Follicular Thyroid Carcinoma: A Perspective

Abstract

Introduction

Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are both well-differentiated thyroid cancers derived from thyroid follicular epithelium. Apart from this superficial similarity and a common ability to concentrate (radioactive) iodine, they share little in common. PTC and FTC differ markedly in epidemiology, ultrasound examination, cytological findings, genetic landscape, pathological findings, and clinical behavior. The 2015 American Thyroid Association (ATA) guidelines for thyroid nodules and thyroid cancer (1) focus primarily on PTC. Although much is known about FTC (2), many important questions remain unanswered (3). This commentary summarizes the recent literature on FTC and also reflects my perspective from over four decades of clinical experience with FTC. It is designed to highlight the distinctions between PTC and FTC as well as the many uncertainties concerning FTC.

Review

The clinical spectrum of PTC ranges from indolent papillary thyroid microcarcinomas (microPTC) (<1 cm) to large, highly aggressive tall cell or hobnail variants of PTC. Similarly, FTC is not a single homogeneous entity. Yet, in my experience, many clinical endocrinologists treat FTC as a single disease requiring total (or completion) thyroidectomy followed by radioactive iodine (RAI) therapy. In the United States, universal administration of RAI for PTC >1 cm is no longer the standard of care; a far more nuanced approach is recommended and practiced (1). The extent of surgery and the use of RAI should also be tailored to the disease risk in FTC. However, FTC outcomes vary considerably between studies, suggesting a lack of uniformity in disease criteria.

Hürthle cell thyroid carcinoma (HCTC) is traditionally considered a variant of FTC. However, HCTC is a unique tumor whose pathogenesis and clinical behavior differs from classical FTC (see below). Clinical studies that combine HCTC with FTC, and those which do not comment on the inclusion of HCTC, may result in an imprecise picture of FTC. For purposes of this review, the term FTC excludes HCTC.

Epidemiology

Between 1973 and 2002, the annual incidence of PTC in the United States increased from 3.6 to 8.7 cases per 100,000 (4) and, according to the American Cancer Society, has almost doubled again since 2002. Most of the increase is due to micro- and small (1–2 cm) PTC.

The epidemiology of FTC is more difficult to study because of changes in diagnostic criteria over time. In the 1960s, any thyroid tumor with >50% of the tumor mass composed of follicles was considered FTC, whereas now most such tumors would be considered PTC (5). By the late 1980s, the World Health Organization (WHO) defined FTC as a malignant epithelial tumor with evidence of follicular cell differentiation but lacking diagnostic features of PTC (5). The definition also included HCTC and poorly differentiated thyroid cancer (PDTC) (5). Several studies illustrate this changing diagnostic pattern. Three University of Chicago pathologists re-analyzed 66 cases of FTC diagnosed between 1965 and 2007. Only 19 (29%) were still considered FTC, whereas 24 (36%) were reclassified as PTC (21 classical and 3 follicular variant PTC [FVPTC]), 18 (27%) as follicular adenomas (FA), and 5 (8%) as PDTC (6). Pathologists at Kuma Hospital in Japan re-reviewed 441 FTC diagnosed between 1983 and 2004; 198 (45%) were still considered FTC, whereas 44 (10%) were reclassified as PDTC, 43 (9.8%) as HCTC, and the remainder benign FA, PTC, or FVPTC (7).

LiVolsi and Asa (8) speculated about “the demise of FTC.” But analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 1980 to 2009 revealed a modest increase in age-adjusted FTC rates in women (31.9%) and men (35.9%) (9) with an incidence rate of 0.88 cases per 100,000 person years. A marked regional difference in incidence rates was found, raising important questions about the uniformity of diagnosis. At the same time the ratio of PTC to FTC increased from 3.98 (1980–1984) to 9.88 (2005–2009); thus over 90% of well-differentiated thyroid cancers are PTC. Over these years, FVPTC supplanted FTC as the most common follicular patterned thyroid malignancy (9).

The incidence ratio of PTC to FTC is lower in iodine deficient countries and rises with iodine supplementation (10). Although iodine repletion may explain a decline in FTC in some countries, the U.S. population is generally iodine replete. In some iodine-deficient countries the current incidence ratio of PTC to FTC remains close to 1 (11).

Cytology

The hallmark nuclear changes of PTC are often evident on cytological examination. Thus the pathological diagnosis of PTC (Bethesda VI) after a fine needle aspiration biopsy (FNAB) will be correct in almost 100% of cases, whereas over 50% of FNAB suspicious for PTC (Bethesda V) will be PTC (12). Although a minority of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) FNAB (Bethesda III) are malignant, nuclear atypia (AUS) increases the risk of malignancy compared with architectural atypia (FLUS) (13).

In contrast, FTC may be suspected but generally cannot be diagnosed by FNAB. The distinction between a FTC (malignant tumor with capsular and/or vascular invasion) and a benign FA (no invasion) requires pathological examination of the tumor capsule after tumor excision. The risk of malignancy with a FNAB reading of follicular neoplasm (Bethesda IV) is 10–40% and 6–28% with AUS/FLUS (Bethesda III) (12). Whereas in the past the most common malignancy diagnosed after FNAB of follicular neoplasm was FTC, it is now FVPTC (14). One recent series represents an extreme example of this trend. Of 1379 thyroid nodules undergoing surgery for FN, 34% had a malignant tumor but none were FTC (15).

Ultrasonography

Thyroid nodules with the following characteristics have an increased risk of malignancy: solid, taller than wide, hypoechoic or markedly hypoechoic, and/or irregular or spiculated borders or calcifications (either micro or macro) (1,16). While these criteria help diagnose PTC, they are less helpful for the diagnosis of FTC. Compared with PTC, FTC are generally larger, tend to be isoechoic, have a hypoechoic rim and more often lack the suspicious ultrasound features which characterize PTC (17,18). Hoang et al. (17) compared PTC to FTC and found the following statistically significant (p < 0.002) differences: round/tall (74.0% vs. 26.1%), hypoechoic (72.4% vs. 34.8%), irregular margin (92.9 vs. 60.9%), fine calcifications (33.9% vs. 0%), no hypoechoic rim (74.0% vs. 13.0%), and no cystic change (98.4% vs. 82.6%). Similarly, BRAF ^V600E mutant tumors (characteristic of PTC) have an ultrasound appearance that differs from those with RAS mutations (characteristic of FTC) (19). Ultrasound cannot reliably distinguish between FA and FTC unless a highly vascularized tumor grossly protrudes beyond its capsule—an uncommon finding (20).

Genetic landscape

BRAF ^V600E is the most common oncogenic mutation in PTC, occurring in around 50% of classical PTC and in a higher percentage of the tall cell and hobnail variants. All thyroid tumors which contain BRAF ^V600E mutations are considered malignant. RET/PTC, NTRK, ALK, and BRAF oncogenic fusions occur in a minority of PTC cases and are not necessarily specific for malignancy (21,22). BRAF ^V600E and these oncogenic fusions are mutually exclusive, and none occur in FTC. Oncogenic fusions are more common in radiation induced thyroid cancer (e.g., post-Chernobyl) (23). TERT (telomerase reverse transcriptase) promoter mutations may also occur in PTC and are independent of the driver mutations and fusions. PTC is generally a diploid tumor with little chromosomal instability.

Familial PTC (familial non-medullary thyroid carcinoma) is a heterogeneous group of disorders and occurs in about 5% of all PTC (24). PTC may occur in many rare hereditary tumor syndromes, but these make up a small percentage of familial PTC. These hereditary tumor syndromes (with associated mutations in parentheses) include familial adenomatous polyposis (FAP); Cowden's Syndrome (PTEN and others); LiFraumani (p53); DICER 1 (DICER 1); Lynch syndrome (DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM); Werner syndrome (WRN); and Carney Complex (PRKAR1A) (25).

Oncogenic drivers in FTC are primarily RAS point mutations (NRAS, HRAS, and less frequently KRAS) and PAX8PPARγ rearrangements; RAS and PAX8PPARγ are mutually exclusive. The prevalence of RAS and PAX8PPARγ varies considerably between studies. RAS mutations are found in up to 40–50% of FTC and 20–40% of FA; PAX8PPARγ fusions are found in 30–40% of FTC and a smaller percentage of FA (2–13%) (26). Finding the same oncogenic drivers in FTC and FA means that these drivers are not diagnostic of malignancy and also raises the question of whether FA with these drivers are premalignant or carcinomas in situ. RAS mutations and PAX8PPARγ fusions are not found in classical PTC but are common in FVPTC (see below). Additional oncogenic fusions in FTC include DERL-COX6C and CREB3L2-PPARγ (22). As in PTC, TERT promoter mutations may occur in FTC and are independent of the oncogenic drivers. TERT promoter mutations appear to be far less common in FA than FTC but the data are limited (27).

Chromosomal instability occurs in up to 65% of FTC, including extra copies, unbalanced rearrangements, complex karyotypes, and chromosomal losses. In one study RAS protein activator like 1 (RASAL1) mutations were found in almost 5% of FTC (28). Molecular alterations of the phosphatidylinositol 3-kinase–PTEN–AKT pathway occur in a variable proportion of FTCs, depending on whether mutations and/or gene copy number variations are considered (29).

The prevalence of familial FTC is unknown. FTC may occur in rare hereditary cancer syndromes including Cowden's, Werner's, and Carney complex. The most common mutation in Cowden's syndrome is PTEN (hence the name PTEN-Hamartoma syndrome) but germ-line RASAL1 mutations may also cause a Cowden-like picture (30).

Pathology

The pathological diagnosis of classical PTC is relatively straightforward (31). The characteristic nuclear changes of PTC include nuclear enlargement and overlap, nuclear elongation, irregular nuclear contours, nuclear pseudo-inclusions or prominent longitudinal grooves, empty appearance of the nucleoplasm described as optically clear, or ground glass nuclei. Papillary architecture is common but need not be uniformly present. Psammoma bodies (lamellated calcifications) occur in about one-half of PTC. Multifocal disease is present in 20% or more cases. Tumor spread via lymphatics to lymph nodes is common and occurs in at least 25% of PTC cases. When applied to PTC, the term “lymphovascular invasion” generally connotes lymphatic rather than true vascular invasion. Lymphatic invasion correlates with lymph node metastases (LNM); lymphovascular invasion without LNM may be a surrogate for subsequent LNM (32). The prevalence of true (large vessel) vascular invasion in PTC is uncertain. One study from a large referral center found large vessel invasion in 47/698 PTC (6.7%); the median number of affected blood vessels was 1 (range 1–11) (33). It is unknown whether this experience can be generalized.

FVPTC is the most common variant of PTC; other variants include tall cell, morular cribriform (commonly associated with familial adenomatous polyposis), columnar cell, hobnail, diffuse sclerosing, clear cell, Warthin-like, solid/trabecular, and insular subtypes (31).

MicroPTCs are very common, comprising about one-half of all PTC reported in the recent Korean PTC “epidemic” (34) with an even larger reservoir of undiagnosed microPTC.

Conversely, the pathological diagnosis of FTC is more difficult and requires great attention to detail (31). FTC does not display cellular or nuclear atypia, hence the difficulty in diagnosing FTC by FNAB. Invasion of the tumor capsule or capsular blood vessels is the sine qua non of FTC; without invasion, follicular tumors are benign (FA). A thick tumor capsule (the pathological correlate of the hypoechoic rim on ultrasound) is generally found in FTC and FA but tends to be thicker in FTC.

The WHO (31) defines capsular invasion (CI) as a tumor that completely transgresses the tumor capsule, often mushrooming beyond the capsule; follicular cells within the capsule are considered an artifact, likely related to prior FNAB. However, one Armed Forces Institute of Pathology study diagnosed tumors with <50% capsular invasion as FTC (35). The WHO and other pathologists define true vascular invasion (VI) as invasion into veins with tumor cells adherent to the vessel walls, either covered by endothelium or within a thrombus or fibrin; in other words, large vessel invasion (5,31).

Heffess' and Thompson's (36) comment from 2001 is likely still true today: “Notwithstanding the wide acceptance of the diagnostic criteria established by the World Health Organization for the classification of follicular carcinomas in particular, they have been difficult to apply and have led to a great deal of confusion. … This confusion is compounded when applied to ‘low-grade’ or ‘minimally invasive’ follicular carcinoma because of the poor reproducibility of the classification and the variable results reported in the literature.” It may also be difficult to be certain whether and how much vascular invasion is present. Common diagnostic errors include diagnosis of benign tumors as malignant, diagnosis of malignant tumors as benign, and classifying tumors with extensive VI as having minimal VI.

The diagnosis of CI or VI requires examination of multiple sections through the excised tumor, but this examination lacks standardization. Lang et al. (37) recommended at least 10 sections through the nodule, but most pathologists recommend examination of the entire tumor capsule. Since examination of a larger nodule will require more sections than a smaller nodule, it may be more appropriate to recommend a certain number of sections per cm of tumor. Lang et al. (38) evaluated 162 patients with minimally invasive FTC (CI alone and/or <4 foci of VI). The number of tissue blocks examined per cm tumor was the only variable which significantly correlated with distant metastatic disease (DM). None of 82 patients with examination of >4 blocks/cm developed DM compared with 7/80 (8.8%) with examination of <3 blocks/cm. Although open to many interpretations, it is plausible to assume that more extensive VI was missed when fewer sections were taken, thus downgrading these FTC to the minimally invasive category.

Given the difficulty in precisely diagnosing FTC, it is no surprise that important intra- and interobservation variation in diagnosis exists. For example, five leading French pathologists reviewed 41 cases previously diagnosed as FTC (39). The final consensus diagnosis was cancer in 30 (73%) cases but only 24/30 (80%) were diagnosed as FTC (59% overall). There was unanimous agreement about 13/24 (54%) cases of FTC, with the highest agreement in those with more extensive VI. Diagnostic discrepancies occurred in 4/7 (57%) cases of minimally invasive FTC. There was a tendency to defer to the opinion of the group leader at the consensus conference even when the individual pathologist did not agree with that opinion (known as the “leadership phenomenon”).

Given these diagnostic difficulties, many pathologists are reluctant to diagnose FTC by frozen section, although some institutions routinely use frozen section for diagnostic purposes (40,41).

If HCTC is excluded, variants of FTC are uncommon to rare and include the clear cell variant and mixed medullary follicular variant (31,32). Clear cell change also occurs in PTC but is more common in FTC (42). Some FTC are described as having an insular, solid, or trabecular component, but the significance of these findings is uncertain; these are not currently considered specific FTC variants.

The terms “minimally invasive” and “extensively invasive” FTC have many different meanings, leading to many different ways of subclassifying FTC. The WHO (31) currently divides FTC into three main pathological categories: (1) minimally invasive (CI alone); (2) encapsulated angioinvasive (without regard to number of blood vessels) and (3) widely (i.e., grossly) invasive. In 2014 the Armed Forces Institute of Pathology subdivided minimally invasive into those with CI alone, limited VI (<4 blood vessels), and extensive VI (>4 blood vessels) (31). The term “widely invasive” was reserved for grossly invasive FTC. Most recent publications define minimally invasive FTC as CI alone and/or minimal VI. Minimal VI generally refers to <4 blood vessels involved, although some authors consider up to 10 blood vessels as minimally invasive (43). The 2015 ATA guidelines recommend distinguishing between FTC with CI alone, with minimal VI (<4 blood vessels) and with extensive VI (>4 blood vessels) (1). Some studies utilize four distinct FTC categories: CI, minimal VI (+ CI), extensive VI and gross extrathyroidal extension (ETE) (44), whereas most studies use the term extensively invasive FTC to include either extensive VI or gross ETE. Some studies (45) conform to the current WHO categories. One study refers to all FTC except for those with CI as “classical FTC” (46). Minimally invasive FTC is generally far more common than widely invasive FTC, but there are notable exceptions (see below). Given the ambiguity of these terms, it may be time to retire the terms minimally invasive and extensively invasive FTC in favor of more specific but admittedly arbitrary criteria (namely: CI alone, minimal VI [<4] + CI, extensive VI [>4] or extensive ETE). Although the validity of the distinction between <4 and >4 blood vessels is unproven, this analysis seems reasonable until more data are available. Sharing a common diagnostic language is a minimum requirement for valid comparisons.

FTC tends to be larger than PTC. The SEER database (1988–2003) evaluated 30,504 PTC and 2584 FTC and reported a median diameter (interquartile range) of 1.5 cm (0.8–2.5) and 3.0 cm (2.0–4.5), respectively; only 8% of PTC were larger than 4 cm compared with 27% of FTC (47). The SEER database (1988–2009) found 60 times as many microPTC as microFTC (22,174 and 371, respectively) compared with an overall PTC:FTC ratio of 10:1 (48). It is possible that follicular tumors <1 cm are not routinely scrutinized for invasion or that it is difficult to be certain of capsular or vascular invasion in small follicular tumors.

Single institution–based publications may paint a different picture compared with large national database studies. Single institution publications have the advantage of relative diagnostic homogeneity, particularly with pathology re-review, but the disadvantages of small numbers of patients and institutional biases. Analyses from national databases have the advantage of larger numbers and homogenization of results across many institutions. However, without the possibility of pathological review, diagnostic uncertainty reigns.

My mental picture of FTC reflects my experience at the Massachusetts General Hospital (MGH) but may not be an accurate picture for other institutions. FTC is a unifocal tumor, with rare LNM, that uncommonly demonstrates extrathyroidal extension (ETE) and is primarily minimally invasive. To confirm this impression, I reviewed the MGH pathology reports of all cases of FTC diagnosed from January 2003 through March 2018 with institutional review board approval. The pathology specimens were not re-reviewed; HCTC, FVPTC, and PDTC were excluded, although diagnostic uncertainty was apparent in some cases. Only 1/231 (0.4%) had LNM; that tumor was noted to have insular and papillary features. Two additional patients had LNM from concomitant PTC. Only a single patient had equivocal multiple foci of FTC (0.4%). ETE occurred in 7 patients (3%), but 5 of these had unusual features such as an insular component, being solid and insular, being solid and trabecular, being a clear cell variant, and having features of FTC, PTC, and clear cell tumor, respectively. Between 1990 and 2015, 85% of FTC pathology specimens reviewed at MGH were minimally invasive; only 15% were widely invasive (49).

WHO experts agree that that lymphatic invasion is so rare in FTC that when it is present, the diagnosis of FVPTC should be considered instead (31). Lodewijk et al. (50) found contralateral cancer (a surrogate for multifocality) in 280/794 (35%) PTC and 20/115 (17%) FTC. However, only 1 of the 20 contralateral tumors in the FTC cases was also FTC (0.8% overall.) FTC series which report multifocal disease generally do not specify the pathology of the additional tumor foci. Cowden's syndrome should be suspected when FTC is truly multifocal, and when FTC is found in conjunction with multiple follicular adenomas (including adenolipomas and microadenomas) (51).

The prevalence of LNM, multifocal disease, ETE and the relative distribution of minimally invasive and widely invasive FTC varies considerably between recent publications, some of which are summarized below. These disparities may be due to the intentional inclusion of HCTC or the inadvertent inclusion of FVPTC or PDTC (see below), but differences in diagnostic criteria and extent of tumor section are also likely explanations. Locations with a high rate of discovery of incidental thyroid nodules may diagnose FTC at an earlier stage and at a smaller size, which may influence the pathological features such as LNM. Based on a study of 112,128 patients with thyroid cancer, Nguyen et al. (52) (SEER 2004–2014) reported an “extremely low risk of LNM” for FTC primary tumors <5 cm; above 5 cm “the risk increases slightly but remains less than 20%.” Absolute numbers cannot be determined from the data provided. It is also possible that actual disease behavior differs between ethnic groups or geographic areas. Examples of the differences between studies follow. Song et al. (2017) (53) compared FTC (likely including HCTC) diagnosed in three time periods: 1973–1995 (n = 68), 1996–2005 (n = 231), and 2006–2015 (n = 391). Widely invasive tumors (not otherwise specified) were found in 10.3%, 16.0%, and 12.3%, respectively; multifocal tumors in 16.2%, 17.7%, and 13.3%, respectively; ETE in 17.2%, 17.9%, and 11.0%, respectively; and LNM in 0%, 3.5%, and 2.6%. The decline in ETE was statistically significant (p = 0.0033).

Machens et al. (2005) (54) studied 134 FTC (including HCTC) diagnosed between 1994 and 2004; many of these tumors were considered clinically aggressive. Multifocal tumors were found in 9.0%, LNM in 19.4%, and ETE in 17.2%. Like the WHO, O'Neil et al. (45) divided FTC (excluding HCTC, FVPTC, and PDTC) into three groups: CI alone (n = 61), any angioinvasion (n = 52), and widely invasive disease (gross ETE) (n = 11). LNM were present in 3.2% overall but in 36% of widely invasive tumors. Podda et al. (55) found no LNM in 42 minimally invasive FTC (CI and/or <3 foci of VI). LNM were found in 5 of 29 (17.2%) widely invasive FTC (>3 foci VI). Overall LNM were found in 7.0% and multifocal disease in 2.8%. Huang et al. (2011) (40) found no LNM in 89 (0%) minimally invasive (CI and/or minimal VI) FTC, whereas 4/145 (2.8%) widely invasive FTC (widespread infiltration into blood vessels and/or adjacent thyroid tissue) had LNM. Overall 1.7% had LNM. In this study 62% of FTC were widely invasive.

Based on analysis of SEER data (1988–2003), Zaydfudin et al. (47) reported LNM metastases in 22% of 30,504 PTC compared with 2% of 2584 FTC. Goffredo et al. (SEER 2000–2009) (56) reported LNM in 0.9% of 1200 minimally invasive (not otherwise specified) FTC and 3.6% of 4208 widely invasive FTC (not otherwise specified) or 2.8% overall; ETE was found in 3.9% and 12.4%, respectively. Overall 78% of FTC were considered widely invasive. HCTC was likely included. Goffredo et al. (57) (National Cancer Database 2010–2011) compared 333 FTC with CI alone with 284 FTC with minimal VI (+ CI). Multifocal disease was found in 15.0 and 11.4%, respectively; ETE in 5.4% and 9.2%, respectively; and LNM in 2.0% and 0%, respectively. VI was correlated with larger tumor size. The number of involved blood vessels was not specified and HCTC was likely included.

Outcomes: recurrent/persistent disease, distant metastases, and mortality

For many aggressive malignancies, there is a close correlation between disease recurrence and disease-specific mortality (DSM). For example, women with recurrent stage I breast cancer have a 15-year DSM of 32%, and with recurrent stage II breast cancer the 15-year DSM is 59% (58).

PTC has a low risk of death (classical 2.7%, tall cell variant 6.7%, FVPTC 0.6%) (59) but a high risk of recurrence. The precise prevalence of recurrent/persistent PTC is uncertain, but likely ranges from at least 25% for structural recurrences (60) to as high as 45% (61) when biochemical persistent disease (elevated thyroglobulin (Tg) without structural disease) is included. LNM are the most common site of recurrent/persistent PTC; non-nodal soft tissue recurrences and distant metastatic disease (DM) are far less common. Risk factors for recurrent PTC (1,62) include LNM, extra-thyroidal extension, multifocal disease, age, and tumor size. The mortality risk for PTC increases with age, extent of extra-thyroidal extension, DM, and to some extent, LNM. By multivariate analysis vascular invasion in classical PTC is not considered an independent risk factor (33). For the same disease stage, DM that are 18F-fluoro-deoxyglucose (FDG)/positron emission tomography (PET) positive have a worse prognosis than those which are FDG/PET negative (63).

It is uncertain whether BRAF ^V600E mutations independently predict mortality in PTC (64) when comparable pathological stages are considered and less aggressive variants (e.g., FVPTC) are excluded, but associated TERT promoter mutations likely increase the risk of recurrences, DM and DSM (65). BRAF ^V600E mutations also make tumors less likely to be RAI-avid (66).

Some PTC variants (tall cell, columnar cell, diffuse sclerosing, hobnail) appear to predict more aggressive disease and higher DSM, but it is uncertain whether that risk is independent of tumor stage (67).

In contrast to PTC, when FTC recurs DM are usually present; recurrent LNM are rare in FTC (68). As with PTC, DM are primarily found in the lung and bone, but metastases to the liver, brain and other sites also occur. Although FTC DM are not uniformly fatal, DSM in FTC is rare without DM. Radioactive iodine (RAI) therapy has great efficacy, but cure of bulky thyroid cancer metastases is rare (69,70).

It is generally accepted that DM and DSM rates are higher with FTC than PTC. For example, in a single institution study (71) of 1503 well differentiated thyroid cancers, the 19 deaths from FTC (of 221 FTC, 8.6%) was almost identical to the 18 deaths from PTC (of 1282 PTC, 1.4%) despite a PTC:FTC ratio of 5.8:1.0. Similarly, based on the SEER database (1988–2009) PTC accounted for 52.1% of DM (56) compared with 40.4% from FTC and 7.4% from HCTC, despite the annual incidence ratio of PTC:FTC of 10:1. However, another study using SEER (1988–2004) reported DM in 1.0% of PTC (305/30,504) compared with 3.0% in FTC (78/2584; possibly including HCTC); overall 80% of DM were from PTC (47).

The risk of DM in FTC ranges from a low of 3.0% to almost 30% (see below). Possible explanations for these variations include inclusion of HCTC (or less commonly PDTC), early diagnosis of FTC due to incidental detection of thyroid nodules, insufficient duration of follow-up, less stringent criteria for FTC (i.e., inclusion of FA), and reports from centers of excellence where patients with DM may be referred prior to surgery, thus increasing the risk of DM. Once DM are present, either from PTC or FTC, the outcome is very similar, with a high correlation between macroscopic disease progression and mortality (70). However, RAI avidity is more common in RAS than BRAF ^V600E mutant tumors (69). Up to one-half of the DM in FTC are present at diagnosis (or within one year of diagnosis). Early onset DM is reported to have a higher mortality (72), a finding possibly related to lead-time bias.

Some FTC studies report a decline in DM, DSM or tumor size and an increase in disease-free survival over time. Song et al. (53) compared FTC outcomes in three periods (1973–1995, 1996–2005, and 2006–2015) and noted a decline in the rate of DM (14.7% of 68, 11.3% of 231 and 5.2% of 391), a change that was apparently not significant based on a survival analysis. Yu et al. (73) compared 1997–2001, 2002–2006 and 2007–2011, with 3-year disease-free survival rates of 77.8%, 93.7%, and 100%, respectively, (p = 0.008) and a decline in the median tumor diameter (4.2 cm to 2.8 cm and 2.9 cm, respectively), possibly due to earlier diagnosis.

Many clinicians assume that the risk of DM and DSM in FTC increases with pathological progression from CI alone to minimal VI (<4 blood vessels) to widely invasive with extensive VI (>4 blood vessels) or gross ETE. The ATA low risk of recurrence group includes FTC with CI alone or minimal VI (<4 blood vessels) + CI. The high risk of recurrence group includes extensive VI (>4 foci) (1). However, the WHO (31) currently does not subclassify the extent of VI. Increased tumor size, older age and, possibly, the molecular profile also correlate with DM and mortality. Multivariate analyses of risk for DM (summarized by Grani et al. (2)) from many different institutions report increased risk associated with older age, larger tumor size, stage, angioinvasion, and ETE.

One single institution study is instructive, particularly concerning the timing of DM appearance. Sugrino et al. (72) evaluated 134 FTC patients diagnosed between 1989 and 1998. All pathology specimens were re-reviewed to exclude HCTC, clear cell FTC, FVPTC, and PDTC. Follow-up was sufficiently long to discover DM. DM were present in 13 (9.7%) at presentation or within 1 year of diagnosis; 9 of these 13 died of their disease, with disease specific survival (DSS) of 41.0 and 30.8% at 5 and 10 years, respectively. An additional 23 (19.1%) patients subsequently developed DM (overall DM: 26.8%) at a mean interval of 70 months after surgery (range 12–189 months), and 9 of these 23 (39%) died of their disease, with overall 10-, 15-, and 20-year DSS in this group of 89.9%, 84.6%, and 79.2%, respectively. Late DM were found in 3/32 (10.3%) without VI (it is uncertain if these were CI alone), 20/111 (18%) with minimally invasive FTC (CI and/or limited VI), 3/10 (30%) with widely invasive FTC (extensive VI or gross ETE), and 3/7 (42.9%) with LNM. Overall, the majority of patients developing DM had minimally invasive FTC. Comparing those with primary tumors <4 or >4 cm, DM occurred in 4/45 (8.9%) and 19/76 (25%), respectively (p = 0.03). For age <45 years or >45 years, DM occurred in 4/58 (6.9%) and 19/76 (30.2%), respectively (p = 0.001). For those without DM, presentation age >45 and size >4cm were independent predictors of DM, whereas for the entire group widely invasive disease was an independent predictor of DM.

The reported DM and DSM risk of each FTC invasive category varies considerably from study to study. Several small single institution studies report either no DM or no DSM in FTC with CI alone (46,49,74). Some studies report no DM or DSM in minimally invasive FTC (CI and/or minimal VI) (40,55). However, most studies report at least some DM in each category of invasion as well as all size and age categories.

In a concerning but fortunately unique study, D'Avanzo et al. (75) reported deaths in 5/45 (11%) FTC (likely including HCTC) patients with CI alone. One patient presented with distant metastatic disease and 5 developed local recurrence, 4 of whom died. The pathology slides were not available to confirm the diagnosis or extent of ETE (personal communication).

O'Neill et al. (45) found DM in 2/61 (3.3%) FTC with CI alone, 6/52 (11.5%) FTC with vascular invasion and 5/11 (45.0%) FTC with wide local invasion; disease free survival at 40 months in these three groups was 97.0%, 81.0%, and 49.0%, respectively (p < 0.01). DM were found in 1/55 (1.8%) patients under age 45 compared with 12/57 (17.5%) >age 45 (p = 0.02) and in 5/38 (13.1%) with tumors <20 mm, 4/56 (7.1%) between 21 and 40 mm, and 4/30 (13.3%) >40 mm (p = .055; not significant, p < 0.05).

Kim et al. (44) evaluated 204 FTC (including 17 HCTC) diagnosed between 1995 and 2010 after pathological re-review. DM occurred in 5/85 (6.0%) with CI alone, 8/80 (10.0%) with minimal VI, 4/13 (31.0%) with wide invasion without VI, and 12/26 (46.0%) with extensive VI. Overall DM occurred in 14.0%.

Glomski et al. (49) reported DM in 22/218 (10.0%) FTC but excluded an additional 25 cases of FTC with DM at presentation (19.0%) overall. Of 145 cases with complete tumor capsule examination 1/123 (0.8%) with CI and/or minimal VI developed new DM compared with 8/21 (38.0%) with widely invasive FTC (extensive >4 blood vessels VI or ETE). When the tumor capsule was incompletely evaluated, 1/45 (2.2%) with minimally invasive disease developed DM, compared with 11/17 (65.0%) with widely invasive disease.

Podda et al. (55) evaluated 234 pathologically confirmed FTC (possibly including HCTC) diagnosed between 1977 and 2007. Widely invasive FTC (widespread infiltration of thyroid tissue and/or vascular invasion) was found in 0/4 (0%) tumors <1 cm, 2/11 (17.0%) tumors 1 to <2 cm; 15/40 (37.5%) tumors 2–4 cm and 12/16 (75%) tumors >4 cm.

Huang et al. (40) reported DM in 41/145 (28.3%) with widely invasive disease (extensive VI or gross ETE) all of whom died. No DM were found in 89 minimally invasive FTC. It is worth noting that there was an unusual prevalence of widely invasive disease in this study.

Goffredo et al. (SEER 1988–2009 (56)) reported DM in 6/1200 (0.5%) minimally invasive FTC (CI and/or minimal VI, not otherwise specified) compared with 29/4208 (6.9%) widely invasive FTC likely including HCTC (p < 0.001). Overall, 1.8% had DM. The unusual 3.5:1.0 ratio of widely to minimally invasive FTC is noteworthy. In a separate analysis based on the National Cancer Database (2010–2011), DM were found in 1/333 (0.3%) FTC with CI alone compared with 3/284 (1.1%) with minimal VI + CI (number of vessels not specified) (57).

Kuo et al. (48) reported DM in 15/371 (4.1%) micro tumors (FTC + HCTC), with 10-year DSS of 95.4%. DM were also found in 110/22,174 (0.5%) microPTC with a 10-year DSS of 99.3%. Of note, the DM rate for microFTC in this study is higher than for all FTC (47), possibly indicating selection bias based on overreporting of aggressive microFTC or the possible difficulty diagnosing FTC in sub-centimeter nodules.

If HCTC is excluded, the behavior of FTC variants is uncertain. Clear cell changes are more common in FTC than PTC (42), with reports of more aggressive and equally aggressive behavior compared with FTC (31). Little is known about the behavior of mixed medullary/follicular carcinoma. The impact of insular, trabecular, or solid changes in FTC is unknown. The behavior of FTC in genetic syndromes such as Cowden's or Werner's is also unknown.

The impact of molecular abnormalities on FTC outcome, beyond conventional pathological staging, is also uncertain, although some studies suggest they may be helpful (76). Song et al. (53) reported an association between RAS mutant FTC and persistent disease and DM. Fukahori et al. (77) reported a positive association between NRAS codon 61 mutations and DM and RAS mutations in general with poor overall survival. Some studies suggest that tumors with PAX8PPARγ are smaller and present at a younger age but are more likely to have vascular invasion (26). Melo et al. reported a positive association between TERT promoter mutations and DM, ETE, VI, LNM and older age in 12/43 FTC patients with these mutations, but the number of specimen studied was small (78). It would be surprising if RAS or PAX8PPARγ alone provided important prognostic information beyond tumor stage, given the presence of these changes in both FA and FTC and common genetic landscape of these tumors when more extensive molecular testing is performed (79).

Therapeutic considerations and surveillance

Surgery for PTC is designed to minimize the risk of recurrent disease (primarily LNM) and to facilitate RAI therapy when necessary. The appropriate role of hemi-thyroidectomy in PTC versus total thyroidectomy is evolving (1), but decisions about the extent of surgery are generally made after a likely diagnosis of PTC based on FNAB. After a total thyroidectomy, the serum Tg concentration 6 weeks postsurgery may help inform the decision about whether to administer RAI; in some patients, a diagnostic radioactive iodine scan may be useful. Measurement of serum Tg may also be helpful after a hemithyroidectomy but has somewhat less utility than after a total thyroidectomy (80). After either hemi- or total thyroidectomy, post-operative ultrasound surveillance uncovers most recurrent PTC (1).

RAI is generally not administered for patients in the low risk ATA category for recurrence, but it is generally administered for patients at high risk of recurrence and considered for patients at intermediate risk of recurrence with PTC (1). Which intermediate recurrence risk patients with PTC should receive RAI is currently the subject of debate.

Conversely, FTC may be suspected but is rarely confirmed prior to surgery. After obtaining a Bethesda III or IV FNA cytology result, the final pathology will be benign or low grade follicular malignancy in the majority of cases, even when integrating results of modern molecular testing. Therefore, many (if not most) patients diagnosed with FTC undergo hemi- rather than total thyroidectomy. After hemithyroidectomy for FTC, if RAI is deemed necessary, (81) either completion thyroidectomy or RAI lobe ablation is required. FTC is primarily a unifocal disease where the primary tumor is completely removed. Local recurrences are rare. Therefore, RAI for FTC is generally administered to treat or discover DM, rather than to prevent local recurrences. Compared with PTC, postoperative ultrasound surveillance is far less useful for FTC because LNM and nodal recurrences are rare (82). When FTC has extensive local invasion, ultrasound may be more useful.

RAI therapy is strongly recommended for FTC patients who present with DM and for those with extensive (>4 foci) of VI or extensive ETE, all of which fall into the ATA high recurrence risk category (1). FTC with CI alone and/or minimal VI (<4 blood vessels) fall into the ATA low recurrence risk group; by inference RAI is not recommended for these patients. However, some FTC patients with CI and/or minimal VI require RAI, but it is uncertain which of these patients require RAI and whether and how the risk for DM varies. After hemithyroidectomy, we recommend levothyroxine for all FTC patients regardless of thyroid function testing. For FTC with CI alone, we do not recommend completion thyroidectomy or radioactive iodine therapy. For FTC with extensive VI or gross ETE, we recommend completion thyroidectomy (or lobe ablation) followed by radioactive iodine therapy. For FTC with minimal VI (< 4 blood vessels), we generally do not recommend completion thyroidectomy or RAI, except for larger (>5 cm) tumors. It is important to emphasize the important role of the pathologist at each institution. Practice patterns would prompt more liberal use of completion thyroidectomy and RAI at a given institution, if a significant minority of FTC patients with CI alone or minimal VI develop DM. Many important questions can be posed: Can tumor size, patient age and/or molecular profile help decide which FTC patients with CI and or minimal VI need RAI? How effective is serum Tg monitoring at uncovering DM after total thyroidectomy without RAI? What is the utility of serum Tg monitoring for discovering DM after hemithyroidectomy for FTC? Can that utility be improved by levothyroxine therapy to lower serum thyrotropin (TSH) and serum Tg? In other words, are smaller changes in Tg more meaningful if the baseline (postoperative Tg) is lower? What is the role of cross-sectional imaging such as CT or FDG PET/CT after hemithyroidectomy when RAI is deemed unnecessary? How do we weigh the benefit of early discovery of DM or the reassurance of a negative scan against the anxiety resulting from a false positive scan (e.g., small indeterminate pulmonary nodules)? Does early detection and treatment of FTC DM improve DSS or disease associated morbidity? Unfortunately, we do not have complete answers to any of the foregoing questions.

Staging

Compared with prior editions, the eighth edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System (AJCC TNM) classification for differentiated thyroid cancer improves our ability to predict the risk of death from PTC (83). The ATA risk categories for recurrent/persistent PTC have also been validated in many studies (1). However, neither AJCC TNM, 8th edition, nor ATA recurrence risk categories have been validated specifically for FTC.

In 2007 Lang et al. (84) compared several staging systems for FTC and, at the time, considered TNM AJCC 6th edition to be the best, although 13/14 staging systems were considered highly predictive of DSS. However, these staging systems were applied to an atypical population of 181 patients diagnosed with FTC between 1961 and 2001, 49% of whom had extensively invasive disease. Current discussions concerning potential new FTC staging systems primarily focus on the age cutoff for younger versus older patients (85).

Although not universally accepted, most FTC studies consider the presence or extent of VI as important risk factor for DM or DSM, yet VI is not included in the AJCC TNM 8th edition classification. It is possible that age and tumor size are valid predictors of outcome in FTC, but these are likely to be, at best, surrogates for VI. It is important to develop new TNM staging systems for FTC that incorporate VI and validate these by evaluating FTC patients with adequate duration of follow-up from many different institutions. In the future, it is likely that molecular abnormalities will also be incorporated into these staging systems. Validation of the current TNM classification and ATA recurrence risk categories for FTC is also necessary.

It is likely that many FTC patients will be adequately staged by the current systems. For patients over age 55 years, those with DM at presentation will be stage IV, and those with extensive local invasion will be stage II or III. Most FTC patients with CI alone or minimal (<4 blood vessel) VI have an excellent prognosis and will be either stage I or II. However, patients with extensive VI will be either stage I or stage II (if >4 cm), which may not adequately predict their risk for DM or DSM. These patients are included in the ATA high risk of recurrence group. Two cases provide a microcosm of the problem: (1) a 65-year-old man with a 4.1 cm FTC with CI alone is TNM stage II; and (2) the same patient with a 3.9 cm FTC with extensive VI is stage I. It is likely (but as yet unproven) that the risk is overestimated in the first patient and underestimated in the second.

Clinical scenarios

It is important to recognize several rare FTC clinical scenarios. FTC may cause hyperthyroidism (or thyrotoxicosis) by three different mechanisms. Rarely, activating TSH receptor mutations occur in FTC, clinically mimicking an autonomously functioning adenoma (“hot” nodule) with hyperthyroidism at presentation or when distant metastases appear and grow. This is an exception to the rule that almost all “hot” nodules on radioiodine scanning are benign (86,87). Some patients with concomitant Graves' disease and FTC develop hyperthyroidism as stimulating TSH receptor antibodies (TRAb) drive the DM to produce thyroid hormone (88,89). Hyperthyroidism in FTC due to autonomous function or TRAb stimulation generally responds to methimazole or RAI therapy. 3,5,3′-triiodothyronine (T3) thyrotoxicosis may also occur in FTC with bulky DM due to increased conversion of administered levothyroxine to T3 by type 2 iodothyronine deiodinase (90,91). In this scenario, elevated (or high normal) serum T3 occurs when levothyroxine is administered, and profound hypothyroidism occurs when levothyroxine is discontinued. Because a fully suppressed serum TSH is often the therapeutic goal in FTC patients with DM, unless serum T3 (or free T3) is measured, deiodinase induced hyperthyroidism will be missed. If radioactive iodine is not successful in treating the metastases, the thyrotoxicosis may be very difficult to treat. Propylthiouracil inhibits type 1 deiodinase but not type 2. Lenvatinib successfully treated one patient with T3 thyrotoxicosis due to increased conversion of T4 to T3 (92). Other potential unproven treatments include progressively lowering the levothyroxine dosage or prescribing multiple daily doses of liothyronine to suppress serum TSH without causing symptomatic thyrotoxicosis (93). Cowden's syndrome should be suspected in patients with rapid growth of thyroid nodules after a less than total thyroidectomy or when FTC is found in conjunction with multiple microadenomas, FA, and adenolipomas (51). Classic Cowden's syndrome includes macrocephaly, trichilemmomas, and papillomatous papule as well as an increased risk for breast cancer, thyroid cancer, endometrial cancer, colonic polyps, and possibly kidney cancer (30). Although of unproven benefit, we measure head circumference in patients with FTC, particularly young patients. If the head circumference is above the 95th percentile for height and sex (94) or above 58.6 cm in a male or 57.8 cm in a female, we consider germline genetic testing for PTEN mutations or PTEN immunostaining on the pathology specimen.

Follicular variant of papillary thyroid cancer

The Cancer Genome Atlas divided PTC into two broad groups based on their molecular landscapes: (1) with BRAF ^V600E-like changes and (2) with RAS-like changes (95). BRAF ^V600E mutations occur in up to one-third of FVPTC (96). These tumors are locally infiltrative, are often associated with LNM, and in general behave similarly to conventional PTC, albeit with a follicular architecture. Some investigators suggest diagnosing and treating these tumors as classical PTC (97,98). PTC with RAS-like changes are all FVPTC and behave differently from those with BRAF ^V600E mutations. These RAS mutant tumors are encapsulated; the diagnosis of malignancy depends on the presence of capsular and/or vascular invasion. In other words, they share a molecular profile and pathological criteria with follicular, not papillary, tumors. Encapsulated, noninvasive FVPTC (often with RAS mutations) have recently been renamed as “noninvasive follicular tumors with papillary like nuclear features” (NIFTP) (99). Despite the nuclear atypia, these tumors behave in an indolent fashion. On the other hand, encapsulated invasive FVPTC (CI and/or VI) are essentially identical to FTC in their behavior, molecular profile, and pathological criteria, except for the nuclear changes noted in FVPTC. Although it may be premature to expect pathologists to rename these tumors (e.g., FTC with nuclear atypia), it is not premature to recommend that these tumors be analyzed in parallel with FTC with assessment of outcome based on CI, minimal VI, extensive VI, ETE, size, age, and molecular profile. If these encapsulated invasive FVPTC are indeed identical to FTC (in all respects except nuclear atypia), changing the name to FTC would result in an effective doubling of the annual incidence of FTC (adding 1 case per 100,000 per year). This calculation is based on the annual incidence of PTC (around 15/100,000), the fraction of PTC which are FVPTC (30%) (100) and the fraction of FVPTC that are considered encapsulated invasive (23–31%) (101,102). Subtracting NIFTP from the annual incidence of FVPTC will not change this result; the ratio of FVPTC/PTC will decline but the percentage of encapsulated invasive FVPTC will rise proportionally.

Metastasizing follicular “adenomas”

In rare cases, DM compatible with FTC occurs many years after a thyroid tumor was originally diagnosed as benign (FA). After careful review of the original pathology—often reviewing additional tumor sections if possible—the original diagnosis may be changed to FTC (or FVPTC) (49,103), but in some cases the original tumor cannot be diagnosed as malignant even after careful pathological re-review. Considering the rarity of these events, it is difficult to know whether there are any pathological or molecular characteristics of FA that would warrant heightened surveillance, or in rare cases treatment, as if the tumor was a FTC. Without supporting data, we have adopted this approach. We often recommend long-term surveillance (with serum Tg monitoring) for patients with very large FA (arbitrarily over 5 cm) particularly when the pathologists use terminology that acknowledges either uncertainty or features which are atypical but insufficient to diagnose FTC. In some particularly concerning cases after discussion with the patient, we recommend radioactive iodine therapy/scanning. If the initial operation was a hemithyroidectomy, this approach requires completion thyroidectomy or RAI lobe ablation followed by RAI therapy. There are insufficient data to know if Tg monitoring with or without levothyroxine therapy, appropriate cross-sectional imaging, or a specific molecular profile would be helpful in providing guidance for atypical FA. It is also reasonable to express similar concerns about very large or atypical NIFTP tumors.

Hürthle cell thyroid cancer

HCTC has traditionally been classified as a variant of FTC. However, it is a unique tumor requiring separate analysis and classification, a position supported by the ATA guidelines (1) and the WHO (31). The Hürthle cell, also known known as the oncocytic or oxyphilic cell, is large with increased granular cytoplasm, large nuclei, and an increased cytoplasmic-to-nuclear ratio. The cell is packed with an increased number of abnormally enlarged mitochondria. Hürthle cell tumors may infarct after a FNA. Like FTC, HCTC tends to be encapsulated, and capsular and/or vascular invasion are necessary for the diagnosis of malignancy. Like FTC, HCTC with vascular invasion spreads to distant sites, but unlike FTC, LNM and soft tissue recurrences are more common. HCTC demonstrates intense FDG uptake on PET scans even with relatively small tumors. In contrast to FTC, HCTC is much less likely to be RAI avid. Given the propensity for local recurrence, ultrasound surveillance may be helpful for HCTC. The inclusion of HCTC in many studies of FTC may prejudice the results.

Like FTC, HCTC is currently categorized in different ways. Although it seems logical to categorize HCTC on the basis of CI, minimal VI, extensive VI, LNM, and gross ETE, this categorization is not specifically mentioned by the WHO (31). Classification of HCTC by these criteria, as well as sex, age and molecular profile, requires additional studies to assess the DSM and recurrence risk for these categories. The genetic landscape of HCTC is different from the one in FTC and PTC. The HCTC genome is marked by recurrent mitochondrial DNA mutations in complex 1 of the electron transport chain (104), and widespread loss of heterozygosity across many chromosomes often with genome-wide haploidization (105). These tumors also exhibit a distinct gene expression profile (106); RAS point mutations and PAX8PPARγ fusions are much less common than in FTC (106).

Although HCTC has a reputation for being a particularly aggressive form of well differentiated thyroid cancer, it is uncertain whether the prognosis differs from FTC when comparable disease stage is compared (107). Some data suggest that the prognosis for HCTC may be improving over time and that survival is comparable or superior to FTC; however, additional studies are necessary. It is also uncertain whether the diagnostic criteria for HCTC have changed over time (108,109).

Poorly differentiated thyroid cancer

PDTC (31) has a prognosis intermediate between well-differentiated thyroid cancer and anaplastic (undifferentiated) thyroid cancer, with a high prevalence of LNM, gross ETE, DM, and DSM. The Turin diagnostic criteria include conventional criteria for follicular cell–derived carcinoma, solid trabecular or insular growth pattern, absence of the conventional nuclear features of PTC, and at least one of the following three features: (1) convoluted nuclei, (2) >3 mitoses per 10 high power fields, and/or (3) tumor necrosis. Geographic differences in diagnosis are apparently common (110).

We include PDTC in this commentary for several reasons. First, FTC series with a high prevalence of gross ETE might include cases with PDTC. Second, PDTC often develops from well-differentiated FTC. Third, when only a small percentage of the tumor has poorly differentiated features, it might be categorized as FTC but behave in a more aggressive fashion. Although it is generally assumed that PDTC is not RAI-avid, we have seen patients with PDTC with RAI-avid DM, suggesting that the DM are from the FTC rather than the PDTC component. It is uncertain whether insular or solid/trabecular features in an FTC are signs of a more aggressive tumor and possible transition to PDTC.

Guidelines

Guidelines serve many purposes, such as providing guidance for clinicians, and they are important educational and reference resources for experts and nonexperts alike. An additional benefit is the necessary focus on what is known, what is unknown, and what is only suspected or assumed. Codifying the unknown and the assumed invariably raises important questions and leads to research studies to answer those questions.

The ATA 2015 guidelines (1) focus almost exclusively on PTC with little discussion of the controversies concerning FTC. Although anaplastic thyroid carcinoma and medullary thyroid carcinoma in aggregate have a lower annual incidence compared with FTC, each has its own set of ATA guidelines. It is clearly the right time to provide new separate guidelines for FTC, HCTC and PDTC to shine the spotlight on these important and problematic tumors.

Directions for future study

We do not know how well the WHO, AJCC TNM, eighth edition, or ATA risk of recurrence categories apply to FTC outcomes, specifically FTC with CI, minimal VI, or extensive VI. We do not know how well size, age and molecular profile predict outcomes independent of ETE or extent of vascular invasion. Until we have better information, it is difficult to provide appropriate guidance about the utility of RAI in FTC patients with CI and/or minimal VI.

To provide better answers, we need to standardize the diagnosis, nomenclature, and reporting of FTC. In private, pathologists admit that review of multiple tumor sections is, at a minimum, tedious, raising the question of a potential role for artificial intelligence/machine learning for surveying these sections. Given the relatively small numbers of cases at any single institution, multicenter collaboration with central pathology review in conjunction with advanced molecular diagnostics is likely necessary to advance knowledge and treatment of FTC. Given the length in time to appearance of DM, these studies will need to utilize samples from earlier dates or extend the studies over many years. In the absence of a clearly superior diagnostic schema, it seems reasonable to analyze four diagnostic categories (CI, minimal VI, extensive VI, ETE) and correlate these with size, age, molecular analysis, and outcomes. Encapsulated invasive FVPTC cases should be studied in parallel to decide whether these are indeed FTC or distinct tumors. Using these same criteria, a less ambitious but possibly highly informative project would analyze data from many institutions on the “outlier” cases—those patients with “metastasizing FA” or FTC with CI and/or minimal VI who develop DM. Preliminary studies of this population are beginning to appear (76). The terms “minimally invasive FTC” and “widely invasive FTC” are ambiguous and might profitably be abandoned. Additional molecular testing comparing FA and FTC and indolent versus aggressive FTC may provide additional diagnostic or therapeutic information. Only with appropriate collaborative studies can we begin to understand whether the different outcomes reported by different institutions are due to differences in pathology assessment or the nature of the tumor.

Clinicians also need more practical information. What is the role of levothyroxine therapy after hemithyroidectomy for FTC? Does TSH suppressive therapy prevent recurrences? Does lowering serum TSH with levothyroxine improve the prognostic value of serum Tg measurements by starting at a lower baseline? How well does serum Tg concentration predict DM after total thyroidectomy with or without RAI? Does Tg surveillance facilitate earlier diagnosis of DM? Does early diagnosis of DM improve the DSM or decrease morbidity of DM? What is the role of cross-sectional imaging to discover DM in patients not treated with RAI? Is there a role for long-term surveillance or treatment of large or atypical FA or NIFTP?

New staging systems incorporating VI as an important variable should be explored for FTC and compared with the current TNM and risk of recurrence classifications.

Despite major knowledge gaps, publication of specific guidelines for FTC, HCTC and PDTC will undoubtedly advance knowledge and treatment for these tumors.

Although beyond the scope of this perspective, new therapies for radioactive iodine refractory FTC are needed. These include further exploration/improvement of redifferentiation therapy as well as development of novel targeted therapies, immunotherapies, and combination therapies.

Conclusion

After his totally inaccurate obituary was published in 1897, Samuel Clemens (Mark Twain) commented, “The report of my death was an exaggeration” (111). Similarly, the “demise” of FTC is an exaggeration. Unfortunately, FTC continues to be a serious, sometimes lethal disease which requires additional thought and study.

Footnotes

Acknowledgments

I would like to thank Josh Murphy for his excellent editorial assistance.

Author Disclosure Statement

There are no disclosures or conflicts of interest to disclose.

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