Two distinct pathogenic pathways of digital papillary adenocarcinoma — BRAF mutation or low‐risk HPV infection

Abstract

Digital papillary adenocarcinoma (DPA) is a rare neoplasm that can exhibit local recurrence and distant metastasis. We present a series of eight cases of DPA showing 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. Histopathologically, these tumors were composed of glandular structures lined by cuboidal epithelium with luminal papillary infoldings. Only rare mitotic figures and minimal squamoid differentiation were present, and cellular necrosis was absent. All four cases were positive for the BRAF V600E immunohistochemistry but negative for p16, low-risk and high-risk HPV in situ hybridization (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. Cellular necrosis, numerous mitotic figures, and prominent squamoid differentiation were seen. All cases were negative for the BRAF V600E IHC. 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 the current classification of DPA encompasses tumors that show 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 V600E have less aggressive clinical features, low-grade morphologic findings, mild to absent squamoid differentiation, and negative HPV infection.

Digital Papillary Adenocarcinoma in Nonacral Skin

“…To note, the lack of detection of most HPV genotypes in other tumors of anogenital mammarylike glands is especially important as the use of in situ hybridization using a mix of low-risk HPV probes including the HPV42 genotype has recently been proposed to confirm the diagnosis of DPA. 38 We believe that the cases reported in this paper represent true examples of DPA occurring at an extra-acral location as the overall histologic, immunohistochemical, and genetic findings are identical to those seen in acral DPAs. The main histologic difference that needs to be highlighted is the fact that all of our cases were predominantly solid and papillae were very focal and not a prominent feature.…”

“…Similarly, HPV seems not to be involved in the oncogenesis of other lesions of anogenital mammary-like glands 37 which might constitute additional challenges in the differential diagnosis of DPA. To note, the lack of detection of most HPV genotypes in other tumors of anogenital mammary-like glands is especially important as the use of in situ hybridization using a mix of low-risk HPV probes including the HPV42 genotype has recently been proposed to confirm the diagnosis of DPA 38 …”

Acral BRAF‐mutated tubular adenoma should be distinguished from HPV42‐related digital papillary adenocarcinoma

“…In their article, Bui et al 18 reported a series of eight acral sweat glands tumors diagnosed as “DPA.” In contrast to prior observations with a larger set of tumors 5,14,16 they claim to have identified two “DPA” groups with distinct phenotypes, genetics, and outcomes. “Group A” ( n = 4) included painless slow‐growing nodules microscopically characterized by small, well defined dermal tumors forming independent glandular structures.…”

“…Unfortunately, there are confusing published data suggesting a gray zone/progression between tubular adenoma and DPA. [18][19][20] We believe that there is a clear distinction between these two tumors, which is crucial for surgical management and assessment of recurrence risk. DPA is a cancer with metastatic potential, 1,3 while tubular adenoma is a benign neoplasm.…”

“…5,[14][15][16][17] Indeed, DPA genome was found in 96%-100% of tested DPA tumors, 5,16 but not in any other sweat gland neoplasm or adenocarcinoma. 5 In their article, Bui et al 18 reported a series of eight acral sweat glands tumors diagnosed as "DPA." In contrast to prior observations with a larger set of tumors 5,14,16 they claim to have identified two "DPA" groups with distinct phenotypes, genetics, and outcomes.…”