Head and neck squamous cell carcinomas (HNSCCs) are caused by tobacco and alcohol consumption and by infection with high-risk types of human papillomavirus (HPV). Tumours often develop within preneoplastic fields of genetically altered cells. The persistence of these fields after treatment presents a major challenge, because it might lead to local recurrences and second primary tumours that are responsible for a large proportion of deaths. Aberrant signalling pathways have been identified in HNSCCs and inhibition of epidermal growth factor receptor (EGFR) has proved a successful therapeutic strategy. In this Review, we discuss the recent literature on tumour heterogeneity, field cancerization, molecular pathogenesis and the underlying causative cancer genes that can be exploited for novel and personalized treatments of patients with HNSCC.

The molecular biology of head and neck cancer

The concept of "field cancerization" was first introduced by Slaughter et al. [D. P, Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular findings support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. In the initial phase, a stem cell acquires genetic alterations and forms a "patch," a clonal unit of altered daughter cells. These patches can be recognized on the basis of mutations in TP53, and have been reported for head and neck, lung, skin, and breast cancer. The conversion of a patch into an expanding field is the next logical and critical step in epithelial carcinogenesis. Additional genetic alterations are required for this step, and by virtue of its growth advantage, a proliferating field gradually displaces the normal mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected with dimensions of >7 cm in diameter, whereas they are usually not detected by routine diagnostic techniques. Ultimately, clonal divergence leads to the development of one or more tumors within a contiguous field of preneoplastic cells. An important clinical implication is that fields often remain after surgery of the primary tumor and may lead to new cancers, designated presently by clinicians as "a second primary tumor" or "local recurrence," depending on the exact site and time interval. In conclusion, the development of an expanding preneoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed.

https://cancerres.aacrjournals.org/content/canres/63/8/1727.full.pdf

A Genetic Explanation of Slaughter’s Concept of Field Cancerization: Evidence and Clinical Implications

The concept of a two-step process of cancer development in the oral mucosa, i.e., the initial presence of a precursor subsequently developing into cancer, is well-established. Oral leukoplakia is the best-known precursor lesion. The evidence that oral leukoplakias are pre-malignant is mainly derived from follow-up studies showing that between < 1 and 18% of oral pre-malignant lesions will develop into oral cancer; it has been shown that certain clinical sub-types of leukoplakia are at a higher risk for malignant transformation than others. The presence of epithelial dysplasia may be even more important in predicting malignant development than the clinical characteristics. Three major problems, however, are attached to the importance of epithelial dysplasia in predicting malignant development: (1) The diagnosis is essentially subjective, (2) it seems that not all lesions exhibiting dysplasia will eventually become malignant and some may even regress, and (3) carcinoma can develop from lesions in which epithelial dysplasia was not diagnosed in previous biopsies. There is, therefore, a substantial need to improve the histologic assessment of epithelial dysplasia or, since epithelial dysplasia does not seem to be invariably associated with or even a necessary prerequisite for malignant development, it may be necessary to develop other methods for predicting the malignant potential of pre-malignant lesions. As a consequence of these problems, numerous attempts have been made to relate biological characteristics to the malignant potential of leukoplakias. Molecular biological markers have been suggested to be of value in the diagnosis and prognostic evaluation of leukoplakias. Markers of epithelial differentiation and, more recently, genomic markers could potentially be good candidates for improving the prognostic evaluation of precursors of oral cancer. As yet, one or a panel of molecular markers has not been determined that allows for a prognostic prediction of oral pre-cancer which is any more reliable than dysplasia recording. However, these new markers could be considered complementary to conventional prognostic evaluation.

https://journals.sagepub.com/doi/pdf/10.1177/154411130301400105

Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics.

Head and neck squamous-cell carcinoma (HNSCC) is the sixth most common cancer worldwide and, disappointingly, survival rates are not improving. Moreover, HNSCC has a severe impact on the quality of life of patients and survivors, and the significant morbidity subsequent to treatment often mandates long-term multidisciplinary care, which places significant financial pressures on the treating institution. Therefore, prevention and early diagnosis of high-risk pre-malignant lesions are high priorities for reducing deaths due to head and neck cancer. Recent advances have begun to elucidate the different aetiologies of HNSCCs in relation to previous pre-malignancies and to identify which pre-malignant lesions are likely to progress to malignancy.

Profiling early head and neck cancer.

Purpose: Genetically altered cells could become widespread across the epithelium of patients with oral cancer, often in clinically and histologically normal tissue, and contribute to recurrent disease. Molecular approaches have begun to yield information on cancer/risk fields; tissue optics could further extend our understanding of alteration to phenotype as a result of molecular change. Experimental Design: We used a simple hand-held device in the operating room to directly visualize subclinical field changes around oral cancers, documenting alteration to fluorescence. A total of 122 oral mucosa biopsies were obtained from 20 surgical specimens with each biopsy being assessed for location, fluorescence visualization (FV) status, histology, and loss of heterozygosity (LOH; 10 markers on three regions: 3p14, 9p21, and 17p13). Results: All tumors showed FV loss (FVL). For 19 of the 20 tumors, the loss extended in at least one direction beyond the clinically visible tumor, with the extension varying from 4 to 25 mm. Thirty-two of 36 FVL biopsies showed histologic change (including 7 squamous cell carcinoma/carcinomas in situ, 10 severe dysplasias, and 15 mild/moderate dysplasias) compared with 1of the 66 FV retained (FVR) biopsies. Molecular analysis on margins with low-grade or no dysplasia showed a significant association of LOH in FVL biopsies, with LOH at 3p and/or 9p (previously associated with local tumor recurrence) present in 12 of 19 FVL biopsies compared with 3o f 13 FVR biopsies (P =0 .04). Conclusions: These data have, for the first time, shown that direct FV can identify subclinical high-risk fields with cancerous and precancerous changes in the operating room setting.

/pdf/fluorescence-visualization-detection-of-field-alterations-in-9md8hn0sxx.pdf

Fluorescence Visualization Detection of Field Alterations in Tumor Margins of Oral Cancer Patients

Distinguishing true precursor lesions on the basis of clinical or histological features alone is unreliable but is important so that appropriate intervention can be instigated. Preliminary studies have shown that a microsatellite assay may provide important new prognostic information. To build on these observations, we have performed a case-control study to establish whether we can be confident about incorporating this new information into clinical practice. We have determined the frequency of allelic imbalance (AI) within key chromosomal regions, by matching 39 cases with dysplastic oral lesions that developed a tumor on the same side of the mouth, for as many variables as possible, with controls presenting with similar lesions that did not progress to malignancy when followed for the same period. Our findings confirm that the group that developed tumor had precursor lesions that harbor AI at more loci (P = 0.002). However, no consistent patterns of AI were associated with the three grades of dysplasia: mild, moderate, and severe. One-third of the tumors developed at the same site as the dysplastic lesion and two-thirds at a different site, which revealed that the presence of these aberrations in a dysplastic lesion provided information about the risk of malignant change within a larger field. This suggests that the process of field cancerization is more widespread than previously recognized. On the basis of these findings, we advocate complete excision of all suspicious areas that show AI at two or more key loci, regardless of the degree of dysplasia. However, because the remaining mucosa is also "at risk," these cases should also be targeted to receive dietary advice and chemoprevention, to minimize their risk of tumor formation at a distant site.

https://cancerres.aacrjournals.org/content/canres/60/14/3893.full.pdf

A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization.

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A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization.