Vulvar metastasis from colorectal adenocarcinoma is extremely rare, with few cases reported in the literature. We present the case of a 49-year-old woman with a history of locally advanced, moderately to well-differentiated invasive adenocarcinoma of the distal rectum treated with neoadjuvant chemotherapy and abdominoperineal resection, including partial posterior vaginal wall resection. One year later, she developed a vulvar lesion associated with metrorrhagia. Pelvic magnetic resonance imaging showed an isolated vulvar lesion without pelvic recurrence. Histopathology and immunohistochemistry confirmed metastatic colorectal adenocarcinoma. A multidisciplinary decision led to systemic chemotherapy with irinotecan, leucovorin, and 5-fluorouracil plus bevacizumab. This case highlights the importance of integrating clinical evaluation, histopathology, immunohistochemistry, and imaging in diagnosing rare metastatic sites and emphasizes the role of multidisciplinary board decisions in guiding systemic therapy and optimizing patient management.

Hypertrophic lichen sclerosus (HLS) is poorly characterized. A recent study described an atypical form of LS (p53 wild type) with a CK17/D2-40 immunohistochemical profile intermediate between classic LS and differentiated vulvar intraepithelial neoplasia (dVIN). Our study aims to characterize HLS through IHC and molecular profiling to determine if it is a classic or atypical LS lesion. We reviewed HLS diagnosed in 12 biopsies (2014 to 2025) and 5 resections for vulvar squamous cell carcinoma (vSCC) (1998 to 2015) from our institution (mean patient age 59; range: 37 to 97). We defined HLS by nonexophytic acanthosis, hyperkeratosis +/- parakeratosis, granular layer retention, irregular dermal-epidermal junction, lack of severe basal layer atypia, homogenization of the superficial dermis, and +/- lichenoid inflammatory infiltrate. In the 5 resections, CK17 expression was suprabasal in 4 (80%) and superficial in 1 (20%) of HLS adjacent to vSCC. D2-40 intensity was moderate in all 5 (100%). All 5 vSCC were p16-/p53 aberrant with intense D2-40 expression and showed diffuse CK17 in 4 (80%) and suprabasal staining in 1 (20%). All 12 HLS biopsies were p16-; 7 (58%) were p53 wild type and 5 (42%) were aberrant. Seven (58%) showed CK17 suprabasal staining; 5 (42%) were diffuse. D2-40 intensity ranged from absent (1/12; 8%) to faint (3/12; 25%) to moderate (3/12; 25%) to intense (5/12; 42%). Frequently altered genes were SDHA (3/6; 50%) and TP53 (2/6; 33%). HLS shows neither the classic morphology of LS nor dVIN but can be p53 aberrant/mutant. Because of its CK17/D2-40 immunophenotype, it should be considered as atypical LS.

The 2026 ISSVD terminology for vulvar intraepithelial neoplasia (VIN) and squamous intraepithelial lesions (SIL) requires p16 and p53 immunohistochemistry for classification into human papillomavirus (HPV)-associated (HPVa) or HPV-independent (HPVi) disease. p16 and p53 are tumor suppressor proteins; block positive p16 staining is a surrogate marker for genomic integration of oncogenic HPV while null or overexpressed p53 staining correlates with TP53 mutation. HPVa and HPVi VIN represent two distinct entities with different diagnostic considerations, treatments, surveillance strategies, and prognoses. The designation of 'neoplasia' versus 'lesion' reflects biological behavior, with neoplasia signifying an established risk of progression to cancer. HPVa disease maintains a two-tier nomenclature: HPVa vulvar intraepithelial neoplasia (VIN) for precursors to vulvar squamous cell carcinoma (SCC) versus low grade SIL (LSIL) and condyloma for transient HPV manifestations. While HPVa VIN is preferred, high-grade SIL (HSIL) is retained as acceptable in some settings to maintain consistency with nomenclature for analogous lesions across the lower genital tract. HPVi disease almost always arises from longstanding lichen sclerosus. The updated terminology for HPVi precursors to SCC is HPVi VIN, subcategorized as p53 mutant or p53 wild type. Verrucous VIN is a subtype of p53 wild type HPVi VIN and the usual precursor to verrucous carcinoma. Vulvar aberrant maturation (VAM) encompasses HPVi lesions of uncertain neoplastic potential arising in lichen sclerosus that raise concern for but are not diagnostic of HPVi VIN. Collaboration between clinicians and pathologists is essential to achieve accurate diagnosis, optimal individualized treatment, and consistent application of this terminology in practice and research.

Lichen sclerosus (LS) is a chronic inflammatory condition of the vulva. Although LS is thought to arise from autoimmune mechanisms, it is unclear whether disease drivers differ by menopausal status-an important distinction given its potential progression to differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar squamous cell carcinoma (VSCC). We performed a retrospective review of 182 biopsy-proven LS cases (2020-2025), stratified by menopause status. In addition, we examined 27 VSCC cases for PD-L1 staining to assess immune modulation and potential therapeutic relevance. Premenopausal patients were diagnosed at a much younger age (37.8 vs. 67.5 yr, P<0.001) and experienced longer delays to diagnosis (3.9 vs. 1.5 yr, P<0.001). Their biopsies were less often reported with definitive LS terminology (40% vs. 75%, P<0.001), suggesting under-recognition in younger women. Comorbidities were more common in this group, especially autoimmune disease (46.7% vs. 10.9%, P<0.001), whereas postmenopausal patients more frequently had atrophic vaginitis (15.9%, P=0.02). Progression to dVIN or VSCC occurred more often in postmenopause (13.1% vs. 8.9%), though this was not statistically significant. PD-L1 expression was frequent in VSCC and precursor lesions (HSIL: 80%; dVIN: 81%) and less common in LS (50%), though these differences were not statistically significant. Expression patterns varied by lesion type, suggesting potential differences in the local immune microenvironment. Taken together, these findings support differences in clinical presentation and immune features of LS by menopausal status, warranting further investigation in larger cohorts.

Persistent genital arousal disorder/genito-pelvic dysesthesia (PGAD/GPD) is a rare and distressing condition characterized by unwanted genital arousal without associated sexual desire. While cases of PGAD/GPD in association with interstitial cystitis, urethritis, urinary tract infection, and urethral diverticulum have been described, bladder cancer has not yet been reported. To our knowledge, the present report describes the first known case of PGAD/GPD as the initial presentation of low-grade papillary urothelial carcinoma of the bladder in a young female.

Neuroendocrine differentiation in tumors of the female genital tract is an uncommon but diagnostically consequential finding. Its interpretation is challenging because neuroendocrine marker expression does not necessarily define a neuroendocrine neoplasm. Focal or aberrant staining for synaptophysin, chromogranin A, CD56 or INSM1 may occur in otherwise conventional gynecologic carcinomas, whereas true poorly differentiated neuroendocrine carcinomas represent aggressive tumors with distinct prognostic and therapeutic implications. This narrative review examines neuroendocrine differentiation across the cervix, endometrium, ovary, vagina and vulva from an integrated clinicopathologic perspective. We emphasize that neuroendocrine differentiation should be approached as a diagnostic and biological spectrum, ranging from incidental immunophenotypic expression to carcinoma with neuroendocrine differentiation, mixed neuroendocrine/non-neuroendocrine tumors, well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Morphology remains the diagnostic anchor, while immunohistochemistry, molecular context and clinicoradiologic correlation refine classification and help exclude mimics or metastatic disease. Site-specific interpretation is essential: cervical neuroendocrine carcinoma is commonly HPV-associated and clinically aggressive; endometrial tumors require integration with p53, mismatch repair, POLE and SWI/SNF-related contexts; ovarian lesions demand distinction between primary well-differentiated neuroendocrine tumors, poorly differentiated carcinomas and metastases; and vaginal or vulvar tumors require careful exclusion of adjacent extension, cutaneous mimics and extragenital primaries. We propose a practical diagnostic framework that separates incidental marker expression from clinically meaningful neuroendocrine differentiation and links this distinction to reporting, prognosis and treatment. The central diagnostic question is not whether neuroendocrine markers are expressed but whether their expression defines a morphologically, biologically and clinically meaningful tumor category.

Vulvar squamous cell carcinoma (VSCC) and its precursor lesions are relatively rare malignancies of the gynecologic tract. In recent years, international organizations and pathologic reporting guidelines endorse the subdivision of VSCC into human papillomavirus (HPV)-associated and HPV-independent types. There is also growing evidence for the further separation of HPV-independent into p53 abnormal and p53 wild-type cancers. Although the diagnosis and subclassification of VSCC is often straightforward, using immunohistochemical markers such as p16 and p53 as surrogate markers for high-risk HPV infection and TP53 mutation respectively, rare and unusual scenarios exist that can complicate VSCC classification. Herein we discuss these challenging scenarios in VSCC classification, as well as emerging VSCC prognostic biomarkers such as cyclin D1. In addition, the pathologic diagnosis of VSCC precursor lesions, particularly those of HPV-independent type, are frequently challenging to distinguish from benign conditions of the vulva. We discuss the recent literature describing the added diagnostic value of immunohistochemical biomarkers p53, CK17, CK13, SOX2, GATA3, GLUT1 and others, which may be particularly helpful when morphology is inconclusive. It is anticipated that with improved VSCC classification and precursor recognition, avenues for more tailored therapeutic strategies and earlier therapeutic intervention can be achieved.

Despite vulvar cancer's rarity, meaningful advances have been made to improve the clinical care of affected patients-particularly with respect to vulvar squamous cell carcinoma (VSCC). These advances are reflected in changes to tumor classification, surgical strategies, early detection of precursors, and targeted therapeutic exploration. Refinements in histopathologic and molecular classification have enhanced diagnostic precision, enabling more accurate prognostication and facilitating personalized therapeutic decision-making, particularly tailored surgical strategies that can be explored through clinical trials-to improve patient outcomes while reducing patient morbidity. Increased awareness of VSCC precursors have also opened avenues for earlier intervention. This review highlights the key changes in the evolution of VSCC care, with particular emphasis on the expanding responsibilities of pathologists in tumor subtyping [by human papillomavirus (HPV) and p53 status], biomarker-based prognostication, margin evaluation, recognition of precursors and alignment of precursor terminology (particularly HPV independent p53 wild-type lesions). By highlighting both progress and limitations, this review aims to inform future strategies that will further optimize patient outcomes and advance the standard of care in VSCC.

Primary vulvar adenocarcinomas are rare, and tumours arising from anogenital mammary-like glands (A-AMG) are exceptionally uncommon. These glands share morphological and immunophenotypic features with breast tissue.We report the case of a woman in her 90s with no previous gynaecological follow-up or breast cancer screening, admitted with septic shock and multiorgan dysfunction. As part of the investigation for the source of infection, an abdominopelvic CT scan revealed a perineal mass. Gynaecological examination confirmed a firm 5 cm lesion involving the right labia majora and extending to the lower third of the vagina. Histological examination demonstrated an adenocarcinoma arising from A-AMG.Further investigation showed no evidence of a breast primary or distant metastases, supporting the diagnosis of a primary vulvar tumour. The patient declined surgical management and was managed conservatively. This case highlights the diagnostic challenges posed by this rare entity and emphasises the importance of careful histopathological evaluation.

Photoimmunotherapy using ASP-1929 (ASP1929-PIT) is a novel approach targeting epidermal growth factor receptor (EGFR)-expressing tumors. ASP-1929, an anti-EGFR monoclonal antibody conjugated to IRDye 700DX (IR700), binds to EGFR in tumor cells. Upon exposure to 690-nm red laser light, IR700 is activated, disrupting the cellular membrane. Approved in Japan for head and neck cancer, this therapy is the first of its kind globally. Given its mechanism, ASP-1929 may also treat other EGFR-positive malignancies accessible to red light. Thus, we are conducting a phase II clinical trial of ASP1929-PIT for localized recurrent and persistent vulvar, vaginal, and cervical cancers refractory to radiotherapy (RT). These severely impact quality of life, highlighting an unmet need.

Neurofibromas are benign peripheral nerve sheath tumors that infrequently involve the vulva. Giant vulvar neurofibromas are exceedingly rare, particularly in young patients, and may pose diagnostic challenges due to their unusual location and broad differential diagnosis. We report the case of a 19-year-old female who presented with a slowly enlarging left vulvar mass. Magnetic resonance imaging (MRI) demonstrated a large, well-circumscribed, lobulated soft-tissue lesion with signal characteristics suggestive of a benign peripheral nerve sheath tumor, without invasion of adjacent structures. Complete surgical excision was performed, and histopathological examination confirmed the diagnosis of neurofibroma using S100 immunohistochemical staining. This case highlights the pivotal role of MRI in lesion characterization, surgical planning, and differentiation from other vulvar masses.