Thyroid malignancies are classified on the basis of the origin of cells into medullary thyroid cancer (MTC), which originates from the parafollicular cells, and nonmedullary thyroid cancer (NMTC), which originates from the follicular cells. NMTC mainly includes papillary and follicular thyroid cancer (PTC and FTC). Both PTC and FTC are differentiated thyroid cancers that constitute the vast majority of thyroid cancers (>90%) and carry an excellent prognosis with an overall 5-year survival exceeding 95%. ^1–4

Both MTC and NMTC can occur sporadically or as part of an inherited syndrome or familial predisposition. This chapter will focus on the diagnosis and management of nonsyndromic familial NMTC (FNMTC) and NMTC associated with inherited syndromes (Table 50-1). Inherited syndromes involving MTC such as multiple endocrine neoplasia type 2 (MEN2a, familial MTC and MEN2b) are not covered in this chapter.

Familial NMTC is commonly defined by the presence of well-differentiated thyroid cancer (WDTC) in two or more first-degree relatives in the absence of predisposing hereditary syndromes (i.e., Cowden syndrome, Gardner’s syndrome) or environmental factors (ionizing radiation to the neck, iodine deficiency). ^5,6 It is estimated that FNMTC accounts for 3% to 10% of all the thyroid cancer cases with an autosomal dominant pattern of inheritance with incomplete penetrance. ^6–9 However, the true incidence of FNMTC is not known, and it is estimated that PTC is in fact sporadic in 45% to 69% of the cases with only two affected family members. ¹⁰

The most common histologic subtype of FNMTC is PTC. Women seem to be affected approximately two to three times more than men and the age at diagnosis for patients with FNMTC seems to be less than that of sporadic cases (41 vs. 47). ^6,8,10–12 This, however, may be an artifact of early screening for patients with a family history of thyroid cancer. The risk of thyroid cancer in at-risk family members is significant. Studies have shown that the cumulative risk of WDTC by age 60 is 46 times that of the general population and 164 times in at-risk men. ¹³

Pathogenesis

The pathogenesis of nonsyndromic FNMTC is not as well characterized. It is thought to be inherited in an autosomal dominant pattern; however, the penetrance is variable and there is no one gene that is responsible for FNMTC. Since FNMTC cannot be tested genetically, the diagnosis is based solely on family history. As mentioned before, in cases with only two affected family members, PTC is still often sporadic up to 70% of the time. However, in families with three or more members affected with NMTC, the likelihood of possessing the familial trait is 96%. ^10,14 Family members of patients with FNMTC are at increased risk to develop benign thyroid diseases, including follicular adenoma, Hashimoto’s thyroiditis, and multinodular goiter (MNG), which may also be in part due to increased screening. Furthermore, a large number of pedigrees present with a range of penetrance, therefore a polygenic etiology cannot be ruled out and the genetic predisposition is likely very complex. ^4,14–17

Due to the genetic heterogeneity of FNMTC, no specific genetic basis has been identified. Several different potential genetic candidates have been suggested, including MNG1, FTEN, FOXE1, and telomere/telomerase complex, but the data have been conflicting. ¹⁸

Management

A screening protocol is recommended for any family with two or more members with FNMTC. All members of affected families should be evaluated, even if asymptomatic. The protocol should consist of a detailed history focusing on family history, environmental exposure, locoregional symptoms, and presence of other pathologies that may be a part of another thyroid cancer-associated genetic syndrome. ^4,5

Studies have shown that patients with FNMTC have an increased incidence of benign and malignant thyroid disease. ^{6,12,16,19,20} Locoregional symptoms such as pain, dysphagia, dyspnea, hoarseness, and growing neck mass should be evaluated in all FNMTC patients, as it has been demonstrated in several studies that the local invasion and extrathyroidal disease may be increased in these patients. ^4,19,21,22 Several studies have suggested that FNMTC is associated with increased tumor aggressiveness with increased frequency of multicentric disease, lymph node metastasis, local invasion, and recurrence. ^9,12,19,22 Therefore, any family history should raise clinicians’ awareness and a screening neck ultrasound should be considered in all family members. ^4,5

There are no studies that address the age at which screening should begin for asymptomatic family members. Studies have shown that FNMTC patients present up to 10 years earlier than patients with sporadic disease; however, the data are conflicting and not all studies agree with this finding. ^8,9,11,19,23 Despite the lack of good evidence, it may be reasonable to begin screening 10 years earlier than the youngest age of diagnosis within the family. ^4,5,24 A recent study showed that patients with even one affected family member may have more aggressive disease, so even family members with only one first-degree relative should be considered for screening if there are high-risk features. ²² Since genetic testing is not available and the genetic association of specific mutations to FNMTC is not yet established, clinicians must take a careful family history and have a high index of suspicion when the family history includes multiple family members with either benign or malignant thyroid disease.

Total thyroidectomy is recommended for patients with FNMTC. Therapeutic central lymph node dissection should be performed in patients with clinical or radiologic nodal involvement. The role for elective prophylactic central lymph node dissection is controversial. Since there is some evidence for aggressive disease, extrathyroidal extension, extensive multifocality, positive lymph nodes, especially in patients with three or more affected family members, routine central lymph node dissection may be considered for all FNMTC patients with tumors larger than 1 cm. ^4,6,25,26 Overall, the surgical approach for patients with FNMTC should not differ from patients who have sporadic papillary thyroid cancer.