Kyle M. Devins

Ovarian sex cord-stromal tumors are a diverse class of neoplasms including both benign tumors and those with malignant potential. These tumors can cause a variety of diagnostic issues for pathologists due to their morphologic diversity and the relative rarity of some neoplasms in this group. The basic clinicopathologic features of these tumors are well known and illustrated. Thus, herein we discuss select entities, emphasizing recent advances, molecular genetic findings, and commonly encountered diagnostic issues. These include issues regarding FOXL2 and DICER1 mutational analysis, high grade/anaplastic transformation in granulosa cell tumors, evolving understanding of Sertoli-Leydig cell tumors, and recent insights into the enigmatic gynandroblastoma. Relevant features of Sertoli cell, signet ring, and microcystic stromal tumors are also discussed, along with the unique immunohistochemical and genetic features of select tumors that mimic sex cord-stromal neoplasms. The latter category includes endometrioid carcinomas with sex cord-like morphology which are frequently PAX8-negative, as well as recently described entities defined by specific gene alterations including GLI1 , EWSR1/FUS::CREB1/CREM , and STK11 .

Outcomes of vulvar squamous cell carcinoma (vSCC) are driven by human papillomavirus (HPV) and p53 status. As tumor budding activity (TBA) and tumor-stroma ratio (TSR) are prognostic in other carcinomas, we evaluated their significance in vSCCs. Tumors diagnosed from 1990 to 2022 were identified, and clinicopathologic data, TBA, and TSR were assessed. The cohort included 172 tumors: 73 (42.5%) HPV-associated, 74 (43%) HPV-independent/p53-abnormal, and 25 (14.5%) HPV-independent/p53-wild-type. Median patient age was 69.5 (22 to 98) years. Most tumors were staged as pT1b (132, 76.7%). Lymphovascular invasion (LVI) was present in 25 (14.5%), and lymph node metastases in 24.6% (33/134) of cases with nodal evaluation. The median TBA was 2 (0-45)/1 high-power field (HPF), 4 (0-198)/5 HPF, and 5 (0-304)/10 HPF. The median TSR was 60% (10% to 90%). Seventy (40.7%) patients experienced recurrences (median: 14 mo, 2-141). Increased TBA at ≥20/10 HPF was associated with shorter recurrence-free survival (RFS) in the entire cohort ( P =0.002) and HPV-independent/p53-abnormal vSCCs ( P =0.003). This association persisted in the HPV-independent/p53-abnormal vSCCs after adjusting for LVI, and T and N categories of pTNM stage ( P =0.012), and in the entire cohort after adjusting for tumor subtype and other covariates ( P =0.01). TBA was also associated with shorter disease-specific ( P =0.048) and overall ( P =0.009) survival after adjusting for tumor subtype, LVI, and T and N categories. Our study suggests that high TBA is associated with shorter recurrence-free survival in vSCC, particularly the HPV-independent/p53-abnormal subgroup, as well as with shorter disease-specific and overall survival after adjusting for tumor subtype, LVI, T and N categories. The findings warrant further validation.

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We performed a retrospective review of cases sent in consultation wherein physiological ovarian follicles, corpora lutea, or their constituent cells raised concern for malignancy based on architectural or cytologic features. The 57 cases were broadly divided into 4 groups. The largest (n=31) showed tangential sections through the granulosa (n=18) or theca (n=13) layers of developing follicles. The irregular appearance, high baseline mitotic activity (median: 20 mitoses/10 high-power fields), and occasional Call-Exner–like spaces (n=6) contributed to concern. The second group (n=20) consisted of corpora lutea in which tangential sectioning or partial involution imparted an unusually complex architecture; mitoses were prominent in 8 of these cases, and endocrine-type atypia was seen in 5. The third group consisted of 2 cases in which corpora albicantia formed an appreciable mass. The final group consisted of 4 cases where artifactually detached granulosa cells from developing follicles were present within vascular spaces, mimicking intravascular malignancy. Extensive sampling revealed no associated ovarian neoplasm. In discussing these unusual appearances of physiological granulosa and theca cells, we briefly review the histology of developing follicles and other benign proliferations that may mimic sex cord-stromal neoplasia. Awareness of these variations of normal histology is critical to prevent misdiagnosis of malignancy.

Introduction: Reliability of intraoperative assessment of donor liver allografts for steatosis, an important risk factor for future graft dysfunction, is limited by poor inter‐observer agreement. To address this issue, consensus guidelines by the Banff working group in 2022 proposed a standardized steatosis algorithm to improve agreement; however, the practical impact of the proposal has not been well‐validated across subspecialty practices and experience levels. Methods: This single‐institution inter‐observer agreement study entailed two rounds of evaluation of 27 frozen donor liver biopsies by 15 pathologists with a range of subspecialty expertise and experience levels. Raters estimated the amount of macrovesicular steatosis (MVS) by individual methods and, subsequently, using the proposed Banff algorithm. Results: Moderate agreement was observed among pooled raters, irrespective of method used (ICC 0.55 vs. 0.47 for individual and Banff methods, respectively) for precise estimation of MVS. Importantly, though, when precise estimates were reduced to clinically relevant grades, the Banff method improved agreement from ‘fair’ to ‘substantial’ compared with individual methods, with the most marked improvement among gastrointestinal subspecialists and pathologists with > 10 years of experience. The Banff method also resulted in overall lower grade estimates, with no ‘grade 3’ estimates provided, including from biopsies with abundant and azonal MVS, which are notoriously challenging. Conclusion: The findings support utilization of the Banff method as a means of improving inter‐rater agreement among diverse pathologists, resulting in more reliable estimation of MVS at clinically significant thresholds.

Vulvar smooth muscle tumors have been evaluated using site-specific (1979 and 1996 Vulvar Criteria) or Uterine Criteria. We compared the performance of 3 classification systems for predicting clinical behavior in the largest series of 35 such tumors to date. Follow-up was available for 30 patients (median: 63 mo, 1 to 346). Most presented as a painless mass in premenopausal patients and showed spindled or myxoid morphology. Diagnoses were concordant across all 3 classification systems in most cases (80%, 28/35), including 22 leiomyomas and 6 leiomyosarcomas. Of the 7 discordant tumors, 3 with ≥5 cm, moderate to marked cytologic atypia, 5 mitoses per 10 high-power fields (HPF), and no tumor cell necrosis or infiltrative borders were diagnosed as smooth muscle tumors of uncertain malignant potential (STUMP) by the Uterine Criteria but as leiomyosarcoma/low-grade leiomyosarcoma by the site-specific criteria. Two tumors (≥5 cm, 8 to 9 mitoses per 10 HPF, no cytologic atypia or tumor cell necrosis, and unevaluable borders) were classified as mitotically active leiomyoma by the Uterine Criteria and the 1996 Vulvar Criteria but as low-grade leiomyosarcoma by the 1979 Vulvar Criteria. Two tumors with tumor cell necrosis, moderate atypia, 9 and 66 mitoses per 10 HPF, but <5 cm and well-circumscribed borders were categorized as leiomyosarcoma by the Uterine Criteria but as leiomyoma by both site-specific criteria. Our findings support the validity of the Uterine Criteria relative to the site-specific criteria for vulvar smooth muscle tumors, although the applicability of these criteria to the STUMP category warrants further study.

Serous carcinomas are copy-number-high (p53-abnormal) endometrial carcinomas with adverse outcomes. We aimed to assess the prognostic value of classic morphologic features in these tumors. Treatment-naive uterine serous carcinomas diagnosed from 1995 to 2022 were identified, and clinical-pathologic features were evaluated. The median age was 71 (52 to 95) years. Of 138 tumors, most (87 [63%]) were myoinvasive, and 51 (37%) were endometrium-confined, including 11 (21.6%) with only intraepithelial growth and 40 (78.4%) with stromal invasion within polyps and/or background endometrium. Predominant growth pattern was papillary in 63 tumors (45.6%), glandular in 60 (43.5%), and solid in 15 (10.9%). Lymphovascular invasion (LVI) was present in 49 (35.5%) cases, with nodal micro/macrometastases in 25/106 (23.6%) and isolated tumor cells in 3/106 (2.8%). Of 126 patients with follow-up (median: 38 mo, 0.9 to 230.7), 49 (38.9%) experienced recurrences and 27 (21.4%) died of disease. Both recurrence-free and disease-specific survival were associated with T category of pTNM staging, FIGO stage, endometrial stromal invasion, myoinvasion, margin status, cervical, lower uterine segment, and uterine serosal involvement (all P P ≤0.002), predominant growth pattern, surrounding intraepithelial growth, and multinucleated tumor cells ( P ≤0.01). Patients with only intraepithelial growth experienced no recurrence or cancer-related death. LVI was associated with decreased recurrence-free ( P P P =0.0049) and uterine serosal involvement ( P =0.0514) were independent predictors of recurrence-free survival, with T category ( P =0.03) also predicting disease-specific survival. The presence of only intraepithelial growth portends a favorable prognosis in serous carcinoma, whereas the clinical significance of the extent of LVI is limited.

Sex cord-like morphology is now a well-known feature of occasional examples of endometrioid carcinoma of the ovary or fallopian tube. Recently, we have observed that these tumors are frequently negative for PAX8, prompting us to review their morphologic, immunohistochemical, and genomic spectrum. Twenty tumors (17 ovarian, 3 fallopian tube) with available tissue were identified in patients ranging from 32 to 78 (median 60) years. Sex cord-like patterns included cords/trabeculae (n=17), small tubular glands (n=16), and “granulosa-like” nests (n=12). In addition, 1 had ependymoma-like features with perivascular pseudorosettes and 3 had focal spindled cells. Conventional endometrioid glands were often sparse. All had conspicuous fibromatous stroma and 11 tumors had background endometrioid adenofibromas. Six tumors had associated endometriosis. PAX8 was positive in only 2/20 (diffuse in both), while SOX17 was positive in all (focal in 1, diffuse in 19). Beta-catenin showed aberrant nuclear staining in 17/20. Of the 10 sequenced tumors, 9 showed activating pathogenic variants in CTNNB1; each of these also showed nuclear beta-catenin staining. All lacked alterations in mismatch repair genes, TP53 , and POLE . In summary, adnexal endometrioid carcinomas with sex cord-like features are frequently PAX8-negative, which may result in diagnostic difficulty. However, SOX17 is typically positive and thus useful to establish the diagnosis. Most of these tumors are classified in the “no specific molecular profile” subgroup and have high rates of nuclear beta-catenin/ CTNNB1 alterations. Awareness of these morphologic and immunohistochemical associations may help avoid misclassification as sex cord-stromal or other neoplasms.