W. Glenn McCluggage

A wide variety of mesenchymal lesions arise in the vulvovaginal region, some relatively site-specific. We report 4 cases of a novel vulvovaginal mesenchymal lesion, which we term vulvovaginal epithelioid mesenchymal neoplasm with “deciduoid” morphology, reflecting the predominant morphologic feature of epithelioid cells with a granular glassy “deciduoid” appearance. The tumors arose in women aged 34 to 48 years and involved the vagina (2 cases) or the vulval Bartholin’s gland region (2 cases). The size ranged from 25 to 55 mm and they were solid and well-circumscribed. The tumors were composed of epithelioid and lesser numbers of spindle-shaped cells with abundant granular glassy eosinophilic cytoplasm, imparting a “deciduoid” morphology; there was prominent vascularity and a mild lymphoid infiltrate. Immunohistochemistry showed consistent diffuse estrogen receptor, progesterone receptor, CD63, and vimentin positivity with no other consistent immunophenotype. Two of the tumors showed immunohistochemical BAP1 loss and exhibited inactivating germline BAP1 variants (BAP1 tumor predisposition syndrome). On molecular testing, all tumors showed copy number loss of genes in 14q and/or 17q regions. Alterations of genes involved in the MAPK pathway were also present in all cases (including NF1 loss, a likely pathogenic variant in FLT3 , and variants of unknown significance in FLT3, BMPR1A , and RUNX1 ). One of the cases harbored a novel FBXL20::MSI2 fusion. On follow-up (8 mo to 15 y), none of the tumors recurred. In reporting this novel neoplasm, we describe in detail the morphologic, immunohistochemical, and molecular features, discuss the differential diagnosis and histogenesis, and establish this novel entity as part of the BAP1 tumor predisposition syndrome.

Adenosquamous carcinoma is a rare malignancy described in a variety of body sites, including the uterine cervix. These tumors exhibit morphologically unequivocal areas of squamous and glandular differentiation and are typically associated with an aggressive clinical course. Primary adenosquamous carcinoma of the vulva, arising outside the Bartholin gland, has only been described in a few case reports, is poorly characterized and is currently not included in the 5th Edition WHO Classification of Female Genital Tumours. We report a series of 3 primary vulvar HPV-independent adenosquamous carcinomas, all arising in the upper vulva close to the junction with the vagina, in close proximity to the urethral meatus. All tumors showed surface ulceration, and there were no features of lichen sclerosus or vulvar intraepithelial neoplasia in the adjacent squamous epithelium. The squamous components ranged from 40% to 70% of the neoplasms. All tumors exhibited mutation-type p53 expression and negative/non–block-type staining for p16. Molecular testing confirmed a TP53 mutation in all tumors and showed an additional AMER1 mutation in one. Two patients presented with lymph node metastasis at the time of diagnosis or shortly thereafter. None of the patients died of their disease, with follow-up ranging from 2 to 81 mo. Our findings suggest that primary vulvar HPV-independent adenosquamous carcinoma is a distinct morphologic entity that warrants inclusion in future classifications of primary vulvar neoplasms.

Aims: The distinction between ovarian immature teratoma (IT) and mature teratoma (MT) relies on the identification of immature neuroectodermal tissue in the former, a task that may be challenging in some tumours and carries significant prognostic and therapeutic implications. SRY‐box transcription factor 2 (SOX2) has been proposed as a marker of immature neuroepithelium, although its expression in mature components of ovarian teratomas has not been systematically investigated. We aimed to assess the diagnostic value and limitations of SOX2, in comparison with SALL4, in differentiating immature from mature neuroectodermal elements. Methods and results: We retrospectively analysed a multicentric cohort of 61 ovarian teratomas (52 MTs and 9 ITs). SOX2 and SALL4 immunohistochemical expression was evaluated across all tissue components with correlation to detailed morphological assessment. SOX2 showed diffuse expression in both immature neuroepithelium and mature neuroectodermal tissues, including glia and ependymal structures, as well as a characteristic layer‐restricted pattern in retinal tissue, while cerebellar tissue was consistently negative; some non‐neural mature epithelial tissues were also positive. SALL4 expression was variably positive in immature neuroectodermal components (specifically in neuroectodermal rosettes) and was absent in all mature components. Notably, heterogeneous SOX2 expression in rosette‐like structures prompted systematic morphological reassessment, leading to reclassification of 5/9 (55.6%) cases initially diagnosed as IT into MT. These findings highlight that SOX2 expression alone may represent a significant diagnostic pitfall, particularly in distinguishing immature neuroepithelium from mature ependymal rosettes. Conclusions: SOX2 is a sensitive marker of neuroectodermal lineage but does not discriminate between immature and mature elements. Its interpretation requires integration with morphology and SALL4 expression to avoid overdiagnosis and inappropriate tumour classification and grading of ITs. A pattern‐based approach to SOX2 staining may improve diagnostic accuracy in ovarian teratomas.

Aims: Papillary squamous intraepithelial lesion (PSIL), also known as papillary immature metaplasia, is a rare anogenital lesion associated with low‐risk human papillomavirus (HPV) infection. The molecular pathogenesis of PSIL remains unclear. This study aims to investigate the activation of YAP1, a Hippo pathway co‐activator, in PSIL and compare it to condyloma and papillary HSIL. Methods and results: YAP1 activation was evaluated by immunohistochemistry using an antibody specific for activated/unphosphorylated YAP1 (act‐YAP1) in 36 PSIL cases, 20 condyloma and 2 papillary HSIL cases. HPV genotyping and chromogenic in situ hybridization (CISH) were performed to determine HPV status. Low‐risk HPV, predominantly HPV6, was detected in 78.6% of PSILs. CISH revealed a diffuse fine punctate distribution of low‐risk HPV E6/E7 transcripts in PSIL, distinct from the large focal clusters seen in condyloma, but similar to high‐risk HPV in HSIL. All PSILs showed non‐block p16 expression. Act‐YAP1 immunostaining demonstrated YAP1 activation in 86.1% of PSILs (72.2% diffuse, 13.9% focal), resembling the pattern in papillary HSIL but differing from condyloma, which exhibited nuclear act‐YAP1 only in basal and granular layers. No significant associations were found between YAP1 activation and HPV status or immunoprofiles of p16, p53, Rb1 and CK7. Conclusions: PSILs demonstrate prominent YAP1 activation, implicating Hippo pathway disruption as a potential driver of PSIL pathogenesis. These findings support a distinct molecular profile of PSIL and provide insight into the biological mechanisms underlying this rare lesion.

We report a unique case of a primary ovarian neoplasm with morphological and immunohistochemical features identical to a pleomorphic salivary adenoma in a 56-year-old female. Morphologically the tumour was composed of cellular nodules of bland glands lined by a double cell layer of epithelial and myoepithelial cells; cartilaginous elements were also present with focal osseous and bone marrow metaplasia. No teratomatous elements were present. Immunohistochemistry confirmed the presence of a double layer of epithelial and myoepithelial cells (S100, p40, p63, SOX10, calponin and smooth muscle actin positive) and showed diffuse nuclear positivity of both cell types for HMGA2. A HMGA2::WIF1 fusion was identified on molecular testing; this fusion is found in some pleomorphic salivary adenomas. As far as we are aware, this is the first report of a pleomorphic adenoma of salivary gland type within the ovary. We speculate on the histogenesis and review “salivary gland-type” neoplasms arising within the ovary.

Primary carcinomas of the vagina are uncommon tumours, accounting for <1% of female cancers; these are also less common than metastatic carcinoma, which constitutes a significant majority of vaginal epithelial neoplasms. The most common primary tumour type is squamous cell carcinoma. Primary adenocarcinomas of the vagina are extremely rare and of various morphological types, many of which are broadly similar to those arising in the cervix. When faced with a probable primary vaginal adenocarcinoma, the pathologist faces a dilemma since the normal vagina does not contain glands, making the origin difficult to explain, and a metastasis should always be excluded. In this review, we discuss primary vaginal adenocarcinomas and provide practical points for the pathologist in typing and reporting these neoplasms and in excluding a metastasis. We also review rare benign vaginal glandular lesions, neoplastic and non‐neoplastic.

Introduction and aims: Lymphovascular space invasion (LVSI) is associated with increased nodal involvement and disease recurrence in cervical squamous cell carcinoma (SCC). While LVSI is currently included in some clinical risk assessment algorithms, the reproducibility of diagnosing LVSI remains understudied in cervical SCC. We aimed to assess the inter‐observer agreement for LVSI diagnosis using digital whole slide images (WSIs) of haematoxylin and eosin‐stained (H&E) slides with presumed true LVSI ( n = 20) and LVSI mimics ( n = 20) from early‐stage cervical SCC identified in an international cohort. Methods and results: The reference diagnosis for LVSI status was established by 2 pathologists through consensus review. Ten independent pathologists from North and South America, Europe, Asia and South Africa were included for blinded scoring of true LVSI versus LVSI mimics. Complete concordance was seen in 57% of cases. Overall percent agreement was 88% with the κ value being 0.76, reflecting substantial agreement on LVSI diagnosis based on H&E WSIs. Conclusions: Our findings support the diagnostic feasibility and reliability of including LVSI as a parameter in routine histologic evaluation for risk stratification of cervical SCC. While the inter‐observer agreement in our study is acceptable, there remains a need for standardised diagnostic criteria and guidance on the use of immunohistochemical studies for the detection or confirmation of LVSI in daily practice.

Adenosquamous carcinoma is an uncommon cervical malignancy which is composed of a morphologically recognisable malignant squamous and glandular component. In the current 5th edition WHO Classification of Female Genital Tumours, adenosquamous carcinoma of the cervix is regarded as a high-risk human papillomavirus (HPV)-associated neoplasm. However, in recent years, there have been occasional reports of cervical HPV-independent adenosquamous carcinomas. We report a series of 5 cervical HPV-independent adenosquamous carcinomas in women aged 45 to 68 years; 4 of 5 patients were postmenopausal. The percentage of the squamous component ranged from 10 to 90%. In all cases, the glandular component was gastric-type. All tumours exhibited negative/non-block-type staining with p16 and were also negative for HPV on molecular testing. Molecular testing (4 of 5 cases) revealed no recurrent variants. However, in individual cases, pathogenic or likely pathogenic variants were present in BRAF, CDK12, RB1, FGFR2, FGFR3, BRCA1, KRAS, CDKN1A, CDKN2A, TP53, and STK11. In addition, deletions of CDKN2A/CDKN2B and TP53 were present in 1 case. The tumours were advanced stage at diagnosis: stage IIB (1 case), IIIC1 (2 cases), and IVB (2 cases). Our findings suggest that cervical adenosquamous carcinoma should be classified into HPV-associated and HPV-independent types and this should be reflected in updated WHO Classifications.