Genes Protooncogenes and Thyroid Cancers

This section is limited to:

• RET protooncogene and MTC

• RET protooncogene and PTC

• Thyroid carcinomas and familial adenomatous polyposis (FAP)

• Thyroid carcinoma and Cowden's disease

RET protooncogene encodes a transmembrane receptor that is a member of the receptors of the tyrosine kinase family and is found on chromosome 10 (lOql 1.2).31123 The gene is expressed normally in thyroid gland, adrenal gland, nerve tissue, and developing kidney and pathologically in neuroendocrine tumors (MTC, pheochromocytomas) and hyperplasia and neoplasia of parathyroid glands.

The RET gene derived its name from an experiment in which it induced classic NIH 3T3 transformation, NIH 3T being an NIH assay (rearranged during iransfection).14 The gene encodes a transmembrane receptor, tyrosine kinase, that acts as a link between the extracytoplasm and plasma membrane and the nucleus of the cell by the transduction of signals.

The RET receptor is part of a complex of proteins that serve as coreceptors on the cell membrane. The coreceptors increase the affinity of RET receptors for three ligands, of which glial cell line-derived neurotrophic factor (GDNF) is the most prominent. GDNF is associated in the pathogenesis of Hirschsprung disease.31123

The RET protooncogene has been conclusively identified in the MEN 2A and 2B syndromes and FMTC. The characteristics associated with medullary carcinoma and the MEN syndromes can be summarized as follows31123:

• Germline mutations may be associated with specific areas of the gene.

• 95% of patients with MEN 2A have mutations in exons 10 and 11 on chromosome 10.

• 90% of patients with MEN 2B have changes in ex on 16, codon 918.

• FMTC is associated with mutations in exons 10, 11, and 13, codons 768, 609, 611, 620, and 634.

• Patients with MEN 2A who have changes in codon 63 with Cys 634 to Arg are at a greater risk for the development of parathyroid disease.

The mutations that occur in RET are31:

• Missense germline mutations, found in 97% of patients with MEN 2A and 86% of patients with FMTC (codon 609,611,620, or 634)

• Mutations involving the tyrosine kinase domain, nearly exclusively in FMTC (codon 768, 790, 804, 844, or 891)

• Unique mutations in exon 13 or 14

• Mutations involving the tk domain, codon 883 or 918, in virtually all patients with MEN 2B

The data for sporadic MTC are

• Missense mutations in exon 16, substitution of methionine for threonine in codon 918.

• Other mutations at codon 768, exon 13; codon 883, exon 15.

• Mutations at exons 10 and 11 may not lead to development of MTC but may prime the C cells before transformation occurs.

About 23% of patients with sporadic MTC have mutations affecting exon 16 and codon 918. Because identical mutations are found in MEN 2B, familial and sporadic MTCs may result from similar changes in the gene. One report concluded that a mutation in codon 918 in the RET protooncogene in sporadic MTC is associated with a poor prognosis, with frequent distant metastases and recurrences.

The characteristics of pheochromocytomas with or without MEN changes are:

• Sporadic pheochromocytomas have mutations in codon 768.

• There are mutations in codon 634 (cysteine to arginine) in MEN 2A families (with at least one member with pheochromocytoma and parathyroid hyperplasia).

• Mutations involve codon 609, 611, 618, or 620 in families with parathyroid hyperplasia and FMTC without pheochromocytoma.

• There is a significant association of hyperparathyroidism and pheochromocytoma with mutation at codon 634.

• No specific mutation correlates with familial pheochromocytoma.

Parathyroid hyperplasia in MEN 2A, pheochromocytomas in MEN 2A and 2B, and the other somatic lesions, such as marfanoid habitus, intestinal ganglioneuromatosis, skeletal abnormalities and, rarely, parathyroid hyperplasia, reflect the presence of the RET protooncogene in their respective normal counterparts.

RET mutations, missense and nonsense, in exons 2, 3, 5, and 6 have been found in patients with Hirschsprung disease. The mutations lead to inactivation of RET rather than the activation found with medullary thyroid cancer. The normal activity of RET, in reference to the nervous system, is to develop the enteric autonomic nervous system. Its absence leads to the neural defect of Hirschsprung disease (absence of ganglion cells in colonic enteric plexuses).31

The clinical significance of mutations of the RET gene in sporadic MTC is controversial. Such tumors appear to be aggressive and result in poor outcomes because of frequent development of distant metastases and recurrences. However, these findings have not been firmly established.

The rate of de novo mutations in MEN 2A and FMTC is approximately 10%, whereas the rate in MEN 2B is approximately 50%.

The finding of RET protooncogene in familial forms of medullary carcinoma syndromes has altered the screening procedures for medullary carcinoma (MTC). Before the discovery of the association of MTC with RET protooncogene, screening was accomplished using intravenous pentagastrin and calcium, a procedure fraught with discomfort for the patient and a small but significant number (approximately 15%) of false-negative and false-positive results. Biochemical screening has now been largely replaced by genetic screening. Blood levels of calcitonin, either basal or after provocation, are now primarily used to observe patients for recurrent or persistent MTC after thyroidectomies.79

The associations of the RET gene with PTC are14'31123124:

• RET/PTC rearrangements are unique to human PTC.

• The rearrangements are oncogenes, formed by translocation of three different genes of the tyrosine domain of the RET protooncogene.

• Four forms are recognized, RET/PTC1 to RET/PTC4.

• There is loss of differentiated functions of the thyroid gland: thyroglobulin, thyroperoxidase, and thyrotropin receptor gene expression.

• Thyrotropin-independent cell growth is promoted.

• Frequency of RET/PTC activation in PTCs varies from 2% to 60% but is significantly higher in the

4- to 30-year-old age group; this may account for the contribution of age to the clinical features of PTC.

• No connection of RET/PTC rearrangements to the aggressiveness of papillary carcinomas has yet been demonstrated.

• All thyroid carcinomas with RET rearrangements show a well-differentiated phenotype and do not progress to aggressive, poorly differentiated forms.

• RET/PTC1 is dominant in sporadic tumors and both RET/PTC1 and RET/PTC3 are common in radiation-induced tumors.

• RET/PTC arrangements are common in papillary microcarcinomas, so they are early developments in thyroid neoplasia.

The incidence of RET/PTC rearrangements in clinically significant papillary carcinomas is not known, although a frequency of 2.5% to 50% has been reported.14

Immunohistochemical staining for RET/PTC rearrangements can now be employed to identify definitively papillary carcinomas that mimic follicular lesions. Follicular variants of papillary carcinomas can now be more precisely identified.

Eighty percent of papillary microcarcinomas have the rearrangements, as well as 50% of clinically significant tumors.14 Using RET/PTC rearrangements as markers for papillary differentiation, Hurthle cell tumors can now be more accurately subdivided into Hurthle cell adenomas, Hurthle cell carcinomas, and Hurthle cell papillary carcinomas.

The association of FAP with thyroid carcinoma has been well documented.125"129 The extracolonic manifestations of the syndrome include upper gastrointestinal adenomas, congenital hypertrophic retinal pigment epithelial lesions, desmoids, osteomas, epidermoid cysts of skin, and dental abnormalities.

Relevant data concerning FAP-associated thyroid carcinomas can be summarized as follows:

• Age: younger patients, mean age 25 to 34 years.

• Histopathology: unique papillary carcinoma with papillary pattern plus cribriform and solid areas with spindle cells, squamoid cells, and whorled spindle cells; numerous multifocal and bilateral microcarcinomas; Hashimoto-like parenchymal changes.126

• Genetics: autosomal dominant; adenomatous polyposis coli (APC) germline mutations on chromosome 5q21.

• Coexisting RET/PTC rearrangements: RET/PTC1 and RET/PTC3 in 80% of PTCs.

• Treatment: total thyroidectomy because of unilateral and bilateral multifocal lesions.

• Prognosis: presumably good; carcinomas appear to be variants of papillary carcinoma, and no genetic or other findings suggest poor clinical outcomes.

The APC gene is a tumor suppressor gene and does not participate in the progression of sporadic thyroid cancer. Interactions between the RET/PTC 1 activation and APC mutations are postulated in the development of FAP-associated thyroid carcinomas.

The age and sex in FAP-associated carcinomas are in keeping with usual papillary carcinomas. Bilateral and multicentric tumors are analogous to pathologic findings in PTCs.

The cribriform and solid histology in these tumors may be sufficiently distinctive for pathologists to suggest the presence of the APC gene in patients in whom thyroid cancers are the initial manifestations (Fig. 25-7).126 However, the same histopathologic pattern allegedly occurs in sporadic cases.130 Thyroid cancers are not common in patients with APC. Only 1% to 2% of patients develop thyroid carcinomas.

Cowden's syndrome, the multiple hamartoma syndrome, is an autosomal dominant disorder characterized by multiple benign and malignant neoplastic lesions found in many organs, including the thyroid gland and breast.131"134

The thyroidal lesions are multinodular goiters, follicular adenomas, or carcinomas. The specific change in the follicular neoplasms is loss of heterozygosity on chromosome arm lOq. A novel tumor suppressor gene, PTEN, mapped to 10q23.3 is the susceptibility gene for Cowden's syndrome.

The thyroid lesions are the major extracutaneous manifestations of the syndrome and are papillary carcinomas in adenomatous goiters, multicentric follicular adenomas, adenomatous nodules, and follicular carcinomas. As with

FIGURE 25-7. Familial adenomatous polyposis (FAP)-associated thyroid carcinoma.

FAP-associated tumors, it is postulated that the histologic findings in the thyroid gland may be unique to Cowden's disease and its presence can be suggested by the changes in the thyroid gland.133 134 The finding of multiple adenomatous goiters or multiple follicular adenomas, particularly in children and adolescents, should alert physicians to the possibility of an inherited trait, such as Cowden's disease. Because the tumors can be multicentric and can progress, total thyroidectomy is recommended, even though the tumors are usually benign. Progression of an adenoma to carcinoma is not inevitable because there are studies that suggest that adenomas and carcinomas can develop along separate, nonserial pathways.


Fine-needle aspiration of thyroid lesions has made interpretation of the aspirates one of the more important diagnostic steps in the treatment of benign and malignant diseases of the thyroid gland. However, every clinician who treats thyroid diseases should be aware of the limitations of the method. The difficulty encountered in differentiating benign from malignant follicular tumors, as well as the separation of benign Hürthle cell lesions from their malignant counterparts, has been described. There is liberal use of descriptive terminology, such as "follicular neoplasia cannot be excluded," with the connotation that a well-differentiated follicular carcinoma may very well be present. Such cytologic reports may have resulted in the excess expenditure of resources in pursuit of uncommon follicular carcinomas. Suggestions have been made to rectify this situation. The same comments apply to Hürthle cell lesions.

The interpretations of fine-needle aspirates are nearly indispensable in the diagnosis and treatment of papillary and medullary carcinomas of the thyroid gland. Cytologic smears of papillary carcinomas are easily recognized by the syncytia of large follicular cells with nuclear membrane folds (grooves), intranuclear inclusions, and prominent nuclei. The clear nuclei seen on histologic slides are absent, being artifacts of formalin fixation.

Medullary carcinomas are usually easily recognized. In addition, stains for calcitonin and carcinoembryonic antigen can aid in the diagnosis.

The cytopathologic appearances of tall cell and columnar cell carcinomas have been described. However, these lesions are rare, and the recognition of a malignant tumor should suffice without specifying the cell type.

Cytopathologic smears are extremely helpful in establishing the diagnosis of malignant lymphomas of the thyroid gland. Marginal zone lymphomas, per se, have rarely been reported in the thyroid gland. The usual lymphoma of the thyroid gland is a diffuse, large B-cell lymphoma. These lymphomas are characterized by large cells with cleaved or noncleaved nuclei and prominent nucleoli. Flow cytometry, immunohistochemical staining, and gene rearrangement studies on fresh tissue specimens are extremely helpful in establishing the proper diagnosis. The association of autoimmune thyroiditis with lymphomas of the thyroid gland may make the diagnosis difficult. The ancillary studies suggested are very helpful in establishing the proper diagnosis.

Cytopathologic smears can also establish the diagnosis of benign lesions, such as nodular goiters and autoimmune thyroiditis. The nodules of a nodular goiter are often associated with syncytia of cells, as seen in papillary carcinomas; however, none of the nuclear changes of papillary carcinoma are seen, and the nuclei appear bland and benign. Collections of macrophages, some laden with hemosiderin, can be numerous. Typically, sheets of cells, most often Hürthle cells, are surrounded by benign-appearing lymphocytes in autoimmune thyroiditis.

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