Invasive Acantholytic Extramammary Paget's Disease of the Vulva With Mammary Carcinoma-Like Differentiation and MMR Loss: Report of an Unusual Case and Its Clinical Mimics.

A 78-year-old female presented with pruritus and persistent vulvar swelling for several months without palpable nodules. Abnormal bleeding or pelvic pain were not reported at initial presentation. On physical examination, the external genitalia revealed a 5.0 x 3.0 cm erythematous lesion on the left superior vulva, consistent with extramammary Paget's disease. The lesion involved the superior labia majora, near but not involving the clitoral hood or urethra. Urethral involvement or abutment was not observed. The center of the lesion had additional polypoid changes without active bleeding or overt ulceration. The inferior left or right vulva was unremarkable. Speculum examination revealed an atrophic, but otherwise normal-appearing vagina. After biopsy of the vulvar lesions demonstrated carcinoma, a radical hemivulvectomy was performed. On histologic examination, the tumor demonstrated varied morphology, including an in-situ component of Paget’s disease and areas of confluent invasion ( Fig. 1A ). The epidermal portion showed marked epidermotropism with involvement of the basal layer and pagetoid spread of tumor cells. Additionally, the basal epidermal component exhibited prominent acantholytic changes ( Fig. 1B ). The invasive component was composed of basaloid nests ( Fig. 1 C-D) with squamous differentiation and focal duct-like lumen formation, suggestive of adnexal differentiation ( Fig. 1 C, F). Frequent mitoses, apoptotic bodies, and focal comedonecrosis were noted ( Fig. 1E ). Abundant perineural invasion and extension into the subcutaneous adipose tissue and adnexal structures, with the depth of invasion measuring 5 mm, were identified. Fig. 1 A. Overview with in-situ and invasive component, B. Paget’s disease with acantholytic pattern, C. Squamous and adnexal-like differentiation, D. Basaloid component, E. Comedo-necrosis-like pattern, F. Adnexal differentiation. A. Overview with in-situ and invasive component, B. Paget’s disease with acantholytic pattern, C. Squamous and adnexal-like differentiation, D. Basaloid component, E. Comedo-necrosis-like pattern, F. Adnexal differentiation. The tumor cells were positive for CK7, BerEP4, and EMA ( Fig. 2 ); variably positive for GATA-3; and negative for CK20, GCDFP-15, ER, PR, HER2, SOX10, and adipophilin ( Fig. 2 ). In addition, the neoplastic cells showed MSH2 and MSH6 loss ( Fig. 2 ). An increased Ki-67 proliferation index (∼70 %) was observed. p16 showed focal positivity, and p53 demonstrated a wild-type expression pattern. SMMHC highlighted portions of the in-situ component, and p63 was positive in the squamous epithelium. The resection margins were involved by Paget’s disease but free of invasion, supporting a diagnosis of invasive adenocarcinoma associated with EMPD. The pathological tumor stage was pT1b, Nx. Fig. 2 Overview of immunohistochemical markers. Overview of immunohistochemical markers. Comprehensive molecular testing (CARIS) identified microsatellite instability–high (MSI-H) status and high tumor mutational burden (TMB, 31 mut/Mb). Pathogenic variants in PIK3CA (Exon 10, p.E545K) and TP53 (Exon 7, p.R248Q) were detected. As part of routine screening recommended for patients with Paget’s disease, she had a history of normal Pap smears and mammograms; however, colon evaluation identified a synchronous moderately-differentiated adenocarcinoma of the ascending colon, which showed loss of MLH1 and PMS-2. A subsequent BRAF V600E mutation was identified. This was an interesting finding as she had a somatic mutation in addition to germline MSH2 and MSH6 mutations in the vulva. The patient subsequently underwent bilateral inguinal lymph node evaluation with right inguinal lymphadenectomy and left inguinal sentinel lymph node biopsy. The right inguinal lymph node was benign; however, two left inguinal sentinel lymph nodes were positive for metastatic carcinoma without extracapsular extension. The largest metastasis focus was 6.0 x 2.5 mm. The patient was upstaged to FIGO stage IIIB, pT1bN2bM0, invasive adenocarcinoma of the vulva. Subsequent PET/CT imaging did not demonstrate additional areas concerning metastatic disease. After surgical interventions and staging were completed, the patient received concurrent chemoradiation with sensitizing cisplatin. She received 4500 cGy to the whole pelvis, followed by a 600 cGy boost to the bilateral vulva and inguinal region, and an additional 600 cGy boost to the vulva. She has since entered surveillance, with no evidence of refractory or progressive disease.

Jessica Claus: Writing – original draft, Conceptualization. Janina Pearce: Writing – review & editing. Areta Bojko: Writing – review & editing. Padmini Manrai: Writing – review & editing. M.Ruhul Quddus: Writing – review & editing, Project administration. Shivali Marketkar: Writing – original draft, Conceptualization.

Given the rarity of AAEMPD, multi-institutional registries or collaborative studies are needed to define prognostic indicators more clearly (depth of invasion, lymphovascular invasion, nodal status, molecular profile including HER2/PIK3CA/TP53) and to compare outcomes between classic and anaplastic/acantholytic variants. In our case, molecular testing identified MSI-high status and a high tumor mutational burden (TMB), with pathogenic variants in PIK3CA and TP53 − may enable future targeted or immunotherapy approaches.

AAEMPD appears to carry a worse prognosis than classic EMPD due to its greater depth of invasion, frequent lymphovascular invasion, and potential for regional lymph node metastasis. The Sta. Ines et al.'s case demonstrated both lymphovascular invasion and nodal metastases, while our case also revealed left inguinal nodal involvement, leading to upstaging to FIGO IIIB. On follow-up of Sta Ines’ case, the patient underwent another modified radical vulvectomy 16 months after the initial wide local excision for invasive vulvar Paget disease extending to the anal skin and dermis (tumor size 6.8 cm, depth of invasion 4.2 mm) with positive periurethral, introitus, and anal margins, ultimately requiring a skin flap harvested from the thighs for reconstruction. These findings support that the acantholytic–anaplastic variant may behave more aggressively than conventional EMPD and warrant a vigilant therapeutic approach with ongoing surveillance every 3–6 months ( Salani et al., 2017 ). The management of APD typically involves wide local excision with histologically clear margins, or in more extensive cases, radical vulvectomy and lymph node dissection, sometimes coupled with adjuvant chemotherapy or radiation therapy when there is evidence of nodal or deep dermal invasion. Given the infiltrative and recurrent nature of the disease, multidisciplinary management including surgical oncology, dermatopathology, and radiation oncology is essential. In addition, recent studies, including the Paget Trial, have shown that topical 5 % imiquimod cream is effective for treating noninvasive vulvar Paget disease. Imiquimod, a toll-like receptor seven agonist, triggers an immune response that may lead to tumor regression. This non-invasive treatment offers a promising alternative to surgery, especially for localized disease, with fewer complications ( Van der Linden et al., 2022 ). However, its efficacy in invasive or anaplastic forms remains limited and should not replace surgery in these aggressive variants. In cases of invasive APD/AAEMPD, adjuvant radiation may help reduce local recurrence, while systemic therapy − including HER2-targeted or immunotherapy approaches- may be considered in advanced or metastatic disease, particularly when molecular alterations (e.g., HER2 amplification, PIK3CA or TP53 mutations, or MSI-high status) are identified, though this requires further investigation. Regular follow-up with clinical and imaging surveillance is crucial given the high recurrence rate and potential for late metastasis. Due to the aggressive nature of APD, which can mimic other cutaneous neoplasms, early diagnosis and intervention are critical in preventing disease progression and recurrence.

As summarized in Table 1 , both cases demonstrate the aggressive histopathologic spectrum of AAEMPD involving the vulva. Each patient presented with invasive disease of similar depth (3–5 mm) and regional lymph node metastases, underscoring the malignant potential of this rare variant. Morphologically, both tumors shared marked acantholysis, nuclear pleomorphism, and pagetoid epidermal involvement, features that can mimic other adnexal or squamous malignancies. However, important molecular differences were observed. Sta. Ines et al. reported HER2 amplification in an MSI-stable background, whereas our case demonstrated MSI-high status, high tumor mutational burden, and pathogenic PIK3CA (E545K). Both cases showed TP53 mutations, which are again predictors of the aggressive nature of the disease. The findings also suggest molecular heterogeneity within anaplastic EMPD, which may have therapeutic implications − particularly regarding potential responsiveness to immune checkpoint inhibition in MSI-high tumors versus HER2-targeted therapy in HER2-amplified cases. Clinically, both patients underwent radical surgical management, but only our patient received adjuvant chemoradiation due to nodal involvement. The similarity in staging (FIGO IIIB, pT1bN2bM0) highlights the propensity for regional spread even in early invasive lesions. Recognition of these overlapping and divergent features is critical for accurate diagnosis, prognostication, and exploration of personalized treatment strategies in this exceedingly rare and heterogeneous disease entity. Table 1 Clinicopathologic comparison between the present case and Sta. Ines et al., 2024. Feature Present Case (Current Report) Sta. Ines et al., 2024 ( Sta Ines FMG, Salinaro JR, Marchese M, Mathews CA, Quddus MR. Invasive acantholytic anaplastic extramammary Paget disease: A previously unreported neoplasm in the vulva and review of the literature. Gynecol Oncol Rep., 2024 ) Patient demographics 78-year-old female 73-year-old female Anatomic site Left superior vulva (labia majora, near clitoral hood) Left vulva (labia majora) Clinical presentation Pruritus and persistent swelling for several months; erythematous exophytic/polypoid lesion (5.0 × 3.0 cm) Pruritic erythematous plaque (2.0 × 1.5 cm) with crusting and superficial ulceration Histologic type Invasive acantholytic extramammary Paget’s disease (AAEMPD) with anaplastic features Anaplastic extramammary Paget’s disease (APD) with acantholytic areas Morphologic features Pagetoid intraepidermal spread, supra-basal acantholysis, basaloid, adnexal-like, focal squamoid and mammary-like differentiation; comedonecrosis Pagetoid spread with marked nuclear pleomorphism, acantholysis, and single-cell anaplastic infiltration of dermis; solid nests and gland-like formations Depth of invasion 5.0 mm 3.5 mm Lymphovascular invasion Present (suspicious foci) Present Perineural invasion Present Not reported Nodal status Left inguinal lymph node metastases (2 positive, no extracapsular extension) Bilateral inguinal lymph node metastases (4 positive) Immunohistochemistry CK7+, BerEP4+, EMA+, GATA3 (variable), CK20-, GCDFP-15-, ER−, PR−, HER2−, SOX10−, adipophilin−, p53 wild-type, p16 focal+, Ki-67 ≈ 70 % CK7+, EMA+, GATA3+, GCDFP-15+, ER−, PR−, HER2−, p53 wild-type, p16 patchy+, Ki-67 ≈ 80 % Molecular findings MSI-unstable (MSH2 and MSH6 loss on IHC) MSI-high, high TMB (31 mut/Mb), PIK3CA (E545K) , TP53 (R248Q) MSI-stable, ERBB2 (HER2) amplification , TP53 mutation , low TMB Treatment Radical hemivulvectomy, bilateral inguinal lymph node evaluation, chemoradiation (cisplatin-based, 4500 + 1200 cGy boosts) Radical vulvectomy with bilateral inguinal lymphadenectomy; no adjuvant therapy reported Pathologic stage FIGO IIIB, pT1bN2bM0 FIGO IIIB, pT1bN2bM0 Outcome / Follow-up No evidence of disease on surveillance Repeat modified radical vulvectomy 16 months later for recurrent invasive Paget disease (6.8 cm, 4.2 mm depth of invasion) with positive periurethral, introitus, and anal margins; reconstruction required bilateral thigh skin flap Key features / significance First reported vulvar acantholytic–anaplastic EMPD with documented molecular alterations (MSI-high, PIK3CA mutation) First documented vulvar anaplastic EMPD with HER2 amplification Clinicopathologic comparison between the present case and Sta. Ines et al., 2024. An additional significant molecular finding in our case is loss of mismatch repair (MMR) proteins (MSH2/MSH6). MMR deficiency and MSI-high status are well-described drivers in endometrial and colorectal tumorigenesis and have been reported, though uncommonly, across other tumor types including breast carcinomas ( Cheng et al., 2020 ). A large cohort from British Columbia found MMR protein loss in ∼ 1.9 % of invasive breast cancers and associated this loss with higher grade, low progesterone receptor expression and worse outcome ( Cheng et al., 2020 ). MMR loss in vulvar carcinomas appears to be far less common: one study of 44 vulvar squamous cell carcinomas did not detect MSI-instability and presume MMR-deficiency to be an uncommon finding ( Bujko et al., 2012 ). Thus, MMR loss in a vulvar primary is an uncommon but plausible event and should prompt consideration of germline testing and multidisciplinary management. An alternative and biologically plausible explanation could be a tumor arising from ectopic endometrial-type epithelium: endometriosis-associated carcinomas (predominant endometrioid-type) have been reported to acquire MMR deficiency during malignant transformation ( Farolfi et al., 2022 ). Although no residual endometriosis was identified in the extensively sampled specimen, published series showing progression from endometriosis to MMR-deficient carcinoma support raising this possibility as part of the differential − especially in the presence of MMR loss. Finally, an important consideration is the relation between MSI and cutaneous adnexal neoplasms, such as sebaceous tumors/carcinomas which are associated to syndromes like Muir-Torre syndrome or Lynch Syndrome and do frequently show loss of MSH2/MSH6 ( Ponti et al., 2005 , Alharthi H, Alnuaim H, Aljarbou O, Arabi H. Sebaceous carcinoma of the vulva: a case report and review of the literature. Avicenna J Med., 2021 ). In contrast, MSI-instability in microcystic adnexal carcinomas (MAC) or other non-sebaceous neoplasms appear to be rare and are not recognized as molecular driver mutations ( Ross et al., 2014 , Chan et al., 2020 ).

This case highlights the morphological diversity of invasive EMPD and the importance of comprehensive histopathologic and immunohistochemical evaluation for accurate diagnosis. Anaplastic Paget’s disease (APD) is a rare and aggressive form of Paget’s disease, characterized by poorly differentiated, anaplastic cells in the epidermis. While it is most found in mammary and extramammary locations, such as the scrotum and esophagus, its occurrence in the vulva is extremely uncommon, with only one documented case in the literature ( Sta Ines FMG, Salinaro JR, Marchese M, Mathews CA, Quddus MR. Invasive acantholytic anaplastic extramammary Paget disease: A previously unreported neoplasm in the vulva and review of the literature. Gynecol Oncol Rep., 2024 ). In the existing literature, anaplastic Paget’s disease and acantholytic anaplastic Paget’s disease are often used interchangeably. This case contributes to a deeper understanding of APD's clinical and histopathological features, particularly in rare anatomical sites. A recent case report by Sta. Ines et al. (2024) described the first documented case of vulvar anaplastic extramammary Paget’s disease (APD), which demonstrated acantholytic morphology, deep dermal invasion (3.5 mm), and bilateral inguinal lymph node metastases, classified as FIGO stage IIIB. This report, together with the present case, provides complementary insight into the morphologic spectrum and biologic behavior of anaplastic and acantholytic variants of EMPD. Both cases presented with invasive disease ranging in depth from 3-5 mm, which emphasizes the need to further explore the diagnostic and prognostic factors of this rare entity and to differentiate it from other acantholytic lesions. APD involving the breast typically appears as red, scaly, erythematous plaques on the nipple or areola complex ( Mobini, 2009 ). Microscopically, it resembles Bowen’s disease, with full-thickness epidermal atypia, loss of normal maturation, marked cellular atypia or anaplasia, and characteristic intraepidermal acantholysis. There are sometimes clusters of classic Paget cells. In extramammary sites, such as the male genital area, AAEMPD presents differently, with varying clinical manifestations. For example, Oh et al. ( Oh et al., 2011 ) reported a case involving the scrotum, in which the condition presented as a pruritic, erythematous plaque and a verrucous papule. The verrucous papule displayed Bowenoid features, while the erythematous plaque showed acantholytic epidermal changes. These features of acantholytic EMPD underline the disease's capacity for diverse presentation in non-mammary sites.

In recent literature, a new entity, acantholytic anaplastic extramammary Paget’s disease (AAEMPD) of the vulva, has been described. Anaplastic extramammary Paget’s disease has been reported in the scrotum and esophagus but only once in the vulva. This exceedingly rare entity can mimic other dermatoses, including Bowen’s disease or acantholytic squamous cell carcinoma.” While this entity is exceedingly rare, it can mimic a variety of other dermatologic conditions, including Bowen’s disease, acantholytic squamous cell carcinoma, acantholytic dyskeratosis (including Gower’s disease), Hailey-Hailey disease, or acantholytic dyskeratoma. Immunohistochemical studies are strongly recommended for a definite diagnosis. In our and the previously reported case, AAEMPD appears to mainly affect older women.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Given the morphological overlap with entities such as Bowen disease or acantholytic dyskeratosis, IHC is essential in distinguishing AAEMPD. Key diagnostic immunomarkers include CK7, EMA, BerEP4, and GATA-3, with negativity for p63, high-molecular-weight cytokeratins (CK5/6), and other lineage markers depending on site ( Detweiler et al., 2019 ). In the Sta. Ines case ( Sta Ines FMG, Salinaro JR, Marchese M, Mathews CA, Quddus MR. Invasive acantholytic anaplastic extramammary Paget disease: A previously unreported neoplasm in the vulva and review of the literature. Gynecol Oncol Rep., 2024 ), Paget cells were positive for CK7, CK8/18, CEA, and HER2, negative for p63, and showed only rare mucin. In our case, we found positivity for CK7, CK20, BerEP4, and EMA; variable positivity for GATA-3; and negativity for ER, PR, HER2, SOX10, and adipophilin. p16 showed focal positivity, and p53 demonstrated a wild-type expression pattern. These findings align with the concept that AAEMPD may retain classic Paget phenotype markers but also express squamoid/adnexal features, reflecting its variant morphology.