Histopathologic risk factors in oral and oropharyngeal squamous cell carcinoma variants: an update with special reference to HPV-related carcinomas

Abstract

Accurate identification of the microscopic risk factors of oral and oropharyngeal (OP) squamous cell carcinomas (SCC) and their morphologic variants is of at most importance, as these generally determine treatment modalities, prognosis and overall patient outcome. The great majority of oral and oropharyngeal squamous cell carcinomas are microscopically described as kerartinizing squamous cell carcinoma (KSCC). They bear certain resemblance to keratinizing stratified squamous epithelium. Tobacco habits and excessive consumption of alcoholic beverages have been considered to be the main etiologic agents in these carcinomas. The tumors occurred in older patients more commonly affected the oral tongue and floor of the mouth with well established morphologic risk factors including tumor grade, pattern of invasion and perineural involvement. Within the last 30 years however, the advent and expanding prevalence of high risk human papillomavirus (HPV) as an important etiologic agent for head and neck squamous cell carcinoma, particularly in the OP, has resulted in a significant change in the established morphologic criteria for risk assessment. The majority of HPV relate carcinomas of the OP are nonkeratinizing squamous cell carcinoma (NKSCC). These tumors are found to be more responsive to treatment with a favorable patient outcome and good prognosis. Consequently, alterations in treatment protocols aimed at de-escalation are currently being evaluated. More recently, other morphologic variants that are HPV positive are reported with increasing frequency in the OP and other head and neck sites. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in the HPV-related variants. Examples of HPV-related squamous cell carcinoma variants that will be addressed here are: basaloid squamous cell carcinoma (BSCC), undifferentiated carcinoma (UCa), papillary squamous carcinoma (PSCC) and small cell carcinoma. Some studies have suggested favorable prognosis in some variants, analogous to that of the (NKSCC), while others showed poorer outcome. So far the number of studies on this subject is limited and the number of cases evaluated in each investigation is few. Because of that, it is prudent at this stage, not to alter management protocols as a result of identification of HPV in these variants and to await additional information.

Figure 1

A) Nonkeratinizing squamous cell carcinoma. Sheets and large nests of tumor cells are seen with well defined borders and central comedo necrosis. B) Higher magnification showing small ovoid and spindle shaped tumor cells with hyperchromatic nuclei and indistinct cell bordrs. C) Strong and diffuse p16 immunostaining, both nuclear and cytoplasmic. D) Ki-67stain showing high labeling score of more than 80%.

Figure 2

A) Nonkeratinizing squamous cell carcinoma with focal areas of keratinocytic maturation (hybrid variant). B) Nonkeratinizing hybrid variant with peripheral partial maturation of basaloid cells.

Figure 3

Basaloid squamous cell carcinoma. A) Illustrates biphasic pattern with conventional dysplastic squamous surface component associated with basaloid elements (arrow heads) and conventional squamous cell carcinoma intimately associated with basaloid component (arrow). B) Closely packed basaloid cells forming a "jigsaw puzzle" appearance. Microcystic cribriform-like pattern is also observed.

Figure 4

Undifferentiated (lymphoepithelial) carcinoma. Undifferentiated epithelial cells forming a syncytium and intermingled with lymphocytes and plasma cells. The tumor cells have large vesicular nuclei.

Figure 5

Papillary squamous cell carcinoma. A) Keratinizing type, the dysplastic cells show maturation with minimal parakeratin formation. B) Nonkeratinizing type with immature basaloid cells. C) strong and diffuse p16 staining. D) Positive ISH for high risk-HPV DNA (blue nuclear staining).