CARCINOMA THYROIDETIOLOGY

A.RASAGNAMODERATOR: DR.U.SUMAN

ASSISTANT PROFESSOR OF SURGERY

ETIOLOGY

Thyroid cancer is twice as common in women as men, but male gender is associated with a worse prognosis.

EXTERNAL BEAM RADIATION

Low-dose therapeutic radiation has been used to treat conditions such as tinea capitis (6.5 cGy), enlarged tonsils and adenoids (750 cGy), acne vulgaris (200 to 1500 cGy), and other conditions such as hemangioma and scrofula.

Radiation (approximately 4000 cGy) is also an integral part of the management of patients with Hodgkin's disease.

It is now known that a history of exposure to low-dose ionizing radiation to the thyroid gland places the patient at increased risk for developing thyroid cancer.

The risk increases linearly from 6.5 to 2000 cGy, beyond which the incidence declines as the radiation causes destruction of the thyroid tissue.

The risk is maximum 20 to 30 years after exposure, but these patients require lifelong monitoring.

During the nuclear fallout from Chernobyl in 1986, I131 release was accompanied by a marked increase in the incidence of both benign and malignant thyroid lesions noted within 4 years of exposure, particularly in children.

Most thyroid carcinomas following radiation exposure are papillary, and some of these cancers with a solid type of histology and presence of RET/PTC translocations appear to be more aggressive.

In general, there is a 40% chance that patients presenting with a thyroid nodule and a history of radiation have thyroid cancer.

FAMILY HISTORY

A family history of thyroid cancer is a risk factor for development of both medullary and non-medullary thyroid cancer.

Familial MTCs occur in isolation or in association with other tumors as part of multiple endocrine neoplasia type 2 (MEN2) syndromes.

MEN2 SYNDROMES:MEN2A is associated with medullary thyroid

carcinoma and pheochromocytoma (in 50%) or parathyroid adenoma (in 20%)

MEN2B is associated with medullary thyroid carcinoma, marfanoid habitus, mucosal neuromas, and ganglioneuromatosis.

Nonmedullary thyroid cancers can occur in association with other known familial cancer syndromes such as Cowden’s syndrome, Werner’s syndrome (adult progeroid syndrome), and familial adenomatous polyposis.

They can also occur independently of these syndromes as the predominant tumors in the families.

FNMTC is now recognized as a distinct clinical entity associated with a high incidence of multifocal tumors and benign thyroid nodules.

Several candidate loci that predispose to these tumors have been identified, including MNG1 (14q32), thyroid carcinoma with oxphilia (TCO, on 19p13.2), fPTC/papillary renal neoplasia (PRN, on 1q21), NMTC (2q21), FTEN (8p23.1-p22), and the telomere-telomerase complex.

OTHER RISK FACTORS:Iodine: Iodine deficient diets may lead

to increase the TSH levels and considered goitrogenic.

Thyroiditis: (Hashimoto's thyroiditis) may develop into a form of cancer called lymphoma.

MOLECULAR GENETICS OF THYROID TUMORIGENESIS

Several oncogenes and tumor suppressor genes are involved in thyroid tumorigenesis.

RET:The RET proto-oncogene plays a significant

role in the pathogenesis of thyroid cancers.It is located on chromosome 10 and encodes a

receptor tyrosine kinase, which binds several growth factors such as glial-derived neurotrophic factor and neurturin.

The RET protein is expressed in tissues derived from the embryonic nervous and excretory systems. Therefore, RET disruption can lead to developmental abnormalities in organs derived from these systems, such as the enteric nervous system (Hirschsprung's disease) and kidney.

Germline mutations in the RET proto-oncogene are known to predispose to MEN2A and MEN2B, and familial MTCs, and somatic mutations have been demonstrated in tumors derived from the neural crest, such as MTCs (30%) and pheochromocytomas.

Mutations in cysteine residues at 1. codons 609, 611, 618, 620, and 634 ——

MEN2A and FMTC2. codon 918 —— MEN2B3. codons 768 and 804 —— FMTC

The tyrosine kinase domain of RET can fuse with other genes by rearrangement. These fusion products also function as oncogenes and have been implicated in the pathogenesis of PTCs. Young age and radiation exposure seem to be independent risk factors for the development of RET/PTC rearrangements.

It has now been established that RET/PTC signaling involves the mitogen-activated protein kinase (MAPK) pathway via other signaling molecules such as Ras, Raf and MEK.

p53 GENE:The p53 gene is a tumor suppressor gene

encoding a transcriptional regulator, which causes cell cycle arrest allowing repair of damaged DNA, thus helping to maintain genomic integrity.

Mutations of p53 are rare in PTCs but common in undifferentiated thyroid cancers and thyroid cancer cell lines.

Other cell cycle regulators and tumor suppressors such as p15 and p16 are mutated more commonly in thyroid cancer cell lines than in primary tumors.