Anatomic pathology selected abstracts

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Correspondence: Dr. J. Putra at juan.putra@sickkids.ca

Evaluation of HPV-positive squamous cell carcinoma of the larynx, oral cavity, and hypopharynx

Human papillomavirus is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCC), for which it is strongly associated with improved survival. Human papillomavirus (HPV) is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCC), and its pathogenic role and prognostic value in these tumors is unclear. The authors evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV positive based on p16 IHC and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n = 27), oral cavity (n = 21), and hypopharynx (n = 4). While most cases (n = 34, 65 percent) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n = 13, 25 percent) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (four-year disease-free survival of 100 percent versus 66 percent, P = .069). The presence of transcriptionally active HPV detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. The authors concluded that while most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.

Rooper LM, Windon MJ, Hernandez T, et al. HPV-positive squamous cell carcinoma of the larynx, oral cavity, and hypopharynx: clinicopathologic characterization with recognition of a novel warty variant. Am J Surg Pathol. 2020;44(5):691–702.

Correspondence: Dr. William H. Westra at william.westra@mountsinai.org

Link between differentiated exophytic vulvar intraepithelial lesion and verrucous carcinoma of the vulva

Verruciform proliferations of the vulva unrelated to human papillomavirus infection are rare. The term differentiated exophytic vulvar intraepithelial lesion (DEVIL) was recently proposed for these entities that harbor recurrent PIK3CA mutations. It is unclear whether DEVIL is related to verrucous carcinoma, a neoplasm characterized by persistence and local recurrence but no risk of distant spread. The authors conducted a study to document the clinical, histopathologic, and molecular alterations involved in DEVIL and verrucous carcinoma to identify features that could explain their potential relationship and the histogenesis of verrucous carcinoma. They reviewed specimens identified using the words “verruciform” and “verrucous.” The diagnosis of DEVIL required verruciform acanthosis; hyperkeratosis or parakeratosis, or both; hypogranulosis; cytoplasmic pallor; and bland nuclei. Verrucous carcinoma also required discontinuous, bulbous, puzzle-like nests in the stroma. Targeted next-generation sequencing using a custom 11-gene panel was performed. Eighteen specimens corresponding to 10 patients with DEVIL or verrucous carcinoma, or both, were included. The median age at presentation was 66 years for DEVIL and 70 years for verrucous carcinoma. A similar spectrum of prevalent mutations was found in both lesions, involving HRAS, PIK3CA, and BRAF. DEVIL preceded verrucous carcinoma or was diagnosed concurrently or in subsequent follow-up in five patients. In four of these cases, the same mutation was identified in DEVIL and synchronous or metachronous carcinoma. All cases showed wild-type p53 staining and lacked pathogenic TP53 mutations. DEVIL is a rare form of squamous proliferation characterized by prevalent PIK3CA and HRAS mutations. Its temporal relationship with verrucous carcinoma and their shared mutational profile in some patients suggest that DEVIL is a precursor of verrucous carcinoma. Moreover, given their morphologic and molecular overlap and that verrucous carcinoma has no risk for distant spread, it is conceivable that DEVIL and verrucous carcinoma represent a spectrum of the same entity.

Akbari A, Pinto A, Amemiya Y, et al. Differentiated exophytic vulvar intraepithelial lesion: Clinicopathologic and molecular analysis documenting its relationship with verrucous carcinoma of the vulva [published online ahead of print May 19, 2020]. Mod Pathol. doi:10.1038/s41379-020-0573-5

Correspondence: Dr. Carlos Parra-Herran at carlos.parraherran@sunnybrook.ca