Elsevier

Oral Oncology

Volume 42, Issue 10, November 2006, Pages 965-978
Oral Oncology

REVIEW
Tumours of familial origin in the head and neck

https://doi.org/10.1016/j.oraloncology.2006.03.002Get rights and content

Summary

Individuals with inherited cancer syndromes are at significant risk of developing both benign and malignant tumours as a result of a germline mutation in a specific tumour suppressor gene. Tumours of familial origin are a rare event in the head and neck but despite this, they deserve a growing interest. Familial paragangliomas are most of the time limited to the paraganglionar system, but also may be part of different syndromic associations. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis in the search of SDHB, SDHC and SDHD mutations in families of affected patients plays a front-line diagnostic role, leading to more efficient patient management. Multiple endocrine neoplasia type 1 is characterized by the simultaneous occurrence of at least two of the three main related endocrine tumours: parathyroid, enteropancreatic and anterior pituitary. These tumours arise from inactivating germline mutations in the MEN-1 gene. No clear correlation of MEN-1 genotype with phenotype has emerged to date, and MEN-1 mutation testing in tumours is not used clinically because it has no implications for tumour staging. Multiple endocrine neoplasia type 2 is due to a germline mutation in the RET proto-oncogene. Hallmarks of MEN-2A (the most common phenotypic variant) include medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The most central clinical difference with MEN-1 is that the associated cancer can be prevented or cured by early thyroidectomy in mutation carriers. Individuals with neurofibromatosis type 1 present early in life with pigmentary abnormalities, skinfold freckling and iris hamartomas, as result of NF1 gene mutation.

Neurofibromatosis type 2 is caused by inactivating mutations of the NF2 gene, and is characterized by the development of nervous system tumours (mainly bilateral vestibular schwannomas), ocular abnormalities, and skin tumours. The molecular genetic basis of nasopharyngeal carcinomas remains unknown, but there is evidence for the linkage of these tumours to chromosome 3p. Finally, the high rate of p16 mutations in squamous cell carcinomas and the association of p16 with familial melanoma propose p16 as an ideal candidate gene predisposing to familial squamous cell carcinomas. The elucidation of the cellular processes affected by dysfunction in familial tumours of the head and neck may serve to identify potential targets for future therapeutic interventions.

Introduction

Individuals with inherited cancer syndromes are at significant risk of developing both benign and malignant tumours as a result of starting life with a germline (inherited) mutation in one of the two copies of a specific tumour suppressor gene. Since affected individuals are heterozygous for a loss of function mutation in one copy of a tumour suppressor gene, only one additional genetic alteration (loss of the wild-type allele) is needed to facilitate tumour development. This two-step process of tumour suppressor gene inactivation was coined the ‘two-hit hypothesis’ by Alfred Knudson1 in his classic monograph on retinoblastoma. In this fashion, a cell that undergoes inactivation of both copies of a specific tumour suppressor gene has an increased growth advantage relative to cells with wild-type tumour suppressor gene function.

The proteins encoded by tumour suppressor genes mutated in cancer predisposition syndromes are growth regulators critical for the maintenance of orderly cell growth and differentiation. A simplified view of tumour suppressor gene function envisions three main intracellular compartments important for regulating cell proliferation and survival, including: (i) the cell membrane where cues from the environment are transduced to the interior of the cell; (ii) the cytoplasm, where these extracellular signals are transmitted to the nucleus; and (iii) the nucleus, where cell cycle regulation dictates whether a cell will initiate DNA synthesis and undergo mitosis. Dysregulated function of proteins in any of these three compartments can result in an increased growth advantage and can, by itself, predispose the cell to transformation or do so in concert with other genetic changes. The identification of tumour suppressors mutated in specific inherited cancer syndromes allows us to pinpoint critical signal transduction pathways, cell cycle regulatory events and extracellular cues that instruct a particular cell type to proliferate or differentiate. The elucidation of the cellular processes affected by dysfunction of these molecules may serve to identify potential targets for future therapeutic interventions.

Section snippets

Epidemiological and clinical aspects

Paragangliomas (PGLs) are neoplasms of neuroectodermal origin, embryologically derived from the neural crest cells, which originate in the paraganglia, a collection of small neuroendocrine organs that are distributed throughout the body, from the middle ear and the skull base to the pelvic floor. These tumours are usually divided into two categories, those developing in the head and neck region and those arising elsewhere, with the adrenal medulla being the major site. Adrenal PGLs are usually

Clinical characteristics

Multiple endocrine neoplasia type 1 (MEN-1 or Wermer syndrome) is characterized by the simultaneous occurrence of at least two of the three main MEN-1 related endocrine tumours: parathyroid, enteropancreatic and anterior pituitary. The estimated frequency of MEN-1 is one in 30,000.

  • (a)

    Parathyroid tumours. Primary hyperparathyroidism (HPT) is the most common and earliest endocrine manifestation, presenting in more than 90% of MEN-1 patients. HPT is generally asymptomatic, occurring earlier in MEN-1

Clinical characteristics

Multiple endocrine neoplasia type 2 (MEN-2) is a hereditary syndrome that is transmitted in an autosomal dominant pattern, occurring with a similar frequency than MEN-1. MEN-2A, MEN-2B, and familial medullary thyroid cancer (MTC) comprise the MEN-2 syndrome. Hallmarks of MEN-2A (the most common phenotypic variant) include MTC, pheochromocytoma, and HPT. MEN-2B is associated with an earlier onset and more aggressive behaviour of MTC and pheochromocytoma, the absence of HPT, and the presence of

Familial hyperparathyroidism

Familial hyperparathyroidism (FHPT) is a hereditary disease characterised by uni- or multiglandular parathyroid disease where HPT is transmitted in an autosomal dominant fashion. FHPT consists of a variety of diseases such as multiple endocrine neoplasia type 1 (MEN-1) and type 2 (MEN-2), familial isolated hyperparathyroidism (FIHPT) with single adenoma and with multiple adenomas (or hyperplasia), and FHPT with jaw-tumour (FHPT-JT). Several loci of genetic interest have been identified in

Familial papillary carcinoma of the thyroid

The most common familial thyroid tumour is MTC, which is generally part of the MEN syndrome. However, there appears to be an increasing association of familial nature in well differentiated papillary thyroid carcinoma. Whether this is mere coincidence, or there is any genetic predilection, needs to be defined. However, there appears to be an increasing incidence of familial papillary thyroid carcinoma, as well as increasing literature suggestive of the familial nature of papillary thyroid

Carney complex

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome characterized by spotty skin and mucosal pigmentation, primary pigmented nodular adrenocortical disease, cardiac and cutaneous myxomas, growth hormone and prolactin-producing pituitary adenomas, testicular tumours, thyroid adenoma or carcinoma and ovarian cysts. CNC is inherited as an autosomal dominant trait and has some clinical similarities to McCune-Albright syndrome. Recently, genes related to stimulation of

Clinical characteristics

The NF1 (von Recklinghausen’s neurofibromatosis) is an autosomal dominant disorder with an overall incidence of one in 3000 worldwide.67 The disorder has almost 100% penetrance but variable expression, and there can be large variation in the clinical manifestations within a family. Furthermore, 50% of cases are sporadic (they arise from germ-cell mutations).

Diagnosis of NF1 is based on clinical criteria (Table 4). Typically, individuals with NF1 present early in life with pigmentary

Clinical characteristics

Neurofibromatosis type 2 (NF2) is an hereditary disease caused by inactivating mutations of the NF2 gene, and is characterized by the development of nervous system tumours, ocular abnormalities, and skin tumours. NF2 is much less frequent than NF1, with a birth incidence of between one in 33,000–40,000, and prevalence within the population is one in 210,000.80 It is likely that the prevalence is higher due to asymptomatic NF2 mutation carriers and increased patient survival from improvements in

Familial nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a relatively uncommon disease in the western countries with a reported incidence of less than 1 case per 100,000 persons each year. However, NPC is a prevalent malignancy in Southeast Asia in areas such as southern China, Hong Kong, Singapore, Malaysia, and Taiwan. The reported incidence in these countries ranges from 10 to 53 cases per 100,000 persons. The incidence is also high among Eskimos in Alaska and Greenland and in Tunisians, ranging from 15 to 20

Familial squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy worldwide, accounting for an estimated 37,900 new cases in the United States in 2002, which cater for roughly 3% of all new cases of cancer and for 1.15% of cancer deaths annually.110 HNSCC tend to occur sporadically at a much higher incidence, but closer examination of a subset of tumour patients has revealed familial clustering in oral squamous cell carcinoma suggestive of an autosomal dominant mode of inheritance.111

Conflict of Interest statement

“None declared”.

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