Tumor Biology of Head and Neck Cutaneous Squamous Cell Carcinoma

Abstract

Epidemiologic studies worldwide have consistently shown that the incidence of cutaneous squamous cell carcinoma (cSCC) has steadily increased over the last four decades, possibly due to a combination of depletion of the ozone layer, an aging population, increasing use of immunosuppression, and changing social trends. In fact, the incidence of cutaneous malignancies has reached endemic proportions in New Zealand and Australia, as a result of the additional factors of a predominantly Anglo-Celtic population and a high level of ambient solar irradiation. 75% of cSCC arise in the head and neck, and metastatic disease is not uncommon. Metastatic cSCC to the parotid and cervical lymph nodes carries high morbidity and mortality in both the disease and treatment. Despite its high prevalence, the tumor biology of cSCC is poorly understood.

The previous (sixth) American Joint Committee on Cancer (AJCC) TNM staging system for cSCC that existed during much of the duration of this PhD study was rudimentary, and lacking in its power to prognosticate for more advanced disease. A comprehensive staging system with adequate stratification of disease severity was necessary for comparison of treatment outcome in research, and for guiding clinical decision making in whether intensification or de-escalation of treatment is necessary. This provided the impetus for a local study based in Wellington of survival outcome in patients with metastatic head and neck cSCC. This regional study then extended to include the four major head and neck cancer centers in New Zealand.

There is an increasing interest and an expanding role in oncology for more-targeted therapies, e.g., immunotherapy and targeted molecular therapy. Among the immune cells (i.e., tumor-associated macrophages, dendritic cells, neutrophils, T cells and mast cells) in the microenvironment, the mast cell has received the least attention despite well-established evidence for its roles in carcinogenesis. In this study, mast cells were shown to deregulate key apoptotic and cell cycle genes, including tumor necrosis factor-related apoptosis-related ligand (TRAIL), baculoviral inhibitor of apoptosis repeat-containing protein 4 (BIRC4), cyclin-dependent kinase 6 (CDK6) and cyclin G2 (CCNG2) in human squamous cell carcinoma cell line SCC25 in vitro, and causing an overall inhibitory effect on the growth of SCC25. Within the tumor microenvironment, angiogenesis is strongly associated with the metastatic phenotype, but the interaction between mast cells and angiogenesis remains to be elucidated.

Epidermal growth factor receptor (EGFR) targeted molecular treatment has enjoyed reasonable success in the treatment of colorectal, lung and head and neck mucosal squamous cell carcinoma. This PhD study showed that the role of EGFR is not as straight-forward in cSCC. Whilst clearly over-expressed in primary lesions that subsequently metastasized, EGFR was only weakly detectable in established nodal disease, with a clear implication for EGFRtargeted treatment in metastatic cSCC. The mechanisms of EGFR overexpression, and hence, potential points of intervention remain as yet unclear.

This research contributes to better understanding of the tumor biology of head and neck cSCC, which is essential in the future development of novel therapies.