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Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to a somatic fumarate hydratase mutation. Germline mutations account for the hereditary leiomyomatosis and renal cell carcinoma syndrome, which predisposes for cutane

The aim of this study was to determine whether the presence and extent of lymphovascular invasion (LVI) is prognostic in surgical stage I cervical squamous cell carcinoma (SCC). All available tumour slides and/or paraffin blocks from 426 patients with stage I cervical SCC treated surgically with curative intent were collected from 18 institutions and retrospectively analysed. Presence and extent of LVI (focal <5 spaces, extensive ≥5 spaces) were assessed on scanning magnification in large haematoxylin and eosin slide sets in 366 cases. Progression-free survival (PFS) was calculated as the time from surgery to first progression or death or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death or last follow-up. Clinicopathological and statistical analyses were performed on 97 patients with the International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA and 329 patients with stage IB SCC of the cervix. LVI, both focal and extensive, was more frequent in stage IB than in stage IA (p<0.001). Patients with stage IB carcinomas with extensive LVI had worse PFS [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.49, 5.49; p=0.005] and OS (HR 2.88; 95% CI 1.38, 6.02; p=0.012) than those with focal or no LVI. In stage IA, in contrast, the presence and extent of LVI did not associate with PFS (p=0.926) or OS. Extensive LVI was not statistically correlated with PFS and OS in substages IA1, IA2 or IB2. PFS (HR 3.7; 95% CI 1.61, 8.46; p<0.001) and OS (HR 4.18; 95% CI 1.58, 11.04; p=0.002) in stage IB1, and PFS (HR 7.78; 95% CI 0.87, 69.82; p=0.039) in stage IB3 were diminished in the presence of extensive LVI. In conclusion, in patients with FIGO stage I cervical SCC, the presence and extent of LVI has prognostic significance in stage IB carcinoma, and quantifying LVI is recommended., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

We compared grading systems and examined associations with tumor stroma and survival in patients with cervical squamous cell carcinoma. Available tumor slides were collected from 10 international institutions. Broders tumor grade, Jesinghaus grade (informed by the pattern of tumor invasion), Silva pattern, and tumor stroma were retrospectively analyzed; associations with overall survival (OS), progression-free survival (PFS), and presence of lymph node metastases were examined. Binary grading systems incorporating tumor stromal changes into Broders and Jesinghaus grading systems were developed. Of 670 cases, 586 were reviewed for original Broders tumor grade, 587 for consensus Broders grade, 587 for Jesinghaus grade, 584 for Silva pattern, and 556 for tumor stroma. Reproducibility among grading systems was poor (κ = 0.365, original Broders/consensus Broders; κ = 0.215, consensus Broders/Jesinghaus). Median follow-up was 5.7 years (range, 0-27.8). PFS rates were 93%, 79%, and 71%, and OS rates were 98%, 86%, and 79% at 1, 5, and 10 years, respectively. On univariable analysis, original Broders ( P < 0.001), consensus Broders ( P < 0.034), and Jesinghaus ( P < 0.013) grades were significant for OS; original Broders grade was significant for PFS ( P = 0.038). Predictive accuracy for OS and PFS were 0.559 and 0.542 (original Broders), 0.542 and 0.525 (consensus Broders), 0.554 and 0.541 (Jesinghaus grade), and 0.512 and 0.515 (Silva pattern), respectively. Broders and Jesinghaus binary tumor grades were significant on univariable analysis for OS and PFS, and predictive value was improved. Jesinghaus tumor grade ( P < 0.001) and both binary systems (Broders, P = 0.007; Jesinghaus, P < 0.001) were associated with the presence of lymph node metastases. Histologic grade has poor reproducibility and limited predictive accuracy for squamous cell carcinoma. The proposed binary grading system offers improved predictive accuracy for survival and the presence of lymph none metastases., Competing Interests: N.A.R. reports research funding paid to the institution from GRAIL. A.I. reports consulting fees from Mylan. The remaining authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Cervical cancer is the fourth most common cancer among women globally. Historically, human papillomavirus (HPV) infection was considered necessary for the development of both precursor and invasive epithelial tumors of the cervix; however, studies in the last decade have shown that a significant proportion of cervical carcinomas are HPV-independent (HPVI). The 2020 World Health Organization (WHO) Classification of Female Genital Tumors separates both squamous cell carcinomas (SCCs) and endocervical adenocarcinomas (ECAs) by HPV status into HPV-associated (HPVA) and HPVI tumors. The classification further indicates that, in contrast to endocervical adenocarcinomas, HPVI and HPVA SCCs cannot be distinguished by morphological criteria alone and suggests that HPV testing or correlates thereof are required for correct classification. Moreover, while HPVA SCC precursor lesions (ie, high-grade squamous intraepithelial lesion) are well known and characterized, precursors to HPVI SCCs have only been described recently in a small number of cases. We studied 670 cases of SCCs from the International Squamous Cell Carcinoma Project (ISCCP) to analyze the reproducibility of recognition of invasive SCC growth patterns, presence of lymphovascular space invasion, tumor grade, and associations with patient outcomes. Consistent with previous studies, we found histologic growth patterns and tumor types had limited prognostic implications. In addition, we describe the wide morphologic spectrum of HPVA and HPVI SCCs and their precursor lesions, including tumor growth patterns, particular and peculiar morphologic features that can lead to differential diagnoses, and the role of ancillary studies in the diagnosis of these tumors., Competing Interests: Outside the current work, A.I. reports consulting fees from Mylan. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We aimed to determine the frequency of human papillomavirus-independent (HPVI) cervical squamous cell carcinoma (SCC) and to describe clinicopathologic characteristics. Among 670 patients with surgically treated SCCs in an established multi-institutional cohort, 447 had available tissue. Tissue microarrays were constructed and studied by in situ hybridization (ISH) for high-risk and low-risk human papillomavirus (HPV) mRNA and immunohistochemistry for p16 and p53. Tumors were HPVI if negative by HPV ISH and they failed to show diffuse p16 positivity by immunohistochemistry, and human papillomavirus-associated (HPVA) if positive by HPV ISH. Ten HPVI SCCs and 435 HPVA SCCs were identified; 2 cases were equivocal and excluded from analysis. The overall rate of HPVI SCC was low (2%) but was higher among older patients (7% in patients above 60 y of age and 17% in patients above 70 y of age). Compared with HPVA, patients with HPVI SCC were significantly older (median age, 72 vs. 49, P <0.001) and diagnosed at a higher stage (40% vs. 18% with stage III/IV disease, P =0.055). p53 expression was varied; 2 cases (20%) had null expression and 8 (80%) had wild-type expression. HPVI SCCs were heterogenous, with keratinizing, nonkeratinizing, and warty morphologies observed. Several cases had a precursor lesion reminiscent of differentiated vulvar intraepithelial neoplasia, with prominent basal atypia and hypereosinophilia or a basaloid-like morphology. Two patients (20%) had distant recurrences within 12 months, and 3 (30%) died of disease during follow-up. HPVI SCCs are rare tumors that are more common among older patients with higher stage disease and have important clinical and histologic differences from HPVA SCCs., Competing Interests: Conflicts of Interest and Source of Funding: Funded in part by the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant P30 CA008748. Outside the submitted work, N.R.A.-R. reports research funding paid to the institution from GRAIL. A.I. reports consulting fees from Mylan. For the remaining authors none were declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gynecologic carcinomas with RAS mutations may show a wide spectrum of histologic types, including mixed types. We present the case of a 63-yr-old patient diagnosed with an ovarian tumor harboring a mesonephric-like adenocarcinoma in a background of mixed mesonephric-like, mucinous, and endometrioid components. Molecular analysis revealed that all 3 components shared the same clonal KRAS mutation (p.G12A) and chromosome 1q gain. Based on shifts in clonality, copy number gains, and acquisition of an additional mutation, our data suggest that the mucinous component likely constituted the substrate from which the mesonephric-like and endometrioid components arose., Competing Interests: B.W. reports ad hoc membership of the scientific advisory board of Repare Therapeutics, outside the scope of the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

With the advancement of diagnostic molecular technology and the molecular classification of endometrial endometrioid carcinoma (EEC), it remains to be seen whether conventional International Federation of Gynecology and Obstetrics (FIGO) grading retains clinical significance in certain molecular subtypes of EECs. In this study, we explored the clinical significance of FIGO grading in microsatellite instability-high (MSI-H) and POLE-mutant EECs. A total of 162 cases of MSI-H EECs and 50 cases of POLE-mutant EECs were included in the analysis. Significant differences in tumor mutation burden (TMB), progression-free survival, and disease-specific survival were seen between the MSI-H and POLE-mutant cohorts. Within the MSI-H cohort, there were statistically significant differences in TMB and stage at presentation across FIGO grades, but not survival. Within the POLE-mutant cohort, there was significantly greater TMB with increasing FIGO grade, but there were no significant differences in stage or survival. In both the MSI-H and POLE-mutant cohorts, log-rank survival analysis showed no statistically significant difference in progression-free and disease-specific survival across FIGO grades. Similar findings were also seen when a binary grading system was utilized. Since FIGO grade was not associated with survival, we conclude that the intrinsic biology of these tumors, characterized by their molecular profile, may override the significance of FIGO grading., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Ovarian serous borderline tumors (SBTs) harboring the BRAFV600E mutation are associated with decreased risk of progression to low-grade serous carcinoma, and often prominently feature tumor cells with abundant eosinophilic cytoplasm. Since eosinophilic cells (ECs) may be a marker of the underlying genetic driver, we proposed morphologic criteria and evaluated the interobserver reproducibility for assessing this histologic feature. Following the completion of an online training module, representative tumor slides from 40 SBTs ( BRAFV600E -mutated, n=18, BRAF -wildtype, n=22) were independently reviewed by 5 pathologists. For each case, reviewers provided a semiquantitative assessment of the extent of ECs (0: absent, 1: <10%, 2: 10%-50%, or 3: >50%, of tumor area). Interobserver reproducibility for estimating the extent of ECs was moderate (κ=0.41). Applying a cut-off score of ≥2, the median sensitivity and specificity for predicting BRAFV600E mutation were 67% and 95%, respectively. With a cut-off score of ≥1, median sensitivity and specificity were 100% and 82%, respectively. Morphologic mimics of ECs, including tumor cells with tufting or hobnail change and detached cell clusters in micropapillary SBTs, were possible contributing factors for discordant interobserver interpretations. BRAFV600E immunohistochemistry showed diffuse staining in BRAF -mutated tumors, including those with few ECs. In conclusion, the finding of extensive ECs in SBT is highly specific for BRAFV600E mutation. However, in some BRAF -mutated SBTs, ECs may be focal and/or difficult to distinguish from other tumor cells with overlapping cytologic features. The morphologic finding of definitive ECs, even when scarce, should therefore prompt consideration for BRAFV 600E mutation testing., Competing Interests: M.H.C. has received an honorarium from Roche, outside of the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma., Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes., Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors., Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype., Competing Interests: Conflicts of interest Roisin O'Cearbhaill - reports personal fees from once off advisory boards from Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Immunogen, R-Pharm, Miltenyi, 2seventybio and Bayer, outside the submitted work; received honoraria for lectures from Gynecologic Oncology Foundation, Curio, PER/MJH, SITC, Gynecologic Oncology Canada and support to attend meetings from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech, Acrivon, Link Therapeutics and Transgene. NRG representative for the ComboMATCH and iMATCH studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation, Acrivon and Lyell Immunopharma. Robert Soslow is a co-editor for the journal Modern Pathology. Dmitriy Zamarin has grants/contracts from AstraZeneca, Merck, Plexxikon, Synthekine and Genentech. He has patient licensng fees through Merck. He has received consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa, Kalivir, Xencor and GSK. Patents planned, issued or pending include Merck for use of oncoltic NDV for cancer therapy. He also has stock options for Accurius, Immunos and Calidi Biotherapeutics. Kathleen Moore's institution receives research funding from PTC Therapeutics, Lilly, Clovis, Genentech, GSK and Verastem. Her Royalties/licenses are up to date. She received consulting fees from AstraZeneca, Aravive, Alkemeres, Aadi, Blueprint pharma, Clovis, Caris Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Inxmed, Imab, Iovance, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, OncXerna, Onconova, Tarveda, VBL Therapeutics and Verastem. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from PRIME, RTP, Medscape, Great Debates and Updates. She has received support for attending meetings and/or travel from AstraZeneca. She has a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid through GOG P Associate Director. Mark Shahin received grants or contracts from GSK, AstraZeneca and Merck. He also received consulting fees from GSK, AstraZeneca and Immunogen. He received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, AstraZeneca, Merck, Eisai, Immunogen and SeaGen. He has a leadership or fiduciary role with UniteForHer. Premal Thaker's institution received grants/contracts from Merck and GSK. He has received consulting fees from Novartis for endometrial cancer, Merck, AstraZeneca, Clovis Oncology, GSK, Novocure, R-Pharm, Immunon, Zentalis and Aadi Bioscience. Andrea E. Wahner-Hendrickson has an NCI grant (P50 CA 136393) for Mayo Ovarian Cancer SORE (Co-project leader), TORL – Site PI Clinical Trial and Prolynx – IIT. She ha received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from George Washington University for Medical Oncology Board Review (CME) – ovary and uterine. She participates on a Data Safety Monitoring Board or Advisory Board at Mayo Clinic DSMB NCI CIRB (early emphasis). She has unpaid Leadership or fiduciary roles in other board, society, committee or advocacy group with Oxcia Advisory Board and MN ovarian cancer advisory board. Carol Aghajanian received clinical trial funding to institution (MSK): Abbvie – MSK PI, GOG 3005, AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator & MSK PI, DO81RC00001; ENGOT – ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 & 3; Genentech/Roche – MSI PI, GOG 3015 (Imagyn050). She has received consulting fees from Abbvie – Advisory Board 5/8/20; Roche/Genentech – Advisory Board 8/21/20; Eisai/Merck – Advisory Board 9/12/20; AstraZeneca/Merck – Advisory Boards 9/30/20 & 10/14/20; and Repare Therapeutics – Advisory Board 10/15/20. She has participated on an Advisory Board – 6/30/21 (no consulting fee) for Blueprint Medicine. She also served as Leadership or fiduciary role in other board, society, committee or advocacy group for GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology Board of Directors (unpaid). Austin Miller, Heather Lankes, Deborah Delair, Sheila Segura, Shweta S. Chavan, Robert DeBernardo, and John Moroney have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We evaluated clinicopathologic parameters of patients with cervical squamous cell carcinoma (SCC) who were treated with initial surgical management and assessed their relation to survival outcomes. Specifically, we evaluated the relation between extent of lymphovascular invasion (LVI) and survival outcomes., Methods: All available tumor slides from patients with initially surgically treated cervical SCC were collected from 10 institutions and retrospectively analyzed. Standard clinicopathological parameters, tumor stroma, and extent of LVI were assessed (focal: <5 spaces, extensive: ≥5 spaces). PFS and OS were evaluated using Kaplan-Meier methodology. Univariable and multivariable Cox proportional hazards models were created to determine prognostic survival-related risk factors., Results: A total of 670 tumor samples were included in the analysis. Median age at diagnosis was 47 years (IQR: 38-60), 457 patients (72%) had a 2018 International Federation of Gynecology and Obstetrics (FIGO) stage I tumor, and 155 tumors (28%) were flat and/or ulcerated. There were 303 nonkeratinizing tumors (51%), 237 keratinizing tumors (40%), and 356 histologic grade 2 tumors (61%). Quantifiable LVI was present in 321 cases (51%; 23% focal and 33% extensive). On multivariable analysis for PFS, extensive and focal LVI had worse outcomes compared to negative LVI (HR: 2.38 [95% CI: 1.26-4.47] and HR: 1.54 [95% CI: 0.76-3.11], respectively; P = 0.02). The difference did not reach statistical significance for OS., Conclusion: Presence of LVI is a prognostic marker for patients with cervical SCC. Quantification (extensive vs. focal vs. negative) of LVI may be an important biomarker for oncologic outcome., Competing Interests: Declaration of Competing Interest Outside the submitted work, N.R. Abu-Rustum reports research funding paid to the institution from GRAIL. A. Iasonos reports consulting fees from Mylan. All other authors have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: We sought to compare outcomes between minimally invasive surgery (MIS) and laparotomy in patients with clinical stage I uterine serous carcinoma (USC)., Methods: Patients who underwent surgery for newly diagnosed USC between 11/1/1993 and 12/31/2017 were retrospectively identified and assigned to either the MIS cohort or the laparotomy cohort. Patients with conversion to laparotomy were analyzed with the MIS cohort. Chi-square and Mann-Whitney tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival and compared using the log-rank test., Results: In total, 391 patients met inclusion criteria; 242 underwent MIS (35% non-robotic and 65% robotic-assisted laparoscopies) and 149 underwent laparotomy. Age, BMI, stage, and washings status did not differ between cohorts. Patients who underwent MIS were less likely to have lymphovascular space invasion (LVSI; 35.1% vs 48.3%), had fewer nodes removed (median, 9 vs 15), and lower rates of paraaortic nodal dissection (44.6% vs 65.1%). Rates of adjuvant therapy did not differ between cohorts. Median follow-up times were 63.0 months (MIS cohort) vs 71.0 months (laparotomy cohort; P = .04). Five-year PFS rates were 58.7% (MIS) vs 59.8% (laparotomy; P = .1). Five-year OS rates were 65.2% (MIS) compared to 63.5% (laparotomy; P = .2). On multivariable analysis, higher stage, deep myometrial invasion, and positive washings were associated with decreased PFS. Age ≥ 65 years, higher stage, LVSI, and positive washings were associated with shorter OS., Conclusions: MIS does not compromise outcomes in patients with newly diagnosed USC and should be offered to these patients to minimize surgical morbidity., Competing Interests: Declaration of Competing Interest N.R. Abu-Rustum reports research funding paid to the institution from GRAIL. M.M. Leitao Jr. reports research funding paid to the institution from KCI/Acelity, ad-hoc speaker for Intuitive Surgical, Inc., and advisory board participation for JnJ/Ethicon and Takeda. V. Makker reports advisory board participation (unpaid) for Eisai, Merck, Clovis, Faeth, Duality, Morphyes, Karyopharm, Novartis, Lilly, and Immunocore. All other authors have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes., Experimental Design: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype., Results: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab., Conclusions: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339., (©2023 American Association for Cancer Research.)

We describe a very unusual cervical tumor in a 12-yr-old patient with a clinical history indicative of DICER1 syndrome. Morphologic, immunohistochemical, and molecular genetic analysis together helped to diagnose this lesion as a cervical pleuropulmonary blastoma-like tumor, associated with TP53 and DICER1 mutations. The tumor displayed usual histologic features including mixtures of embryonal rhabdomyosarcoma, sarcomatous cartilage, compact blastema, primitive spindle cells and anaplasia, akin to type III pleuropulmonary blastoma, and trabecular and retiform patterns. In addition to expanding the phenotypic spectrum of DICER1 -associated conditions, we draw attention to genotype-phenotype correlations in DICER1 -associated tumors, particularly as they relate to the discovery of a heritable tumor predisposition syndrome., Competing Interests: B.W. reports ad hoc membership of the scientific advisory board of Repare Therapeutics, outside the scope of the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Objective: Chromatin remodeling genes (CRGs) encode components of epigenetic regulatory mechanisms and alterations in these genes have been identified in several tumor types, including gynecologic cancers. In this study, we sought to investigate the prevalence and clinicopathological associations of CRG alterations in endometrial carcinoma (EC)., Methods: We performed a retrospective analysis of 660 ECs sequenced using a clinical massively parallel sequencing assay targeting up to 468 genes, including 25 CRGs, and defined the presence of somatic CRG alterations. Clinicopathologic features were obtained for all cases. Immunohistochemical interrogation of ARID1A and PTEN proteins was performed in a subset of samples., Results: Of the 660 ECs sequenced, 438 (66.4%) harbored CRG alterations covered by our panel. The most commonly altered CRG was ARID1A (46%), followed by CTCF (21%), KMT2D (18%), KMT2B (17%), BCOR (16%), ARID1B (12%) and SMARCA4 (11%). We found that ARID1A genetic alterations were preferentially bi-allelic and often corresponded to altered ARID1A protein expression in ECs. We further observed that ARID1A alterations were often subclonal when compared to PTEN alterations, which were primarily clonal in ECs harboring both mutations. Finally, CRG alterations were associated with an increased likelihood of myometrial and lymphovascular invasion in endometrioid ECs., Conclusion: CRG alterations are common in EC and are associated with clinicopathologic features and likely play a crucial role in EC., Competing Interests: Declaration of Competing Interest B.W. reports ad hoc membership of the scientific advisory board of REPARE Therapeutics, outside the current work. R.A.S. reports medical legal consultant (Shook Hardy Bacon); royalties from Modern Pathology/USCAP, AFIP/ARP, Cambridge Univ Press and Springer publishing. C.A. reports membership of advisory boards/ personal fees from Tesaro, Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, Repare Therapeutics, and grants from Clovis, Genentech, AbbVie, Astra Zeneca, all outside the submitted work. N.R. Abu-Rustum reports Stryker/ Novadaq and GRAIL grants paid to the institution, outside the current study. The remaining authors have no relevant conflicts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Villoglandular adenocarcinoma of the cervix is a rare histologic entity that typically develops in young women, characterized by an association with oral contraceptives and excellent prognosis, though this point is controversial. These tumors have not been studied in the context of the International Endocervical Adenocarcinoma Criteria and Classification (IECC) or Silva Pattern Classification. We analyzed 31 cases that met strict diagnostic criteria, including being completely excised with negative margins. These were categorized according to IECC and Silva Pattern Classification and the association with various pathologic parameters analyzed. Most patients were young with a mean age of 41.1 (range 25-79). There were 14 (45.2%) pattern A, 11 (35.5%) pattern B, and 6 (19.3%) pattern C cases. Only 1 of 22 patients (4.5%) presented with lymph node metastasis at the time of diagnosis (pattern C, stage IB1) and 3 (9.7%) had lymphovascular invasion (2 pattern C, 1 pattern B). Overall survival was 100%, while recurrence-free survival was 96.2% for the entire cohort with only 1 case (3.2%) recurring 25 mo after surgery (IB2, pattern B). Kaplan Meier analysis (log rank test) revealed no significant correlation for recurrence-free survival at 5 and 10 yr associated with depth of invasion, tumor size, Silva pattern, FIGO stage, lymphovascular invasion, or lymph node metastasis. Cox univariate analysis demonstrated no independent prognostic factors predicting recurrence-free survival. These results indicate that completely excised villoglandular adenocarcinoma generally has an excellent prognosis and when Silva Pattern Classification is applied, those tumors that potentially have a higher chance for adverse outcomes can be identified., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Although both the 2014 and 2020 World Health Organization (WHO) criteria require unequivocal glandular and squamous differentiation for a diagnosis of cervical adenosquamous carcinoma (ASC), in practice, ASC diagnoses are often made in tumors that lack unequivocal squamous and/or glandular differentiation. Considering the ambiguous etiologic, morphologic, and clinical features and outcomes associated with ASCs, we sought to redefine these tumors. We reviewed slides from 59 initially diagnosed ASCs (including glassy cell carcinoma and related lesions) to confirm an ASC diagnosis only in the presence of unequivocal malignant glandular and squamous differentiation. Select cases underwent immunohistochemical profiling as well as human papillomavirus (HPV) testing by in situ hybridization. Of the 59 cases originally classified as ASCs, 34 retained their ASC diagnosis, 9 were reclassified as pure invasive stratified mucin-producing carcinomas, 10 as invasive stratified mucin-producing carcinomas with other components (such as HPV-associated mucinous, usual-type, or ASCs), and 4 as HPV-associated usual or mucinous adenocarcinomas with benign-appearing squamous metaplasia. Two glassy adenocarcinomas were reclassified as poorly differentiated HPV-associated carcinomas based on morphology and immunophenotype. There were no significant immunophenotypic differences between ASCs and pure invasive stratified mucin-producing carcinomas with regard to HPV and other markers including p16 expression. Although limited by a small sample size, survival outcomes seemed to be similar between all groups. ASCs should be diagnosed only in the presence of unequivocal malignant glandular and squamous differentiation. The 2 putative glassy cell carcinomas studied did not meet our criteria for ASC and categorizing them as such should be reconsidered., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Competing Interests: The authors declare no conflict of interest.

We present the case of a 71-year-old patient, with vaginal bleeding, dyspnea, headache, loss of appetite and weakness. Clinical examination revealed a pediculated vaginal mass of 25 mm diameter, of dark-red color and soft spongy consistency, with an ulcerated surface and originating from the anterior wall, which was surgically removed. The morphology was dominanted by large, round to polygonal tumor cells, arranged in a predominantly tubulo-cystic architecture, surrounding numerous blood vessels that dominated the appearance, suggesting a perivascular epithelioid cell tumor (PEComa) or hemangioblastoma but the presence of pleomorphic nuclei, numerous mitoses together with immunohistochemistry helped for a correct diagnosis of vaginal .

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability 1-4 patterned by distinct mutational processes 5,6 , tumour heterogeneity 7-9 and intraperitoneal spread 7,8,10 . Immunotherapies have had limited efficacy in HGSOC 11-13 , highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8 + T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research., (© 2022. The Author(s).)

Low-stage, low-grade endometrioid endometrial carcinoma (EEC), the most common histologic type of endometrial cancer, typically has a favorable prognosis. A subset of these cancers, however, displays an aggressive clinical course with early recurrences, including distant relapses. All statistical tests were 2-sided. Using a combination of whole-exome and targeted capture sequencing of 65 FIGO stage IA and IB grade 1 EECs treated with surgery alone, we demonstrate that chromosome 1q gain (odds ratio [OR] = 8.09, 95% confidence interval [CI] = 1.59 to 54.6; P = .02), PIK3CA mutation (OR = 9.16, 95% CI = 1.95 to 61.8; P = .01), and DNA mismatch repair-deficient molecular subtype (OR = 7.92, 95% CI = 1.44 to 87.6; P = .02) are independent predictors of early recurrences within 3 years in this patient population. Chromosome 1q gain was validated in an independent dataset of stage I grade 1 EECs subjected to whole-exome sequencing. Our findings expand on the repertoire of genomic parameters that should be considered in the evaluation of patients with low-stage, low-grade EEC., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The International Collaboration on Cancer Reporting (ICCR) seeks to produce standardized, evidence-based protocols for the reporting of tumors with the aim of ensuring that all cancer reports generated worldwide will be of similar high quality and record the same elements. Herein, we describe the development of the data set for the reporting of uterine malignant and potentially malignant mesenchymal tumors by a panel of expert pathologists and a single clinician and provide the commentary and rationale for the inclusion of core and noncore elements. This data set, which incorporates the recent updates from the 5th edition of the World Health Organization Classification of Female Genital Tumors, addresses several subjects of debate including which mesenchymal tumors should be graded, how to document extent of invasion, mitotic counts, and the role of ancillary testing in tumor diagnosis and patient management. The inclusion of elements is evidence-based or based on consensus of the expert panel with clinical relevance being the guiding standard., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Mullerian adenosarcoma is an uncommon mesenchymal tumor of the gynecologic tract. Most cases are low-grade, while high-grade adenosarcomas are rare and not well studied. Herein, we characterize the clinicopathologic and molecular features of 27 adenosarcomas of gynecologic origin, enriched for high-grade tumors subjected to targeted panel sequencing. Sarcomatous overgrowth was more frequently seen in high-grade compared to low-grade tumors (12/17, 71%, vs 1/10, 10%, p = 0.004) and heterologous elements were exclusive to high-grade cases (n = 7, p = 0.03). All deaths were from high-grade disease (advanced primary, n = 2, or recurrence, n = 5). Genetic alterations specific to high-grade adenosarcomas have known associations with chromosome instability, including TP53 mutations (n = 4) and amplifications of MDM2 (n = 2) and CCNE1 (n = 2). Somatic ATRX frameshift mutations were found in 2 patients with high-grade recurrences following a primary low-grade adenosarcoma and ATRX deletion in 1 high-grade adenosarcoma with an adjacent low-grade component. The fraction of genome altered by copy number alterations was significantly higher in high-grade compared to low-grade adenosarcomas (P = 0.001). Other recurrent genetic alterations across the entire cohort included BAP1 homozygous deletions (n = 4), DICER1 mutations (n = 4), ARID1A mutations (n = 3), TERT promoter mutations (n = 2) and amplification (n = 1), as well as alterations involving members of the PI3K and MAPK signaling pathways. One tumor harbored an ESR1-NCOA3 fusion and another had an MLH1 homozygous deletion. Immunohistochemical analysis for BAP1 revealed loss of nuclear expression in 6/24 (25%) cases, including all four tumors with BAP1 deletions. Notably, out of 196 mesenchymal neoplasms of gynecologic origin, BAP1 homozygous deletion was only found in adenosarcomas (P = 0.0003). This study demonstrates that high-grade adenosarcomas are heterogeneous at the molecular level and are characterized by genomic instability and TP53 mutations; ATRX loss may be involved in high-grade transformation of low-grade adenosarcoma; and BAP1 inactivation appears to be a specific pathogenic driver in a subset of adenosarcomas., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Purpose: The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome., Methods: From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm., Results: In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed., Conclusion: IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.

Endometrial carcinomas (ECs) classified by The Cancer Genome Atlas (TCGA) as copy number-low (also referred to as "no specific molecular profile" [NSMP]) have a prognosis intermediate between POLE-mutated and copy number-high ECs. NSMP-ECs are a heterogeneous group, however, comprising both relatively indolent and aggressive ECs. We identified a total of 472 NSMP-ECs among 1,239 ECs that underwent clinical sequencing of 410-468 cancer-related genes. Somatic mutation and copy number alteration data were subjected to unsupervised hierarchical clustering, which identified three genomic clusters. Random sampling with stratification was used to choose ~80 endometrioid ECs from each cluster, resulting in a study size of 240 endometrioid ECs as well as an additional 44 non-endometrioid NSMP-ECs. Cluster 1 (C1, n = 80) consisted primarily of NSMP-ECs with PTEN and PIK3R1 mutations, Cluster 2 (C2, n = 81) of tumors with PTEN and PIK3CA mutations and Cluster 3 (C3, n = 79) of NSMP-ECs with chromosome 1q high-level gain and lack of PTEN mutations. The majority (72.7%) of non-endometrioid NSMP-ECs mapped to C3. NSMP-ECs from C3 were more likely to be FIGO grade 3 (30%), estrogen receptor-negative/weak (54.5%) and FIGO stages III or IV. In multivariate analysis, molecular clusters were associated with worse overall survival outcomes with C3 tumors having the worst (hazard ratio: 4) and C1 tumors having the best outcome. In conclusion, NSMP-ECs are a heterogenous group of tumors and comprise both aggressive and clinically low-risk ECs that can be identified based on mutation and copy number data., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Silva invasion pattern can help predict lymph node metastasis risk in endocervical adenocarcinoma. We analysed Silva pattern of invasion and lymphovascular invasion to determine associations with clinical outcomes in stage IA and IB1 endocervical adenocarcinomas. International Federation of Gynecology and Obstetrics (FIGO; 2019 classification) stage IA-IB1 endocervical adenocarcinomas from 15 international institutions were examined for Silva pattern, presence of lymphovascular invasion, and other prognostic parameters. Lymph node metastasis status, local/distant recurrences, and survival data were compared using appropriate statistical tests. Of 399 tumours, 152 (38.1%) were stage IA [IA1, 77 (19.3%); IA2, 75 (18.8%)] and 247 (61.9%) were stage IB1. On multivariate analysis, lymphovascular invasion (p=0.008) and Silva pattern (p<0.001) were significant factors when comparing stage IA versus IB1 endocervical adenocarcinomas. Overall survival was significantly associated with lymph node metastasis (p=0.028); recurrence-free survival was significantly associated with lymphovascular invasion (p=0.002) and stage (1B1 versus 1A) (p=0.002). Five and 10 year overall survival and recurrence-free survival rates were similar among Silva pattern A cases and Silva pattern B cases without lymphovascular invasion (p=0.165 and p=0.171, respectively). Silva pattern and lymphovascular invasion are important prognostic factors in stage IA1-IB1 endocervical adenocarcinomas and can supplement 2019 International Federation of Gynecology and Obstetrics staging. Our binary Silva classification system groups patients into low risk (patterns A and B without lymphovascular invasion) and high risk (pattern B with lymphovascular invasion and pattern C) categories., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

High-grade endometrial stromal sarcomas (HGESSs) are more aggressive and have higher rates of resistance to endocrine therapy than low-grade endometrial stromal sarcomas (LGESSs). The pathogenesis of hormonal resistance in these lesions has yet to be defined. Here we sought to histologically and genetically characterize 3 LGESSs and their recurrences that underwent histologic high-grade transformation following endocrine therapy. For this, DNA from primary tumors and select subsequent recurrences were subject to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutation analyses were performed using validated bioinformatics methods. In addition, RNA from each case was evaluated for the presence of gene fusions using targeted RNA-sequencing. All patients initially presented with LGESS, developed HGESS recurrences, and received at least 2 lines of hormonal suppressive therapy. Gene fusions classically described as associated with LGESS were identified in all 3 cases, including JAZF1-PHF1, EPC1-PHF1 and JAZF1-SUZ12 fusions for Cases 1, 2 and 3, respectively. Targeted sequencing analysis revealed that none of the primary LGESS, however the HGESS recurrences of Cases 1 and 3, and the LGESS and HGESS recurrences of Case 2 post endocrine treatment harbored ESR1 p.Y537S hotspot mutations. These ESR1 ligand-binding domain mutations have been found as a mechanism of acquired endocrine resistance in breast cancer. Also, a reduction in estrogen receptor (ER) expression was observed in recurrences. Our findings suggest that the ESR1 p.Y537S hotspot mutation in LGESS with histologic high-grade transformation may be associated with endocrine resistance in these lesions. Furthermore, our data suggest that genetic analyses may be performed in recurrent LGESS following hormonal therapy, development of high-grade morphology, and/or altered/diminished ER expression., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Squamous cell carcinoma is the most frequent epithelial malignant tumor of the cervix and among the most frequent neoplasm in women worldwide. Endocervical adenocarcinoma is the second most common malignancy. Both tumors and their precursors are currently classified based on human papillomavirus status, with prognostic and predictive value. Various prognostic biomarkers and alternative morphologic parameters have been recently described and could be used in the management of these patients. This pragmatical review highlights recent developments, emerging issues as well as controversial areas regarding the cause-based classification, diagnosis, staging, and prognostic parameters of epithelial malignant tumors of the cervix., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated., Competing Interests: Conflicts of Interest and Source of Funding: Funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 (R.A.S., K.J.P., N.A.-R.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

HIK1083 and trefoil factor 2 (TFF2) are known to be expressed in gastric-type carcinoma (GAS), but they do not reliably mark all GASs, and focal expression can be missed in biopsy specimens. We aimed to investigate whether claudin-18 and alpha-methylacyl-CoA racemase (AMACR) could be surrogate markers to separate GAS from other types of endocervical adenocarcinoma (ECA) and to compare their usefulness with that of HIK1083 and TFF2. Claudin-18 and AMACR immunohistochemistry was performed, and the results were compared with that of TFF2 and HIK1083, using whole sections of 75 ECAs (22 GASs and 53 non-GASs) and 179 ECAs with tissue microarrays (TMAs). TMAs were built to simulate the assessment of immunohistochemical stains in small biopsies. Any membranous (claudin-18) or cytoplasmic/membranous (AMACR, TFF2, HIK1083) staining of >5% of tumor cells was considered positive. Of 75 ECAs with whole sections, claudin-18 was significantly more frequently expressed in GASs (21/22) compared with non-GASs (8/53) (P<0.01). In ECAs with TMAs, claudin-18 expression was significantly frequent in GASs (15/23, 65.2%) than in non-GASs (3/152, 2.0%; all usual-type) (P<0.01). All claudin-18-positive GASs showed intense staining except 1 case. Claudin-18 shared the same degree of sensitivity and specificity with HIK1083 and TFF2. Three clear cell carcinomas were positive for claudin-18, but none showed intense staining. AMACR was expressed in a subset of ECAs and showed no impact in distinguishing between GAS and other ECAs. Our results suggest that claudin-18 is a promising surrogate marker to separate GAS from other types of ECA, including clear cell carcinoma., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 (R.A.S., K.J.P.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND)., Methods: We identified newly diagnosed CS patients who underwent primary surgical management from January 1996-December 2019. The SLN cohort underwent SLN biopsy alone with bilateral SLNs identified. The systematic LND cohort did not undergo SLN biopsy., Results: Ninety-nine patients underwent SLN biopsy, and 100 patients underwent systematic LND. There was no difference by age, stage, body mass index, myoinvasion (<50%, ≥50%), lymphovascular space invasion, or positive washings. Eighty-five SLN (85.9%) and 15 LND (15%) underwent minimally invasive surgery (P < 0.001). The median total node count was four (range, 1-13) for SLN and 19 (range, 2-50) for LND (P < 0.001). Nodal metastasis occurred in 23 (23.2%) SLN and in 22 (22%) LND (P = 0.4). Postoperative therapy was administered to 85 (85.9%) SLN and 71 (71%) LND (P = 0.02). Median follow-up was 33 months (range, 1-205) for SLN and 55.3 months (range, 1-269) for LND (P = 0.001). The three-year progression-free survival (PFS) was 62.9% (SE 5.2%) for SLN and 52.3% (SE 5.3%) for LND (P = 0.13). The three-year overall survival (OS) was 72.1% (SE 5.1%) for SLN and 71.6% (SE 4.6%) for LND (P = 0.68). An isolated nodal recurrence occurred in two (2%) SLN and four (4%) LND (P = 0.26)., Conclusions: There is no difference in PFS or OS among CS patients who undergo SLN biopsy vs. systematic LND. SLN biopsy detects nodal metastasis without compromising oncologic outcomes., Competing Interests: Declaration of Competing Interest Outside the submitted work, Dr. Makker reports industry support and unpaid consultant fees from Astra Zeneca, Eisai, Merck, Lilly, Karyopharm, Takeda, Genentech, Clovis, Novartis, Faeth, Zymeworks, GSK, and Moreo. Dr. Makker also discloses personal fees from IBM Watson. Dr. Abu-Rustum reports institutional grants from Stryker/Novadaq and GRAIL. Dr. Leitao reports grants from KCI/Acelity, personal fees from Takeda, J&J/Ethicon, and Intuitive Surgical. All other authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The 2018 International Federation of Gynecology and Obstetrics (FIGO) update on cervical cancer staging eliminated horizontal tumor extent (HZTE) as a staging parameter in stage IA (microscopic) disease. We aimed to determine whether HZTE correlates with outcomes in early stage ECAs and FIGO should reinstate HZTE as a staging parameter in futures updates., Methods: We retrospectively analyzed 416 FIGO 2009 stage I ECAs from 17 institutions and re-assigned stage using FIGO 2018. Correlation between HZTE, overall (OS) and recurrence free survival (RFS) was performed using univariable and multivariable analyses., Results: Re-staging 416 cases resulted in 126 (30.3%) IA and 290 (69.7%) IB cases; 85 (67.5%) IA tumors had HZTE ≤ 7 mm, while 41 (32.5%) were > 7 mm; 32 (11%) IB tumors had HZTE ≤ 7 mm, while 258 (89%) were > 7 mm (p = 0.0001). Four (3.2%) IA (1 IA1, 3 IA2) patients developed recurrence (3 ≤ 7 mm, 1 > 7 mm) compared to 41 (14.1%) IB patients (p = 0.002). Fourteen IB and no IA patients died of disease (8 IB1, 1 ≤ 7 mm). Cox univariate analysis demonstrated that only RFS is significantly influenced by HZTE (p = 0.01), while OS and RFS were not influenced by HZTE on multivariate analysis., Conclusion: HZTE has limited prognostic value in early stage ECAs and is only associated with RFS on univariate but not multivariate analysis. HZTE does not improve prognostication of patients with stage I ECAs as per 2018 FIGO staging. Consequently, the rationale to remove this variable from FIGO staging is justified for ECAs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Histologic assessment of response to progestogen therapy is a cornerstone of nonsurgical management of atypical hyperplasia/low-grade endometrioid carcinoma. Pathologists are required to assess whether there is ongoing preneoplastic or neoplastic change in the biopsies (often multiple) taken during therapy. There have been few studies documenting the specific histologic changes induced by therapeutic progestogens and currently there are no guidelines on terminology used in this scenario. Given the need for uniformity in reporting and the lack of guidance in the current literature, we initiated an online survey (including questions, categories of reporting, and scanned slides for assessment) which was sent to all members of British Association of Gynaecological Pathologists (BAGP) and the International Society of Gynecological Pathologists (ISGyP) with the aim to assess the variability among pathologists in reporting these specimens and to come up with a consensus-based terminology for reporting of endometrial biopsies from women on progestogen therapy for endometrial atypical hyperplasia/endometrioid carcinoma. In total, 95 pathologists participated in this survey. This manuscript elaborates on the results of the survey with recommendations aimed at promoting uniform terminology in reporting these biopsies., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

The Silva pattern of invasion, recently introduced to stratify patients at risk for lymph node metastases in human papillomavirus-associated endocervical adenocarcinomas (HPVAs), can only be assessed in cone and loop electrosurgical excision procedure excisions with negative margins or in a hysterectomy specimen. Previous studies found associations between destructive stromal invasion patterns (Silva patterns B and C) and mutations in genes involved in the MEK/PI3K pathways that activate the mammalian target of rapamycin (mTOR) pathway. The primary aim of this study was to use cervical biopsies to determine whether markers of mTOR pathway activation associate with aggressive invasion patterns in matched excision specimens. The status of the markers in small biopsy specimens should allow us to predict the final and biologically relevant pattern of invasion in a resection specimen. Being able to predict the final pattern of invasion is important, since prediction as Silva A, for example, might encourage conservative clinical management. If the pattern in the resection specimen is B with lymphovascular invasion or C, further surgery can be performed 34 HPVA biopsies were evaluated for expression of pS6, pERK, and HIF1α. Immunohistochemical stains were scored semiquantitatively, ranging from 0 to 4+ with scores 2 to 4+ considered positive, and Silva pattern was determined in follow-up excisional specimens. Silva patterns recognized in excisional specimens were distributed as follows: pattern A (n=8), pattern B (n=4), and pattern C (n=22). Statistically significant associations were found comparing pS6 and pERK immunohistochemistry with Silva pattern (P=0.034 and 0.05, respectively). Of the 3 markers tested, pERK was the most powerful for distinguishing between pattern A and patterns B and C (P=0.026; odds ratio: 6.75, 95% confidence interval: 1.111-41.001). Although the negative predictive values were disappointing, the positive predictive values were encouraging: 90% for pERK, 88% for pS6 and 100% for HIF1α. mTOR pathway activation assessed by immunohistochemistry in cervical biopsies of HPVA correlate with Silva invasion patterns., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Prior data suggested that women with incidentally detected occult invasive ovarian cancer (OIOC) at the time of risk-reducing salpingo-oophorectomy (RRSO) for BRCA mutation may have poorer prognoses than would be expected based on disease stage. We sought to evaluate prevalence and outcomes of patients with OIOC in a tertiary referral center., Methods: Patients with BRCA mutation undergoing RRSO from 01/2005 to 05/2017 were identified, and their records reviewed. Women with incidentally detected OIOC were included; those with clinical features raising preoperative suspicion for malignancy were excluded., Results: 548 patients with BRCA mutation who underwent RRSO were identified. 26 (4.7%) had an OIOC (median age 55 years; range 42-75); 15(58%) patients, BRCA1; 9(34%), BRCA2; 2(8%) had a mutation in both genes. All OIOCs were high-grade serous: 10 (38%) Stage I; 8 (31%) Stage II; 8(31%) Stage III. 24(92%) patients received adjuvant platinum/taxane therapy. Of Stage III patients, 4 (50%) were identified intraoperatively; the remaining 4 (50%) had microscopic nodal disease on final pathology only. At median follow-up of 67.3 months (28-166) no Stage I patients have recurred; 2 Stage II and 6 Stage III patients recurred. 5-year progression-free survival (PFS) was 72% (95%CI, 50.2-85.7%); median PFS for the cohort was 129 months (95%CI, 75.3-not estimable). 5-year disease-specific survival (DSS) was 96% (95%CI, 76-99%); median DSS not reached., Conclusion: Consistent with prior reports, almost 5% of patients had an OIOC at RRSO. The majority with early-stage disease had excellent PFS and DSS outcomes, as would be expected based on disease stage., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs)., Methods: EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410-468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons., Results: Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas., Conclusions: Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes., Competing Interests: Declaration of Competing Interest R.A. Soslow reports NIH grant funding. S. Chiang serves as a consultant for AstraZeneca, outside the scope of the submitted manuscript. J.S. Reis-Filho reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. C.F. Friedman reports institutional research support from Bristol Myers Squibb, Merck, Astra Zeneca and Genentech as well as membership of the scientific advisory boards of Merck and Genentech, outside the scope of the submitted manuscript. D. Zamarin reports personal/consultancy fees from Merck, Synlogic Therapeutics, Xencor, Biomed Valley Discoveries, Trieza Therapeutics, Tesaro, and Agenus, outside of the scope of this work. D. Zamarin reports institutional research support from Astra Zeneca, Plexxikon, and Genentech, outside of the scope of this work. V. Makker reports study funding from Merck, Eisai, Karyopharm, AstraZeneca, Clovis, Takeda, Lilly and Genentech, and honoraria/consultancy fees from Merck, Eisai, Karyopharm and Clovis, all outside the scope of this study. M.M. Leitao Jr. reports personal fees from JnJ/Ethicon and is an ad hoc speaker for Intuitive Surgical, Inc., outside the submitted work. N.R. Abu-Rustum reports institutional research grants from GRAIL and Stryker, outside the submitted work. C. Aghajanian reports grant support by Clovis, Genentech, AbbVie, AstraZeneca, and personal/ advisory board fees from Tesaro, Immunogen, Clovis, Eisai/Merck, Mersana Therapeutics, Roche/ Genentech, Abbvie, AstraZeneca, all outside the scope of the submitted manuscript. B. Weigelt reports membership of the ad hoc scientific advisory board of REPARE Therapeutics, outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Copy number-high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53 -altered endometrial carcinomas of four histologic types., Experimental Design: TP53 -mutated endometrial carcinomas, defined as TP53 -mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified ( n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410-468 cancer-related genes. Somatic mutations and CNAs ( n = 238), and clinicopathologic features were determined ( n = 185, initial treatment planning at our institution)., Results: TP53 -mutated endometrial carcinomas encompassed uterine serous ( n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades ( n = 28, 15.1%), and clear cell carcinomas ( n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53 -mutated histologic types (7.7%-18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival., Conclusions: TP53 -mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53 -mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant., (©2021 American Association for Cancer Research.)

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)