Molecular Pathology of Ovarian Epithelial Neoplasms: Predictive, Prognostic, and Emerging Biomarkers.

This review focuses on the diagnostic, prognostic, and predictive molecular biomarkers in ovarian epithelial neoplasms in the context of their morphologic classifications. Currently, most clinically actionable molecular findings are reported in high-grade serous carcinomas; however, the data on less common tumor types are rapidly accelerating. Overall, the advances in genomic knowledge over the last decade highlight the significance of integrating molecular findings with morphology in ovarian epithelial tumors for a wide-range of clinical applications, from assistance in diagnosis to predicting response to therapy.

Erythrasma of the Vulva: An Invisible Dermatosis.

Erythrasma is a prevalent superficial bacterial infection typically caused by Corynebacteria species and preferentially affecting intertriginous sites including axillary, interdigital, and inguinal skin folds. However, erythrasma of the vulva is uncommon, with only 2 cases previously reported. Although erythrasma can be diagnosed clinically using Woods lamp examination, it may not always be considered in the differential diagnosis for patients presenting with persistent vulvar pruritus. We report 12 cases of vulvar erythrasma identified by histopathology, with a review of clinical and histologic features. The mean patient age was 60.1 yr and the mean patient BMI was 30.5. Five of 12 patients presented with pruritic rash. The time from symptom onset to diagnosis was 9 mo in 1 case, >18 mo in 4 cases, and unknown in the remaining cases. The characteristic histologic features were compact orthokeratosis and mild perivascular chronic inflammation. In all 12 cases, Periodic Acid-Schiff-diastase (PAS-D) staining highlighted intracorneal filamentous rods which were not readily appreciable on H&E. After the diagnosis of erythrasma, 4 patients were treated with topical lincomycin, of whom 3 had clinical improvement in symptoms. One patient was treated with topical macrolide antibiotic and also reported improvement in symptoms. Consideration of erythrasma on the differential for patients presenting with vulvar rash and pruritus may shorten the time to diagnosis and treatment, minimize patient discomfort, and reduce the scope and cost of diagnostic testing.

Interobserver Agreement on the Interpretation of Programmed Death-ligand 1 (PD-L1) Combined Positive Score (CPS) Among Gynecologic Pathologists.

The anti-programmed cell death (PD-1) checkpoint inhibitor pembrolizumab is approved for the treatment of cervical carcinoma with a programmed cell death-ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1. We assessed interobserver agreement in cervical carcinoma PD-L1 CPS to identify whether it may affect patient selection for immunotherapeutic candidacy. Twenty-nine cervical carcinomas were stained for PD-L1 (Dako 22C3), and slides were interpreted by 5 subspecialty-trained gynecologic pathologists with experience reading PD-L1 immunohistochemistry. Expression was scored using CPS and read out as positive (≥1) or negative (<1); in positive cases, a final score was assigned (1 to 100). There was consensus agreement across all 5 pathologists for 90% (26/29) (Fleiss Kappa value for interobserver agreement: 0.799). The 3 cases with disagreement were composed of 2 squamous cell carcinomas and 1 small cell carcinoma. Of the 26 with unanimous agreement, 88% (23/26) were positive and 12% (3/26) were negative. All (16/16) pure squamous cell carcinomas with full consensus were interpreted as positive, whereas tumors with glandular components were commonly consensus negative (33%, 3/9); this difference was significant ( P =0.037). Disagreements were attributable to low CPS versus negative reads (2 cases) and difficulty discerning glandular involvement from pushing invasion (1 case). In summary, experienced gynecologic pathologists showed substantial interobserver agreement in the interpretation of PD-L1 CPS at the Food and Drug Administration-approved treatment threshold, with the majority of tumors being classified as positive. Pure squamous histology was strongly associated with a consensus-positive read, whereas a subset of tumors with glandular differentiation was negative by all readers. Disagreements occurred in tumors with low versus negative CPS values and in the setting of limited invasion.

Uterine Tumors Resembling Ovarian Sex Cord Tumors: A Clinicopathologic Study of 75 Cases Emphasizing Features Predicting Adverse Outcome and Differential Diagnosis.

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs), first characterized by Drs Clement and Scully in 1976, are rare neoplasms showing clinical, morphologic, and immunohistochemical overlap with a number of other uterine tumors, most being mesenchymal. Criteria for aggressive behavior are not clearly established. We report 75 tumors from patients ranging from 21 to 84 (mean=52.4) years. Seventy-one patients were treated by hysterectomy and 4 by conservative total excision. Thirty-eight tumors were intramyometrial, 34 submucosal, and 3 cervical; they ranged from 0.6 to 20 (mean=4.9) cm and were typically tan-yellow. Sixty-eight neoplasms were well-circumscribed and 7 had infiltrative borders (4 only minimally). In 56 tumors, a smooth muscle component was intimately admixed with the neoplastic cells ("pseudoinfiltration"; extensive in 29). Architectural patterns included cords (n=53), diffuse (n=51), hollow tubules (n=48), nests (n=38), trabeculae (n=37), retiform (n=23), solid tubules (n=21), pseudoangiomatoid (n=11), pseudopapillary (n=4), and whorled (n=2); typically, more than 1 pattern was seen. Tumor cells were epithelioid (n=62), epithelioid and spindled (n=12), or spindled (n=1) and/or rhabdoid (n=20; extensive in 2). Cytologic atypia was absent to mild in 57, moderate in 16, and moderate to severe in 2 tumors. Fifty-seven UTROSCTs had ≤2mitoses/10 high power fields (HPF), 12 had 3 to 5/10 HPF, and 6 >5/10 HPF. Necrosis was present in 3 and lymphovascular invasion in 1. Tumor cells showed a polyphenotypic immunohistochemical profile (with positivity for sex cord, smooth muscle, and epithelial markers), most commonly inhibin (17/33+) and calretinin (22/31+) positive. Five of 58 patients with follow-up (22 to 192; mean=73.2 mo) had recurrences/metastases from 30 to 144 months, and 2 died of disease. Malignant tumors showed >3 of the following 5 features compared with benign tumors: size >5 cm, at least moderate cytologic atypia, ≥3 mitoses/10 HPF, infiltrative borders, and necrosis. One of the 5 malignant tumors showed an extensive rhabdoid morphology. UTROSCTs are uncommon, show a wide morphologic spectrum, often pose problems in differential diagnosis, and typically have a benign outcome. Rare tumors are associated with late recurrences and a combination of more than 3 of the 5 features listed above predicted aggressive behavior in this series.

BAP1 and Claudin-4, But Not MTAP, Reliably Distinguish Borderline and Low-grade Serous Ovarian Tumors From Peritoneal Mesothelioma.

Peritoneal mesothelioma (PM) and serous neoplasms can be difficult to differentiate, particularly in small biopsies. BRCA1-associated protein 1 (BAP1) is expressed in benign tissues, but over 50% of PMs demonstrate complete loss of nuclear expression. Claudin-4, a tight junction protein, is expressed in most epithelial tumors but not in mesotheliomas. Methylthioadenosine phosphorylase (MTAP) is frequently co-deleted with cyclin-dependent kinase inhibitor 2a in mesotheliomas. These markers have proven useful in separating mesothelioma from its mimics, particularly when tumors are pleural based. In the peritoneum, BAP1 loss has been rarely reported in high-grade serous carcinomas, but overall, these markers have been minimally evaluated in ovarian serous borderline tumors and low-grade serous carcinomas. Thus, we assessed the utility of BAP1, claudin-4, and MTAP in the differential diagnosis of PM and low-grade serous neoplasms. Eighteen PM (16 epithelioid, 1 biphasic, and 1 sarcomatous), 24 low-grade serous carcinomas, and 25 serous borderline tumors were stained for BAP1, claudin-4, and MTAP. Loss of BAP1 nuclear expression was observed in 12 (67%) PM (11 epithelioid, 1 biphasic) but was retained in all serous tumors. Claudin-4 was positive in all serous tumors and negative in all PM. Complete loss of cytoplasmic MTAP was noted in 3 (17%) PMs and 1 (4%) serous borderline tumor, while all low-grade serous carcinomas showed retained expression. BAP1 loss reliably distinguishes PM from serous tumors, although it lacks sensitivity. Claudin-4 is a reliable marker to exclude PM. MTAP loss may occur in both PM and serous tumors, and thus is not useful in distinguishing these entities.

Vulvar angiomyofibroblastoma is molecularly defined by recurrent MTG1-CYP2E1 fusions.

Angiomyofibroblastoma (AMF), a rare benign vulvovaginal mesenchymal tumour, poses a diagnostic challenge due to histologic and immunohistochemical overlap with other vulvar mesenchymal tumours. Recently, MTG1-CYP2E1 fusion transcripts were reported in 5/5 AMFs; no other genetic alterations have been described to date. Herein, we sought to investigate the frequency of the MTG1-CYP2E1 fusion and the presence of other potential genetic alterations in a cohort of AMFs (n = 7, patient age range: 28-49 years). Tumours demonstrated classic morphologic features including alternating hypo/hypercellular areas, capillary channels surrounded by epithelioid/spindled tumour cells, and variable amounts of mature adipose tissue. reverse transcription-polymerase chain reaction (RT-PCR) for MTG1-CYP2E1 fusion, performed in all seven cases, showed the fusion transcript in five of six cases (one case with technical failure). Two tumours, including the one lacking the fusion, were subjected to targeted next-generation sequencing (104 genes) and a sarcoma fusion assay (28 genes); the fusion negative AMF also underwent RNA sequencing. No additional mutations, copy number alterations, or fusion genes were identified with the assays employed. We conclude that the majority of AMFs harbour recurrent MTG1-CYP2E1 fusion transcripts and identification of this fusion may aid in the diagnosis.

Implementation and Clinical Adoption of Precision Oncology Workflows Across a Healthcare Network.

BACKGROUND: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. METHODS: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. RESULTS: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. CONCLUSION: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

HPV-independent, p53-wild-type vulvar intraepithelial neoplasia: a review of nomenclature and the journey to characterize verruciform and acanthotic precursor lesions of the vulva.

Vulvar squamous cell carcinomas and their precursors are currently classified by the World Health Organization based on their association with high-risk human papillomavirus (HPV). HPV independent lesions often harbor driver alterations in TP53, usually seen in the setting of chronic vulvar inflammation. However, a group of pre-invasive vulvar squamous lesions is independent from both HPV and mutant TP53. The lesions described within this category feature marked acanthosis, verruciform growth and altered squamous maturation, and over the last two decades several studies have added to their characterization. They have a documented association with verrucous carcinoma and conventional squamous cell carcinoma of the vulva, suggesting a precursor role. They also harbor recurrent genomic alterations in several oncogenes, mainly PIK3CA and HRAS, indicating a neoplastic nature. In this review, we provide a historical perspective and a comprehensive description of these lesions. We also offer an appraisal of the terminology used over the years, going from Vulvar Acanthosis with Altered Differentiation and Verruciform Lichen Simplex Chronicus to Differentiated Exophytic Vulvar Intraepithelial Lesion and Vulvar Aberrant Maturation, the latter term having been recently proposed by the International Society for the Study of Vulvovaginal Diseases. In line with the recognition of these lesions by the 2020 World Health Organization Classification of Tumours as a neoplastic precursor, we herein propose the term HPV-independent, p53-wild-type verruciform acanthotic Vulvar Intraepithelial Neoplasia (HPVi(p53wt) vaVIN), which better conveys not only the pathology but also the neoplastic nature and the biologic risk inherent to these uncommon and challenging lesions. We outline strict morphologic and immunohistochemical criteria for its diagnosis and distinction from mimickers. Immunohistochemistry for p16 and p53 should be performed routinely in the diagnostic work-up of these lesions, and the morphologic alternative term vaVIN should be reserved for instances in which p16/HPV/p53 status is unknown. We also discuss management considerations and the need to further explore precursors within and beyond the spectrum of verruciform acanthotic vulvar intraepithelial neoplasia.

Cystic Granulosa Cell Tumors of the Ovary: An Analysis of 80 Cases of an Often Diagnostically Challenging Entity.

CONTEXT.­: Granulosa cell tumors (GCTs) of both adult (AGCT) and juvenile (JGCT) types can rarely be completely or dominantly cystic, creating diagnostic difficulty because the cyst lining epithelium is often denuded. OBJECTIVE.­: To describe clinical, gross, microscopic, immunohistochemical, and molecular features of cystic GCTs with an emphasis on their differential diagnosis. DESIGN.­: We report 80 cystic GCTs (24 AGCTs and 56 JGCTs) in patients from ages 3 to 83 years (average ages, 35 years for AGCT and 22 years for JGCT). RESULTS.­: Nineteen of 43 patients with known clinical information (3 AGCT and 16 JGCT) had androgenic manifestations. All tumors were greater than 8 cm (average, 17 cm) with minimal to absent gross solid component. Denudation of cells lining the cysts was prominent. Invagination of the epithelium into the cyst walls was a key diagnostic feature, was present as cords, trabeculae, solid nests, and small and large follicles, and was identified in most tumors (17 AGCTs and 45 JGCTs). Cytologic atypia was essentially absent in AGCTs, whereas 14 JGCTs showed moderate to severe atypia of bizarre type. A theca cell component was present in all tumors and was extensive in 54. A FOXL2 hotspot mutation was identified in 1 of 4 AGCTs tested. CONCLUSIONS.­: Despite extensive denudation, the finding of typical architectural patterns and cytologic features as well as, in some cases, androgenic manifestations helps differentiate cystic GCTs from follicle cysts, the most common and challenging differential diagnosis, as well as other cystic neoplasms that may enter the differential diagnosis. FOXL2 sequencing may show a false-negative result in cystic AGCT because of the limited number of cells present within the tumor sample.

Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury.

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Sclerosing stromal tumour: a clinicopathological study of 100 cases of a distinctive benign ovarian stromal tumour typically occurring in the young.

AIMS: Since the sclerosing stromal tumour (SST) of the ovary was first described in 1973, few studies have expanded upon its histological features or overlap with other tumours. We thus investigate these aspects based on our experience with 100 cases. METHODS AND RESULTS: The patients, 14 of whom were pregnant, ranged from 12 to 63 years (median = 26 years). Ten patients had hormonal manifestations (seven oestrogenic, three androgenic). Bilateral ovarian involvement was present in two cases. Size ranged from 1 to 23 cm (mean = 8.4 cm). Most tumours were solid and white with focal yellow areas; oedema with cystic degeneration (seen in 25 cases) resulted in eight being predominantly cystic. On microscopic examination, alternating cellular and paucicellular areas (pseudolobulation) were prominent in 94 cases but seen to a limited degree in the remaining neoplasms. Admixed spindled and luteinised cells were present in all tumours, but 13 demonstrated mainly spindled cells and 19 demonstrated mainly lutein cells; 14 of the latter were from pregnant patients. The stroma was typically oedematous or collagenous, but in 14 cases was prominently hyalinised and, in four, myxoid. Prominent vascularity was present in most cases. The mitotic rate ranged from 0 to 8/10 high-power fields (HPF), but most demonstrated <1/10 HPF. CONCLUSIONS: The differential diagnosis of SST is broad, including fibromas, thecomas, solitary fibrous tumours, pregnancy luteomas, myxomas, other ovarian sex cord-stromal tumours with sclerosis and, rarely, Krukenberg tumours. Strict adherence to the requirement of pseudolobulation, prominent (usually ectatic) vessels, and lutein cells and fibroblasts admixed in a jumbled manner, will distinguish the neoplasm from others in the differential.

Müllerian Mucinous Cystadenomas of the Ovary: A Report of 25 Cases of an Unheralded Benign Ovarian Neoplasm Often Associated With Endometriosis and a Brief Consideration of Neoplasms Arising From the Latter.

A subset of ovarian mucinous tumors demonstrates müllerian-type epithelium, with such lesions variably designated "endocervical-like" and seromucinous since their popularization based on a report of borderline examples in 1989. While müllerian mucinous borderline tumors and carcinomas have been highlighted in the literature, there has been minimal attention given to benign müllerian mucinous tumors, particularly müllerian mucinous cystadenomas. Given the paucity of literature describing the features of müllerian mucinous cystadenomas/cystadenofibromas, diagnostic difficulties may arise when papillary features are present and in cases that show a subtle transition from endometriosis. We thus reviewed 25 cases of müllerian mucinous cystadenoma/cystadenofibroma to highlight the notable characteristics of this entity, including gross, cytologic, and architectural features that aid in the distinction from müllerian mucinous borderline tumors as well as, rarely, metastatic tumors. The patients ranged in age from 26 to 85 yr old. Bilateral ovarian involvement was frequent (40%). The ovaries ranged from 2.3 to 26 cm in greatest dimension. Most were multicystic (18 cases) and contained tenacious mucoid material (14 cases). All cases demonstrated predominantly columnar mucinous epithelium with abundant pale-pink cytoplasm. A minor component of ciliated and endometrioid epithelium was seen in 15 and 2 cases, respectively. Broad papillary formations were frequently encountered (9 cases) as was epithelial papillary tufting comprising <10% of the tumor (6 cases). Endometriosis was present in 9 cases, with a transition from endometriosis to mucinous epithelium noted in 8 cases. This series highlights the morphologic features of a relatively uncommon, benign, endometriosis-associated ovarian tumor that may be confused with a müllerian mucinous borderline tumor or bland metastatic mucinous tumors. It also provides an argument for the terminology "müllerian mucinous cystadenoma" or "cystadenofibroma" rather than "seromucinous cystadenoma" due to the frequent association with endometriosis as well as the dominant mucinous epithelium.

Lobular Carcinoma of the Breast Metastatic to the Ovary: A Clinicopathologic Study of 38 Cases.

We evaluated the clinicopathologic features of 38 cases of metastatic lobular (n=33) or predominantly lobular (n=5) carcinoma involving the ovary. The patients were from 39 to 91 years of age (mean: 53 y). In 2 cases, the breast primary and ovarian metastasis were diagnosed synchronously, and in 5, the breast primary was only discovered after the metastatic carcinoma in the ovary was found. In the majority of cases (79%), both ovaries were involved; the mean ovarian tumor size was 5.9 cm. The ovarian tumors demonstrated a range of architectural patterns including macronodular (71%), diffuse/solid growth (87%), single-cell infiltration (87%), cords (74%), and small nests/clusters (50%). Nine cases demonstrated focal signet ring cell morphology. The associated stromal reaction ranged from none to marked, with almost half of cases demonstrating a marked stromal response, largely prominent sclerosis. A variety of neoplasms, most typically sex cord-stromal tumors, lymphoma/leukemia, and desmoplastic small round cell tumor, may enter the differential. In addition to the obvious help afforded in most cases by the clinical history, a combination of judicious sampling, particularly to unearth the delicate cords or single-cell growth of lobular carcinoma, appropriate consideration of the cytologic features of the neoplastic cells, and immunohistochemistry can resolve the diverse issues in differential diagnosis that may arise.

Molecular Pathology of Ovarian Epithelial Neoplasms: Predictive, Prognostic, and Emerging Biomarkers.

This review focuses on the diagnostic, prognostic, and predictive molecular biomarkers in ovarian epithelial neoplasms in the context of their morphologic classifications. Currently, most clinically actionable molecular findings are reported in high-grade serous carcinomas; however, the data on less common tumor types are rapidly accelerating. Overall, the advances in genomic knowledge over the last decade highlight the significance of integrating molecular findings with morphology in ovarian epithelial tumors for a wide-range of clinical applications, from assistance in diagnosis to predicting response to therapy.

Defining Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Placentitis.

CONTEXT.­: Case reports and rare case series have demonstrated variable placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In rare small studies demonstrating infection of the placental parenchyma, histologic manifestations have included variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and syncytiotrophoblast necrosis. OBJECTIVE.­: To characterize the placental pathologic features of SARS-CoV-2-infected placentas, irrespective of fetal-maternal transmission, and to examine the frequency of C4d activation in such cases. DESIGN.­: A retrospective study of 7 placentas from mothers with active SARS-CoV-2 infection and placental infection as demonstrated by RNA in situ hybridization was conducted. RESULTS.­: There were 6 placentas from live-born neonates (5 singletons, 1 nonfused diamniotic-dichorionic twin placenta), and 1 was from a stillbirth. A total of 5 of the 8 neonates (including the stillbirth) tested negative for SARS-CoV-2, and all were negative for neonatal infection. The remaining 3 neonates were well at time of discharge. All placentas were positive for SARS-CoV-2 infection by RNA in situ hybridization and demonstrated variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. Three cases demonstrated features of fetal vascular malperfusion. CD68 highlighted intervillous histiocytes. C4d expression was present along the villous borders in 6 of 7 cases. CONCLUSIONS.­: SARS-CoV-2 placentitis is defined by the triad of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. The features may occur in cases without confirmed transplacental transmission. The damage caused by SARS-CoV-2 placentitis is likely mediated by complement activation.

Endometrial Tumor Classification by Histomorphology and Biomarkers in the Nurses' Health Study.

OBJECTIVE: Endometrial cancers have historically been classified by histomorphologic appearance, which is subject to interobserver disagreement. As molecular and biomarker testing has become increasingly available, the prognostic significance and accuracy of histomorphologic diagnoses have been questioned. To address these issues for a large, prospective cohort study, we provide the results of a centralized pathology review and biomarker analysis of all incidental endometrial carcinomas occurring between 1976 and 2012 in the Nurses' Health Study. METHODS: Routine histology of all (n = 360) cases was reviewed for histomorphologic diagnosis. Cases were subsequently planted in a tissue microarray to explore expression of a variety of biomarkers (e.g., ER, PR, p53, PTEN, PAX2, AMACR, HNF1ß, Napsin A, p16, PAX8, and GATA3). RESULTS: Histologic subtypes included endometrioid (87.2%), serous (5.6%), carcinosarcoma (3.9%), clear cell (1.7%), and mixed type (1.7%). Biomarker results within histologic subtypes were consistent with existing literature: abnormal p53 was frequent in serous cases (74%), and HNF1ß (67%), Napsin A (67%), and AMACR (83%) expression was frequent in clear cell carcinomas. Our dataset also allowed for examination of biomarker expression across non-preselected histologies. The results demonstrated that (1) HNF1ß was not specific for clear cell carcinoma, (2) TP53 mutations occurred across many histologies, and (3) GATA3 was expressed across multiple histotypes, with 75% of positive cases demonstrating high-grade features. CONCLUSIONS: Our findings establish the subtypes of endometrial cancer occurring in the Nurses' Health Study, corroborate the sensitivity of certain well-established biomarkers, and call into question previously identified associations between certain biomarkers (e.g., HNF1B) and particular histotypes.

Dysgerminoma of the Ovary: An Analysis of 140 Cases Emphasizing Unusual Microscopic Findings and Resultant Diagnostic Problems.

One-hundred fourty pure dysgerminomas were evaluated with particular focus on the microscopic features as seen in 125 cases with available slides. The patients ranged from 8 to 59 years of age (mean, 24.1 y). The tumors, bilateral in 4% of the cases and with a mean tumor diameter of 13 cm, were typically soft, lobulated, homogeneous, and creamy white to tan to yellow but necrosis was found in 13%, hemorrhage in 20%, and focal cystic change in 15%. On microscopic examination, the patterns and other notable features encountered, including their frequency, were as follows: an alveolar pattern resulting from delicate fibrovascular septa (51%), diffuse (33%), macronodular (14%), insular (26%), cords (28%), solid tubular (17%), microspaces (sometimes simulating glands) (12%), follicle-like spaces (5%), prominent fibrous bands (65%), stromal edema (56%), stromal luteinization (9%), granulomatous infiltrate (46%), lymphocytic infiltrate (100%), Langhans cell type giant cells (35%), syncytiotrophoblast giant cells (6%), prominent population of cells with pale to clear cytoplasm (73%), cells with amphophilic to eosinophilic cytoplasm (53%) and vacuolated occasionally signet ring-like cells (7%). Various constellations of the above findings often resulted in an appearance different from that usually portrayed in the literature and certain tumors of very different nature being in the differential such as undifferentiated carcinoma not otherwise specified, small cell carcinoma of hypercalcemic type, and malignant lymphoma. The correct diagnosis can be arrived at by considering the usual relative youth of the patient, often rather characteristic gross features, and most crucially careful attention to the microscopic features and awareness of variant morphologic findings. Those that are particularly problematic based on this study are diffuse growth with inconspicuous fibrovascular septa, macronodules, cords, solid tubular formations, spaces ranging from small to large, and mimicking glands or follicles, prominent fibrous to edematous stroma, and cells with amphophilic to eosinophilic cytoplasm. According to the degree of difficulty and confidence of the interpreter, well-known immunohistochemical features of dysgerminoma, which largely differ from those of other neoplasms in the differential, will aid if felt indicated.