units incorporated in certified gynecologic cancer center. Materials and Methods We carried out a retrospective database search of data collected prospectively from 1 July 2014 to 31 December 2019 at the dysplasia unit at the Department of Gynecology and Obstetrics, Erlangen University Hospital, which was the first dysplasia unit to be certified in 2014. Results A total of 5594 patients presented at the unit, and 16061 colposcopic, vulvoscopic, and anoscopic examinations were performed. Approximately 4100 examinations of the cervix, vagina, vulva, and anus are carried out each year, 1600 of these were exclusively cervix colposcopies. A total of 12197 cytology results were assessed, as well as 4850 histology results, and 8193 high-risk HPV tests. The quality indicators required by the dysplasia unit for annual recertification were met each year. Conclusion Certified dysplasia units and consultations form the central component in the algorithm for further investigating abnormal screening results; but they are also the first point of contact for a large number of patients with acute or chronic complaints in the genital region.
EVALuna2:542837

STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis - Heichler, Christina; Scheibe, Kristina; Schmied, Anabel; Geppert, Carol-Immanuel; Schmid, Benjamin; Wirtz, Stefan; Thoma, Oana Maria; Kramer, Viktoria; Waldner, Maximilian; Büttner, Christian; Farin, Henner; Pešić, Marina; et al. (Gut, 2019)
Objective: Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood. Design: We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI-) on STAT3 activation (IL-6 vs IL-11). Results: The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts. Conclusion: Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.
CRIS-Team Scopus Importer:2019-11-19
Keywords: colorectal cancer

Status der Verfügbarkeit und Anwendung von „next generation sequencing“ (NGS) beim Harnblasenkarzinom – eine Umfrage in der Arbeitsgemeinschaft Uropathologie - Ortiz-Brüchle, N.; Muders, M.; Toma, M.; Esposito, I.; Hartmann, Arndt; Stöhr, Robert; Reis, H.; Wild, P.; Köllermann, J.; Bremmer, F.; Leichsenring, J.; Stenzinger, A.; et al. (Urologe, 2019)
Background: Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. Aim: Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. Methods: We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. Results: A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. Discussion: So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.
CRIS-Team Scopus Importer:2019-11-05
Keywords: Bladder cancer; Molecular pathology; Next generation sequencing; Precision oncology; Targeted treatment

Streptococcal toxic shock syndrome with associated necrotising fasciitis necessitating amputation of the lower extremity – A case report - Strecker, Thomas; Treutlein, Christoph; Agaimy, Abbas; Wehrfritz, Andreas (SAGE Open Medical Case Reports, 2023)
Streptococcal toxic shock syndrome is a severe, invasive and life-threatening infection associated with a high risk of rapid multiorgan failure. It is associated with high morbidity and mortality. Streptococcal toxic shock syndrome is very commonly caused by group A-Streptococcus pyogenes, ß-haemolytic streptococcus, a typical human-specific gram-positive bacterial pathogen. We present here the case report of a 54-year-old man with a rapidly progressive streptococcal toxic shock syndrome due to necrotising fasciitis of the left lower limb and describe the successful treatment through close interdisciplinary care.
CRIS-Team Scopus Importer:2023-10-27
Keywords: amputation; computer tomography; group A-Streptococcus pyogenes; necrotising fasciitis; Streptococcal toxic shock syndrome; β-haemolytic streptococcus

Strong expression of EZH2 and H3K27me3 is associated with poor survival time in small cell lung cancer - Fernandes, Ana Paula; Alves, Rita Decassia S.; Watte, Guilherme; Kunze, Philipp; Roehe, Adriana Vial; Schneider-Stock, Regine (CANCER RESEARCH, 2019)
CRIS-Team WoS Importer:2019-10-22

Style-Extracting Diffusion Models for Semi-supervised Histopathology Segmentation - Öttl, Mathias; Wilm, Frauke; Steenpaß, Jana; Qiu, Jingna; Rübner, Matthias; Hartmann, Arndt; Beckmann, Matthias; Fasching, Peter; Maier, Andreas; Erber, Ramona; Kainz, Bernhard; Breininger, Katharina (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 2025)
Deep learning-based image generation has seen significant advancements with diffusion models, notably improving the quality of generated images. Despite these developments, generating images with unseen characteristics beneficial for downstream tasks has received limited attention. To bridge this gap, we propose Style-Extracting Diffusion Models, featuring two conditioning mechanisms. Specifically, we utilize 1) a style conditioning mechanism which allows to inject style information of previously unseen images during image generation and 2) a content conditioning which can be targeted to a downstream task, e.g., layout for segmentation. We introduce a trainable style encoder to extract style information from images, and an aggregation block that merges style information from multiple style inputs. This architecture enables the generation of images with unseen styles in a zero-shot manner, by leveraging styles from unseen images, resulting in more diverse generations. In this work, we use the image layout as target condition and first show the capability of our method on a natural image dataset as a proof-of-concept. We further demonstrate its versatility in histopathology, where we combine prior knowledge about tissue composition and unannotated data to create diverse synthetic images with known layouts. This allows us to generate additional synthetic data to train a segmentation network in a semi-supervised fashion. We verify the added value of the generated images by showing improved segmentation results and lower performance variability between patients when synthetic images are included during segmentation training. The code of the method is publicly available at https://github.com/OettlM/STEDM.
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Subclassification, survival prediction and drug target analyses of chemotherapy-naïve muscle-invasive bladder cancer with a molecular screening - Rinaldetti, Sebastien; Rempel, Eugen; Worst, Thomas Stefan; Eckstein, Markus; Steidler, Annette; Weiss, Cleo Aaron; Bolenz, Christian; Hartmann, Arndt; Erben, Philipp (Oncotarget, 2018)
Background: Transcriptome expression studies identified distinct muscle invasive bladder cancer (MIBC) subtypes closely related with breast cancer subclasses. Here we developed a sensitive quantification method for MIBC subclassification (luminal, basal, p53-like). In addition, the subtype specific expression of drug targets has been investigated. Methods: Absolute quantification (nCounter) of a 64-gene panel was performed on MIBC patients (n=47) treated exclusively with radical cystectomy (RC). In conjunction of 170 MIBCs from 3 independent cohorts, a minimal set of consensus genes has been established. Survival of the consensus subtypes has been assessed by multivariate analysis. Relevant drug targets were tested for their subtype specificity in a clustering independent assessment. Results: A reduced 36-gene panel stably clustered into 3 subtypes throughout the cohorts (luminal, basal, infiltrated). Patients treated by RC only, showed worst 8-year disease specific survival (DSS) for the luminal subtype in contrast to the infiltrated subtype (17% vs. 73%, p=0.011). In multivariate analyses, the risk stratification based on luminal versus not-luminal MIBC proved to be an independent predictor for DSS superior to the TNM system in patients with RC. Drug targets (e.g. ERBB2, FGFR, AR, PDGFRB) showed a distinct subtype attribution. The subtypes based on this nCounter screening could further be validated by the TCGA cohort. Conclusion: This MIBC subtype screening predicted survival and allowed an analysis of subtype specific drug targets, thus being a powerful tool for the translation of personalized MIBC treatment concepts.
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Submandibular gland pleomorphic adenoma: Histopathological capsular characteristics and correlation with the surgical outcome - Mantsopoulos, Konstantinos; Goncalvesa, Miguel; Koch, Michael; Iro, Heinrich; Agaimy, Abbas (Annals of Diagnostic Pathology, 2018)
Pleomorphic adenoma (PA) of the submandibular gland is known to have a very low recurrence rate. The aim of this study was to investigate the histopathological and capsular characteristics of submandibular gland PA, looking for any differences between submandibular PA and the reported data for PA of the parotid gland as possible explanation for its low recurrence rate. We reviewed 72 submandibular gland PM resected at our center between 2000 and 2016. Patient age ranged from 14 to 77 years (mean, 47.2). At least follow (range, 12 to 170 months; mean, 82), none of the 72 patients developed a local recurrence. Histologically, all of the tumors were encased by a complete and intact anatomical capsule (100%). Pseudopodia were detected in 11 (15.3%) and satellite nodules in 3 (4.2%) cases. The histological subtype (according to Seifert et al.) was classic (mixed) in 39 (54.2%), stroma-rich/myxoid in 18/72 (25%) and cellular in 15 (20.8%) cases. A complete rim of healthy pericapsular tissue encasing the tumor and its capsule was observed in only 23/72 (31.9%) cases. In conclusion, submandibular PAs are characterized by consistent presence of an intact anatomical capsule, infrequent occurrence of pseudopodia, a remarkably infrequent occurrence lower frequency of secondary satellite tumor nodules and a comparatively lower proportion of the fragile risky myxoid subtype. Despite the fact that surgery of the submandibular gland can frequently lead to focal capsular exposure, the aforementioned capsular characteristics of submandibular gland PA are probably responsible for the excellent oncologic results.
EVALuna2:34875

Subtype specific expression and survival prediction of pivotal lncRNAs in muscle invasive bladder cancer - Rinaldetti, Sebastien; Worst, Thomas Stefan; Rempel, Eugen; Kriegmair, Maximilian C.; Hartmann, Arndt; Porubsky, Stefan; Bolenz, Christian; Erben, Philipp (Scientific Reports, 2020)
Comprehensive transcriptome expression analyses of bladder cancer revealed distinct lncRNA clusters with differential molecular and clinical characteristics. In this study, pivotal lncRNAs were assessed for their impact on survival and their differential expression between the molecular bladder cancer subtypes. FFPE samples from chemotherapy-naïve patients with muscle invasive bladder cancer (MIBC) were analyzed on the Nanostring nCounter platform for absolute quantification. An established 36-gene panel was used for molecular subtype classification into basal, luminal and infiltrated MIBC. In a second step, 14 pivotal lncRNAs were assessed for their molecular subtype attribution, and their predictive value in disease-specific survival. In silico validation was performed on a total of 487 MIBC patients (MDA, TGCA and Chungbuk cohort). Several pivotal lncRNAs showed a distinct molecular subtype attribution: e.g. MALAT1 showed a downregulation in the basal subtype (p = 0.009), TUG1 and CBR3AS1 showed an upregulation in the luminal subtype (p ≤ 0.001). High transcript levels of SNHG16, CBR3AS1 and H19 appeared to be predictive for a shorter disease-specific survival. Patients overexpressing putative oncogenes MALAT1 and TUG1 in MIBC tissue presented prolonged survival, suggesting tumor suppressive effects of both lncRNAs. The Nanostring nCounter proved to be a valid platform for the quantification of low-abundance transcripts including lncRNAs.
CRIS-Team Scopus Importer:2020-12-04

Successful BRAF/MEK inhibition in a patient with BRAFV600E-mutated extrapancreatic acinar cell carcinoma - Busch, Elena; Kreutzfeldt, Simon; Agaimy, Abbas; Mechtersheimer, Gunhild; Horak, Peter; Brors, Benedikt; Hutter, Barbara; Fröhlich, Martina; Uhrig, Sebastian; Mayer, Philipp; Schröck, Evelin; Stenzinger, Albrecht; et al. (Cold Spring Harbor Molecular Case Studies, 2020)
Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAFV600E-mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAFV600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
CRIS-Team Scopus Importer:2020-09-04
Keywords: neoplasm of the pancreas

Successful Long-term Treatment of Diversion Colitis with Topical Coconut Oil Application - Zundler, Sebastian; Dietz, Lisa; Matzel, Klaus E.; Geppert, Carol-Immanuel; Becker, Emily; Rath, Timo; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2018)
CRIS-Team WoS Importer:2019-02-22

Successful targeting of BRAF V600E mutation with vemurafenib in a treatment-resistant extragonadal non-seminomatous germ cell tumor - Meintker, Lisa; Haller, Florian; Tögel, Lars; Schmidt, Daniela; Waibel, Heidi; Mackensen, Andreas; Meidenbauer, Norbert (ONCOLOGY RESEARCH AND TREATMENT, 2019)
CRIS-Team WoS Importer:2020-10-02

Successful Targeting of BRAF V600E Mutation With Vemurafenib in a Treatment-Resistant Extragonadal Nonseminomatous Germ-Cell Tumor - Meintker, Lisa; Haller, Florian; Tögel, Lars; Schmidt, Daniela; Waibel, Heidi; Hartmann, Arndt; Mackensen, Andreas; Meidenbauer, Norbert (JCO Precision Oncology, 2020)

Successful Therapy of Crohn's Disease-Associated Pulmonary Necrobiotic Nodules on Ustekinumab Therapy - Ganzleben, Ingo; Hirschmann, Simon; Köhler, Juliane; Fuchs, Florian; Rieker, Ralf; Baer, Eva; Klenske, Entcho; Nagore, Daniel; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2020)
CRIS-Team Scopus Importer:2020-07-10

Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients - Gill, Anthony J.; Hes, Ondrej; Papathomas, Thomas; Sedivcova, Monika; Tan, Puay Hoon; Agaimy, Abbas; Andresen, Per Arne; Kedziora, Andrew; Clarkson, Adele; Toon, Christopher W.; Sioson, Loretta; Watson, Nicole; et al. (American Journal of Surgical Pathology, 2014)
Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.
EVALuna2:6664

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma - Agaimy, Abbas (Pathologe, 2016)
Succinate dehydrogenase (SDH) represents a type II mitochondrial complex related to the respiratory chain and Krebs cycle. The complex is composed of four major subunits, SDHA, SDHB, SDHC and SDHD. The oncogenic role of this enzyme complex has only recently been recognized and the complex is currently considered an important oncogenic signaling pathway with tumor suppressor properties. In addition to the familial paraganglioma syndromes (types 1-5) as prototypical SDH-related diseases, many other tumors have been defined as SDH-deficient, in particular a subset of gastrointestinal stromal tumors (GIST), rare hypophyseal adenomas, a subset of pancreatic neuroendocrine neoplasms (recently added) and a variety of other tumor entities, the latter mainly described as rare case reports. As a central core subunit responsible for the integrity of the SDH complex, the expression of SDHB is lost in all SDH-deficient neoplasms irrespective of the specific SDH subunit affected by a genetic mutation in addition to concurrent loss of the subunit specifically affected by genetic alteration. Accordingly, all SDH-deficient neoplasms are by definition SDHB-deficient. The SDH-deficient renal cell carcinoma (RCC) has only recently been well-characterized and it is included as a specific subtype of RCC in the new World Health Organization (WHO) classification published in 2016. In this review, the major clinicopathological, immunohistochemical and genetic features of this rare disease entity are presented and discussed in the context of the broad differential diagnosis.
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SUNNIFORECAST - A phase II study of Nivolumab in combination with Ipilimumab versus Standard of care in advanced or metastatic non-clear cell renal cell carcinoma - Scheich, S.; Ahrens, M.; Goekbuget, N.; Boleti, E.; Burkholder,; Escudier, B. J.; Goebell, Peter; Gruenwald,; Gschwend, J.; Retz, M.; Hartmann, Arndt; Maroto Rey, J. P.; et al. (2018)
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