Gulisa Turashvili

Isolated morular squamous metaplasia in endometrial biopsies and curettings: is there a role for repeated sampling?

Aims Endometrial atypical hyperplasia and low‐grade endometrioid carcinoma are often associated with morular squamous metaplasia. Limited evidence suggests that the finding of isolated morular squamous metaplasia without concomitant glandular neoplasia in biopsies is associated with a 6.5% risk of endometrial cancer in subsequent samples and warrants close follow‐up. However, its prognostic value has not been clearly determined. Methods and results The Massachusetts General Hospital pathology database was queried to identify endometrial samples with a diagnosis of ‘adenoacanthosis’, ‘morular metaplasia’, ‘squamous metaplasia’ or ‘morular squamous metaplasia’ between 2012 and 2024. Cases associated with endometrioid carcinoma, non‐atypical or atypical hyperplasia, atypical polypoid adenomyoma and gland crowding insufficient for diagnosis of atypical hyperplasia were excluded. Clinicopathologic data were collected. Outcomes were categorized as regression, persistence and progression to carcinoma. Of 32,800 endometrial samples reported during the study period, isolated morular squamous metaplasia was diagnosed in 57 (0.17%), including 42 (73.7%) biopsies and 15 (26.3%) curettings. The median patient age was 45 (21–70) years. Histologic follow‐up (at least one follow‐up sample) was available in 22 patients (median 30 months, 1–120) and included endometrial biopsy, curettage or hysterectomy. Of these 22 patients, a single follow‐up biopsy was performed in 9 (40.9%), a single curettage in 1 (4.5%), hysterectomy in 6 (27.3%), a single biopsy followed by hysterectomy in 2 (9.1%), multiple biopsies in 3 (13.6%) and a curettage followed by multiple biopsies and hysterectomy in 1 (4.5%). The median number of follow‐up samples was 2 (2–9) per patient. Histologically, the follow‐up samples were unremarkable (regression) in most patients (19/22, 86.4%), 2 (9.1%, aged 49 and 57 years) were diagnosed with grade 1 endometrioid carcinoma in subsequent hysterectomies, and 1 (4.5%, age 62) had persistent squamous morular metaplasia (follow‐up 69 months). In 15 patients with clinical follow‐up but no further pathology sampling, none had clinical symptoms at their last visit (100% clinical regression). Thus, the overall rate of endometrioid carcinoma was 5.4% (2/37). Conclusions Isolated squamous morular metaplasia without associated glandular neoplasia is a rare finding, reported only in 0.17% of endometrial samples. The risk of subsequent endometrioid neoplasia appears to be low (5.4%), although the possibility of undersampled atypical hyperplasia/endometrioid carcinoma cannot be completely ruled out without additional sampling. Persistent squamous morular metaplasia is relatively uncommon (4.5%) and may not lead to the subsequent diagnosis of endometrial cancer, questioning the utility of numerous repeat samplings in patients without progression after one repeat sample.

Malignant Brenner Tumor of the Ovary: A Critical Reappraisal

Malignant Brenner tumors (MBTs) are rare epithelial tumors of the ovary, most likely arising from benign and borderline Brenner tumors. MBTs may be misdiagnosed as other primary carcinomas or nonepithelial tumors of the ovary as well as metastatic carcinomas. Accurate diagnosis usually requires clinical-radiologic correlation, extensive sampling, and immunohistochemical studies. Treatment is not standardized and may include surgery with or without chemotherapy. More than half of MBTs are diagnosed at stage I, with 47.7% and at least 20% recurrence and mortality rates, respectively. Awareness of key diagnostic features and pitfalls is essential to differentiate MBT from its mimics and ensure optimal clinical management. This comprehensive review includes classification, etiopathogenesis, historical overview, epidemiology, clinical features, treatment, prognosis, gross pathology, key morphologic features, ancillary testing, and differential diagnostic considerations for ovarian MBTs.

Comparison of HER2 Scoring Systems in Endometrial Cancer

Endometrial carcinomas (EC) show variable HER2 protein expression or gene amplification and may be eligible for HER2-directed therapy (trastuzumab or antibody-drug conjugates (ADCs) such as trastuzumab-deruxtecan). HER2 testing is currently recommended in advanced-stage/recurrent serous carcinomas and carcinosarcomas. However, no universally adopted reporting guidelines exist, and institutional practices vary. We aimed to analyze our experience with HER2 testing and compare gynecologic (GyC), gastric (GaC), and breast (BrC) criteria. We identified ECs with available HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) results where applicable. HER2 IHC was reassessed using GyC, GaC, and BrC. The overall HER2-positivity rates were 31% by GyC and BrC, and 35.7% by GaC. The scoring systems significantly differed, with 69.8% concordance between GaC and GyC (P<0.001) and 99.2% concordance between BrC and GyC. Our results emphasize the importance of using the appropriate HER2 scoring criteria depending on the type of intended HER2-directed therapy as well as comprehensive yet perspicuous reporting of HER2 status to ensure optimal clinical outcomes in EC patients.

Analysis of Human Epidermal Growth Factor Receptor 2 (HER2) Heterogeneity at the Protein and Gene Levels in Endometrial Cancer: Refining HER2 Reporting and HER2-Directed Therapies

Targeted therapy directed against human epidermal growth factor receptor 2 (HER2) has shown promising results in HER2-positive endometrial cancer. Recent limited data suggest significant intratumoral heterogeneity in HER2 expression in serous carcinomas. We aimed to evaluate HER2 heterogeneity at the protein and gene levels and the impact of variable definitions in endometrial carcinomas including nonserous subtypes. We retrospectively identified biopsies and surgical specimens with available HER2 immunohistochemical (IHC) stains and fluorescence in situ hybridization (FISH) results. IHC stains and FISH data were reevaluated to assess variability in the HER2 protein expression and gene amplification. The overall HER2-positivity rate was 31% using the endometrial criteria, and 42.6% by the gastric criteria. Heterogeneous IHC staining was observed in 45.7% of tumors, predominating in 2+/3+ scores (P < .001). Re-evaluation of FISH revealed a 31% rate of heterogeneous gene amplification. Our study demonstrates a high frequency of HER2 heterogeneity at both the protein and the gene levels. Further studies on HER2 heterogeneity and treatment response are warranted for refining standardized testing and reporting algorithms.

A Distinctive DICER1-Related Wilms-Like Uterine Tumor: A Report of Eight Cases

The presence of DICER1 mutations associated with overlapping morphologic features in tumors arising at different sites has been suggested to define an emerging category of DICER1-related neoplasms. We undertook a clinicopathologic and molecular characterization of uterine tumors originally diagnosed as Wilms tumors to ascertain if they belong to the spectrum of DICER1-related neoplasms. Of 8 patients with a median age of 36.5 (17-69) years, 5 underwent hysterectomy, 2 endometrial curettings, and 1 polypectomy. Most tumors were centered in the endometrium, and 6 were polypoid with a median size of 8 (3.5-16) cm. All showed a variable admixture of primitive mesenchyme and epithelial-like elements set in a hypocellular, edematous to focally myxoid stroma. The epithelial-like elements were the most extensive component, showing a lobular arrangement, including variably sized and shaped primitive tubules with focal confluent/solid growth and cribriforming, as well as glomeruloid and rosette-like structures. Some primitive tubules had intraluminal projections in 3 tumors, imparting an adenosarcoma-like appearance. Scattered glands with fetal-type epithelium were seen in 7 tumors. Rhabdomyosarcomatous differentiation was present in 6 tumors, and neuroectodermal differentiation and fetal-type cartilage in 3 tumors each (including 2 with both features). DICER1 sequencing was successful in 5 of 6 tumors tested, with 4 harboring DICER1 mutations, including all 3 with neuroectodermal differentiation and adenosarcoma-like foci. Fetal-type cartilage was present in 2 of 4 DICER1-mutant tumors and 1 tumor with unknown DICER1 status. Follow-up was available for 6 patients. The patient with DICER1 wild-type tumor (associated with low-grade endometrial endometrioid carcinoma and KRAS mutation) died of disease at 9 months. Of 4 patients with DICER1-mutant tumors, 1 recurred at 7.5 months, 2 were alive without disease at 12 and 38 months, respectively, and 1 was alive with unknown disease status at 31 months. Another patient with unknown DICER1 status was alive at 196 months. Uterine tumors diagnosed as Wilms tumors belong to the spectrum of DICER1-related neoplasms at this site and are best described as a "DICER1-related Wilms-like uterine tumor." These unique tumors are likely part of the larger category of "DICER1-related primitive polyphenotypic neoplasm," warranting further studies.

ADNP (Activity Dependent Neuroprotector Homeobox): A novel oncogene driving poor prognosis in high-grade serous carcinoma

Vulvar Cellular Angiofibroma With Cytologic Atypia and Sarcomatous Transformation: A Clinicopathologic Analysis

Cellular angiofibromas (CAFs) are benign mesenchymal neoplasms of the vulva and lower genitourinary tract. Although most cases are benign with excellent prognosis, data on CAFs with cytologic atypia (aCAF) and sarcomatous transformation (tCAF) is limited. We identified 13 vulvar CAFs comprising 4 aCAFs and 9 tCAFs. The median age at presentation was 49  yr (40–84). All tumors involved the subcutis with a median size of 4.75 cm (0.8–11.7). Vascular and stromal hyalinization was present in all cases. Fascicular growth pattern and chronic perivascular inflammation were seen in 10 cases, followed by wispy collagen in 11 and stromal inflammation in 12. Common features were fat entrapment (n=8), stromal edema (n=7), and hemangiopericytoma-like vessels (n=5), while myxoid change, necrosis (n=3 each), hemorrhage, collagen bundles (n=2 each), solitary fibrous tumor-like appearance, and large hyalinized vessels (n=1 each) were rare. The atypia ranged from isolated atypical cells to foci of multinucleated cells, with brisk mitoses in 1 case. The sarcomatous transformation involved 10% to 80% of total tumor volume and comprised features of well-differentiated liposarcoma, pleomorphic liposarcoma, leiomyosarcoma, and spindle and epithelioid cell sarcoma. Diffuse p16 expression was present in 2 tCAFs. Of 10 patients with available follow-up (median: 103.3 mo, 13.3–156.6), 2 (20%) recurred at 41 mo and 66 mo and remained disease-free at 157 and 99  mo post reexcision, respectively. The study provides a detailed clinicopathologic characterization of rare variants of CAF, aCAFs, and tCAFs, and reports rare recurrences, most likely due to incomplete surgical excision.

Presence and extent of lymphovascular invasion in surgical stage I squamous cell carcinoma of the cervix: a comprehensive, international, multicentre, retrospective clinicopathological study

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.

DICER1-Associated Gynecologic Neoplasms: An Update and Review

DICER1 plays a crucial role in the biogenesis and maturation of microRNAs. Germline mutations in the DICER1 gene are associated with an increased risk of developing a wide range of benign and malignant neoplasms. The same tumors may also arise sporadically due to somatic DICER1 mutations. In syndromic patients, a germline loss-of-function DICER1 mutation is usually followed by a somatic hotspot mutation in the tumor as a second hit. In the gynecologic tract, DICER1 -associated neoplasms include most commonly embryonal rhabdomyosarcoma and moderately to poorly differentiated Sertoli-Leydig cell tumor, and less frequently pleuropulmonary blastoma-like peritoneal sarcoma, adenosarcoma, gynandroblastoma, juvenile granulosa cell tumor, and Sertoli cell tumor. Irrespective of the primary site of origin, DICER1 -associated neoplasms frequently share characteristic morphology, including primitive mesenchyme, fetal-type epithelium, fetal-type cartilage, rhabdomyoblastic and/or neuroectodermal differentiation, osteoid formation, and anaplasia. Recognition of these distinctive features in gynecologic tumors should prompt consideration of a DICER1 -associated neoplasm followed by genetic testing, thereby facilitating surveillance for patients and their families. As illustrated in this review, the morphologic spectrum of most DICER1 -mutant gynecologic neoplasms (eg, DICER1 -related Wilms-like uterine tumor) appears to be wider than that of any known type of sarcoma. Therefore, we propose that the term “ DICER1 -related primitive polyphenotypic neoplasm” may be more inclusive of the diverse histologic features and thus more appropriate for these unique neoplasms.