Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

Spindle Cell Sarcoma of the Uterine Corpus With Adipose Metaplasia: Expanding the Morphologic Spectrum of Neoplasms With MEIS1-NCOA2 Gene Fusion.

We report a spindle cell sarcoma arising in the uterine corpus of a 26-yr-old patient. The patient underwent a simple hysterectomy and the uterine corpus contained a 9 cm tumor showing nodular and "finger-like" myometrial invasion. Histologically, the tumor was composed of a monomorphic population of atypical spindle cells which contained widespread foci of cytologically benign adipocytes. Immunohistochemistry revealed diffuse strong positivity for CD10, CD56, and CD99 and diffuse weak positive staining with ER and WT1 while smooth muscle markers, S100, TLE1, and cyclin D1 were negative. Total RNA sequencing identified an in-frame fusion between exon 6 of MEIS1 and exon 12 of NCOA2. Copy number analysis revealed few aberrations with no deletions or amplifications identified. No adjuvant therapy was given and the patient is disease-free 9 yr after initial diagnosis. This case represents the second report of a uterine sarcoma harboring a MEIS1-NCOA2/1 gene fusion and expands the morphologic spectrum of recently reported spindle cell sarcomas arising in the genitourinary tract harboring MEIS1-NCOA2/1 gene fusions. This is the first reported case of such tumors with an adipocytic component.

Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup.

Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations. Interestingly, only rare cases of extrauterine DICER1-associated ERMS, mostly located in the genitourinary tract, have been reported to date. Our goal was to study clinicopathologic and molecular profiles of DICER1-mutant (DICER1-mut) and DICER1-wild type (DICER1-wt) ERMS in a cohort of genitourinary tumors. We collected a cohort of 17 ERMS including nine uterine (four uterine corpus and five cervix), one vaginal, and seven urinary tract tumors. DNA sequencing revealed mutations of DICER1 in 9/9 uterine ERMS. All other ERMS of our cohort were DICER1-wt. The median age at diagnosis of patients with DICER1-mut and DICER1-wt ERMS was 36 years and 5 years, respectively. Limited follow-up data (available for 15/17 patients) suggested that DICER1-mut ERMS might show a less aggressive clinical course than DICER1-wt ERMS. Histological features only observed in DICER1-mut ERMS were cartilaginous nodules (6/9 DICER1-mut ERMS), in one case accompanied by foci of ossification. Recurrent mutations identified in both DICER1-mut and DICER1-wt ERMS affected KRAS, NRAS, and TP53. Copy number analysis revealed similar structural variations with frequent gains on chromosomes 2, 3, and 8, independent of DICER1 mutation status. Unsupervised hierarchical clustering of array-based whole-genome DNA methylation data of our study cohort together with an extended methylation data set including different RMS subtypes from genitourinary and extra-genitourinary locations (n = 102), revealed a distinct cluster for DICER1-mut ERMS. Such tumors clearly segregated from the clusters of DICER1-wt ERMS, alveolar RMS, and MYOD1-mutant spindle cell and sclerosing RMS. Only one tumor, previously diagnosed as ERMS arising in the maxilla of a 6-year-old boy clustered with DICER1-mut ERMS of the uterus. Subsequent sequencing analysis identified two DICER1 mutations in the latter case. Our results suggest that DICER1-mut ERMS might qualify as a distinct subtype in future classifications of RMS.

Single cell transcriptomes of normal endometrial derived organoids uncover novel cell type markers and cryptic differentiation of primary tumours.

Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of secretory cells (MPST) and several markers of ciliated cells (FAM92B, WDR16, and DYDC2) were validated by immunohistochemistry on organoids and tissue sections. We performed single cell sequencing on endometrial and ovarian tumours and found both secretory-like and ciliated-like tumour cells. We found that ciliated cell markers (DYDC2, CTH, FOXJ1, and p73) and the secretory cell marker MPST were expressed in endometrial tumours and positively correlated with disease-specific and overall survival of endometrial cancer patients. These findings suggest that expression of differentiation markers in tumours correlates with less aggressive disease, as would be expected for tumours that retain differentiation capacity, albeit cryptic in the case of ciliated cells. These markers could be used to improve the risk stratification of endometrial cancer patients, thereby improving their management. We further assessed whether consideration of MPST expression could refine the ProMiSE molecular classification system for endometrial tumours. We found that higher expression levels of MPST could be used to refine stratification of three of the four ProMiSE molecular subgroups, and that any level of MPST expression was able to significantly refine risk stratification of the copy number high subgroup which has the worst prognosis. Taken together, this shows that single cell sequencing of putative cells of origin has the potential to uncover novel biomarkers that could be used to guide management of cancers. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fertility-sparing surgery and reproductive-outcomes in patients with borderline ovarian tumors.

BACKGROUND: Borderline ovarian tumors (BOT) are considered a biological category with increased epithelial proliferation and cellular atypia in the absence of invasive growth. Since BOT occur often in young patients fertility sparing surgery (FSS) is an important issue. With this study we aimed to evaluate risk factors for relapses and fertility of patients after FSS. METHODS: Patients diagnosed with BOT and treated between 2000 and 2018 were included. External pathological review was done in all patients. FSS was performed after individual discussion and a complete surgical staging according to FIGO, without lymphadenectomy and with a waiver for preservation of uterus and one ovary. RESULTS: Among 352 Patients 80.2% had FIGO I and 63.9% had a serous BOT. Eighteen patients (5.1%) relapsed and 4 cases of malignant transformation were reported (1.1%). One patient of the latter died, all others have no evidence of disease. The overall recurrence-rate was 1.1% in FIGO-Stage I and 25.5% in FIGO III-IV (HR = 27; 95%-CI 7.7-95; p ≤.001). 95 patients underwent FSS. Thirteen (13.7%) of these patients relapsed, all as BOT. In multivariate analysis FIGO stages II-IV (HR = 27; 95%-CI: 8.1-102; p ≤.001) and FSS (HR = 12; 95%-CI: 2.9-47; p = .001) remained significant risk factors for recurrent disease. Pregnancy rate among forty-one patients attempting to conceive was 82.9%. 29 patients experienced at least one life-birth, in total 38 life-births were reported. CONCLUSION: FSS in stage I is a safe procedure and life-birth-rates after FSS are high. More advanced FIGO stages have to be discussed individually and relapse rates have to be weighed against FSS. A central review of pathology, as we performed routinely, is mandatory and may have contributed to our low rate of invasive relapses.

Correction: TERT promoter mutation in adult granulosa cell tumor of the ovary.

The original version of this Article omitted the author Hannah van Meurs from the Department of Gynecology, Center for Gynecologic Oncology Amsterdam, Academic Medical Center, 1100 DD Amsterdam, The Netherlands. This has been corrected in both the PDF and HTML versions of the article.

Tubo-Ovarian Transitional Cell Carcinoma and High-grade Serous Carcinoma Show Subtly Different Immunohistochemistry Profiles.

Tubo-ovarian transitional cell carcinoma (TCC) is grouped with high-grade serous carcinoma (HGSC) in the current World Health Organization classification. TCC is associated with BRCA mutations and a better prognosis compared with HGSC. Previous papers examining the immunohistochemical features of TCC have studied limited numbers of samples. No marker reflecting the biological difference between TCC and HGSC is known. We collected a large cohort of TCC to determine whether TCC and HGSC could be distinguished by immunohistochemistry. A tissue microarray was built from 89 TCC and a control cohort of 232 conventional HGSC. Immunohistochemistry was performed, scored, and statistically analyzed for routine markers of HGSC and urothelial tumors: PAX8, WT1, p53, p16, ER, p63, and GATA3. Using scoring cutoffs commonly employed in clinical practice, the immunohistochemical profile of TCC was indistinguishable from HGSC for all markers. However, more detailed scoring criteria revealed statistically significant differences between the 2 groups of tumors with respect to ER, PAX8, and WT1. HGSC showed more diffuse and intense staining for PAX8 (P=0.004 and 0.001, respectively) and WT1 (P=0.002 and 0.002, respectively); conversely, TCC showed more intense staining for ER (P=0.007). TCC and HGSC therefore show subtle differences in their immunohistochemical profiles which might reflect underlying (epi)genetic differences. Further studies using proteomic analysis will focus on the identification of differentially expressed proteins that might serve as markers of TCC-like differentiation, which could help explain biologic differences between TCC and HGSC and might identify other cases of HGSC with a better prognosis.

L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile.

BACKGROUND: The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort. METHODS: ProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated. RESULTS: Expression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035). CONCLUSION: L1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.

Extrauterine high-grade serous carcinomas with bilateral adnexal involvement as the only two disease sites are clonal based on tp53 sequencing results: implications for biology, classification, and staging.

A previous multicenter study of 67 cases of Stage I/II tubo-ovarian high-grade serous carcinoma with complete tubal sampling identified 7 cases in which there were only two disease sites, comprising tumor involving opposite adnexa with no extra-adnexal involvement. This study aimed to determine whether such low-stage extrauterine high-grade serous carcinomas with only two sites of involvement, located on opposite adnexa, have identical or different TP53 mutations in order to investigate their clonal relationship. DNA extracted from both sites of involvement was subjected to TP53 sequencing (n=6) or sequencing of one site and mutation confirmation by droplet digital PCR for the other site (n=1). Of the 7 cases analyzed, 1 case had unilateral serous tubal intraepithelial carcinoma with contralateral ovarian high-grade serous carcinoma, 3 had tubal high-grade serous carcinomas (±serous tubal intraepithelial carcinoma) with contralateral ovarian high-grade serous carcinoma, 2 had bilateral ovarian high-grade serous carcinomas with normal tubes, and 1 had bilateral fallopian tube high-grade serous carcinoma with normal ovaries. All 7 cases showed identical TP53 mutations in tumor from both disease sites. Therefore, these rare cases of high-grade serous carcinoma confined to opposite adnexa all show clonal identity between the two sites of involvement, suggesting unifocal origin and metastasis rather than multifocal origin. Our results suggest that serous tubal intraepithelial carcinoma or adnexal high-grade serous carcinoma can metastasize to the contralateral adnexa without peritoneal involvement. Given the clonal relationship between the two sites, such cases should be considered stage II, with stage I reserved for cases with unilateral and unifocal adnexal involvement. Furthermore, serous tubal intraepithelial carcinoma without invasion should be taken to constitute a disease site for staging purposes.

TERT promoter mutation in adult granulosa cell tumor of the ovary.

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERT promoter have increased expression of TERT mRNA and exhibited significantly longer telomeres compared to those with wild-type TERT promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log-rank test). In seven adult granulosa cell tumors, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERT C228T promoter mutations may have an important role in progression of adult granulosa cell tumors.

DICER1 hot-spot mutations in ovarian gynandroblastoma.

AIMS: Gynandroblastoma is a rare ovarian sex cord-stromal tumour characterised by the presence of both male (Sertoli and/or Leydig cells) and female (granulosa cells) components. We investigated the mutational status of DICER1, FOXL2 and AKT1 genes at hot-spot regions that are known to be the key driving events in the development of Sertoli-Leydig cell tumour (SLCT), adult granulosa cell tumour (aGCT) and juvenile granulosa cell tumour (jGCT), respectively, to gain insights into the molecular pathogenesis of gynandroblastoma. METHODS AND RESULTS: Sixteen cases of gynandroblastoma were studied. All contained SLCT or Sertoli cell tumour components. aGCT and jGCT components were identified in seven and 10 cases, respectively, with one presenting both components. Heterozygous hot-spot mutations in the RNase IIIb domain of DICER1 were discovered in three cases, including one case with heterologous mucinous elements, all of which were composed of moderately or poorly differentiated SLCT and jGCT components, and harboured the mutations in both histological components. None of the 16 cases displayed mutations at the p.C134W (c.402C→G) of FOXL2 or within the pleckstrin-homology domain of AKT1. All cases showed FOXL2 immunostaining in both male and female components. CONCLUSION: DICER1 hot-spot mutation is the key-driving event in a subset of gynandroblastomas containing components of SLCT and jGCT. Gynandroblastomas composed of SLCT and jGCT may represent morphological variants of SLCT. The molecular basis of gynandroblastoma containing a component of aGCT is different from pure aGCT.

Disease Distribution in Low-stage Tubo-ovarian High-grade Serous Carcinoma (HGSC): Implications for Assigning Primary Site and FIGO Stage.

The latest FIGO and TNM (eighth edition) staging systems for ovarian, tubal, and peritoneal neoplasms require primary site assignment as tubal/ovarian/peritoneal, but provide no guidance or criteria. Fewer than 10% of extrauterine high-grade serous carcinoma (HGSC) cases present at low stage (stage I/II). Low-stage cases offer a unique opportunity to understand the pattern of disease early in its evolution prior to wide dissemination and provide valuable evidence for guiding specimen handling and tumor staging. This study aimed to examine disease distribution in low-stage tubo-ovarian HGSC. Anonymized pathology reports of 152 stage I/II extrauterine HGSCs from 6 teaching hospitals were analyzed: group 1 (n=67) comprised cases with complete tubal examination by Sectioning and Extensively Examining the FIMbriated end of the tube (SEE-FIM) and group 2 (n=85) consisted of cases without documentation of both tubes being fully examined by the SEE-FIM or a SEE-FIM-like protocol. The stage, site/pattern of involvement, site/size of largest tumor focus and laterality of tubal and ovarian involvement were recorded. Tubal mucosal involvement was present in 95% of optimally examined cases and many factors influenced detection of tubal disease. Bilateral involvement, suggestive of metastasis, was significantly more frequent in the ovaries (35%) than the tubes (9%) (P<0.0001, Fisher exact test). No case showed a complete absence of tubal/ovarian involvement, questioning the biological existence of primary peritoneal HGSC. Disease distribution in low-stage cases supports a tubal origin for most HGSCs. Detailed tubal sampling upstages some apparent stage I cases through detection of microscopic tubal involvement.

The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumour samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry, with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis, and neuron-like differentiation. EZH2 inhibitors suppressed tumour growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.

Second Opinion Expert Pathology in Endometrial Cancer: Potential Clinical Implications.

OBJECTIVE: In cancer patients, the pathology report serves as an important basis for treatment. Therefore, a correct cancer diagnosis is crucial, and diagnostic discrepancies may be of clinical relevance. It was the aim of this study to perform a specialized histopathology review and to investigate potential clinical implications of expert second opinion pathology in endometrial cancer. METHODS: Patients treated for endometrial carcinoma at the Tübingen University Women's hospital between 2003 and 2013 were identified. Original pathology reports were reviewed, and contributing pathologists were asked to submit original slides and paraffin blocks. Case review was subsequently performed by 3 pathologists specialized in gynecological pathology who were blinded for clinical information. For histological typing, the World Health Organization 2014 classification was used, grading and staging were performed according to International Federation of Gynecology and Obstetrics 2009. Risk assignment was performed based on the 2013 European Society for Medical Oncology clinical practice guidelines. RESULTS: In 565 of 745 cases, which had originally been diagnosed as endometrial carcinoma, archival histological slides and blocks were available. In 55 (9.7%) of 565 cases, a major diagnostic discrepancy of potential clinical relevance was found after expert review. In 38 of these 55 cases, the diagnostic discrepancy was related to tumor type (n = 24), grade (n = 10) or myoinvasion (n = 4). In 17 cases, the diagnosis of endometrial carcinoma could not be confirmed (atypical hyperplasia, n = 10; endometrial carcinosarcoma, n = 4; neuroendocrine carcinoma, n = 1; leiomyosarcoma, n = 1; atypical polypoid adenomyoma, n = 1). Minor discrepancies not changing risk classification were also noted in 214 (37.9%) of 565, most frequently for grade within the low-grade (G1/G2) category (n = 184). CONCLUSIONS: A retrospective gynecopathological case review was shown to reveal limited but significant discrepancies in histological diagnoses as well as typing and grading of endometrial carcinomas, some directly impacting clinical management. Second opinion pathology therefore not only helps to improve the quality of translational research study cohorts but might also help to optimize patient care in difficult cases.

Pathology of Ovarian Cancer: Recent Insights Unveiling Opportunities in Prevention.

Ovarian carcinomas were formerly referred to as "surface epithelial carcinomas," reflecting the belief that they all arise from the ovarian surface epithelium. It is now appreciated that most ovarian carcinomas originate from either fallopian tube or endometriotic epithelium, and how we approach prevention will thus differ between histotypes. The 5 histotypes of ovarian carcinoma (high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous, in descending order of frequency) can be reproducibly diagnosed, and are distinct disease entities, differing with respect to genetic risk factors, molecular events during oncogenesis, patterns of spread, and response to chemotherapy.

Ovarian carcinoma diagnosis: the clinical impact of 15 years of change.

BACKGROUND: Until recently ovarian carcinoma was considered to be a single disease, and treatment decisions were based solely on grade and pre- and postoperative tumour burden. New insights into molecular features, treatment response, and patient demographics led the scientific community to conclude that ovarian carcinoma histotypes are different disease entities. METHODS: In 2002, the pathology specimens from patients in a clinical trial were reviewed by an experienced gynaecopathologist (pathologist A) for translational research purposes. All cases were typed according to what were then current criteria. The identical cohort was now reassessed by the same expert pathologist and independently reviewed by another gynaecopathologist (pathologist B) applying WHO 2014 diagnostic criteria. Survival analyses were done based on the original as well as the new diagnoses, and historical biomarker study results were recalculated. RESULTS: Upon re-review, pathologist A rendered the same histotype diagnosis in only 54% of cases. In contrast, pathologists A and B independently rendered the same diagnosis in 98% of cases. Histotype was of prognostic significance when 2014 diagnoses were used, but was not prognostic using the original (2002) histotype diagnoses. CONCLUSIONS: Our study demonstrates a marked shift in ovarian carcinoma histotype diagnosis over the past 15 years. The new criteria are associated with a very high degree of interobserver reproducibility, allowing for treatment decisions based on histotype. Finally, biomarkers of putative prognostic significance were revealed to be primarily histotype-specific markers, confirming the critical importance of obtaining up-to-date diagnoses rather than accepting archival histotype data in clinical research.

The Value of Serum CA125 in the Diagnosis of Borderline Tumors of the Ovary: A Subanalysis of the Prospective Multicenter ROBOT Study.

OBJECTIVE: The value of the serum tumor marker CA125 in borderline tumors of the ovary (BOTs) is not well defined, with unclear benefit in both diagnosis and follow-up. The aim of the present project was to identify the predictive value of CA125 for stage and relapse. METHODS: CA125 data were extracted from the ROBOT multicenter study of patients with BOT treated between 1998 and 2008 in 24 German centers. While patients' data were retrieved retrospectively from hospital records and clinical tumor registries, follow-up and independent central pathology review were performed prospectively. RESULTS: We identified 127 patients from the ROBOT database fulfilling the eligibility criterion of available CA125 at initial diagnosis. Eighty-three (65.3%) patients had increased CA125 levels (>35 U/L). Of the patients, 85.0% presented with serous and 13.4% with mucinous BOT histology, whereas 29.9% had stage I disease. Fifteen (11.8%) patients experienced a relapse. Multivariate analysis identified raised CA125, young age, and serous histology as independent predictors of peritoneal implants of any type at initial presentation. Raised CA125 at initial diagnosis was, however, not an independent predictor of future relapse. DISCUSSION: Elevated CA125 seems to be associated with the presence of peritoneal implants of any type at initial diagnosis of serous BOT, but failed to have any independent predictive value on future relapse. Prospective multicenter studies are warranted to evaluate CA125 measurements in the follow-up management of BOT.

Comparison of molecular abnormalities in vulvar and vaginal melanomas.

Malignant melanoma of the vulva and vagina is relatively uncommon and accounts for <5% of all melanomas in women. The aim of our study was to establish the biological properties and evaluate potential therapeutic targets in these tumors. We collected a series of 65 cases from three centers and re-evaluated the tumor tissue for predominant growth pattern (superficial spreading, nodular, and mucosal lentiginous) and tumor thickness. KIT (CD117) expression was detected immunohistochemically. In addition, tumors were screened for BRAF, NRAS, and KIT mutations by PCR and DNA sequencing as well as for KIT amplifications by fluorescence in situ hybridization. None of the cases contained BRAF mutations. NRAS mutations and KIT amplifications were detected in similar frequency (∼12%) in tumors of the vulva and vagina. In contrast, KIT mutations were present in 18% of primary melanomas of the vulva, but in none of the tumors arising in the vagina. Moderate or strong KIT protein expression was detected in 30 cases, including all tumors with KIT mutations and 6 of the 7 with KIT amplifications. In conclusion, BRAF mutations are virtually absent in melanomas originating from the vulva or vagina, whereas NRAS mutations and KIT amplifications occur in both locations. KIT mutations appear to be specific for melanomas of the vulva, suggesting that in spite of the anatomic proximity, the development of vulvar and vaginal melanomas involves different molecular alterations which may be targeted by novel treatment approaches.