Squamous and Neuroendocrine Specific Immunohistochemical Markers in Head and Neck Squamous Cell Carcinoma: A Tissue Microarray Study

Abstract

The performance characteristics of neuroendocrine-specific and squamous-specific immunohistochemical markers in head and neck squamous cell carcinomas (SCC), in particular in oropharyngeal tumors in this era of human papillomavirus (HPV)-induced cases, are not well-established. The differential diagnosis for poorly differentiated SCCs, for nonkeratinizing oropharyngeal SCCs, and for other specific SCC variants such as basaloid SCC and undifferentiated (or lymphoepithelial-like) carcinomas includes neuroendocrine carcinomas. Given that neuroendocrine carcinomas of the head and neck are aggressive regardless of HPV status, separating them from SCC is critically important. In this study, we examined the neuroendocrine markers CD56, synaptophysin, and chromogranin-A along with the squamous markers p40 and cytokeratin 5/6 in a large tissue microarray cohort of oral, oropharyngeal, laryngeal, and hypopharyngeal SCCs with known HPV results by RNA in situ hybridization for the oropharyngeal tumors. Results were stratified by site and specific SCC variant. The neuroendocrine stains were rarely expressed in SCC (<1% overall) with CD56 the least, and chromogranin-A the most, specific markers. Further, p40 and cytokeratin 5/6 were very consistently expressed in all head and neck SCC (>98% overall), including very strong, consistent staining in oropharyngeal HPV-related nonkeratinizing SCC. Undifferentiated (or lymphoepithelial-like) carcinomas of the oropharynx are more frequently p40 or cytokeratin 5/6 negative or show only weak or focal expression. In summary, markers of neuroendocrine and squamous differentiation show very high specificity and sensitivity, respectively, across the different types of head and neck SCC.

HPV‐associated neuroendocrine carcinomas of the head and neck in FNA biopsies: Clinicopathologic features of a rare entity

“…Squamous differentiation was excluded by consistent negativity for p63 and/or p40. Immunohistochemistry for neuroendocrine markers is helpful for cytologic samples of high‐grade basaloid malignancies that show some features suggestive of neuroendocrine differentiation in the setting of a suspected oropharyngeal primary, especially because synaptophysin and chromogranin are consistently negative in HPV‐associated squamous cell carcinomas . Furthermore, the newly described immunomarker for the transcription factor INSM1 has been shown to have high sensitivity and specificity for neoplasms with neuroendocrine differentiation, including small cell carcinomas and large cell neuroendocrine carcinomas of the head and neck, and would also be useful for challenging cases.…”

Cytopathologic characteristics of HPV‐related small cell carcinoma of the oropharynx

“…Unfortunately, IHC has limitations in detecting small cell carcinoma. For example, SqCC in its pure form is rarely positive for neuroendocrine markers; however, neuroendocrine markers lack sensitivity and specificity for the detection of small cell carcinoma . As a result, it is important to rely on the cytomorphologic findings and to thoroughly evaluate all the material for a patient with a possible oropharyngeal primary.…”

“…For example, SqCC in its pure form is rarely positive for neuroendocrine markers; however, neuroendocrine markers lack sensitivity and specificity for the detection of small cell carcinoma. 33,34 As a result, it is important to rely on the cytomorphologic findings and to thoroughly evaluate all the material for a patient with a possible oropharyngeal primary. This point is imperative because it is the presence of small cell carcinoma, and not the HPV status, that will drive the prognosis.…”

Synchronous peritoneal carcinomatosis from a buccal squamous cell carcinoma: a case report focusing on possible metastatic mechanisms and novel therapeutic modalities

“…The tumour cells were negative for cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor-1 (TTF-1) and muscarmine (Figure 6) but positive for cytokeratin 5/6 (CK5/6) and p40 (Figure 7) in histochemistry and immunohistochemistry studies. Thus, a diagnosis of peritoneal carcinomatosis from a buccal cancer was confidently established according to modern recommendations [7, 8]. Immunohistochemistry staining for p16 INK4a , a surrogate biomarker for human papillomavirus infection [9], was negative in both the primary and peritoneal metastatic sites.…”