Update on Neuroendocrine Carcinomas of the Larynx

Carolina Strosberg, MD; Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FACS, FHKCORL, FRCPath, FASCP, IFCAP; Asterios Triantafyllou, PhD (Lond), FRCPath; Douglas R. Gnepp, MD; Justin A. Bishop, MD; Henrik Hellquist, MD, PhD, SAPath (Stockh), FRCPath; Primoz Strojan, MD, PhD; Stefan M. Willems, MD, PhD; Göran Stenman, DMD, PhD, FRCPath; Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg, FACS; Juan C. Hernandez-Prera, MD


Am J Clin Pathol. 2019;152(6):686-700. 

In This Article

Neuroendocrine Carcinomas of the Larynx and HPV

During the past two decades, HPV has emerged as an important etiologic factor for a subset of head and neck squamous cell carcinomas. HPV-related squamous cell carcinomas particularly affect the oropharynx, often show a nonkeratinizing morphology, and are associated with a better prognosis when compared to conventional keratinizing, smoking-related squamous cell carcinomas.[38] Interestingly, a small percentage of oropharyngeal HPV-related carcinomas show extensive neuroendocrine differentiation and therefore are better classified as neuroendocrine carcinomas.[41,46] Bishop and Westra[41] first reported five cases of oropharyngeal HPV-related carcinomas that morphologically and immunohistochemically fell within the spectrum of small cell neuroendocrine carcinoma, and similar results were later observed by Kraft et al[46] in a series of six cases. These cases were diffusely positive for p16 and showed an aggressive clinical behavior with widely disseminated disease despite their viral etiology.

Few studies have addressed the etiologic role of high-risk HPV in laryngeal neuroendocrine carcinomas. In 2013, Halmos et al[47] reported a series of 10 cases of laryngeal neuroendocrine carcinomas ranging from well- to poorly differentiated types. Two of their cases (one moderately differentiated neuroendocrine carcinoma and one large cell neuroendocrine carcinoma) were positive for high-risk HPV (HPV-18 and HPV-16, respectively) using a DNA-based polymerase chain reaction (PCR) platform targeting HPV consensus primers for GP5+/6+ and HPV-16 and HPV-18 specific primers. These two cases had a relatively good outcome when compared with the eight negative HPV cases and therefore the authors concluded that the identification of high-risk HPV could be associated with a better response to therapy and a better prognosis.[47] However, the HPV-positive cases were negative for p16. During HPV-driven oncogenesis, the viral DNA integrates into that of the host, which ultimately leads to the expression of the E7 viral oncoprotein. The latter event is followed by degradation of the retinoblastoma protein and consequently there is an increased expression of p16 as a feedback mechanism.[48] The p16 negativity in the aforementioned cases raises the possibility that these findings could represent cross-contamination with other samples or the detection of nonbiologically significant HPV infection. On these grounds, the study by Halmos et al[47] should be interpreted with caution.

Thompson et al[45] and Alos et al[49] have also investigated the role of HPV in neuroendocrine carcinomas of the head and neck and in their series they included three and seven laryngeal cases, respectively. Collectively, all 10 cases were poorly differentiated neuroendocrine carcinomas (two large cell, two small cell, three combined small cell and squamous cell, and three combined large cell and squamous cell); p16 was reported as strong and diffusely positive in four of them.[45,49] All cases were subjected to HPV testing using a DNA in situ hybridization assay and, in both studies all tumors were negative. The seven cases from Alos et al[49] were also negative using an HPV DNA PCR analysis. More recently, Jo et al[50] presented four cases of confirmed HPV-associated neuroendocrine carcinomas diagnosed by fine-needle aspiration biopsy of metastatic cervical lymph nodes. In this series, one patient presumptively had a laryngeal tumor based on imaging studies; however, no histologic confirmation of the primary site was available. This patient had advanced disease including distant metastasis to the kidney and died while receiving chemotherapy and immunotherapy with nivolumab 15 months after diagnosis.[50]

Overall, the available pertinent literature is limited, with few cases examined and concerns about methodology and/or sampling. It seems, however, that the role of an actively transcribed HPV infection in neuroendocrine carcinomas, in particular poorly differentiated carcinomas, of the larynx is unlikely. It should be stressed that the p16 staining pattern suggestive of a HPV-related carcinoma in the oropharynx can be frequently observed in these laryngeal tumors.[49] Therefore, p16 immunoreactivity is not an effective surrogate marker for HPV infection in laryngeal neuroendocrine carcinomas Image 6D.