Introduction

Aside from stating that a particular tumor is SSC, additional information reported by the pathologist usually includes tumor grade or differentiation. Traditionally, tumor grading has been based on criteria developed over 50 years ago by Broder. Unfortunately, differentiation grade has not been consistently accurate in reflecting the biologic aggressiveness of squamous carcinomas. The difficulty in predicting the behavior of individual tumors is well recognized. Prognosis is influenced by many factors other than grade. These include tumor size; site; vascularity; lymphatic drainage; host immune response; the patient’s age, sex, nutritional, and performance status; and other as yet unrecognized variables.

The comprehensive histologic evaluation of squamous cell carcinomas includes characteristics of tumor-host interactions; Jakobsson and colleagues pioneered their incorporation into the determination of tumor grade. Characteristics considered include degree of keratinization, nuclear grade, mitotic rate, inflammatory response, vascular-stromal response, vascular invasion, and pattern of invasion. These characteristics have variably correlated with biologic behavior. Keratinization is the major determinant of Broder grade. Better-differentiated tumors that produce more keratin are thought to be less likely to metastasize. Nuclear grade assesses nuclear pleomorphism. Enlarged, hyperchromatic nuclei are associated with less-differentiated tumors. Nuclear grade accurately predicts the behavior of advanced laryngeal cancers. Enlarged nuclear size and staining presumably reflect chromosomal abnormalities and increased DNA content. Numerous studies of DNA content have demonstrated high rates of aneuploidy in squamous cell cancers that range from 50% to 70%. Aneuploidy has been associated with poor prognosis. Mitotic rate and labeling index have also been used to reflect proliferative activity, but large-scale studies of head and neck cancers have been lacking.

Features reflecting aggressive disease include lymphatic invasion, perineural invasion, lymph node metastases, and penetration of the tumor through the capsule of involved lymph nodes (extracapsular spread). The presence of regional lymph node metastases is the most important determinant of prognosis in head and neck cancer and is associated with a 50% decrease in survival rates as compared with patients without regional metastases.

More recently, the histologic pattern of invasion of these cancers was systematically studied. Tumors that invade with thin fingerlike projections or single disassociated cells behave more aggressively regardless of differentiation grade and tend to be associated with vascular and neural invasion. The presence of extracapsular spread of tumor in the neck has been directly associated with high rates of distant metastases. These various histologic features play an important role in therapeutic decision-making.

Molecular Pathology

The head and neck surgical oncologist relies heavily on the pathologist’s assessment of surgical margins via frozen section to ensure total excision of the tumor in patients with head and neck cancer. Sidransky and colleagues proposed using contemporary molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with HNSCC. They found that 38% (5 of 13) of patients had molecular positive margins and thatv approximately 50% had molecular identification of p53 mutations in histopathologically negative lymph nodes. Patients with these molecular positive margins had an increased risk of local recurrence. Although advances in molecular techniques are likely to augment enormously what is now considered standard histopathologic assessment, critical studies will be required to determine the meaning and impact of this new pathologic information and appropriate management steps that result.