Histologic Identification of Human Papillomavirus (HPV)-Related Squamous Cell Carcinoma in Cervical Lymph Nodes: A Reliable Predictor of the Site of an Occult Head and Neck Primary Carcinoma

Abstract

Objective Patients with head and neck squamous cell carcinoma (SCC) often present with cervical lymph node metastasis. Occasionally the primary tumor site remains unknown even after thorough investigation. Management of such cases is problematic and may result in over-treatment and consequent increased morbidity. High risk HPV has been advocated recently as an important etiologic factor for a subset of head and neck SCC. These are believed to have a special predilection for the oropharyngeal tonsils and are characterized by nonkeratinizing basaloid morphology, and a strong reactivity to p16 immunostain. Identifying HPV-related SCC in the lymph nodes may thus provide a means for localizing the primary tumor site. Design Ninety-three cases of SCC metastatic to the neck from known primary tumors were classified morphologically into conventional keratinizing SCC (KSCC) and non-keratinizing SCC (NKCa). In situ hybridization (ISH) for high risk HPV as well as immunostaining for p16 were performed on all metastsatic and primary tumors. Results Of the 93 cases of metastatic carcinomas 32 were oropharyngeal, 35 oral, and 26 arose in the laryx/hypopharynx. Twenty-three cases were found to be HPV+ by ISH, of which 22/23 had oropharyngeal origin (P \ 0.0001), with 95.7% sensitivity and 85.7% specificity. Twenty-one of these HPV+ oropharyngeal tumors were NKCa (P \ 0.0001). The remaining case showed overlapping NKCa/KSCC hybrid morphology. All NKCa were HPV+ and stained diffusely and strongly with p16 antibodies. Conclusion We have demonstrated that HPV status of the lymph node metastasis can be assessed not only by ISH and p16 immunoreactivity but also histomorphologically. In addition, a positive microscopic identification of HPVrelated carcinoma is a reliable predictor of oropharyngeal origin.

Quantitative Diffusion-Weighted MRI Parameters and Human Papillomavirus Status in Oropharyngeal Squamous Cell Carcinoma

“…Histopathologically, HPV-related tumors often have distinct features, characterized by a nonkeratinizing morphology and showing excessive mitoses and comedo-type necrosis, while HPV-negative OPSCC shows large polygonal cells and typical keratin formation. 8,15,[20][21][22] In general, HPV-positive OPSCC is more poorly differentiated. 23 Characteristics of poorly differentiated squamous cell carcinomas, such as a higher cell attenuation and an increased nuclear-to-cytoplasmic ratio, reduce extracellular space and thereby the diffusion space of water protons, which could result in relatively low ADC values.…”

Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors

“…Given the non-keratinizing morphology seen in these AsqCA, it appears reasonable to expect that, similar to oropharyngeal and papillary sinonasal non-keratinizing SCC, these may also harbor HPV DNA. Thus, HPV testing and/or p16 immunostaining can be used as ancillary data to further support a surface (or tonsillar crypt epithelium) derivation for a tumor, and in the example of cases 5-7, suggest the oropharynx as the primary site for a nodal metastasis [13][14][15][16][17]. Given limited materials on many of our cases, further subtyping of the HPV present was not possible.…”

Management of lymph node metastases from an unknown primary site to the head and neck (Review)

“…These carcinomas are considered to exhibit a special predilection for the oropharyngeal tonsils and are characterized by non-keratinizing basaloid morphology and a strong reactivity to p16 immunostaining. Identifying HPV DNA or RNA in the lymph nodes may thus provide a means for localizing the primary tumor site in the oropharynx (26). These molecular findings used in conjunction with histology, clinical history and radiological findings, may be used to distinguish the primary site of cervical lymph node metastases of CUP of the head and neck.…”