Follicular Thyroid Cancer

Introduction

Follicular thyroid cancer (FTC) is a subset of follicular cell–derived thyroid cancer. It falls within the broad category of differentiated thyroid cancer (DTC) and is the second most common histologic subtype behind papillary thyroid cancer (PTC). Unlike PTC, the rate of FTC diagnosis is declining over time due to changes in the diagnostic criteria and maybe due to environmental factors such as iodine sufficiency. Compared with PTC its more common counterpart, FTC carries a more severe prognosis due to more frequent distant metastatic spread. Given the rarity of FTC and the changes of the diagnostic criteria over time, compelling evidence regarding FTC management is lacking, and guideline recommendations nearly reflect that of PTC.

Epidemiology

The frequency of FTC has been estimated between 9% and 40% depending on the population studied, iodine intake, and the pathologic criteria used for the diagnosis. In general, FTC represents approximately 10% to 15% of all thyroid cancers, with a majority of these being minimally invasive FTC. The incidence of thyroid cancer in general has nearly tripled since the mid-1970s, but that of FTC has remained stable or decreased, suggesting that current thyroid cancer incidence rates are largely the result of increases in PTC diagnoses.

Caucasians account for the majority of new thyroid cancer diagnoses (> 90%) in the United States. However, the greatest annual percentage increase for both genders was among blacks (4.6% to 5.8%). In another U.S. cohort, the percentage of FTC relative to all thyroid cancer was estimated to be 14.2% between 1985 and 1990 and 11.4% from 1991 to 1995, and approximately 40% of all new FTC diagnoses involved individuals in their third to fifth decades of life. A more recent U.S. analysis revealed that the incidence of FTC remained stable at 1/100,000 between 1973 to 2002, whereas the rate of new PTC diagnoses more than doubled (from 3/100,000 to over 7/100,000). In a large Italian cohort of 4187 patients with DTCs, the prevalence of FTC in patients diagnosed after 1990 was 9%—roughly half that observed (19.5%) among patients diagnosed between 1969 and 1990. One potential factor in the decline in FTC prevalence is the use of iodine prophylaxis in more recent years, as shown in a world trend analysis. An analysis of French thyroid cancer registries showed a decline in the incidence of FTC cases from 1983 to 2000 but the decrease was not as substantial as that observed in Italy, with absolute decreases of 2.2% and 0.5% annually in men and women, respectively.

Some epidemiologic data suggest that increased iodine intake (secondary to supplementation programs or movement from an iodine-deficient region to an iodine-sufficient one) can alter rates of FTC. Like all epidemiologic data correlating iodine status with FTC or DTC, the significance of these data is limited by the lack of a control group and failure to analyze other relevant and potentially confounding variables.

Changes in the pathologic diagnosis of PTCs and FTCs have also influenced the incidence of these tumors. The 1977 description of a follicular-variant PTC by Chen and Rosai stressed the fact that the major criterion for diagnosing a thyroid carcinoma as PTC consists in the presence of altered nuclear morphology rather than the predominance of a papillary rather than follicular pattern, as previously believed ( Figure 22.1 ). This was a paradigm shift that resulted in many cancers previously diagnosed as FTCs (up to 45% according to a study by Verkoojen et al. ) being reported as PTCs, reversing the ratio of FTCs to PTCs among DTC diagnoses. This reclassification has strengthened the correlation between thyroid cancer histology and recurrence-free and cancer-specific survival rates: diagnosis of FTC is clearly associated with worse outcomes than those seen with follicular variants of PTC. It is worth noting that with the 2017 edition of the World Health Organization (WHO) classification, Hürthle cell carcinoma is no longer considered a variant of FTC and is now considered a separate entity.

In summary, epidemiologic data suggest that the incidence and prevalence of FTC are declining as a result of changes made in the criteria for pathologic diagnoses of these tumors and of the increasing use of iodine supplementation throughout the world.

Etiology

The classic clinically evaluable risk factors for DTC include exposure to ionizing radiation (especially in youth) and family history of thyroid cancer. The nuclear reactor accident in Chernobyl, Russia, in 1986, illustrated the effects of radiation exposure on thyroid cancer risk. Most cases of DTC associated with the Chernobyl accident were PTCs with RET/PTC rearrangements, and a few FTC were noted as well. Ionizing radiation appears to be a risk factor for PTC to a greater extent than FTC. FTC can be found in the context of genetic syndromes such as Cowden disease with well-recognized genetic determinants and in familial nonmedullary thyroid cancer (FNMTC) conditions for which no gene signature or gene cluster has yet been identified to predict risk (see Chapter 30 , Familial Nonmedullary Thyroid Cancer). In a case control study of a Swedish population of DTC patients, there was no statistically significant increase in parental thyroid cancer for those subjects with FTC, though there was a greater than fourfold increased risk of thyroid cancer if the parent had PTC. As for other environmental and lifestyle factors, there is limited evidence for the role of diet and body mass index (BMI) as a risk factor, although consumption of iodized salt in a cohort study in Sweden did suggest protection against FTC.

The recent era of molecular medicine has identified mutations important in FTC development (see Figure 22.1 ; see Chapter 18 , Molecular Pathogenesis of Thyroid Neoplasia). Kroll et al. described the PAX8-PPARγ fusion oncogene that acts as a dominant negative transcription factor and is present in a subset of follicular carcinomas. In a study of 15 patients with histologically proved FTC, 8/15 (53%) had the PAX8-PPARγ rearrangement, and of the 3 patients with a history of radiation exposure, 100% had this mutation. A recent review of 17 studies shows that the PAX8-PPARγ rearrangement was identified in 36% (112/310) of FTC, 16% (13/83) of FVPTC, and 11% (27/247) of follicular thyroid adenomas (FTAs), suggesting a significant role of this oncogene in the development of follicular tumors. Giordano and colleagues used global gene expression profiling to compare FTA and FTC with and without the PAX8-PPARγ rearrangement. They identified a 68-gene signature set that provided insight into potential molecular mechanisms governing PAX8-PPARγ dependent FTC. These included genes on chromosome 3p as well as genes involved in fatty acid and carbohydrate metabolism. Another common and distinct mutation associated with FTC is one that activates RAS ( N-RAS, H-RAS , or K-RAS ) through point mutations and thus constitutively activates the mitogen-activated protein kinase (MAPK) oncogenic signaling pathway. RAS mutations were identified in 49% of FTC. RAS mutations or the PAX-PPARγ rearrangement was present in 88% of this sample of FTC. Additionally, recent studies of FTC tissue show a higher percentage of tumors with activated Akt (pAkt) than activated MAPK (pERK), suggesting that FTC is more dependent on the PI3K-Akt pathway than the MAPK pathway, which is important in PTC. Beyond providing evidence for the underlying genetic defects that may lead to FTC, these genetic signatures have proved to be useful for diagnostic purposes, as will be discussed. Table 22.1 summarizes the principal molecular markers of FTCs identified with next generation sequencing techniques.

Diagnosis