Emerging Concepts in Head and Neck Squamous Cell Carcinoma.

The upper aerodigestive tract is lined by a squamous epithelium. This squamous mucosa continuously regenerates from a proliferating basal layer that differentiates and eventually dies as it moves to the surface. Under this overlying squamous mucosal barrier, the tissues in different regions of the upper aerodigestive tract are quite diverse, including connective tissue, muscle, salivary glands, and lymphoid tissue. Though squamous cell carcinoma demonstrates fairly uniform histopathology, the process of carcinogenesis, the invasive and metastatic behavior, and the treatment response of the tumors can be as diverse as the variable microenvironment in the head and neck region. It is therefore not surprising that certain anatomic sites have a predilection for early metastasis. The interaction of squamous cell carcinoma (SCC) with the underlying tissue contributes to the invasive behavior. This issue of the Archives contains a group of 6 papers written by experts in the study of head and neck squamous cell carcinoma (HNSCC). These articles discuss various topics including our growing understanding of the causative agents of HNSCC, the epigenetic differences between different types of SCC, how recent advances in SCC treatment have helped improve patient outcomes, and how evolving surgical approaches and biomarker-driven treatments are playing an increasing role in the personalized care of HNSCC patients. Jimenez et al review the mechanisms responsible for SCC invasion that give rise to locoregional recurrence and metastasis to regional lymph nodes. Local invasion requires the ability to degrade extracellular matrix and infiltrate normal barriers of spread. In a previous study, Harris and colleagues showed that low-level expression of miR-375 microRNA correlates with poor outcome and metastasis, and mechanistic studies demonstrated that miR-375 altered the invasive properties of head and neck squamous cell carcinoma. Jimenez et al in the present research study show that miR-375 regulates a program of invasion that controls the development of invadopodia, specialized structures that localize the cancer cell’s efforts to secrete proteases and degrade matrix at the invading front. In addition to anatomic differences, the carcinogenesis models of head and neck squamous cell carcinoma (HNSCC) are growing more detailed as we gain a growing understanding of the causative agents and of the genetic factors of both the tumor and the patient. There are 2 major risk factors for the development of SCC in the United States: exogenous carcinogens (namely tobacco and alcohol exposure) and infection with the human papilloma virus (HPV). While many tobacco-related cancers are on the decline owing to decreases in smoking among Americans, the number of HPV-related head and neck cancer cases appears to be increasing. Cancers driven by tobacco and alcohol use occur throughout the upper aerodigestive track, while cancers driven by HPV appear to be localized to the oropharynx, specifically in the lymphoid-rich tonsils and base of tongue. Ben-Dayan et al propose that normal cells are robust because they can maintain a normal phenotype while buffering the impact of acquired mutations in their genome, however, cancer cells have lost the ability to maintain a normal phenotype in the face of genomic and transcriptional instability; that is, they demonstrate a disintegration of robustness. The current study assesses the loss of robustness as increased variance in gene expression and shows that carcinogen-driven SCCs have a greater variance in gene expression than HPV-driven cancers. Conceptually, the virus carries a program to initiate transformation and thus, HPV-infected cells accumulate fewer mutations and have a less disrupted genome. This is reflected by a relative decrease in transcriptional variance as compared to mutation-driven cancers. While mutation and transcription profiles differ by cancer etiology, the epigenetic profiles of these HNSCC subtypes differ as well. Anayannis et al review the epigenetic differences between HPV-driven and carcinogen-driven SCC. They discuss the significance of the HPV-associated epigenetic changes and how they may contribute to maintaining a malignant phenotype. The differences in etiology, genetics, epigenetics, molecular biology, and tumor behavior described above are now impacting our understanding of the variability in treatment response demonstrated by HNSCC. Increased knowledge and improved technology are resulting in modifications to treatment approaches. There is substantial evidence that HPV-driven SCC of the oropharynx behaves differently than carcinogen-driven SCC and should be treated differently. There are 3 broad treatment modalities currently available: Accepted for publication July 8, 2015. From the Department of Pathology, Albert Einstein College of Medicine, Bronx, New York. The author has no relevant financial interest in the products or companies described in this article. doi: 10.5858/arpa.2015-0269-ED Reprints: Michael B. Prystowsky, MD, PhD, Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Belfer, Room 711, Bronx, NY 10461 (e-mail: Michael. Prystowsky@einstein.yu.edu).