Malignant thyroid tumors accounts for only 1% of all malignant tumors.1 The incidence of thyroid malignancy has increased at a rate higher than any other known cancer. In the year 2000,2 18,000 new cases of thyroid cancer were reported in the United States whereas 35,000 new cases were reported in 2007.2 Almost 95% of patients have well-differentiated cancer of follicular cell origin. The well-differentiated carcinoma includes papillary (80% to 90%), and follicular (10% to 15%). Approximately 5% of patients will have medullary thyroid cancer.
The advances in molecular genetics have also confirmed the presence of several familial cancer syndromes that have familial follicular cell-derived tumors usually papillary or follicular cancers. These include phosphase and tensin(PTEN)-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Werner syndrome, Carney complex, and Pendred syndrome.3–5 Other syndromes, as McCune Albright syndrome, Peutz-Jeghers syndrome, Ataxia-teleangiectasia syndrome, may possibly be associated with the development of follicular cell-derived tumors, but the link is less established than the above syndromes.
There is a 5% incidence of familial follicular cell-derived tumors in patients with a well-differentiated thyroid cancer.3–5 This compares with 25% of patients with medullary thyroid carcinoma having familial disease.
We will discuss below the clinical and pathological findings of the patients with familial-syndrome-associated tumors: PTEN-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome.
The classification of familial follicular cell thyroid cancer3,5 is shown in Table 1. The inheritance, gene involved, and risks of the familial cancer syndromes for developing thyroid cancer are shown in Table 2. Extrathyroidal clinical features of the familial syndromes associated with thyroid cancer are shown in Table 3. The thyroid lesions in inherited tumor syndromes are shown in Table 4.
PTEN-HAMARTOMA TUMOR SYNDROME/COWDEN SYNDROME
PTEN-hamartoma tumor syndrome is a complex disorder caused by germline inactivating mutations of the PTEN tumor-suppressor gene. PTEN-hamartoma tumor syndrome includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndromes.
Cowden syndrome, also referred to as 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.6–8 Aside from the numerous hamartomas the affected individuals with Cowden syndrome present with, nearly all patients have also mucocutaneous lesions such as acral keratosis, oral papillomatous papules, and trichilemmoma. Patients with Cowden syndrome develop both benign and malignant tumors in a variety of tissues. These patients are at an increased risk of developing tumors of the breast, uterus, and thyroid gland.
Although diagnostic criteria for Cowden syndrome have been established for more than a decade (Table 5), there are no agreed international criteria for the diagnosis of Bannayan-Ruvalcaba-Riley syndrome (Table 6). Bannayan-Riley-Ruvalcaba syndrome, another PTEN-hamartoma syndrome, is characterized by macrocephaly, pigmented macules of the penis, lipomas, vascular hamartomatous lesions, and hamartomatous intestinal polyposis.9 More than 90% of individuals affected with Cowden syndrome manifest a phenotype by age 20. By the end of their third decade nearly all (99%) develop the pathognomonic mucocutaneous lesions, although any feature may be present, including thyroid lesions.9,10 However, these patients are described to have thyroid adenomas and lymphocytic thyroiditis and to be at risk for thyroid carcinoma.
The function of PTEN is not entirely understood, but by downregulating the levels of phosphoinositide-3,4,5-triphosphate (PIP3), PTEN produces an inhibitory (tumor suppressor) effect on the PI3P/AKT pathway, an important carcinogenesis pathway. It is proposed that PTEN has important activity both in the cytoplasm and nucleus. Nuclear PTEN might be required for cell cycle arrest by downregulating cyclin-D1 and preventing phosphorylation of mitogen-activated protein kinase (MAPK) pathway whereas cytoplasmic PTEN seems to be required for apoptosis by downregulating the phosphorylation of AKT and upregulating p27. Therefore, loss of PTEN function results in escape from programmed cell death and G1 arrest in the cell cycle. The PTEN gene is composed of 9 exons, and mutations are dispersed throughout the 9 exons of the gene, with approximately 40% of mutations located in exon 5 that represents 20% of the coding sequence and is known as the mutational “hot spot” in PTEN-hamartoma tumor syndrome. Very few germline mutations have been reported in exon 1, and none in exon 9. Seventy-five percent of the germline mutations result in either truncated protein, lack of protein, or dysfunctional protein.6–17
The thyroid disease in Cowden syndrome is variable, and two thirds of patients develop thyroid tumors. The pathologic findings in this syndrome have been described as involving the follicular cells, and include multinodular goiter, multiple adenomatous nodules, follicular adenoma, follicular carcinoma, and less frequently, papillary thyroid carcinoma.18–28 In a recent review,19 we found a spectrum of thyroid lesions in PTEN-hamartoma tumor syndrome as seen in Table 7.
Follicular thyroid cancer occurs in up to 10% of patients. Patients have also been found to have papillary thyroid carcinoma,23,24 but should be considered coincidental, given the high prevalence of papillary thyroid carcinoma in the general adult population (25% to 34%). C-cell hyperplasia has been identified in patients with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, and is of unknown significance, as C cell-derived medullary thyroid carcinoma is not associated with these syndromes.19,21,24 C-cell proliferations may be either neoplastic or physiologic. Physiologic C-cell hyperplasia is a reactive process associated with hypercalcemia, hypergastrinemia, goitrous hypothyroidism, Hashimoto thyroiditis, and attributed to peritumoral effect. In the case of these syndromes, C-cell hyperplasia may be secondary to the numerous nodules present on the thyroid.24–28
The rate of occurrence and histologic types of thyroid lesions in Bannayan-Riley-Ruvalcaba syndrome has not been widely reported, but has seemed similar to those seen in Cowden syndrome, suggesting a single entity.19
The diagnosis of a thyroid lesion usually precedes the diagnosis of PTEN-hamartoma tumor syndrome by many years. In some patients, a work-up for PTEN-hamartoma tumor syndrome (including PTEN mutation analysis) is triggered by the unusual pathologic findings in the thyroid of a young patient, most specifically, multiple adenomatous nodules.
The current diagnostic criteria for Cowden syndrome consider follicular carcinoma (present in 10% to 15%) as a major criterion, whereas multinodular goiter (including multiple adenomatous nodules) and follicular adenomas are minor criteria (present in 50% to 67%).
The multiple adenomatous nodules, are unusually numerous, in cases reaching over 100 of these nodules, are not encapsulated, homogeneous, firm, yellow-tan, lack gelatinous colloid, and do not exhibit secondary changes (Figs. 1A, B). Histologically, the adenomatous nodules in PTEN-hamartoma tumor syndrome are solid, cellular, and composed of small follicles lacking abundant colloid, side by side with others. Some nodules may have a thin, discontinuous rim of fibrous tissue simulating a capsule (Fig. 2).
Follicular carcinoma is an important feature of both Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. It has been reported that these tumors are frequently multicentric, and are believed to arise from preexisting follicular adenomas, and the majority of carcinomas arise in a background of multiple adenomatous nodules (Fig. 3).
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.
FAMILIAL ADENOMATOUS POLYPOSIS
Familial adenomatous polyposis is inherited as an autosomal dominant trait caused by germline mutation in the adenomatous polyposis coli (APC) gene. APC gene is a tumor-suppressor gene on chromosome 5q21. These patients typically have thousands of adenomas that are primarily located in the colon and rectum (Fig. 4). Virtually all patients will progress to colorectal cancer if familial adenomatous polyposis is not identified and treated surgically with a proctocolectomy. Most patients also 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 more than 200 times that of patients in the general population.29–31
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 familial adenomatous polyposis, there is a less aggressive attenuated familial adenomatous polyposis. Gardner syndrome is the variant that is characterized by extracolonic disease. Turcot syndrome includes patients with familial adenomatous polyposis who have medulloblastoma brain tumors.
Patients with familial adenomatous polyposis are at risk for developing papillary thyroid carcinoma. Papillary thyroid carcinoma is one of the extracolonic manifestations of familial adenomatous polyposis. Young women with familial adenomatous polyposis are at particular risk of developing thyroid cancer, and their chance of being affected is approximately 160 times higher than that of normal individuals, and papillary thyroid carcinoma occurs with a frequency of about 10 times that expected for sporadic papillary thyroid carcinoma.30–38 The prevalence ranges from 2% to 12% of patients with familial adenomatous polyposis.36
Thyroid carcinomas associated with familial adenomatous polyposis is usually bilateral, multifocal, typically multicentric (Fig. 5), with histologic features different from sporadic tumors, with the characteristic histopathology of cribriform pattern with solid areas, and a spindle cell component, most often is associated with marked fibrosis.30
The cribriform-morular variant of papillary thyroid carcinoma is a very rare subtype of papillary thyroid carcinoma representing approximately 0.1% to 0.2% and accounts for <1 in 500 cases of all papillary carcinoma cases.34,35 The overall prognosis of the cribriform-morular variant of thyroid carcinoma is similar to that of classic variant of papillary thyroid carcinoma with less than 10% of cases showing an aggressive clinical behavior. Among patients with familial adenomatous polyposis who have synchronous papillary thyroid carcinoma, over 90% of these cases have been reported to exhibit histologic features of the cribriform-morular variant. Although not all cribriform-morular variant of thyroid carcinoma are associated with familial adenomatous polyposis, as a very significant proportion of the cases are. Among patients with familial adenomatous polyposis who have synchronous papillary thyroid carcinoma, over 90% of these cases have been reported to exhibit histologic features of the cribriform-morular variant. This form of papillary thyroid carcinoma is typically bilateral, presents at a younger age, and is 10 times more common in female patients with familial adenomatous polyposis. We30 recently reviewed 8 cases of familial adenomatous polyposis-associated thyroid tumor and our thyroid pathology findings are summarized in Table 8.
The cribriform-morular variant of thyroid carcinoma present in familial adenomatous polyposis syndrome is characterized by the presence of cribriform, solid, and morular areas (Figs. 6A, B) that lack typical nuclear features of papillary thyroid carcinoma, and has a comparatively benign prognosis with low risk for metastasis. The characteristic cellular and nuclear findings of sporadic papillary thyroid carcinoma as grooved, overlapping, and clear nuclei are absent in this subtype.35–38 Cribriform-morular variant of thyroid carcinoma can be distinguished from other variants of papillary thyroid carcinoma by aberrant nuclear expression of betacatenin (Fig. 7). We also found immunoreactivity for CK19, p53, and Bcl-2, and lack of immunoreactivity for HBME-1 in a series of 8 cases we reviewed.30
This variant has a prognosis similar to classic papillary thyroid carcinoma. It is associated with familial adenomatous polyposis, and therefore any patient with the cribriform-morular variant of papillary thyroid carcinoma should be evaluated for familial adenomatous polyposis. Patients with familial adenomatous polyposis may also develop more common variants of papillary thyroid carcinoma.
As with other familial follicular cell-derived tumor syndromes, the low incidence in patients with familial adenomatous polyposis suggests that the papillary thyroid carcinoma occurs primarily as a result of a susceptibility gene. Investigators have also identified differences in the location of APC germline mutations in familial adenomatous polyposis patients with and without papillary thyroid carcinoma.31 They found that 13 out of 15 (87%) patients with familial adenomatous polyposis-associated papillary thyroid carcinoma 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 (by age 15 y) in patients or kindred with CHRPE and for those with 5′ region exon 15 mutations.
Owing to the low incidence of familial adenomatous polyposis-associated papillary thyroid carcinoma with other APC germline mutations, routine screening of those patients has not been recommended.
The Carney complex is a dominantly inherited syndrome characterized by the spotty skin pigmentation, endocrine overactivity, and myxomas. This was first described in 1985 by J. Aiden Carney, at Mayo Clinic, as “myxomas, spotty pigmentation, and endocrine overactivity.”39
It is defined by the association of multiple endocrine neoplasia and cardiocutaneous manifestations. Patients earlier characterized as LAMB (lentigineses, atrial myxoma, mucocutaneous myxoma, and blue nevi) or NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelide) could be considered as having Carney complex. Numerous organs may be involved in Carney complex and the manifestations vary greatly among patients. Skin pigmentation anomalies include lentigines and blue nevi. The myxomas can occur at multiple sites such as the heart, skin, or soft tissue, external auditory canal, and breast. Cardiac myxomas can develop in any cardiac chamber and may be multiple. These patients may also present with schwannomas and testicular tumors.
The most common endocrine gland involvements are growth hormone-secreting pituitary adenomas (with acromegaly), thyroid tumors, and adrenocorticotropic hormone-independent Cushing syndrome owing to primary pigmented nodular adrenocortical disease (PPNAD). Primary-pigmented nodular adrenocortical disease, a rare cause of Cushing syndrome, is owing to primary bilateral adrenal defect that can be also observed in some patients without other Carney complex manifestations or familial history of the disease.
It is generally assumed that a patient presenting with 2 or more of the manifestations would be diagnosed as having Carney complex (Table 9). This table lists the diagnostic features and the most frequent features, and estimated frequency of Carney complex. It has been established that at least 2 of these manifestations need to be present to confirm the diagnosis of Carney complex. If the patient has a germline PRKAR1-α mutation and/or a first-degree relative affected by Carney complex, a single manifestation is sufficient for the diagnosis.
One of the putative Carney complex genes located on 17q22-24, (PRKAR1-α), has been identified to encode the regulatory subunit of protein kinase A. Heterozygous inactivating mutations of PRKAR1-α were reported initially in 45% to 65% of Carney complex, and may be present in about 80% of the Carney complex families presenting mainly with Cushing syndrome. PRKAR1-α has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. 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. Type 2 patients have been confirmed to have a mutation on chromosome 2p16 that may be a regulator of genomic stability.40–43
The risk of thyroid cancer is low, and the presence of thyroid nodules is very common. The thyroid is multinodular with multiple adenomatous nodules, follicular adenomas, and both papillary thyroid carcinoma and follicular thyroid carcinoma are present in about 15% of patients with Carney complex.
A recent review of Carney complex in 53 patients of 12 kindred found clinically significant thyroid disease in 11% of patients.44 Thyroid cancer has found in 2 patients (4%), 1 follicular cancer and 1 papillary thyroid carcinoma. 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.
Patients with Carney complex or with a genetic predisposition to Carney complex should have regular screening for manifestations of the disease.
Clinical work-up for all the manifestations of Carney complex should be done at least once a year.
This syndrome, known as Pendred syndrome, described by Vaughan Pendred in 1896 as “deaf-mutism and goiter”45 is the most common hereditary syndrome associated with bilateral sensorineural deafness. It is transmitted as an autosomal recessive trait as a result of mutations in the SLC26A4 (PDS) gene that encodes the protein pendrin and is located on chromosome 7q21-34. There have been approximately 100 mutations identified in the PDS gene and most are family specific.46–48 Pendrin is an anion transporter that is involved in the exchange of ions at the apical membrane of thyroid cells. The impaired transportation of iodine into the thyroid follicular lumen may lead to fimpairments in the organification of iodide and subsequent thyroid goiter with possible hypothyroidism.49–51
The thyroid disease in these patients may range from minimal enlargement to large multinodular goiter. Most patients remain euthyroid. Thyroid disease in Pendred syndrome in 16 patients from 6 different kindreds showed thyroid goiter present in 11 patients with 4 had clinical hypothyroidism.47 Metastatic follicular cancer and an oncocytic cell adenoma were documented in 2 of 3 members in 1 family. 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.52 The risk of progression from thyroid goiter to cancer is uncommon and likely related to long-standing untreated hypothyroidism.
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.
Werner syndrome is a rare premature aging syndrome (progeroid) that typically begins in the third decade. The clinical presentation includes an elderly appearance with thin skin, wrinkles, alopecia, and muscle atrophy in proportion to the patient's age. The patients with this syndrome have short stature secondary to an absent pubertal growth period.53,54 The patients also present with age-related disorders such as diabetes, osteoporosis, cataracts, peripheral vascular disease, or different types of malignant tumors. Malignancy and cardiac disease are the most common causes of death in these patients, who have a median life-expectancy of 54 years.53–57
It is an autosomal recessive disease that is caused by mutations in the WRN gene on chromosome 8p11 to p12. This WRN gene encodes a protein that is important in DNA repair and replication. Screening methods for dominant mutations are used in areas that have a higher incidence of Werner syndrome, as in Japan. The diagnosis is made by clinical presentation and confirmed with molecular studies.The mutations of the WRN gene are specifically associated with epithelial-derived malignant tumors, such as soft tissue sarcoma, melanoma, osteosarcomas,58 and well-differentiated thyroid carcinoma.
The patients present at a younger age and have approximately a 3-fold increased risk for follicular carcinoma and 6 times the risk for developing anaplastic thyroid carcinoma.59
The overall incidence of thyroid cancer in Japanese patients with Werner syndrome is 18%.59 The risk of papillary thyroid carcinoma is increased, specifically in White populations. This high prevalence of thyroid cancer in Werner syndrome supports routine thyroid screening in patients with this disorder.
Most of the patients with familial disease are asymptomatic and are discovered through genetic screening in predisposing families. Recent reviews of these syndromes3,5,60–63 have showed that patients with familial syndromes associated with thyroid cancer can be individually categorized based on syndrome risks for developing thyroid cancer. The identification of hereditary cases and early diagnosis makes preventative surgery and adequate treatment possible.
The distinct thyroid pathology in some of these syndromes should alert the pathologist of a possible familial cancer syndrome. The pathology interpretation may lead to further molecular genetic evaluation of the patient and family members.
The clinician should be knowledgeable facing patients with thyroid cancer to recognize the possibility of a familial syndrome.
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familial thyroid carcinoma; inherited tumor syndromes; familial adenomatous polyposis syndrome; PTEN-hamartoma tumor syndrome; Cowden syndrome; Carney complex; Pendred syndrome; Werner syndrome
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