Carlos Parra-Herran

Focal necrotizing endometritis (FNE) is a rare phenomenon consisting of localized periglandular and intraglandular inflammation with luminal accumulation, epithelial cell necrosis, and absence of plasma cells. Since its initial morphologic description, FNE has not been further studied. We document clinical correlates, morphology, and immunophenotype of glandular (using PAX2, PTEN, Β-catenin, MSH6, and PMS2) and inflammatory (using CD3, CD20, CD4, CD8, and CD138) populations in 13 cases of FNE identified over a 4-yr period, representing 0.5% of all endometrial biopsies surveyed. Immunohistochemistry for CD3, CD20, CD4, CD8, CD138, PAX2, PTEN, B-catenin, MSH6, and PMS2 was used to characterize cellular components. The mean patient age was 43 (range: 31–61), and body mass index was 32 (range: 23–54). Biopsy was performed for infertility/recurrent pregnancy loss (n=7), abnormal uterine bleeding (n=5), or postmenopausal bleeding (n=1). In all biopsies, the process was confined to <8 glands. The infiltrate was T-cell predominant in 11/13 cases; in 2 cases, there was similar density of CD20- and CD3-positive cells. In all cases, CD8-positive T cells predominated over CD4-positive cells. CD138 was negative in all FNE areas. Affected glands showed normal nuclear PMS2, MSH6, and PAX2, as well as membranous Β-catenin, in all cases. PTEN consistently showed reduced staining, but no definitive loss compared with uninvolved glands. Three patients received doxycycline. Follow-up biopsies were available for 7 patients, with only one showing persistent FNE. Subsequent pregnancy was achieved in 4/7 patients with FNE and infertility. FNE is an uncommon phenomenon characterized by focal gland involvement by a predominant cytotoxic T-cell population, likely in response to cell damage. The lesion tends not to recur and does not appear to be associated with adverse pregnancy outcomes. A nonaberrant profile of PTEN, PAX2, MSH6, PMS2, and Β-catenin argues against FNE representing a response to early endometrioid neoplasia. Pathologists need to be aware of the occurrence of FNE and distinguish it from clinically actionable inflammation, namely chronic endometritis.

A subset of uterine leiomyomas becomes clinically apparent during pregnancy/delivery and is typically excised during Cesarean section. Although benign, these leiomyomas excised during pregnancy and/or delivery (LEPs) can pose diagnostic challenges due to morphologic changes that mimic malignant mesenchymal neoplasms, such as leiomyosarcoma. This study analyzed 97 LEPs to characterize their histopathologic and immunohistochemical features. Histologic examination revealed predominantly low mitotic activity (mean: 0.5 mitoses/10 HPFs) and mild (87.6% of tumors) to at most focal moderate (9.3% of tumors) nuclear atypia. Ischemic necrosis occurred in 57.7% of tumors. Features attributed to coagulative necrosis were common, including sharp viable-nonviable transition (22.7%), perivascular tumor preservation (9.3%), and ghost outlines of tumor cell nuclei (50.5%). Focal myxoid changes, affecting ≤30% of tumor volume, were seen in 42.3% of tumors. Rare, bizarre cells were identified in 48.5% of tumors. Immunohistochemistry demonstrated the absence of estrogen receptor staining in 65% of tumors, with focal staining in 35.2%, and progesterone receptor expression in 97.7%. Caldesmon (98.9%) and desmin (100%) were positive, with the majority diffuse. CD10 (100%) showed variable staining intensity. Wild-type p53 expression was seen in all tumors tested. Expression of ATRX, MTAP, RB1, and PTEN was predominantly retained with equivocal staining in 35.3% (ATRX) and 3.4% (RB1) of tumors. Although Cyclin D1 expression was common (97.4%), it was always focal, with no diffuse (≥70%) strong nuclear staining. FH loss occurred in 3.2% of tumors. All tumors were negative for MelanA, and 92.4% were negative for HMB45. Calretinin expression was observed in 39% of tumors, typically focal and strong, while only 1 tumor showed positive inhibin staining in <5% of cells. ALK expression was focally positive or equivocal in 9.6% of cases, but no gene rearrangements were identified by in situ hybridization. Follow-up data were available for 71 patients (mean: 56 mo), with no malignant transformation or recurrence. These findings confirm that LEPs exhibit distinct morphologic and immunophenotypic alterations, including features typically attributed to coagulative tumor cell necrosis. However, given benign clinical outcomes, low mitotic activity, and lack of significant atypia, such a finding does not warrant designation as leiomyosarcoma or smooth muscle tumor of uncertain malignant potential in the context of concurrent pregnancy.

Aims: Scarce literature exists regarding the spectrum of vascular neoplasms of the distal female genital tract. Herein, we describe the clinicopathologic features of a cohort of intermediate to malignant endothelial neoplasms of the vulva and vagina. Methods and results: Specimens were identified retrospectively from in‐house and consultation files at our institution. Clinicopathologic data was obtained from review of the chart and available histologic material. Nineteen cases were identified in total. Kaposi sarcoma ( n = 2) was of the enigmatic ‘sporadic’ form in elderly non‐ HIV females. Kaposiform haemangioendothelioma ( n = 1) presented at an older (rather than paediatric) age and was negative for HHV ‐8 by IHC ; both Kaposi sarcomas were positive. Pseudomyogenic haemangioendothelioma ( n = 2) presented in elderly females (rather than young males) with positivity for both FOSB and AE1 / AE3 . Epithelioid haemangioendothelioma ( n = 8), showed variably well‐developed chondromyxoid matrix and consistent positivity for CAMTA1 IHC . Angiosarcomas were disproportionately of the epithelioid subtype, with high‐grade cytologic atypia, destructive infiltration and rare EMA positivity. Conclusions: While many morphologic features of vascular lesions at this site are shared with those of extra‐genital soft tissues, pathologists must be aware that these tumours may occur in the vulvovaginal area and display unconventional clinical profiles. As such, a broad differential for epithelioid and spindle cell neoplasms at this site is prudent.

The term verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) was coined to describe HPV-independent p53-wildtype lesions with characteristic clinicopathologic characteristics and association with vulvar squamous cell carcinoma (vSCC). We aimed to expand on the molecular landscape of vaVIN using comprehensive sequencing and copy number variation profiling. vaVIN diagnosis in institutional cases was confirmed by a second review, plus negative p16 and wildtype p53 by immunohistochemistry. Multigene next-generation sequencing and shallow-whole genome sequencing were used to survey for single-nucleotide variants (SNV), copy number alterations, and structural variants. Targeted TERT promoter sequencing was also carried out. Nineteen patients with vaVIN were included; 4 had concurrent vSCC. The median patient age was 74 (range 56–90) years. Genomic aberrations were noted in 18 cases (95%) as follows: PIK3CA in 10 (53%), CDKN2A in 7 (37%), HRAS in 6 (32%), FAT1 and NOTCH1-2 in 5 each (26%), TSC2 in 2 (11%), and PTEN, ARID2, and KRAS in 1 (5%) each. TERT promoter variants were detected in 11 of 13 cases successfully tested (85%). Five vaVINs harbored a TP53 variant but showed wild-type p53 immunohistochemical expression. In one of these, the concurrent carcinoma showed abnormal p53 and biallelic TP53 mutations. Out of 15 patients with follow-up (mean: 20, range: 2–50 mo), vaVIN persistence/recurrence was seen in 8 (53%), and subsequent vSCC in 2 (13%). At the last encounter, 3 (20%) patients had persistent disease and 1 (7%) died of vSCC. vaVIN is characterized by a wider molecular spectrum, beyond known alterations in PIK3CA, HRAS, and ARID2, to include TERT promoter, CDKN2A, FAT1, and NOTCH1-2, which are characteristic of HPV-independent vSCC. vaVIN can occur with concurrent or subsequent carcinoma, sometimes with fatal outcomes. These findings support the concept of vaVIN as a neoplastic process within the family of HPV-independent vulvar neoplasia.

Gastric-type endocervical adenocarcinomas (GAS) are aggressive HPV-independent neoplasms with molecular alterations in TP53, STK11, CDKN2A, and SMAD4. Claudin-18 (CLDN18) has emerged as a useful marker to distinguish GAS from HPV-associated neoplasia. Its role in separating GAS from benign proliferations and exuberant endocervical glands is unknown. We studied the utility of immunohistochemistry for CLDN18, progesterone receptor (PR), and mutation surrogate stains (P53, STK11/LKB1, MTAP, SMAD4/DPC4) in 46 GAS, 12 benign gastric-type endocervical lesions, 54 benign Mullerian endocervical populations, and 11 HPV-associated endocervical adenocarcinomas. PD-L1 and HER2 immunostains were evaluated in GAS. Gastric-type lesions were more often positive for CLDN18 (100% benign, 78% GAS, most often well to moderately differentiated) compared to benign Mullerian endocervical specimens (all negative) and HPV-associated neoplasia (18%, always focal). Conversely, PR was negative in all gastric-type lesions and positive in 92% of benign Mullerian endocervical populations. GAS revealed aberrant/mutant expression of P53 in 35%, STK11/LKB1 in 25%, MTAP in 23%, and SMAD4/DPC4 in 9% of cases. Abnormal staining in at least one of these 4 mutation surrogate markers was present in 63% of GAS. HER2 score of 3+ was seen in 25% of GAS, and PD-L1 was positive in 37% based on a combined positive score. CLDN18 is a sensitive and highly specific marker of gastric-type benign and malignant endocervical lesions. Once a gastric-type phenotype is confirmed, mutation surrogate immunostains can be used to support a diagnosis of GAS. PD-L1 and HER2 expression is seen in a subset of GAS offering therapeutic options for this aggressive tumor.

Objective: To determine the accuracy of pelvic sentinel lymph node biopsy (SLN) in detecting positive para‐aortic (PA) lymph nodes in high‐grade uterine cancer, and to determine the recurrence rate in patients with high‐grade uterine cancers who did not receive adjuvant chemotherapy based on negative pelvic SLNs. Methods: This was a retrospective cohort study of patients with newly diagnosed, high‐grade endometrial cancer who underwent surgery, including pelvic SLNs with or without PA node dissection, at a tertiary care institution between 2015 and 2020. Baseline demographics, surgical management, pathology data, and outcomes were analyzed using descriptive statistics, and survival analysis. Results: Postoperative histology of the 110 patients meeting inclusion criteria was 45.5% grade 3 endometrioid, 36.4% serous, 10.9% clear cell, and 7.3% carcinosarcoma. On final pathology, 63.7% were stage 1, and 23.6% were stage 3C with positive nodes. A total of 63 patients (57.3%) had a PA lymph node dissection (56 bilateral, 7 unilateral) in addition to the pelvic SLN. Among this group, 5.8% (95% confidence interval 1.2%–16.0%) had a positive PA node despite a negative pelvic SLN. Among those with a negative pelvic SLN and no adjuvant chemotherapy ( n = 75), the rate of distant recurrence was 14.7%, and 3‐year recurrence‐free survival was 71.9%. Conclusion: The rate of isolated PA node metastasis in high‐grade endometrial cancers despite a negative pelvic SLN may be significantly higher than the accepted rate of isolated PA node metastasis in low‐grade endometrial cancer. This supports adjuvant treatment decisions continuing to incorporate primary tumor pathology and molecular classification.