Familial Syndromes Associated with Thyroid Cancer in the Era of Personalized Medicine

Abstract

Background:

Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies, and 5% of these patients will have familial disease. This compares to 25% of patients with medullary thyroid cancer (MTC) having a familial form; however, this accounts for only 1% of all patients with thyroid cancer. Most cases of familial thyroid cancer are nonmedullary (NMFTC), and have been shown to be present in familial cancer syndromes such as familial adenomatous polyposis, Cowden syndrome, Carney complex, Pendred syndrome, and Werner syndrome. This review discusses the contemporary management of the patients with familial-syndrome-associated thyroid cancer based on their individual risks for developing thyroid cancer.

Summary:

Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. The mutations in patients with isolated NMFTC have not been as well defined as in MTC. They are likely autosomal dominant with reduced penetrance. The patients with these familial syndromes most likely have a susceptibility gene that increases the risk of thyroid cancer. Most of the patients with a familial syndrome and NMFTC will have papillary thyroid carcinoma, suggesting that a specific gene for papillary thyroid carcinoma may also be present. In many cases, patients have a known familial syndrome that has defined risk for thyroid cancer.

Conclusions:

Patients with familial syndromes that are associated with thyroid cancer can be individually categorized based on syndrome risks for developing thyroid cancer. The clinician must also be knowledgeable in recognizing the possibility of an underlying familial syndrome when a patient presents with thyroid cancer.

Introduction

T hyroid cancer accounts for only 1% of all malignant tumors (1). In recent years, the incidence of thyroid malignancy has increased at a rate higher than all other cancers (2). In the year 2000, there were ∼18,000 new cases of thyroid cancer in the United States (72% woman), and by the year 2007, there were nearly 35,000 new cases (78% women) (2). The majority (95%) of patients will have well-differentiated cancers that are of follicular cell origin. The well-differentiated cancers include papillary (80%–90%), follicular (10%–15%), and Hürthle cell cancers, of which many consider a variant of follicular cancer. Approximately 5% of patients will have medullary thyroid cancer (MTC).

The increased incidence of thyroid cancer has been attributed to a more liberal use of computed tomography scanning and ultrasonography and the detection of incidental thyroid nodules. The finding that many of these small cancers are behaving more aggressively suggests that the increase may be multifactorial and a history of radiation exposure or genetic predispositions may be contributing factors. Those with a history of radiation-induced thyroid cancer have characteristic abnormalities at the molecular level that increase the susceptibility to developing thyroid cancer. The advances in molecular genetics have also confirmed the presence of several familial cancer syndromes that have nonmedullary familial thyroid cancers (NMFTC), usually papillary or follicular cancers. These include familial adenomatous polyposis (FAP), Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. There is a 5% incidence of NMFTC in the 95% of patients with a well-differentiated thyroid cancer (3). This compares to 25% of patients with MTC having familial disease, which is equivalent only 1% of all patients with thyroid cancer. This review will discuss the contemporary management of the patients with familial-syndrome-associated thyroid cancer based on their individual risks for developing thyroid cancer. Clinical features of the familial syndromes associated with thyroid cancer are shown in Table 1. The genetic profiles and risks of the NMFTC syndromes for developing thyroid cancer are shown in Table 2.

Table 1.

The Clinical Features Associated with Familial Thyroid Cancer Syndromes

Familial thyroid cancer syndrome	Clinical features
Familial adenomatous polyposis	Intestinal: • Gastric and duodenal polyps (periampullary cancer) • >100 colon and rectal adenomas (colorectal cancer) Extraintestinal (Gardner's syndrome): • Osteomas • Dental abnormalities • Epidermal cysts • Desmoids tumors • CHRPE • Hepatoblastoma • Medulloblastoma (Turcot syndrome) • Thyroid cancer
Cowden syndrome	Multiple hamartomas Acral keratosis Oral papillomatous papules Trichilemmoma Benign and malignant breast disease Benign and malignant uterine disease Benign and malignant thyroid disease
Carney complex	Myxomas: • Heart • Skin and soft tissue • External auditory canal • Breast Pituitary adenomas Primary pigmented micronodular adrenal hyperplasia Cushing's syndrome Schwannomas Testicular tumors Thyroid disease
Pendred syndrome	Bilateral sensorineural deafness Thyroid goiter Hypothyroidism
Werner syndrome	Premature aging Short stature Age-related disorders (osteoporosis, cataracts, diabetes, peripheral vascular disease, malignancy) Epithelially derived malignancy (melanoma, soft tissue sarcoma, osteosarcoma)
Multiple endocrine neoplasia type 2	Medullary thyroid cancer Primary hyperparathyroidism Pheochromocytoma

CHRPE, congenital hypertrophy of the retinal pigment epithelium.

Table 2.

Familial Cancer Syndromes Associated with Nonmedullary Thyroid Cancer

Syndrome	Inheritance	Gene mutation	Location	Incidence of thyroid cancer	Type of thyroid cancer	Thyroid screening recommendation ^a
Familial adenomatous polyposis	Autosomal dominant	APC tumor suppressor gene	5q21	2%–12%	PTC cribriform morular variant or classical variant	Patients with CHRPE or exon 15 mutations in the 5′ region
Cowden syndrome	Autosomal dominant	PTEN tumor suppressor gene	10q23.3	10%	Follicular and occasional PTC	Routine
Carney complex	Autosomal dominant	Type 1 PRKAR1-α	Type 1 17q22–24 Type 2 2p16	4% and 60+% with nodules	Follicular and PTC	Routine
Pendred syndrome	Autosomal recessive	SLC26A4 (PDS) (Pendrin)	7q21–34	1%	Follicular	Hypothyroid patients or thyroid cancer phenotype
Werner syndrome	Autosomal recessive	WRN gene (RecQHelicase)	8p11–p12	18%	Follicular anaplastic PTC	Routine

Thyroid screening consists of yearly physical examination and thyroid ultrasound. Thyroid function testing should be obtained as clinically indicated and routinely in patients with Pendred syndrome.

PRKAR1-α, protein kinase A regulatory subunit type 1-alpha; APC, adenomatous polyposis coli; PTC, papillary thyroid carcinoma; PTEN, phosphase and tensin; PDS, Pendred syndrome; WRN, Werner.

Review

Familial adenomatous polyposis

FAP occurs in 1/8300 and is inherited as an autosomal dominant trait. The germline mutation in FAP occurs in the adenomatous polyposis coli (APC) gene, which is a tumor suppressor gene on chromosome 5q21 (4). These patients typically have thousands of adenomas that are primarily located in the colon and rectum. Virtually all patients will progress to colorectal cancer if FAP is not identified and treated surgically with a proctocolectomy. Most patients will also have gastric polyps of the fundus, most of which do not progress to carcinoma. Polyps in the duodenum and periampullary region are adenomatous, with an increased risk for progressing to cancer that is estimated to be >200 times that of patients in the general population (5). Patients may have extraintestinal manifestations that include osteomas, dental abnormalities, epidermal cysts, desmoids tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE), hepatoblastoma, medulloblastoma, and thyroid cancers. In addition to the classic FAP, there is a less aggressive attenuated FAP. Gardner's syndrome is the variant that is characterized by extracolonic disease. Turcot syndrome includes patients with FAP who have medulloblastoma brain tumors.

Patients with FAP are at risk for developing papillary thyroid carcinoma (PTC). The prevalence ranges from 2% to 12% of patients with FAP (6,7). The unique pathology is a cribriform morular variant of PTC, a variant that accounts for <1 in 500 cases of PTC (7,8). This form of PTC is typically bilateral, presents at a younger age, and is 10 times more common in female patients with FAP (6). This variant has a prognosis similar to classical PTC (9). It is associated with FAP, and therefore any patient with the cribriform morular variant of PTC should be evaluated for FAP. Patients with FAP may also develop more common variants of PTC. As with other NMFTC syndromes, the low incidence in patients with FAP suggests that the PTC occurs primarily as result of a susceptibility gene. Somatic mutations of RET-PTC1 and RET-PTC3, similar to those who have had radiation exposure, have been identified (10). Investigators have also identified differences in the location of APC germline mutations in FAP patients with and without PTC (6). They found that 13/15 (87%) patients with FAP-associated PTC had germline mutations and that 12 of these patients had mutations in the genomic region associated with CHRPE and in the mutation cluster region in the 5′ region of exon 15. This led to a recommendation that thyroid screening begin early (age 15 years) in patients or kindred with CHRPE and for those with exon 15 mutations in the 5′ region. Due to the low incidence of FAP-associated PTC, routine screening of all patients has not been recommended.

Cowden syndrome

Cowden syndrome, also referred to as phosphase and tensin (PTEN)-Hamartoma tumor syndrome, is characterized by multiple hamartomas. Germline mutations to the PTEN homolog tumor suppressor gene on chromosome 10q23.3 are found in 85% of patients (11,12). In addition to the hamartomas, the patients are at an increased risk of developing both benign and malignant tumors of the breast, uterus, and thyroid gland. Nearly all patients will have mucocutaneous lesions such as acral keratosis, oral papillomatous papules, and trichilemmoma. Bannayan-Ruvalcaba-Riley is another PTEN-Hamartoma syndrome (12). However, these patients have thyroid adenomas and lymphocytic thyroiditis and do not appear to be at risk for thyroid carcinoma.

The thyroid disease in Cowden syndrome consists of multinodular goiter or multiple follicular adenomas in >50% of patients; with follicular cancer occurring in up to 10% of patients (13). Patients have also been found to have PTC, but this has been considered coincidental. C-cell hyperplasia has been identified in patients with Cowden syndrome and is of unknown significance, as MTC is not associated (13). The high incidence of thyroid pathology in patients with Cowden syndrome warrants routine thyroid screening with ultrasonography and a low threshold for recommending thyroidectomy, particularly in patients with indeterminate fine-needle aspiration biopsies or suspicious characteristics on ultrasonography.

Carney complex

J. Aiden Carney, a Mayo Clinic pathologist, first described this complex consisting of “myxomas, spotty pigmentation, and endocrine overactivity” in 1985 (14). The myxomas can occur at multiple sites such as the heart, skin or soft tissue, external auditory canal, and breast. These patients may also have pituitary adenomas, primary pigmented micronodular adrenal hyperplasia with Cushing's syndrome, schwannomas, testicular tumors, and thyroid disease.

Most cases of this autosomal dominant condition are classified as type 1 and are associated with a mutation to the protein kinase A regulatory subunit type 1-alpha (PRKAR1-α) gene, a probable tumor suppressor gene on chromosome 17q22–24 (15). Type 2 patients have been confirmed to have a mutation on chromosome 2p16, which may be a regulator of genomic stability (16,17).

A review of 53 patients with Carney complex in 12 kindred found clinically significant thyroid disease in 11% of patients (15). Thyroid cancer has found in two patients (4%), one follicular cancer and one PTC. Screening thyroid ultrasonography in 11 euthyroid patients with Carney complex and normal thyroid physical examinations confirmed thyroid nodules in 60% of adults and 67% of children. While the risk of thyroid cancer is low, the presence of thyroid nodules is very common and routine ultrasonography may lead to early identification of thyroid cancer.

Pendred syndrome

“Deaf-mutism and goiter” was first described by Vaughan Pendred in 1896 (18). This syndrome, known as Pendred syndrome, is the most common hereditary syndrome associated with bilateral sensorineural deafness. It accounts for nearly 8% of cases of congenital deafness and is transmitted as an autosomal recessive trait (19). It is the result of mutations in the SLC26A4 (PDS) gene, which encodes the protein pendrin and is located on chromosome 7q21–34. There have been ∼100 mutations identified in the PDS gene and most are family specific (20).

Pendrin is an anion transporter that is involved in the exchange of HCO₃ ⁻, Cl⁻, OH⁻, and I⁻ at the apical membrane of thyroid cells (21). The impaired transportation of iodine into the thyroid follicular lumen may lead to impairments in the organification of iodide and subsequent thyroid goiter with possible hypothyroidism (22). It has also been postulated that pendrin may also be involved in the regulation of anion transporters for acid–base balance in the kidney (23).

A perchlorate discharge test can be performed to identify patients who have defects in iodine transport. This test is performed by giving radioiodine followed by potassium perchlorate, a competitive inhibitor of iodine transport. Thyroid radioactivity is measured before and after administration of the potassium perchlorate. Patients with Pendred syndrome and thyroid involvement will typically have a leakage of radioiodine into the bloodstream and a decrease in thyroid radioiodine content of >10%. This test can be helpful in differentiating patients with Pendred syndrome from other patients with goiter, with or without hypothyroidism.

The thyroid disease in these patients is may range from minimal enlargement to large multinodular goiter. Most patients remain euthyroid (24). Snabboon et al. reported on 16 patients with Pendred syndrome in six different kindreds. Overall, thyroid goiter was present in 11 patients and 4 had clinical hypothyroidism, all with negative thyroid autoantibodies (20). Metastatic follicular cancer and a Hürthle cell adenoma were documented in two of three members in one family, both of which had clinical hypothyroidism. The thyroid disease did show phenotypic variations within each family and the authors attributed this to modified genes or environmental influences, such as iodine supplementation. The association of thyroid cancer and Pendred syndrome may be related to untreated congenital hypothyroidism and chronic stimulation by thyroid-stimulating hormone. This process has also been thought to contribute to the progression of follicular thyroid cancer to anaplastic thyroid cancer in Pendred syndrome (25). The progression from thyroid goiter to cancer is uncommon and the risk is likely related to long-standing untreated hypothyroidism. Therefore, the relatively small risk of thyroid cancer in patients with Pendred syndrome may be reduced with close surveillance to identify and treat hypothyroidism at its onset. The rarity of this association does not appear to warrant routine ultrasound surveillance in all patients with Pendred syndrome. Ultrasound surveillance and routine thyroid examination in a patient who has been found to have hypothyroidism and Pendred syndrome may be helpful for early identification of thyroid cancer. There is no role for routine prophylactic thyroidectomy in patients with Pendred syndrome. A patient in a family with a genotype–phenotype risk for thyroid cancer may need evaluation for possible thyroidectomy, particularly if they have hypothyroidism and thyroid nodules.

Werner syndrome

Werner syndrome is a rare progeroid or premature aging syndrome that typically begins in the third decade. It is an autosomal recessive disease that is caused by mutations in the WRN gene on chromosome 8p11–p12 (26) and has an incidence of 1/1,000,000. This WRN gene encodes a protein that is both a RecQ helicase and exonuclease. It is important in DNA repair and replication. There are >50 different mutations of the WRN gene that cause Werner syndrome (27). The diagnosis is often made clinically and confirmed with molecular studies. The molecular analysis is focused on the inability to detect the normal protein of WRN. Screening methods for dominant mutations are employed in areas that have a higher incidence of Werner syndrome (e.g., Japan with 1/170 heterozygous for WRN mutations and 80% of new cases).

The clinical presentation includes an elderly appearance with thin skin, wrinkles, alopecia, and muscle atrophy. They are of short stature secondary to an absent pubertal growth period. The patient may have age-related disorders such as osteoporosis, cataracts, diabetes, peripheral vascular disease, or malignancy. Malignancy and cardiac disease are the most common causes of death in these patients, who have a median life-expectancy of 54 years (28 –30). The mutations of the WRN gene are specifically associated with epithelially derived malignancies such as melanoma, soft-tissue sarcoma, osteosarcomas (31), and well-differentiated thyroid carcinoma. The patients present at a younger age and have approximately a threefold increased risk for follicular carcinoma and six times the risk for developing anaplastic thyroid carcinoma (32). The overall incidence of thyroid cancer in Japanese patients with Werner syndrome is 18% (32). The risk of PTC is increased, specifically in Caucasian populations. This high prevalence of thyroid cancer in Werner syndrome supports routine thyroid screening in patients with this disorder.

Multiple endocrine neoplasia type 2

Familial syndromes associated with MTC are more easily identifiable than the NMFTC syndromes. Multiple endocrine neoplasia type 2 (MEN 2) is inherited in an autosomal dominant fashion with a high degree of penetrance. Familial disease is often multifocal and bilateral, occurring in up to 40% of patients with MTC (33). The patients with a syndrome will typically have either MEN 2A (54%) or MEN 2B (11%) (33). A subtype of MEN 2 that has only MTC and no associated syndrome, referred to as familial MTC (FMTC), occurs in 27% (33). The MEN 2A patients are characterized by MTC (100%), pheochromocytoma (50%), and parathyroid hyperplasia (20%–30%). This differs from the MEN 2B patients who have a distinct phenotype. The MEN 2B patients have a marfanoid appearance and the presence of mucosal neuromas. They have a more aggressive form of MTC and can develop pheochromocytomas in 33% (34). They do not typically develop parathyroid hyperplasia. There are also some MEN 2 subtypes that may develop cutaneous lichen amyloidosis or Hirshsprung disease.

One of the greatest advancements in the identification of patients with MEN 2 was the identification of the RET (rearranged during transfection) proto-oncogene on chromosome 10 (35,36). The RET proto-oncogene encodes a tyrosine kinase receptor protein (37). RET mutations in MEN 2 confer a gain of function; almost all patients with MEN 2 have germline point mutations in the RET proto-oncogene. The different mutation genotypes have specific clinical phenotypes and have been subclassified by Brandi et al. based on low-, intermediate-, or high-risk tumors (38). In MEN 2A the most common mutation is on codon 634, and in MEN 2B it is codon 918 (38). As noted, MEN 2B is the most aggressive form of MEN 2. Unfortunately, most patients with MEN 2B are the index case and therefore are not be detected by family member screens as the family history was not noted. The MEN 2 mutations associated with Hirshsprung disease include codons 609, 611, 618, and 620.

Genetic testing should be considered in all patients with MTC (39). Each patient should also be preoperatively evaluated for pheochromocytoma whether or not they have an identified mutation because there are some patients who have MEN 2 without a known RET mutation. There are also laboratories that evaluate a defined set of codon mutations. Patients who are considered to have FMTC should also be followed for the development of parathyroid hyperplasia or pheochromocytoma because there can be mutation overlap and the patient found to have FMTC may indeed have MEN 2A. In addition, the recent guidelines on MTC consider FMTC to be a phenotypic variant of MEN 2A that has decreased penetrance of pheochromocytoma and parathyroid hyperplasia rather than a distinct entity (39). The first-degree family members of patients with familial disease should be referred for genetic counseling and testing. Efforts should be made to encourage testing of the patient's children because of the high penetrance of this autosomal dominant disease that can present with MTC in infancy. Patients who develop bilateral pheochromocytomas should also be assessed for MEN 2.

The identification of the genotype–phenotype for each of the MEN 2 mutations has allowed clinicians to base clinical management on specific genotypes. Overall, 19% of patients will be low risk, 68% intermediate risk, and 13% high risk (38). The patients with high-risk MEN 2A genotypes and those with MEN 2B (RET mutations on codons 883, 918, and 922) can be offered surgical intervention in infancy (38,40 –42). RET genotypes of intermediate risk (codons 611, 618, 620, and 634) are referred for surgery before 5 years of age (38,40 –42). RET genotypes of low risk have mutations on codons 609, 630, 649, 768, 790, 791, 804, and 891 (38,40 –42). It has been proposed that patients with RET codon 609 mutations may defer thyroidectomy until 10–15 years of age (43). The 2009 American Thyroid Association (ATA) guidelines further classified the intermediate risk codons into two groups, creating four levels of increasing risk (A, B, C, and D) (39) and allowing for more detailed codon-specific management strategies. The ATA has recommended prophylactic thyroidectomy in the low-risk group (ATA-A) when the calcitonin rises or the patient is between 5 and 10 years of age (39).

Summary

Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. The patients with FMTC can be defined by specific mutations in the RET proto-oncogene. The mutations in patients with NMFTC syndromes have not been as well defined as in MTC. They are most likely autosomal dominant with reduced penetrance. Most patients with these familial syndromes likely have a susceptibility gene that increases the risk of thyroid cancer. The thyroid cancer in many of these patients has been characterized as more aggressive than sporadic well-differentiated thyroid cancer, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset (44). Most of the patients with a familial syndrome and NMFTC will have PTC, suggesting that a specific gene for PTC may also be present. In many cases, patients have a known familial syndrome that has a defined risk for thyroid cancer. These patients can be followed closely and the thyroid cancer can be identified at an earlier stage. In a few patients, the thyroid cancer may be the initial presentation and the treating physician must be astute at recognizing the possibility of an underlying familial syndrome.

Conclusions

Footnotes

Disclosure Statement

The author declares that there are no competing commercial associations and no competing financial interests exist.

Portions of this review were presented at the Spring 2010 Meeting of the American Thyroid Association, “Thyroid Disorders in the Era of Personalized Medicine,” Minneapolis, MN, May 13–16, 2010.

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