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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., (© 2021 The Pathological Society of Great Britain and Ireland.)

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.

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.

Background: A significant number of ovarian borderline tumors (BOTs) and metastatic nonovarian primaries are erroneously diagnosed as ovarian carcinomas. If BOTs are misdiagnosed as cancer, patients may not only experience nonbeneficial morbidity but may have to cope with an incorrect diagnosis of cancer for the rest of their lives. In cases of metastatic disease mistaken for an ovarian primary, more adequate therapeutic modalities may be withheld from some patients. Finally, clinical trials may be biased through unintended disregard of histological inclusion criteria., Methods: Patients were recruited for central pathology review according to a translational subprotocol of a prospectively randomized phase 3 study led by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group. All original slides were requested, and a specialized central pathology review was performed by experienced gynecopathologists. In cases of clinically relevant diagnostic discrepancies, the pathologist responsible for the original diagnosis was contacted. If a given discrepancy could not be resolved, a panel of experts was involved for clarification., Results: Four hundred fifty-four patients with an original diagnosis of ovarian, tubal, or peritoneal epithelial carcinoma were recruited. In 6.8% (31 patients), a major diagnostic discrepancy of clinical relevance was found. Most frequently (15 patients), serous BOT had been misdiagnosed as invasive cancer. Ovarian metastases constituted the second most frequent misdiagnosis (13 patients). Minor discrepancies not affecting patient treatment were found in 28.2% (128 patients)., Conclusions: Specialized central pathology review could help to avoid overtreatment of patients with BOT and inappropriate treatment of patients with ovarian metastases. The implementation of a specialized case review process may translate into enhanced patient safety in clinical trials of ovarian carcinomas. Furthermore, central pathology review may increase the rigor and ultimately the transferability of clinical research into practice and should therefore become a standard procedure in study protocols evaluating new therapies.

Despite considerable success in the treatment of epithelial ovarian cancer (EOC), therapy resistance counteracts improvement of long-term survival. The dual role of survivin as an apoptosis inhibitor and mitotic regulator has been associated with disease outcome. However, the molecular mechanisms involved in the deregulated expression in EOC of survivin need further investigation. Here, we show that high amounts of the nitric oxide (NO) donors, S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) or strong overexpression of the inducible nitric oxide synthase (iNOS) suppressed survivin levels via the p38MAPK pathway and triggered apoptosis in ovarian cancer cell lines (OCC). Importantly, low NO concentrations conferred resistance against carboplatin/paclitaxel-induced apoptosis. Cytoprotection was mediated by survivin because we observed its up-regulation subsequent to low SNAP/SNP doses or ectopic expression of low amounts of iNOS. Also, RNAi-mediated depletion of survivin blocked the antiapoptotic effects of NO signaling. Induction of survivin involves activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, which was antagonized by the PI3K-inhibitor, LY294002. Interestingly, application of the iNOS-inhibitor 1400W together with RNAi-mediated survivin down-regulation cooperatively enhanced drug-induced apoptosis in OCCs. The iNOS/survivin interdependencies seem to be also of clinical relevance because immunohistochemistry revealed that low iNOS levels correlate with survivin expression (P < 0.01) in carboplatin/paclitaxel-treated EOC patients with minimal postoperative residual tumor (n = 54). Also, iNOS and survivin expression were associated with increased risk for disease progression. Our study uncovers a novel molecular mechanism of how NO signaling may contribute to therapy resistance in EOC by modulating survivin expression. Pharmacogenetic iNOS/survivin-targeting strategies may hence be pursued to complement current treatment modalities in EOC.

Anaplastic carcinoma of the thyroid gland (ACT) is a rapidly growing neoplasm with a very poor prognosis. In this study, we examined an ACT with osteoclast-like giant cells expressing matrix--degrading cysteine proteinases and their endogeneous inhibitor cystatin C. Bronchoscopic evaluation of a 50-year-old man suffering from hoarseness, dysphagia, and dyspnea revealed an irregular tumor mass infiltrating into the trachea and the cricothyroid ligament region. On histological examination, a necrotizing undifferentiated anaplastic carcinoma with osteoclast-like giant cells was detected. An immunohistochemical study of the tumor tissue was performed using a panel of 15 antibodies, including double labeling techniques. Most of the osteoclast-like multinucleated giant cells (MGC) expressed CD68 and cathepsin K. Colocalization of cathepsin B and its endogenous inhibitor cystatin C occurred in the majority of MGC. Mononuclear cells (MC) were positive for cathepsin B, cystatin C, and CD 68, but only faintly for cathepsin K. Expression of cathepsins B and K in the MGC of the ACT might contribute to the invasive behavior of this tumor, thus promoting metastatic ability and destruction of the cartilagenous trachea.

We present an occult metastatic signet-ring cell gallbladder carcinoma in a 78-year-old woman, who complained of recurrent headaches, dysarthria, and paresis of the tongue. Cranial imaging showed contrast enhancement of the basal leptomeninges, and the cerebrospinal fluid displayed clusters of adenocarcinoma cells proposed as leptomeningeal carcinomatosis of the breast, lung or gut. However, postmortem examination revealed the gallbladder as the site of the primary carcinoma with focal signet-ring cell differentiation. In patients with progressive neurologic deterioration due to leptomeningeal carcinomatosis, adenocarcinomas from the gastrointestinal and hepatic systems should be considered. It is likely that signet-ring cell carcinomas display an increased affinity to leptomeningeal spread.

A group of 241 nonpretreated breast carcinomas was studied for estrogen receptor (ER) and progesterone receptor (PR) content by both immunocytochemistry (ICC) and biochemical analysis (dextran-coated charcoal [DCC]). While the tumors were judged to be ER positive in 67.6% and PR positive in 65.6% by ICC, DCC analysis showed positive results in 77.6% for both ER and PR. There was only a moderate correlation between the semiquantitative results of ER and PR ICC and the corresponding values for DCC receptor determination. Among tumors shown to be steroid receptor positive by ICC, a majority showed a wide spectrum of staining intensity, from negative to intensely positive (type C staining pattern, ER 87.7%, PR 73.4%). Less frequently, carcinomas showing uniform, intense staining of all epithelial tumor cells were observed (type A staining pattern, ER 11.7%, PR 18.4%). Finally, only very few tumors had both clearly negative and distinctly positive cells (type B staining pattern, ER 0.6%, PR 8.2%). On analyzing the relationship between the expression of steroid receptors (ICC and DCC) and the prognostic factors axillary node status, tumor size, tumor histology, grade and patient age, only a significant correlation between patient age and ER (ICC, r = .46; DCC, r = .43), a weakly significant negative correlation between node involvement and ER, and a weakly significant negative correlation between tumor grade and ER (ICC only) as well as between tumor grade and PR were found. Among all patients, the recurrence-free interval was significantly longer in patients with ER- or PR-positive carcinomas (ICC and DCC).(ABSTRACT TRUNCATED AT 250 WORDS)

This study reports the structure and expression rates of genes of the transforming growth factor-alpha (TGF-alpha) signal transduction pathway (TGF-alpha, epidermal growth factor receptor [EGF-R], jun, myc, and metallothionein [MT]) in 47 specimens of ovarian cancer and 21 nonmalignant tissues. The objective was to establish a direct correlation between the genetic activities and the malignant phenotype of the ovarian cancer. The Southern blot technique identified four samples with myc amplification and two with rearranged EGF-R genes. By using the S1 nuclease assay, the analysis of myc transcription showed a similar use of both promotors. Although the size of the investigated transcripts was unaltered, significant differences in the transcription rates were noticed in malignant tissue probes (using northern blot analysis and RNAase protection assay). The following results of messenger RNA analysis in ovarian cancer were observed: EGF-R, negative in 25%, low in 65%, and strongly positive in 10%; TGF-alpha, negative in 34%, low in 36%, and strongly positive in 30%; myc, negative in 8%, low in 64%, and strongly positive in 28%; jun, negative in 4%, low in 58%, and strong in 38%; and MT, low in 80% and strongly positive in 20%. In most nonmalignant tissues studied, no or only a low expression of TGF-alpha, EGF-R, and myc. was found. A comparison of these messenger RNA results with the clinical data from tumors showed four different subgroups of ovarian carcinomas. The results of chemotherapy were known in 32 cases. Tumors with negative or low expression rates of all investigated genes did not respond to chemotherapy; 13 of 18 tumors with high expression rates did respond. Additional signal transduction chains distinct from the TGF-alpha pathway, however, are likely to influence both the expression and activity of transcription factors and MT.

87 nonpretreated stage III/IV ovarian common epithelial carcinomas were studied for estrogen receptor (ER) and progesterone receptor (PR) content by both immunohistochemistry (IHC) and biochemical (DCC) analysis. While the DCC assay showed tumors to be receptor-positive in 62% (ER) and 66% (PR), receptor-positive malignant epithelial cells were only detected in 38% (ER) and 31% (PR) by IHC. There was only a low correlation between the semiquantitative results of ER and PR IHC and the corresponding values of DCC receptor determination. The finding of steroid receptor-positive stromal cells without any evidence of hormone receptor-positive epithelial tumor cells offers a possible explanation for discrepant results in numerous cases with obviously "false positive" results of DCC analysis. Since the considerable heterogeneity of steroid receptor expression present in many ovarian neoplasms can only be detected by IHC, it seems to be the appropriate method of ER and PR determination. Most patients were treated by both radical cytoreductive surgery (n = 76) and a platinum-based chemotherapy (n = 79). ER was not shown to be of significant prognostic value. However, survival was significantly better in patients with PR positive tumors (IHC and DCC) on univariate analysis. Residual tumor after primary surgery was the only remaining significant prognostic factor after multivariate analysis. Further studies are needed to clarify the biological function of steroid receptor-positive stromal cells in ovarian carcinomas.

The varying tumorbiological behaviour of ovarian carcinomas probably influences operability, response to chemotherapy, being one of the most relevant prognostic factors. Because it is believed that an activation of the epidermal growth factor/transforming growth factor alpha (EGF/TGF alpha) signal pathway could be involved, we analysed the expression of epidermal growth factor receptor (EGFR) and TGF alpha with molecular-chemical, biochemical and immunohistochemical methods in 42 ovarian carcinomas, 4 ovarian metastasis, 2 other malignant ovarian tumours, and in 25 nonmalignant tissues (ovary, myometrium). No major rearrangements or amplification of the EGFR or TGF alpha genes were found. In non-malignant tissues no strong EGFR or TGF alpha signals were detected. TGF alpha is mainly produced by the tumour cells as shown by immunohistochemistry. Four different high molecular weight forms (20-48 kD) were detected in malignant tissues by western blot analysis.

An increasing body of evidence suggests that breast tumour growth is mediated by oncogene products and growth factors which are or which act through cell surface receptors. The aims of the present study were to determine how three of these receptors, c-erbB-2 protein, epidermal growth factor receptor (EGFr) and the beta-subunit of platelet-derived growth factor receptor (PDGFr-beta-subunit), can effectively be demonstrated by immunohistochemical methods in breast tumors, how these receptors are distributed at the cellular level and how their expression correlates with well-established prognostic indicators including hormone receptors and proliferative index. We examined frozen tissue sections of 50 invasive human breast carcinomas, including 45 ductal, four lobular, and one mucinous tumours, by immunocytochemical methods to determine the in situ distributions of c-erbB-2, EGFr, and PDGFr-beta-subunit. We compared staining for c-erbB-2 protein in frozen sections with that in paraffin sections of the same 50 tumours. The immunohistochemical labelling results were compared with tissue hormone receptor content and growth fraction determined by Ki-67 labelling. Strong labelling of tumour cells in frozen sections was detected in 22% of cases, all of the ductal type, stained with rabbit antiserum to c-erbB-2. Labelling for c-erbB-2 protein was generally weaker in paraffin sections than in frozen sections and in six of 11 positive cases, specific staining could be detected only in frozen sections. In immunostains with monoclonal antibody to EGFr, rare cells within tumour were labelled in 60% of the carcinomas. Using a monoclonal antibody to the beta-subunit of PDGFr, consistent labelling of fibrillary cellular processes in the walls of blood vessels and in fibrous stroma around tumour cell nests was detected, but there was no labelling of tumour cells themselves. C-erbB-2 oncoprotein positive tumours were found to be more often oestrogen receptor negative (P less than 0.005) or oestrogen and progesterone receptor negative (P less than 0.01) than c-erbB-2 negative tumours. No significant correlation was observed between c-erbB-2 expression and Ki-67 growth fraction.

A granular cell tumor of the breast in a 20-year-old black pregnant woman is reported. Malignancy had been suspected clinically, radiologically, and on gross pathologic examination. Frozen section provided the correct diagnosis and the lesion was excised, obviating more radical surgery.