Morphologic and immunohistochemical study of HPV-related cervical adenosquamous carcinoma: Reappraisal of a poorly...

Current WHO criteria require distinct glandular and squamous differentiation for diagnosis of adenosquamous carcinoma (AdSq). However, a subset of poorly differentiated cervical carcinoma exhibits ambiguous morphology with diffuse growth pattern. The current study explores whether these tumors belong to the adenosquamous subtype.

After IRB approval, we retrieved 41 AdSq cases diagnosed at our institution between 2007 and 2024. H&E slides were reviewed. Immunohistochemical staining for p16, p40, p63, BerEP4, and Claudin-4 was performed. IHC was scored. Statistical analysis was performed with Python packages.

Based on morphology only, out of the 41 AdSq cases, 11 fulfilled the WHO proposed criteria for classic AdSq (cAdSq). Twenty cases were classified as non-classic AdSq (nAdSq). All the rest also exhibited a solid growth pattern, but were reclassified as endocervical (3), endometrioid (6), and squamous carcinoma (1). Histologically, nAdSq lacked distinct spatially separate components of squamous or glandular differentiation. Instead, tumor cells exhibited ambiguous morphology with diffuse growth or, less frequently, in nests, characteristic vacuolated/foamy cytoplasm, pleomorphic nuclei, and inflamed stroma. All nAdSq showed block positivity for p16 like cAdSq. Significant portion of AdSq cases expressed the squamous marker p40 (58 % in nAdSq vs. 50 % in cAdSq). In contrast to pure adenocarcinomas or squamous cell carcinomas, 47 % (7/15) of nAdSq cases expressed both squamous and adenocarcinoma markers (p40 and BerEP4), with 5 (33 %) cases showing positivity for all four markers. Similarly, two cAdSq cases (22 %) showed universal positivity for all four markers, though p40 positivity was more focal and weaker in other instances. Despite morphological differences, the overall survival outcomes between nAdSq and cAdSq was not significantly different (p = 0.49).

Many cervical carcinomas with diffuse growth pattern are likely the non-classic AdSq that do not contain spatially separate squamous and glandular components. Immunostaining may help in identifying this "non-classic" subtype of AdSq.