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Digital pathology (DP) has emerged as a cutting‐edge technology that promises to revolutionise diagnostics in clinical laboratories. This perspective article explores the implementation planning and considerations of DP in a single multicentre institution in Canada, the University Health Network, discussing benefits, challenges, potential implications and considerations for future adopters. We examine the transition from traditional microscopy to digital slide scanning and its impact on pathology practice, patient care and medical research. Furthermore, we address the regulatory, infrastructure and change management considerations for successful integration into clinical laboratories. By highlighting the advantages and addressing concerns, we aim to shed light on the transformative potential of DP and its role in shaping the future of diagnostics. [ABSTRACT FROM AUTHOR]

Background: Testing for BRCA1/2 gene alterations in patients with high‐grade serous carcinoma (HGSC) is a critical determinant of treatment eligibility for poly(adenosine diphosphate‐ribose) polymerase inhibitors in addition to providing vital information for genetic counselling. Many patients present with effusions necessitating therapeutic drainage, and this makes cytologic specimens (CySs) the initial diagnostic material for HGSC, often before histologic sampling. Initiating somatic BRCA testing on a CyS allows the BRCA status to be determined sooner, and this affects clinical management. Methods: Retrospectively, 8 cases of formalin‐fixed, paraffin‐embedded (FFPE) CySs of peritoneal or pleural fluid from patients with HGSC and known BRCA1/2 alterations previously established by the testing of FFPE surgical specimens (SpSs) underwent next‐generation sequencing (NGS). Prospectively, 11 cases of peritoneal or pleural fluid from patients with HGSC but an unknown BRCA1/2 status underwent NGS with fresh, alcohol‐fixed, and FFPE CySs, and they were compared with subsequent NGS on 4 SpSs. Results: CySs yielded high‐quantity and high‐quality DNA for NGS analysis when sufficient tumor cellularity was present. Fresh, alcohol‐fixed, and FFPE CySs were all suitable for NGS and provided identical NGS results. SpS and CyS BRCA testing was concordant in 10 of 12 cases. The 2 discordant cases showed low tumor cellularity and quality in the CyS and the SpS, respectively. Conclusion: Effusion CySs of HGSC are excellent sources for NGS testing for BRCA1/2 genetic alterations when sufficient tumor cellularity is present. Fresh, alcohol‐fixed, and FFPE CySs are equivalent for NGS of BRCA1/2. NGS testing of HGSC CySs demonstrates good concordance with SpSs for the BRCA1/2 status. BRCA molecular testing of cytologic specimens of high‐grade serous carcinoma shows good concordance with matched surgical specimens. This has implications for treatment eligibility for poly(adenosine diphosphate‐ribose) polymerase inhibitors and for the triaging of germline testing. [ABSTRACT FROM AUTHOR]

Background: Despite recommendations for reflex immunohistochemistry (IHC) for mismatch repair (MMR) proteins to identify Lynch syndrome (LS), the uptake of genetic assessment by those who meet referral criteria is low. The authors implemented a comprehensive genetic navigation program to increase the uptake of genetic testing for LS in patients with endometrial cancer (EC) or nonserous/nonmucinous ovarian cancer (OC). Methods: Participants with newly diagnosed EC or OC were prospectively recruited from 3 cancer centers in Ontario, Canada. Family history questionnaires were used to assess LS‐specific family history. Reflex IHC for MMR proteins was performed with the inclusion of clinical directives in pathology reports. A trained genetic navigator initiated a genetic referral on behalf of the treating physician and facilitated genetic referrals to the closest genetics center. Results: A total of 841 participants (642 with EC, 172 with OC, and 27 with synchronous EC/OC) consented to the study; 194 (23%) were MMR‐deficient by IHC. Overall, 170 women (20%) were eligible for a genetic assessment for LS: 35 on the basis of their family history alone, 24 on the basis of their family history and IHC, 82 on the basis of IHC alone, and 29 on the basis of clinical discretion. After adjustments for participants who died (n = 6), 149 of 164 patients (91%) completed a genetic assessment, and 111 were offered and completed genetic testing. Thirty‐four women (4.0% of the total cohort and 30.6% of those with genetic testing) were diagnosed with LS: 5 with mutL homolog 1 (MLH1), 9 with mutS homolog 2 (MSH2), 15 with mutS homolog 6 (MSH6), and 5 with PMS2. Conclusions: The introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS. A navigated genetic system significantly increases the uptake of genetic assessment for women with endometrial and nonserous/nonmucinous ovarian cancers at high risk of Lynch syndrome. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE‐mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment. METHODS: A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one‐stage meta‐analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC). RESULTS: Three hundred fifty‐nine women with POLE‐mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47‐7.58; log‐rank P <.01). Except for stage (P <.01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease‐specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5‐14.2 years). Adjuvant treatment was not associated with outcome. CONCLUSIONS: Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de‐escalating treatment for these patients. LAY SUMMARY: Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE).Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics.Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE‐mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity.Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment. Despite often having unfavorable pathological features, women with pathogenic DNA polymerase epsilon (POLE)–mutated endometrial cancers have excellent cancer‐specific clinical outcomes, and this highlights the importance of molecular subtyping for endometrial cancer classification. Adjuvant therapy is not associated with improved outcomes for women with pathogenic POLE‐mutated endometrial cancers, and this supports de‐escalation of therapy for these patients in clinical trials. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high‐grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large‐scale, population‐based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor‐only and paired cohorts), reported to date, and our data show that an effectively designed and validated population‐based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk. [ABSTRACT FROM AUTHOR]

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS. Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result. Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR‐deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1‐deficient tumors) followed by MSI for nonmethylated and/or MMR‐intact patients was the most sensitive (92.3%; 95% confidence interval, 64%‐99.8%) and specific (97.7%; 95% confidence interval, 94.2%‐99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%. Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost‐effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS. Although the incidence of mismatch repair deficiency (MMRd) is low (13%) in patients with nonserous and/or nonmucinous ovarian cancer, the likelihood of having Lynch syndrome is high in patients with MMRd (39%). In the current study, immunohistochemistry for mismatch repair proteins (with MLH1 promoter methylation analysis performed on MLH1‐deficient tumors) is found to be highly sensitive (85%) and specific (98%), missing only 2 patients of Lynch syndrome. [ABSTRACT FROM AUTHOR]

Aims: To expand the morphological spectrum of ovarian microcystic stromal tumour, a rare neoplasm considered to have a relatively constant morphology with microcysts, solid cellular regions and hyalinised fibrous stroma. Methods and results: We report four ovarian neoplasms in patients aged 45, 56, 61 and 71 years with the characteristic immunophenotype of microcystic stromal tumour (diffuse nuclear positivity with betacatenin, cyclin D1 and WT1; diffuse cytoplasmic positivity with CD10; negative inhibin, calretinin, oestrogen receptor and progesterone receptor). The tumours had variant morphology (diffuse, nested and corded arrangements in three cases, including one with spindle cell elements; nested, corded and tubular in the other). A CTNNB1 point mutation in exon 3 (c.98C>G,p.S33C; c.100G>A,p.G34R; c.97T>G, p.S33A) was present in the three cases with material available for testing. Conclusions: We feel that the cases we report are related to microcystic stromal tumour but with variant morphology; as such, the morphological spectrum of ovarian microcystic stromal tumour is broader than hitherto reported. [ABSTRACT FROM AUTHOR]

Background: Anti‐tau immunotherapy has become a promising therapy for Alzheimer's disease (AD) and tauopathies. With the hypothesis that tau pathology spreads via cell‐to‐cell transmission, including trans‐synaptic propagation, success of anti‐tau immunotherapy relies, in part, on the identification of efficacious antibodies and their delivery to affected or vulnerable brain regions with sufficient or enhanced exposure in the CNS. We have previously demonstrated broad distribution and expression of vectorized anti‐tau antibodies in the mouse brain using a blood brain barrier penetrant capsid, VOY101, administered intravenously (IV). Method: Several novel anti‐tau antibodies that met the target profile have been generated and are being evaluated in vivo (Liu et al, submitted as a separated abstract in AAIC 2022). Result: One of the antibodies discovered, antibody 1, exhibits strong affinity for PHF‐tau, demonstrates specific binding to tau pathology on brain sections of AD and PSP patients, and potently prevents PHF seeding and propagation in vitro and in vivo. This antibody recognizes a phospho‐specific epitope in the C‐terminal region of tau and shows significant reduction of tau pathology in an AD‐PHF induced P301S hippocampal seeding and propagation model. Furthermore, we have vectorized antibody 1 into an AAV expression vector with by BBB penetrant capsid and are evaluating it in two independent mouse models of tauopathy. Conclusion: This gene therapy‐based approach has potential advantages over traditional passive immunization, including 1) continuous expression of antibody in the central nervous system (CNS) after a single gene therapy administration compared to repetitive administrations of high dose of antibody by passive immunotherapy; 2) increased CNS exposure of tau antibody relative to passive immunotherapy; and 3) the potential to target intracellular tau aggregates which are less effectively accessed by passively delivered antibody. These results add to accumulating evidence that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies. [ABSTRACT FROM AUTHOR]

Abstract: Uterine carcinosarcoma, also known as Malignant Mixed Müllerian Tumour, is a high‐grade biphasic neoplasm composed of sarcomatous elements thought to originate via transdifferentiation from high‐grade endometrial carcinoma. To identify molecular factors contributing to the histogenesis of this tumour, we analyzed DNA extracted from matched carcinoma and sarcoma components from 12 cases of carcinosarcoma by a molecular inversion probe microarray to assess genomic copy number alterations (CNAs) and allelic imbalances. Widespread CNAs were identified in tumours with serous histology in the carcinoma component (9/12), while the remaining three cases with endometrioid carcinoma were near‐diploid. Quantification of the extent of genomic aberrations revealed a significant increase in sarcoma relative to carcinoma in tumours with well‐delineated histologic components. Focal amplification of 13q31.3 was identified in 6/12 profiled tumours, of which four harboured the aberration exclusively in the sarcoma component. This result was verified by fluorescence in situ hybridization against GPC5, the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio ≥ 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio ≥1.5 but <2.2). The functional relevance of Glypican‐5, the gene product of GPC5, in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line in vitro. In conclusion, we identified GPC5 amplification as a molecular event mediating epithelial‐mesenchymal transdifferentiation in a subset of uterine carcinosarcomas. [ABSTRACT FROM AUTHOR]

Aims The histogenesis and cell lineage of small-cell carcinoma of the ovary of hypercalcaemic type ( SCCOHT) is unknown. We aim to provide evidence that this may be a primitive germ-cell neoplasm arising from a teratoma. Methods and results Following the identification of two cases of SCCOHT associated with germ-cell tumours (one dermoid cyst, one immature teratoma with a focus of yolk sac tumour), we undertook a literature review to look for any prior reports of SCCOHT in association with other neoplasms or elements. This revealed two cases associated with immature teratomas, one arising in an ovary where a cystectomy had been undertaken previously for a teratoma and another in association with a mucinous borderline tumour. Mucinous elements have also been reported in SCCOHT, this type of epithelium potentially being of teratomatous derivation. We stained whole tissue sections of nine cases of SCCOHT and a tissue microarray ( TMA) containing 34 different SCCOHT with germ-cell markers SALL4, OCT3/4, alpha fetoprotein ( AFP) and glypican 3. All except one of the whole tissue sections and approximately half the TMA cases were positive with SALL4, while all cases were OCT3/4-, AFP- and glypican 3-negative, except for focal glypican 3 staining in an occasional case. Conclusions Our findings provide additional evidence to that proposed by others that SCCOHT is a primitive germ-cell neoplasm arising from a teratoma. [ABSTRACT FROM AUTHOR]

Aims Molecular investigation of small-cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT) has revealed that it is a monogenetic tumour characterized by alteration of SMARCA4 ( BRG1), encoding a member of the switch/sucrose non-fermentable ( SWI/ SNF) chromatin remodelling complex. A large majority of cases show loss of expression of the corresponding SMARCA4/ BRG1 protein. Furthermore, three cases of SCCOHT with retained SMARCA4 protein expression showed loss of SMARCB1/ INI1 expression. The aim of this study was to assess the sensitivity and specificity of loss of SMARCA4 expression as a diagnostic test for SCCOHT. Methods and results We performed SMARCA4 and SMARCB1 staining in 245 tumours, many of which were potentially in the differential diagnosis of SCCOHT. We also stained 56 cases of SCCOHT for SMARCA4 and 37 of these for SMARCB1. Fifty-four of the SCCOHT cases showed complete absence of SMARCA4 expression. The two cases with retained expression showed molecular alteration of SMARCA4. Of the 217 other neoplasms with interpretable staining, all retained SMARCA4 expression. Although the majority showed diffuse, strong nuclear expression, a heterogeneous, typically weak staining pattern was present in 13% of cases. All 37 cases of SCCOHT tested and all other neoplasms, apart from three malignant rhabdoid tumours, showed retained nuclear SMARCB1 expression. Loss of SMARCA4 expression had a sensitivity of 96.55% and specificity of 100%. Conclusions Loss of SMARCA4 expression is sensitive and specific for SCCOHT. Although some mimics show heterogeneous expression, there is retention of nuclear staining in at least a part of the tumour; therefore, only complete loss of staining should be regarded as being supportive of SCCOHT. [ABSTRACT FROM AUTHOR]

Aims To describe four cases of incidentally detected microscopic ovarian hilar Sertoli cell proliferation, a phenomenon that, as far as we are aware, has not been previously reported, and to discuss the differential diagnosis of these lesions. Methods and results The proliferations occurred in women aged 35-62 years, and were composed of solid and hollow tubules that were morphologically and immunohistochemically in keeping with Sertoli cells. Two cases were bilateral. Conclusions We feel that these uncommon proliferations are likely to represent non-neoplastic embryological remnants rather than hilar Sertoli cell tumours. [ABSTRACT FROM AUTHOR]

Abstract: Uterine carcinosarcoma is a clinically aggressive malignancy composed of a mix of carcinomatous and sarcomatous elements. We performed targeted next‐generation sequencing of 27 uterine cancer and sarcoma genes together with immunohistochemical analyses of selected proteins in 30 uterine carcinosarcomas. This included 13 cases in which the distinct carcinoma and sarcoma components were sequenced separately and 10 cases where the metastatic tumours were analysed in addition to the primary tumours. We identified non‐synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations. The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two‐thirds of the cases. Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases. In cases where the carcinomatous and sarcomatous components were separately analysed, most of the mutations identified were present in both components, indicating a common origin for the two components. Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites. Overall, carcinosarcomas exhibited heterogeneous molecular features that resemble the heterogeneity seen in endometrial carcinomas, with some showing endometrioid carcinoma‐like and others showing serous carcinoma‐like mutation profiles. While patients with serous‐like tumours presented more frequently with advanced‐stage disease compared to patients with endometrioid‐like tumours, there was no statistical difference in outcome between the two groups. Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events. The findings of the different molecular types of uterine carcinosarcoma that parallel the different molecular types in endometrial carcinoma may have future treatment implications with targeted therapies. [ABSTRACT FROM AUTHOR]

Aims To report a previously undescribed phenomenon of incidentally detected microscopic proliferations of sex cord cells, often mimicking adult granulosa cell tumour or sex cord tumour with annular tubules, in extraovarian locations. Methods and results The six cases were in patients aged 23-58 years. The proliferations were located in the fallopian tube in three cases, and in paraovarian connective tissues, the pelvic side wall, and appendiceal serosa (one case each). Microscopically, they were typically composed of well-demarcated nests of regular cells with round/ovoid vesicular nuclei, some containing grooves. Microfollicular and/or cribriform arrangements were present in three cases. In five cases, the sex cord lineage was confirmed by positive staining with inhibin and/or calretinin and other sex cord markers. FOXL2 mutation analysis was performed in one case, but was inconclusive. Bilateral oophorectomies and bilateral cystectomies were performed in three cases and one case respectively; there was no sex cord-stromal neoplasm in the removed ovaries. In the two cases in which the ovaries were not removed, imaging showed no suspicious features. Follow-up in four cases (11 months-6 years) has been uneventful. Conclusions The pathogenesis of these microscopic extraovarian sex cord proliferations is unknown, but they may represent non-neoplastic proliferations of embryonic remnants. [ABSTRACT FROM AUTHOR]

BACKGROUND Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing. METHODS A prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies. RESULTS A total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%. CONCLUSIONS The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years. Cancer 2014;;120:3932-3939. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Aims Prophylactic hysterectomy with bilateral salpingo-oophorectomy is being increasingly undertaken in patients with Lynch syndrome ( LS). The pathological features in such specimens are not well described and, unlike the SEE- FIM protocol for salpingo-oophorectomy specimens in BRCA1/2 mutation carriers and the gastrectomy grossing protocols for patients with CDH1 ( E-cadherin) mutations, guidelines have not been devised for the grossing of prophylactic gynaecological specimens from LS patients. We aimed to review the pathological findings in a series of prophylactic gynaecological specimens from LS patients and develop guidelines for the grossing of these specimens. Methods and results We reviewed the pathological findings in 25 prophylactic gynaecological specimens from LS patients and audited the grossing protocols in different centres across Ontario, Canada. We found a 32% incidence of endometrial carcinoma or a precursor lesion; the two endometrial cancers identified were low-grade, low-stage endometrioid adenocarcinomas. To address the absence of guidelines for pathological examination, we undertook a literature review of gynaecological malignancies and incidental findings in prophylactic specimens in LS patients. Conclusion We provide recommendations regarding the grossing of such specimens which includes in-toto examination of the lower uterine segment, endometrium, ovaries and fallopian tubes with representative sampling of the cervix. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing ( WES) is revolutionizing medical diagnostics and taxonomy. In less than 5 years since its first use, WES has revealed unexpected molecular drivers of numerous cancers. Here, we describe our use of WES to uncover the true nature of an enigmatic pathological entity, small-cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT), which has resisted definitive characterisation since it was first described in 1979. We conducted WES using three families with SCCOHT and identified deleterious mutations in the chromatin-remodelling gene SMARCA4 (encoding BRG1) in all cases. Follow-up of these findings, using both Sanger sequencing and WES of formalin-fixed paraffin-embedded tumours, showed that virtually all SCCOHTs we studied lacked functional SMARCA4/ BRG1. Notably, this gene, and the related SMARCB1 gene, is mutated in most, if not all, atypical teratoid/rhabdoid tumours and malignant rhabdoid tumours. Other groups have similar findings. We review the relationship between these three neoplasms, discuss how they were distinguished from morphologically similar neoplasms, consider their similarities and show how WES has revealed that SCCOHTs are in fact rhabdoid tumours. We propose that SCCOHT be renamed 'malignant rhabdoid tumour of the ovary' ( MRTO) to reflect these observations. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Up-regulated expression of telomerase reverse transcriptase ( TERT) and subsequent maintenance of telomere length are essential in tumour development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynaecological neoplasms. We performed mutational analysis in a total of 525 gynaecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynaecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences ( p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression ( p = 4.4 × 10-9) and PIK3CA mutation ( p = 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BACKGROUND Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. METHODS Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. RESULTS Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% ( P = .14). CONCLUSIONS No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents. Cancer 2014;120:603-610. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Mucinous ovarian carcinomas ( MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas ( MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified ( HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours ( MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry ( IHC), FISH, and CISH, and interpreted per ASCO/ CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis ( p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence ( p = 0.019) or death ( p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hedgehog (Hh) signaling was assessed in patients with primary cervical carcinoma who were receiving chemoradiation. Because the up-regulation of Hh has been reported in response to hypoxia, the authors examined associations between Hh gene expression and measurements of HP5 (the percentage of oxygen pressure readings in each tumor <5 mm Hg) and interstitial fluid pressure (IFP). METHODS: Sonic hedgehog (SHH), Indian hedgehog (IHH), patched 1 and 2 (PTCH1 and PTCH2), smoothened (SMO), and glioma-associated oncogene family zinc finger 1 (Gli1) expression levels were determined using quantitative reverse transcriptase-polymerase chain reaction analysis on 85 frozen samples of primary cervical carcinoma and on 16 normal cervical samples. Clinicopathologic data were collected prospectively. Possible correlations between Hh expression and tumor hypoxia (HP5 and IFP) measured at the time of biopsy, the time to local recurrence, and disease-free survival (DFS) were examined. RESULTS: At least 1 member of the Hh pathway was elevated in all but 1 tumor compared with normal tissue ( P < .0001). Hh gene expression was heterogeneous with SHH, IHH, and GLI exhibiting bimodal distribution. Elevation of SHH expression ( P = .04) and low SMO expression ( P = .0007) were associated with HP5. The risk of local recurrence was associated with the up-regulation of SMO (hazard ratio [HR], 2.41; 95% confidence interval [CI], 1.00-5.82; P = .044), the up-regulation of >3 Hh genes (HR, 2.56; 95% CI, 1.09-6.00; P = .026), tumor size (HR, 1.41; 95% CI, 1.14-1.74; P = .0015), and lymph node-positive disease (HR, 2.82; 95% CI, 1.16-6.86; P = .022). CONCLUSIONS: The proportion of tumors that expressed Hh genes in cervical cancer was very high. The current data support a role for the Hh pathway in repopulation after chemoradiation and suggest that SMO may be a valid therapeutic target. The authors concluded that further investigation into this pathway after radiation and Hh inhibition are warranted. Cancer 2012;118: 3105-15. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endometrial cancer (EC) is the most common extraintestinal malignancy in Lynch syndrome (LS) and often is the sentinel malignancy, yet there is no consensus regarding LS-EC detection algorithms. In this study, the authors determined the efficacy of family/personal history and tumor morphology in predicting LS in a cohort of patients with EC who had mutation-proven LS. METHODS: Amsterdam II (AmII) criteria, revised Bethesda guidelines (rBG), and Society of Gynecologic Oncologists (SGO) clinical screening criteria were applied to the pedigrees of 76 patients with mutation-proven LS who had pathology-proven EC. When tumors were tested for microsatellite instability (MSI) phenotype status or mismatch-repair protein-immunohistochemical (MMR-IHC) expression, those results also were reviewed, and LS-associated histopathologic features were documented in 38 available patients. RESULTS: Of 76 patients, 36%, 58%, 71%, and 93% would have been selected for further testing for LS by pedigree screening at the time of EC diagnosis with rBG, AmII, SGO 20%-to-25%, and SGO 5%-to-10% criteria, respectively. Ninety percent (18 of 20 tumors) of tested ECs had high MSI, and 96% (22 of 23 tumors) had abnormal MMR-IHC expression. At least 1 LS-EC morphologic feature was present in 16 of 38 tumors (42%). CONCLUSIONS: Clinical screening criteria had variable efficacy for the identification of LS-associated EC, and SGO 5%-to-10% criteria performed best. Characteristic pathologic features were present in a minority of patients. Although a high proportion of LS-ECs had the MSI phenotype and were MMR deficient, the specificity of these tests and of clinical screening for LS in unselected patients with EC has been poorly described. Prospective studies to determine the optimal combination of these screening modalities are required. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on the study which suggest that mutations in harbour isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) on patients with Ollier disease or enchondromatosis were not present in ovarian sex cord-stromal tumour (SCST).