Clinical Characteristics of Subtypes of Follicular Variant Papillary Thyroid Carcinoma

Abstract

Background:

Among follicular variant papillary thyroid carcinomas (FVPTCs), the noninvasive encapsulated subtype has an excellent prognosis. For this reason, reclassification of noninvasive encapsulated FVPTC (EFVPTC) as a new entity called “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) has been proposed, but controversy remains. To characterize noninvasive EFVPTC in an Asian population, the clinicopathologic features of each FVPTC subtype were compared in a Korean population.

Methods:

FVPTC patients (n = 142) who underwent thyroidectomy between 2009 and 2014, and whose tumor size was >1 cm, were included in the study. The surgical pathology of each patient was reevaluated by two independent expert pathologists.

Results:

The percentages of noninvasive and invasive EFVPTC and infiltrative FVPTC (IFVPTC) in the study were 30%, 31%, and 39%, respectively. There was no difference in preoperative cytological diagnosis or the extent of surgery between noninvasive and invasive EFVPTC. However, the proportion of Bethesda category IV was lower in IFVPTC (16%) than in noninvasive and invasive EFVPTC (35% and 36%, respectively). Therefore, thyroid lobectomy was more common in noninvasive or invasive EFVPTC (54% or 48%, respectively) than in IFVPTC (16%). Noninvasive EFVPTC showed lower multiplicity, extrathyroidal extension, and BRAF^V600E mutation frequency (three cases; 8%) than did invasive EFVPTC, but other pathological characteristics were similar. However, IFVPTC showed significant differences in tumor size, extrathyroidal extension, lymph node metastasis, Tumor Node Metastasis stage, and American Thyroid Association high-risk category compared with noninvasive and invasive EFVPTC. In the noninvasive EFVPTC group, there were six (14%) cases with multifocality and three (7%) cases with lymph node metastasis. However, only two cases with multifocality and one case with lymph node metastasis originated from noninvasive FVPTC, while the other cases were from coexisting conventional PTCs.

Conclusions:

Noninvasive EFVPTC has favorable pathological features, but lymph node metastasis or BRAF^V600E mutations were observed in some patients. Therefore, in order for the distinction between noninvasive EFVPTC and invasive EFVPTC to have more clinical significance, the criteria for NIFTP need to be more strictly revised.

Introduction

Follicular variant (FV) papillary thyroid carcinoma (PTC) was first described by Crile and Hazard in 1953 (1). Subsequently, Lindsay defined the term FVPTC as a thyroid tumor with nuclear features of PTC but with a follicular growth pattern (2). FVPTC is the second most common variant of PTC, accounting for 7–23% of all PTCs (3 –6). The diagnoses of FVPTC have been increasing in Western countries (7,8), while the diagnosed population remains steady in Asian countries (6). The prognosis of FVPTC has been reported to be better than or similar to that of conventional PTC, even though FVPTC size at the time of diagnosis is occasionally larger. A recent large-scale multinational study demonstrated that FVPTC have lower Tumor Node Metastasis (TNM) stage, recurrence, and mortality rates compared to conventional PTC (9).

FVPTC can be subdivided into encapsulated (EFVPTC) and infiltrative (IFVPTC) subtypes based on the presence of a capsule surrounding the tumor (10). EFVPTC was shown to have a better prognosis than IFVPTC (11). Recently, several studies have reported that a noninvasive subset of EFVPTC that exhibits no capsular invasion of tumor cells has excellent outcomes with no lymph node (LN) metastasis, no recurrence, and no mortality (11 –16). Based on these observations, a nomenclature revision from “noninvasive EFVPTC” to “noninvasive follicular thyroid neoplasm with papillary-like nuclear feature” (NIFTP) was recently proposed (12). However, there is controversy concerning the change because the numbers of subjects analyzed in most studies were relatively small, and, for the most part, the studies were performed in Western countries (11 –16).

To determine the clinical meaning of noninvasive EFVPTC in an Asian population, the clinicopathologic features of each FVPTC subtype were compared in a Korean population.

Materials and Methods

Subjects

There were 337 patients diagnosed with FVPTC after surgery at Seoul National University Hospital between 2009 and 2014. During the period, 6548 patients underwent thyroid surgery for PTC, and 329 (5%) had FVPTC diagnosed based on the surgical pathology reports. Among them, 170 FVPTC were ≤1.0 cm. There were also 17 for which surgical slides were unavailable, and eight cases were reclassified as conventional PTC after reevaluation of pathological findings. After excluding these cases, 142 cases were finally included in this study (M _age = 50 ± 14 years; 39 males [27%]). The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (H 1605-112-763).

Management and follow-up

To characterize a thyroid nodule, fine-needle aspiration (FNA; n = 142) or core-needle biopsy (n = 33) was performed preoperatively. Cytological diagnosis was based on The Bethesda System for Reporting Thyroid Cytopathology (17). The Bethesda system classifies cytological results into six categories: (I) nondiagnostic/unsatisfactory, (II) benign, (III) atypia of undetermined significance/follicular lesion of undetermined significance, (IV) follicular neoplasm/suspicious for follicular neoplasm, (V) suspicious for malignancy, and (VI) malignant.

All included patients underwent thyroid lobectomy or total thyroidectomy. Total thyroidectomy was recommended for patients with a preoperative diagnosis of Bethesda categories V or VI or with suspicious LN metastasis in preoperative images. For cases in Bethesda categories III or IV, total thyroidectomy (n = 26) or thyroid lobectomy (n = 40) was performed after shared discussions with the patients. Total thyroidectomy was preferred in patients with a thyroid nodule >1.5 cm (18), contralateral nodules, or pre-existing hypothyroidism. Although thyroid lobectomy was generally recommended for thyroid nodules of Bethesda categories I or II, total thyroidectomy was performed in two cases with bilateral large thyroid nodules or preexisting hypothyroidism. After thyroid lobectomy (n = 53), patients were informed of the advantages and disadvantages of completion thyroidectomy and radioactive iodine (RAI) therapy, and 25 (45%) patients underwent completion thyroidectomy based on shared decision making. RAI therapy was conducted in 70% (n = 79) of the patients after total thyroidectomy (n = 113). Most patients (n = 72) received RAI remnant ablation with a low activity of 1.1–3.7 GBq, but seven patients with distant metastasis, incomplete tumor resection, or gross extrathyroidal extension (ETE) received a higher RAI activity level (5.6–7.4 GBq). RAI therapy was repeated every 6–12 months until no or faint RAI uptake in a whole-body scan with an undetectable stimulated thyroglobulin concentration was observed. Patient follow-up was performed every 6–12 months and included neck ultrasonography and measurement of serum thyroglobulin and thyroglobulin antibody concentration (19,20).

Pathological classification

Tumors with nuclear features of PTC that were completely or almost entirely (>99% of the tumor) composed of follicles and lacked well-formed papillae were diagnosed as FVPTC. Pathological classification into each FVPTC subtype was determined after reevaluation performed independently by two expert pathologists (J.K.W. and K.C.J.) according to the diagnostic criteria described by Rivera et al. (21). FVPTCs were classified as noninvasive EFVPTC, invasive EFVPTC, or IFVPTC. Tumors that were entirely surrounded by a fibrous capsule were classified as EFVPTC. Especially in the case of EFVPTC, the periphery of the tumor was entirely sectioned to 3 mm thickness and processed for slide examination to check for the presence of invasion. EFVPTC with neither capsular nor vascular invasion were subclassified as noninvasive EFVPTC. If invasion was observed, the tumor was classified as invasive EFVPTC. Tumors with tumor tongues infiltrating the thyroid parenchyma, with or without partial encapsulation, were defined as IFVPTC (11).

BRAF^V600E and RAS mutations

The BRAF^V600E mutation status of each tumor was reviewed retrospectively in medical records. In 109 (77%) patients, the BRAF^V600E mutation status was assessed by direct sequencing. Immunohistochemical (IHC) staining was also performed on some patient samples (n = 9), including all three patients with BRAF^V600E -positive noninvasive EFVPTC. For direct sequencing of the BRAF^V600E mutation, BRAF was amplified by polymerase chain reaction (PCR) from genomic DNA using the following primers: 5′-GCT TGC TCT GAT AGG AAA ATG AG-3′ and 5′-GTA ACT CAG CAG CAT CTC AGG-3′. Direct DNA sequencing with PCR product was performed with a BigDye™ Terminator Cycle Sequencing Kit (Applied Biosystems, Foster City, CA) using an ABI 3130XL Genetic Analyzer (Applied Biosystems). For IHC staining of BRAF, the slides were incubated with a BRAF^V600E mutation-specific antibody (Ventana Medical Systems, Inc., Tucson, AZ). Positive staining was defined as diffuse staining with >90% of the tumor area.

For a case of noninvasive EFVPTC with LN metastasis, direct gene sequencing and IHC staining of RAS mutation were performed. Direct sequencing was performed as outlined above, and the primer sequences used for HRAS gene sequencing were as follows: 5′-GCA TGA GAG GTA CCA GGG AG-3′ and 5′-TGT GGC AAA CAC ACA CAG G-3′. For IHC staining of the HRAS^Q61R mutation by immunohistochemistry (22), a NRAS^Q61R antibody was used (Bio SB, Santa Barbara, CA).

Statistical analyses

The results are expressed as the mean ± standard deviation (SD). Patients were divided into three groups: noninvasive EFVPTC, invasive EFVPTC, or IFVPTC. Categorical and continuous variables were analyzed by using the chi-square test or one-way analysis of variance with Tukey's post hoc test, respectively. A p-value of <0.05 was regarded as significant. All statistical analyses were performed by using IBM SPSS Statistics for Windows v22.0 (IBM Corp., Armonk, NY).

Results

Comparisons of preoperative cytological diagnoses and extent of surgery between FVPTC subtypes

Among the 142 FVPTC patients, the numbers of noninvasive EFVPTC (i.e., NIFTP per new nomenclature), invasive EFVPTC, and IFVPTC were 43 (30%), 44 (31%), and 55 (39%), respectively. Therefore, noninvasive EFVPTC may account for 1.5% of all PTC, considering that the prevalence of FVPTC was 5% of all PTC in the authors' hospital. The patient characteristics, preoperative cytological diagnoses, and extent of surgery are summarized in Table 1. There was no significant difference in age or sex between the three subtypes. Moreover, there was no significant difference in preoperative cytological diagnosis or surgical extent between noninvasive and invasive EFVPTC. However, the percentages of Bethesda category IV in the noninvasive EFVPTC (35%) and invasive EFVPTC (36%) were higher than that in IFVPTC (16%). As a result, 54% of the noninvasive EFVPTC and 48% of the invasive EFVPTC cases underwent initial thyroid lobectomy, while 84% of the IFVPTC cases underwent initial total thyroidectomy (p < 0.01). Central neck dissection was performed in similar proportions in the three subtypes, but lateral neck dissection was performed more frequently in patients with IFVPTC. Similarly, after total thyroidectomy, RAI was performed more frequently in patients with IFVPTC (67%) than in patients with the other two subtypes, and the cumulative dose of RAI in IFVPTC patients (4.1 ± 4.1 GBq) was higher than the activities used in the two EFVPTC subtypes, although there was no statistical significance.

Table 1.

Comparison of Preoperative Cytological Diagnosis and Extent of Surgery Between FVPTC Subtypes

	Noninvasive EFVPTC (n = 43)	Invasive EFVPTC (n = 44)	IFVPTC (n = 55)	p^a	p^b	p^c
Age (years)	49 ± 13	47 ± 14	53 ± 13	0.79	0.28	0.07
Male sex, n (%)	14 (33%)	14 (32%)	11 (20%)	1.00	0.17	0.25
Preoperative diagnosis (Bethesda category), n (%)
Category VI	3 (7%)	10 (23%)	9 (16%)	0.07	0.22	0.45
Category V	14 (32%)	9 (20%)	21 (38%)	0.23	0.67	0.08
Category IV	15 (35%)	16 (36%)	9 (16%)	1.00	0.05	0.04
Category III	8 (19%)	6 (14%)	15 (27%)	0.57	0.35	0.14
Category I or II	3 (7%)	3 (7%)	1 (2%)	1.00	0.32	0.32
Extent of surgery, n (%)
Lobectomy	12 (28%)	10 (23%)	6 (11%)	0.63	0.04	0.17
Completion following lobectomy	11 (26%)	11 (25%)	3 (5%)	1.00	<0.01	<0.01
Initial TT	20 (46%)	23 (52%)	46 (84%)	0.67	<0.01	<0.01
Central ND	13 (30%)	18 (41%)	15 (27%)	0.37	0.82	0.20
Lateral ND	2 (5%)	1 (2%)	10 (18%)	0.61	0.06	0.02
RAI, n (%)	19 (44%)	24 (55%)	37 (67%)	0.43	0.03	0.22
Cumulative dose of RAI, GBq	2.3 ± 0.3	2.9 ± 1.3	4.1 ± 4.1	0.77	0.07	0.24

p-Value between noninvasive and invasive EFVPTC.

p-Value between noninvasive EFVPTC and IFVPTC.

p-Value between invasive EFVPTC and IFVPTC using one-way analysis of variance (ANOVA) with Turkey's post hoc test.

EFVPTC, encapsulated follicular variant papillary thyroid carcinoma; IFVPTC, infiltrative follicular variant papillary thyroid carcinoma; FN, follicular neoplasm; AUS, atypia of undetermined significance; TT, total thyroidectomy; ND, neck dissection; RAI, radioactive iodine therapy.

Comparisons of clinicopathologic characteristics between the FVPTC subtypes

In comparison with invasive EFVPTC, noninvasive EFVPTC showed a significant lower frequency of multiplicity (5% vs. 25%; p = 0.01), ETE (0% vs. 21%; p < 0.01), and BRAF^V600E mutation (8% vs. 29%; p = 0.04), whereas LN metastasis occurrences were similarly infrequent (2% vs. 5%; p = 1.00), and no distant metastases were observed in either type (Table 2).

Table 2.

Comparison of Pathological Characteristics Between FVPTC Subtypes

	Noninvasive EFVPTC (n = 43)	Invasive EFVPTC (n = 44)	IFVPTC (n = 55)	p^a	p^b	p^c
Tumor size,^d cm	2.3 ± 1.2	2.2 ± 1.2	1.7 ± 0.9	0.98	0.04	0.05
Multifocality,^d n (%)	2 (5)	11 (25)	17 (31)	0.01	<0.01	0.65
Bilaterality,^d n (%)	1 (2)	7 (16)	5 (9)	0.06	0.23	0.36
Co-existing cancer, n (%)	3 (7)	5 (11)	8 (15)	0.71	0.34	0.65
Conventional PTC	3 (7)	5 (11)	7 (13)
FTC	0	0	1 (2)
ETE,^d n (%)	0 (0)	9 (21)	34 (62)	<0.01	<0.01	<0.01
Microscopic/gross	0/0 (0/0)	8/1 (18/2)	23/11 (42/20)
LN metastasis,^d n (%)	1 (2)	2 (5)	24 (44)	1.00	<0.01	<0.01
N1a/N1b	1/0 (2/0)	1/1 (2/2)	18/6 (33/11)
Number of positive LN	1.0	8.0 ± 9.9	4.0 ± 3.4
% of positive LN	25	43.5 ± 14.3	42.1 ± 24.7
Size of tumor foci, mm	0.8	0.7 ± 0.8	0.6 ± 0.5
Distant metastasis,^d n (%)	0 (0)	0 (0)	2 (4)	1.00	0.50	0.50
Initial stage, n (%)
TNM stage 3–4	6 (14)	6 (14)	31 (56)	1.00	<0.01	<0.01
ATA high risk	0 (0)	1 (2)	13 (24)	1.00	<0.01	<0.01
BRAF^V600E mutation, n (%)^d	3 (8)	11 (29)	10 (29)	0.04	0.04	1.00
Duration of follow-up (months)	41 ± 17	39 ± 19	45 ± 21	0.78	0.58	0.20
Final disease status, n (BCR/BCD/CD)	0/0/0	0/0/0	0/0/1	1.00	1.00	1.00

p-Value between noninvasive and invasive EFVPTC.

p-Value between noninvasive EFVPTC and IFVPTC.

p-Value between invasive EFVPTC and IFVPTC using one-way ANOVA with Turkey's post hoc test.

Pathological characteristics by conventional PTC were excluded.

FTC, follicular thyroid carcinoma; ETE, extrathyroidal extension; LN, lymph node; TNM stage, AJCC 7th edition/TNM classification system for differentiated thyroid carcinoma; BCR, biochemical remission; BCD, biochemical disease; CD, clinical disease.

Tumor sizes of noninvasive and invasive EFVPTC (2.3 ± 1.2 cm and 2.2 ± 1.2 cm, respectively) were significantly larger than that of IFVPTC (1.7 ± 0.9 cm; p = 0.04 and 0.05, respectively; Table 2). The comparisons of the other pathological characteristics, including ETE, LN metastasis, TNM stage, and American Thyroid Association (ATA) risk revealed significantly less aggressiveness in noninvasive and invasive EFVPTC than in IFVPTC. Only multifocality in invasive EFVPTC (25%) was similar to that in IFVPTC (31%) compared to the significantly lower levels in noninvasive EFVPTC (5%; p < 0.05). Coexisting PTC or FTC were found in 13 (9%) patients, and there was no significant difference between FVPTC subtypes.

Analyses of the BRAF^V600E mutation was done in 109 patients. In noninvasive EFVPTC, three cases had the BRAF^V600E mutation (Supplementary Figs. S1–S3; Supplementary Data are available online at www.liebertpub.com/thy). The proportion of BRAF^V600E mutation in noninvasive EFVPTC was significantly lower compared to the other FVPTC subtypes (p = 0.04). During the mean follow-up period of 42 ± 19 months, no recurrence or mortality was observed within the three groups. There was only one patient with persistent clinical disease with distant metastasis observed in the IFVPTC group.

Multifocality and LN metastasis in patients with noninvasive EFVPTC

Some noninvasive EFVPTC were multifocal (n = 2) or had LN metastasis (n = 1; Table 3). Among all the patients with noninvasive EFVPTC, there were six patients with multifocal tumors. Of these, four patients had coexisting conventional PTC, and the other two had noninvasive EFVPTC. The clinicopathologic features of the patients with multifocal noninvasive EFVPTC are summarized in Table 3 (patients 1 and 2). One case had bilateral tumors.

Table 3.

Clinicopathologic Features of Noninvasive EFVPTC Patients with Multifocality or LN Metastasis

No	Age (years)	Sex	Bethesda category	Surgery	Tumor size (cm)	Number and location of tumors	ETE	Positive LN/removed LN	BRAF^V600E mutation
1	28	F	III	Lobectomy	3.4, 0.1	2, left	None	0/1	Negative
2	68	M	IV	TT	1.7, 1.5	2, bilateral	None	0/9	Negative
3	67	F	V	TT	1.9	1, right	None	1/4	Negative

TT, total thyroidectomy.

There were three patients with LN metastasis among the subjects with noninvasive EFVPTC. One had a coexisting conventional PTC (0.8 cm tumor without ETE). In another case, the LN metastasis was positive for the BRAF^V600E mutation while the primary tumor did not have the BRAF^V600E mutation (Supplementary Fig. S4). Because no additional tumors were found except the noninvasive EFVPTC, it is speculated that a hidden PTMC, not the FVPTC, had metastasized to this LN. Finally, there was only a single patient with a metastasis that is thought to have originated from a noninvasive EFVPTC (Table 3, patient 3; Fig. 1). The metastatic lesion was solitary, and the size of the metastatic focus was 0.2 cm × 0.1 cm. To determine if the LN metastasis arose from the noninvasive EFVPTC, analyses for RAS mutations were performed. In the primary tumor, a HRAS mutation (c. 182A>G, Q61R) was detected by direct sequencing, and IHC staining for RAS mutant protein (Q61R) was positive (Fig. 1C). The metastasized LN was also positive for the RAS mutation (Q61R) (Fig. 1F). There was no recurrence in any of the patients with noninvasive EFVPTC and LN metastasis.

FIG. 1.

Noninvasive encapsulated follicular variant papillary thyroid carcinoma with lymph node (LN) metastasis. A low-power view of the lesion in the thyroid gland (A), higher magnification (200 × ) (B), and immunohistochemical staining for the HRAS^Q61R mutation (C). Metastatic foci in LN (D), at higher magnification (400 × ) (E), and immunohistochemical staining for the HRAS^Q61R mutation (F). The region marked with a rectangle in (A) and (D) is magnified in (B) and (E), respectively. At high magnification, follicular cells show the nuclear features of PTC (E, arrow). Scale bar represents 1 mm (A) or 100 μm (B, D, and E). Color images available online at www.liebertpub.com/thy

Discussion

In this study, noninvasive EFVPTC (now designated as NIFTP) exhibited favorable clinicopathologic features, as previously reported. However, the BRAF^V600E mutation and LN metastasis were observed, even in a few patients with noninvasive EFVPTC, suggesting that not all noninvasive EFVPTC necessarily have an indolent nature. Moreover, there was little difference in clinicopathologic features between noninvasive and invasive EFVPTC. Therefore, the authors concur that noninvasive EFVPTC/NIFTP should be considered as a precancerous/early-stage cancer type within the full FVPTC spectrum.

In this study, the clinicopathologic behavior of noninvasive EFVPTC was similar to invasive EFVPTC but distinct from IFVPTC. Both EFVPTC types were less aggressive than IFVPTC for most pathological features, which is consistent with the results of previous studies (14,15,23). Taken together, the results confirm that EFVPTC, whether noninvasive or invasive, can be managed conservatively compared to IFVPTC.

The importance of FVPTC as a clinical entity is emphasized by the fact that the incidence of FVPTC has increased in Western countries (7,8). The prevalence of FVPTC in studies reported over the last decade was >20% (5,7), and it is higher than the prevalence in preceding decades. The prevalence of EFVPTC has increased along with the increase in FVPTC (12). The reason for the increase in FVPTC is unclear, but the increased emphasis on FVPTC diagnosis could be a factor because the diagnosis of FVPTC is somewhat subjective, and large inter- and intra-observer variability has been reported, even among experienced thyroid pathologists (24,25). However, in Asian populations, the prevalence of FVPTC is relatively low and has not increased (6,26). A recent study reported that when applying the same criteria as those suggested by Nikiforov et al. (12), only 10.2% of PTC in the Korea population and 5% in this study would be classified as FVPTC (26). The reported proportion of noninvasive EFVPTC in FVPTC has ranged from 33% to 61% (11,14,16) and was 30% in this study.

The less aggressive behavior of the noninvasive EFVPTC/NIFTP suggests that it is in general a precancerous lesion (12). However, metastasis, one of the important aggressive characteristics of PTC (27), can be found in noninvasive EFVPTC/NIFTP. One case of noninvasive EFVPTC had cervical LN metastasis in this study, and another case with LN metastasis in noninvasive EFVPTC has been reported previously, even though they were micrometastases (28,29). Moreover, a review of previous studies revealed few recurrent cases of noninvasive EFVPTC (30). There was no recurrence observed in the present study, which might be due to a relatively short follow-up duration (42 months). In addition, the BRAF^V600E mutation is a well-known prognostic marker of PTC (31), and multifocality is also considered as a prognostic marker for recurrence (32). In the present patients with noninvasive EFVPTC, three (8%) cases harbored the BRAF^V600E mutation, and two (5%) cases were multifocal. Among invasive EFVPTCs, there were more multifocal tumors and ETE than in noninvasive EFVPTC, but the frequencies of LN metastasis, TNM stage, or ATA risk were comparable, suggesting a similar indolent nature in the two EFVPTC types. Therefore, for most patients with either noninvasive or invasive EFVPTC, thyroid lobectomy without completion thyroidectomy or RAI therapy would be sufficient, as previously suggested (33). However, if there is a coexisting conventional PTC, more attention is needed. In this study, two cases of noninvasive EFVPTC had LN metastasis from coexisting conventional PTCs.

A preoperative cytological diagnosis of thyroid neoplasm is very important when deciding on the extent of the surgery. Preoperative cytopathologic diagnosis of FVPTC with FNA is more difficult than histopathological diagnosis after surgery (34), and the subtypes of FVPTC can only be distinguished on histopathology. It is difficult to distinguish FVPTC from conventional PTC, follicular adenoma, or follicular thyroid carcinoma. Approximately 45–77% of FVPTCs are classified as indeterminate lesions (Bethesda categories III–V), and only 7–48% are diagnosed as malignant (Bethesda category VI) (35 –39). Recent studies have reported that noninvasive EFVPTC has been diagnosed as Bethesda category III (15–26%), IV (6–56%), or V (27–49%), and there were no statistically significant differences from other FVPTC (28,39 –42). In this study, as many as 80% of all FVPTC subtypes were also diagnosed as indeterminate lesions, and the frequency of each Bethesda category showed little difference between the FVPTC subtypes. Therefore, it is very difficult or impossible to identify FVPTC subtypes preoperatively, and there are no clearly distinguishing characteristics on ultrasonography or core-needle biopsy (28). This suggests that preoperative cytological results may not provide helpful information for decisions concerning the extent of surgery.

The presence of the BRAF^V600E mutation has been proposed as a prognostic molecular marker that can help to determine the surgical extent (31). The molecular profile of FVPTC is closer to follicular adenoma and follicular thyroid carcinoma than it is to conventional PTC. Whereas the prevalence of the BRAF^V600E mutation in FVPTC is lower than that in conventional PTC, RAS mutations are often found in FVPTC (7,43). However, it remains unclear whether molecular profiles differ depending on FVPTC subtype. It has been reported that IFVPTC more frequently harbor a BRAF^V600E mutation, whereas EFVPTC frequently harbor RAS mutations (44,45), suggesting an association between molecular genotype and histological subtype. Some studies have reported no differences in the prevalence of the BRAF^V600E mutation between subtypes of FVPTC (35,39,46), but the criteria for noninvasive EFVPTC were looser than that suggested by Nikiforov et al. (12). Nikiforov et al. reported no BRAF^V600E mutations in all 27 NIFTP cases (12). In the present study, the BRAF^V600E mutation was detected in three cases with noninvasive EFVPTC, but it was significantly lower than that in the other FVPTC subtypes. Recently, it has been argued that more strict criteria are needed to establish the diagnosis of NIFTP. Cho et al. suggested the complete absence of papillae as a diagnostic criterion instead of a frequency of true papillae ≤1%; this was based on the fact that EFVPTC with papillae ≤1% had more LN metastasis and BRAF^V600E mutations than those absent papillae (29). When the slides of three noninvasive EFVPTC positive for BRAF^V600E were reviewed in detail (size of each tumor was 2.4, 1.5, or 1.2 cm), all three cases had small papillae that comprised <1% of the total tumor (Supplementary Figs. S1–S3). These observations support the proposed more rigid criteria that require the absence of papillae (29) and suggest that the presence of a BRAF^V600E mutation can be considered as an exclusion criteria for NIFTP.

This is the first study to compare the clinical characteristics of FVPTC subtypes in an Asian population. Moreover, this study included the second largest number of subjects after that reported by Nikiforov et al. (12). However, one limitation is that it was difficult to investigate the prognostic outcomes because this study had a relatively short follow-up period. Long-term follow-up is required to determine the clinical importance of the subtyping of EFVPTC in clinical practice.

In summary, thyroid tumors diagnosed as noninvasive EFVPTC have less aggressive pathological features. However, LN metastasis and BRAF^V600E mutations were observed in some noninvasive EFVPTC cases. This emphasizes that noninvasive EFVPTC is not a benign entity. Thus, in order to distinguish noninvasive EFVPTC/NIFTP and invasive EFVPTC rigorously and for it to have clinical utility, stricter criteria (i.e., the absence of on papillae and BRAF^V600E mutation) seem to be needed. To clarify the clinical importance of the subtypes of EFVPTC, further studies comparing the long-term outcomes need to be performed.

Footnotes

Acknowledgment

This study was supported by the Korean Endocrine Society of KES Research Award 2016.

Author Disclosure Statement

All authors have nothing to disclose.

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Clinical Characteristics of Subtypes of Follicular Variant Papillary Thyroid Carcinoma

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Subjects

Management and follow-up

Pathological classification

BRAFV600E and RAS mutations

Statistical analyses

Results

Comparisons of preoperative cytological diagnoses and extent of surgery between FVPTC subtypes

Comparisons of clinicopathologic characteristics between the FVPTC subtypes

Multifocality and LN metastasis in patients with noninvasive EFVPTC

Discussion

Footnotes

Acknowledgment

Author Disclosure Statement

References

BRAF^V600E and RAS mutations