Case Letter

Acantholytic Anaplastic Extramammary Paget Disease

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Acantholytic dyskeratosis of the genitocrural area is a rare lesion included in the spectrum of focal acantholytic dyskeratoses described by Ackerman.19 It also has been referred to as papular acantholytic dyskeratosis of the vulva, though histologically similar lesions also have been reported in men.20-22 Histologically, acantholytic dyskeratosis of the genitocrural area has prominent acantholysis and dyskeratosis with corps ronds and grains.19 Familial benign pemphigus (Hailey-Hailey disease) is caused by mutations of the ATP2C1 gene, which encodes for a secretory pathway Ca2+/Mn2+-ATPase pump type 1 (SPCA1) in the Golgi apparatus in keratinocytes.23 Familial benign pemphigus has a histologic appearance similar to acantholytic dyskeratosis of the genitocrural area, but a positive family history of familial benign pemphigus can be used to differentiate the 2 entities from each other due to the autosomal-dominant inheritance pattern of familial benign pemphigus. Both of these disorders can appear similar to AAEMPD because of their extensive intraepidermal acantholysis, but they differ in the lack of Paget cells, intraepidermal atypia, and increased mitotic activity.

Acantholytic Bowen disease is a histologic variant that can be difficult to distinguish from AAEMPD on hematoxylin and eosin–stained sections because of their similar histologic features but can be differentiated by IHC stains.5 Acantholytic Bowen disease expresses high-molecular-weight cytokeratin (eg, CK5/6) but is negative for CK7, CAM 5.2, and CEA. Extramammary Paget disease generally has the opposite pattern: positive staining for CK7, CAM 5.2, and CEA, but negative for high-molecular-weight cytokeratin.13,14,24

Primary cutaneous adenosquamous carcinoma is a rare malignancy of squamous and glandular differentiation known for being locally aggressive and metastatic.25 Histologically, cutaneous adenosquamous carcinoma shows infiltrating nests of neoplastic cells with both squamous and glandular features. It differs notably from AAEMPD in that cutaneous adenosquamous carcinomas tend to arise in the head and arm regions, and their histologic morphology is different. The IHC profiles are similar, with positive staining for CEA, CK7, and mucin; however, they differ in that AAEMPD is negative for high-molecular-weight keratin while cutaneous adenosquamous carcinoma is positive.25

Verrucous carcinoma is an uncommon variant of squamous cell carcinoma with well-differentiated keratinocytes and a blunt pushing border.24 Similar to AAEMPD, this neoplasm can arise in the genital and perineal areas; however, the 2 entities differ considerably in morphology on histologic examination.

Pemphigus vulgaris is an autoimmune intraepidermal blistering disorder of the skin and mucous membranes of which pemphigus vegetans is a subtype.26,27 Pemphigus vulgaris is another diagnosis that can possibly be mimicked by AAEMPD.28 Histologic features of pemphigus vulgaris include intraepidermal acantholysis of keratinocytes immediately above the basal layer of the epidermis. Pemphigus vegetans is similar with the addition of papillomatosis, hyperkeratosis, and an eosinophilic infiltrate.26,27 Immunofluorescence typically demonstrates intercellular C3 and IgG deposits.26 These diseases mimic AAEMPD histologically but differ in their relative lack of atypia and Paget cells.

In summary, we report a case of AAEMPD in a 78-year-old man in whom routine histologic specimens showed marked intraepidermal acantholysis and atypical tumor cells with increased mitoses. The latter finding prompted IHC studies that revealed positive CK7, CEA, pancytokeratin, and LMWCK staining with negative CK20 staining. Hale colloidal iron staining showed moderate to abundant cytoplasmic mucin. The patient was diagnosed with AAEMPD. It is imperative to maintain clinical suspicion for AAEMPD and to examine acantholytic disorders with scrutiny. When there is evidence of atypia or mitoses, use of IHC stains can assist in fully characterizing the lesion.

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