This document discusses risk factors and molecular genetics related to carcinoma of the thyroid gland. It notes that radiation exposure, family history, and certain genetic syndromes can increase cancer risk. Radiation exposure under 2000 cGy linearly increases risk, which is maximum 20-30 years later. Familial syndromes like MEN2A and MEN2B are associated with medullary thyroid carcinoma. The RET proto-oncogene plays a role in thyroid cancers, and mutations cause developmental syndromes and increase cancer risk. Other tumor suppressors like p53 and cell cycle regulators can also be mutated in thyroid cancers.

1. CARCINOMA THYROID
A.RASAGNA
MODERATOR: DR.U.SUMAN
ASSISTANT PROFESSOR OF SURGERY

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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9.  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.

10. 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.

12. 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.

13. MOLECULAR GENETICS OF THYROID
TUMORIGENESIS

14. 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.

15. 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.

16. Mutations in cysteine residues at
1. codons 609, 611, 618, 620, and 634 —— MEN2A and
FMTC
2. codon 918 —— MEN2B
3. codons 768 and 804 —— FMTC

17. 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.