Familial Nonmedullary Thyroid Cancer

Introduction

In 1955, Robinson and Orr published the first report of isolated familial papillary thyroid cancer affecting 24-year-old identical twins. Twenty years later, Nĕmec and colleagues described differentiated thyroid cancer without environmental exposures in a mother and son. Since that time, numerous reports have been published describing families with thyroid cancer of follicular cell origin without other familial syndromes. Population-based studies have established that individuals with a close relative with thyroid cancer have a five- to nine-fold increased risk of developing thyroid cancer. The familial clustering of thyroid cancers of follicular cell origin is now recognized as a discrete entity called familial nonmedullary thyroid cancer (FNMTC), which is characterized by distinct clinicopathologic characteristics. This chapter reviews the epidemiology, classification, clinical features, genetics, treatment, prognosis, and outcomes of FNMTC.

Epidemiology

A familial occurrence and association with multiple endocrine neoplasia (MEN) types 2A and 2B have been well described for medullary thyroid cancer. FNMTCs are nonmedullary cancers that arise from thyroid follicular cells with four predominant histologic subtypes: papillary (85%), follicular (11%), Hürthle (3%), and anaplastic (1%). Although the majority of cases are sporadic, numerous reports have described familial clustering, now known as FNMTC, which accounts for 3.2% to 9.6% of all thyroid cancer cases.

Classification of Familial Disease

Currently, FNMTC is defined by the presence of well-differentiated thyroid cancer of follicular cell origin in two or more first-degree relatives in the absence of other predisposing hereditary or environmental causes. However, statistical estimates by Charkes suggest that 62% to 69% of cases with only two affected family members may, in fact, be sporadic. The likelihood of sporadic disease falls to less than 6% in families with three or more affected members. Furthermore, patients with FNMTC from families with ≥ 3 affected members (compared with those with 2 affected family members) have been shown to have a statistically significant higher risk of bilateral/multifocal thyroid disease, extrathyroidal extension, lateral lymph node metastasis, and an overall worse prognosis compared with patients with sporadic disease.

FNMTC encompasses a heterogeneous group of nonsporadic diseases in isolation but also occurs as part of a syndromic complex. Familial syndromes with a known FNMTC association include familial adenomatous polyposis (FAP), Gardner syndrome, Cowden disease, Carney complex type 1, Werner syndrome, and papillary renal neoplasia, or may occur in isolation (i.e., without other syndromic association). McCune-Albright syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia (Louis-Bar syndrome) may also be associated with the development of FNMTC, but there are more limited data linking these syndromes with FNMTC. Known clinical characteristics and genetic causes of some of these syndromes are shown in Table 30.1 .

Evidence that FNMTC is a distinct entity caused by an inherited genetic predisposition comes in large part from epidemiologic and kindred studies that demonstrate an increase in familial clustering of nonmedullary thyroid cancers (FNMTC) affecting multiple generations.

Several epidemiologic studies have documented a 5- to 10-fold increased risk of thyroid cancer in the first-degree relatives of subjects with FNMTC. In a population-based case-control interview study of 159 cases of thyroid cancer with 285 age- and sex-matched controls in Connecticut, the odds ratio of a first-degree relative developing thyroid cancer was 5.2 times that of the general population. A Utah population database study demonstrated an increased relative risk (8.6, 95% confidence interval [CI], 4.7 to 13.7) of thyroid cancer in first-degree relatives of thyroid cancer subjects. Similarly, a Canadian analysis of 339 patient pedigrees compared with 319 unaffected ethnically matched controls found that 5% of patients with NMTC reported at least one first-degree relative with thyroid cancer. A population-based study of the Swedish cancer registry demonstrated that the risk of developing thyroid cancer in a given individual is higher when the affected family member is a sibling and is even higher when the sibling is an affected sister. The relative risk of developing papillary thyroid cancer (PTC) was 3.21 when a parent was diagnosed with thyroid cancer and 6.24 when a sibling was diagnosed with thyroid cancer. The relative risk was the highest when the two affected siblings were sisters (relative risk, 11.9). From an affected mother, the risk was equally high for sons and daughters; however, when either parent was diagnosed with thyroid cancer, the risk for sons was 4.98 (95% CI, 2.13 to 9.86) and for daughters 3.44 (95% CI, 1.96 to 5.60).

A major drawback of population-based studies is that they cannot control for a selection bias or for confounding factors such as environmental exposures (e.g., radiation exposure, or iodine deficiency or excess) that might contribute to a higher risk of thyroid cancer. However, FNMTC has also been reported in large multigenerational kindreds with up to 16 family members affected and where environmental factors were not uniform.

These studies of affected familial groups also demonstrate characteristics that appear to be unique compared with sporadic disease, further supporting the fact that FNMTC is a distinct entity. These include association with second site malignancy, younger age at presentation (30 ± 11), and a higher rate of affected males than in sporadic cases. For example, a metareview of 15 case reports described a median age of 39 years and a male-to-female ratio of 1:2.2. FNMTC, unlike sporadic cancers, has been associated with nonthyroid adenocarcinomas. Pal and colleagues found that the incidence of any type of cancer was 38% higher in relatives of patients with thyroid cancer. The Utah population database revealed a highly significant association between thyroid tumors with familial clustering and leukemia, and breast, prostate, and soft tissue tumors. Similarly, other studies have demonstrated an association with breast, kidney, colon, and bladder cancers, and melanoma and lymphoma. When comparing 47 cases of first- and second-generation FNMTC patients, Capezzone and colleagues found that offspring show an earlier age at disease onset and have more aggressive disease compared with their parents, a feature known as genetic anticipation. This phenomenon is defined as the occurrence of a genetic disorder at progressively earlier ages and with increased severity in successive generations and is characteristic of inherited neoplasia. In a prospective screening of at-risk family members, thyroid cancer was detected in 4.6% of kindreds with two affected family members compared with 22.7% in kindreds with three or more first-degree relatives. These data taken together suggest that FNMTC is a true familial disease rather than a chance occurrence of sporadic disease, especially in families with three or more first-degree relatives affected.

Clinical Features

Most studies suggest that FNMTC is more aggressive than sporadic thyroid cancer of follicular cell origin with higher rates of extrathyroidal invasion, multicentric tumors, lymph node metastasis, and recurrence rates. It is also often associated with concomitant benign thyroid pathologies. Uchino and colleagues identified 258 patients from 154 families and found that compared with patients with sporadic disease, the FNMTC group had significantly higher rates of coexistent benign thyroid tumors, multicentric tumors, and lymph node metastasis. The 30-year rate of recurrence in local lymph nodes was about 40% for FNMTC compared with 20% in the sporadic cases. There was also a higher recurrence rate and worse disease-free survival in this group. There was no difference in age at diagnosis, primary tumor size, rate of extrathyroidal invasion, distant metastasis, or overall survival between the two groups. However, this study diagnosed patients with FNMTC when at least one first-degree relative was affected by thyroid cancer, thereby possibly including cases of sporadic disease as FNMTC.

A retrospective review of 14 patients with FNMTC found a 93% rate of multicentricity and a 43% rate of bilateral disease. Patients with FNMTC had higher rates of extrathyroidal invasion in 57% compared with 5% to 14% in sporadic cases in addition to an increased recurrence rate of 50%. Another large cohort study with a multicenter case-matched design found a higher recurrence rate of 44% compared with 17% in its control group. The researchers also found that the median disease-free survival rate was significantly shorter for patients with FNMTC compared with their matched controls. The number of family members affected with thyroid cancer and distant metastasis is a known significant predictor of disease severity and disease-free survival in familial cases. Perhaps the most compelling study to demonstrate the aggressive nature of FNMTC is the descriptive study by Lupoli and colleagues of 119 patients with papillary thyroid microcarcinoma, of which seven had FNMTC. The rates of tumor multicentricity, bilobar disease, lymph node metastasis, vascular invasion, and recurrence rates are all significantly higher compared with sporadic cases. Despite the multiple studies suggesting an aggressive nature of FNMTC, not all investigators have found this to be the case. Ito and associates found no difference in disease-free survival after comparing 273 patients with FNMTC to sporadic cases of PTC. The patients with familial PTC had a higher rate of multicentricity but no difference in overall prognosis compared with sporadic cases. The authors also found six families with presumptive familial follicular thyroid cancer (FTC), a prevalence of 1.9%. Aggressive features such as extrathyroidal invasion, tumor size, and lymph node and distant metastases, as well as overall prognosis, did not differ from those with sporadic FTC. A metareview conducted by Loh also did not demonstrate a more aggressive biology when evaluating rates of multicentricity, local invasion, lymph node and distant metastases, and recurrence rates.

Tumor Histology

Familial PTC is the most common type of FNMTC, followed by Hürthle cell carcinoma, then FTC. Familial PTC is characterized by multicentric tumors without any distinguishing pathologic features and multiple adenomatous nodules with or without oxyphilia.