Punctate nuclear low‐risk HPV chromogenic in situ hybridization in digital papillary adenocarcinoma: a practical tool for identifying HPV42 in routine pathology practice

AIMS: Digital papillary adenocarcinoma is a rare, aggressive adnexal tumour with a significant risk of recurrence and metastasis. Recent studies have identified human papillomavirus (HPV) 42 in most cases, suggesting potential diagnostic specificity. As HPV42-specific sequencing is not routinely available, we evaluated the utility of commercially available low-risk HPV chromogenic in situ hybridization (CISH), which includes HPV42, in digital papillary adenocarcinoma and characterized its staining pattern. METHODS AND RESULTS: Twelve cases of digital papillary adenocarcinoma were retrieved from the surgical pathology archives of our institution and compared with eight cases of tubular adenoma. Low-risk HPV CISH was performed in all cases, and BRAF p.V600E immunohistochemistry in selected cases. Clinical, histological and immunohistochemical findings were reviewed. All digital papillary adenocarcinoma cases occurred in male patients (median age: 62 years, range 34-94) and involved the fingers. All were positive for low-risk HPV CISH, whereas all tubular adenomas were negative. Conversely, all tubular adenomas were positive for p.BRAF V600E, while nine tested digital papillary adenocarcinoma cases were negative. The hybridization signal in digital papillary adenocarcinoma was consistently punctate and nuclear rather than diffuse, and in some cases was appreciable only at high magnification. CONCLUSIONS: Low-risk HPV CISH is a practical and reliable method for detecting HPV42-associated digital papillary adenocarcinoma. Recognition of its punctate nuclear staining is important, as this pattern may be subtle in some cases and could be overlooked if diffuse nuclear staining is expected with low-risk HPV assays. These findings support the diagnostic utility of low-risk HPV CISH in digital papillary adenocarcinoma.