Abstract

Digital papillary adenocarcinoma (DPA) is a rare neoplasm that can exhibit local recurrence and distant metastasis. Here we present a series of eight cases of DPA demonstrating two distinct clinical presentations, morphologies, immunophenotypes, and molecular features. Four cases were characterized by painless, slow-growing nodules located on the digits. The lesions were small, well-defined, and confined in the dermis. Histologically, these tumors were composed of glandular structures lined by cuboidal epithelium with luminal papillary infoldings. Only rare mitoses and minimal squamoid differentiation were present, and necrosis was absent. All four cases were positive for the BRAF-V600E immunostain but negative for p16, low-risk and high-risk HPV ISH. In contrast, the remaining four cases were characterized by painful, rapidly-growing masses on the digits. These four lesions were located in the deep dermis and consisted of a solid, tightly packed papillary architecture lined by atypical epithelioid cells with inconspicuous nucleoli. Necrosis, numerous mitotic figures, and prominent squamoid differentiation were seen. All cases were negative for the BRAF-V600E immunostain. However, they showed strong, patchy to diffuse reactivity for p16 and were positive for low-risk HPV ISH and negative for high-risk HPV ISH. Our findings suggest that DPA has two discrete pathogenic pathways - BRAF mutation or low-risk HPV infection. DPAs with low-risk HPV infection exhibit aggressive clinical features, high-grade morphology, marked squamoid differentiation, and wild-type BRAF. DPAs with BRAF mutation have less aggressive clinical features, low-grade morphologic findings, mild to absent squamoid differentiation, and negative HPV infection. 

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