Follicular Variant of Papillary Thyroid Carcinoma: Distinct Biologic Behavior Based on Ultrasonographic Features

Abstract

Background:

Follicular variants of papillary thyroid carcinoma (FVPTCs) have dichotomous ultrasonographic (US) features. We investigated the differences in the biologic behavior of FVPTC according to US features.

Methods:

We reviewed the US findings, pathologic reports, and medical charts of 75 consecutive patients with FVPTC who underwent surgery at our institution from January 2006 to December 2008. FVPTCs were divided into PTC-like and follicular neoplasm (FN)-like based on US findings. PTC-like nodules were defined as having at least one accepted malignant feature (a taller-than-wide shape, an infiltrative margin, marked hypoechogenicity, and micro- or macrocalcifications), whereas FN-like nodules showed oval solid features without malignant features. The prognostic factors were compared.

Results:

Of the 75 FVPTCs, 42 (56%) were PTC-like and 33 (44%) were FN-like. The mean tumor size of PTC-like FVPTC was significantly smaller than that of FN-like FVPTC (p=0.0483). PTC-like FVPTC showed a significantly higher rate of multifocality than FN-like FVPTC (48% and 15% respectively; p=0.0031). Extrathyroidal extension occurred in 55% of PTC-like FVPTCs compared to 12% of FN-like FVPTCs (p=0.0001). Lymph node metastasis was more frequent in PTC-like FVPTC than in FN-like FVPTC (36% vs. 12%; p=0.0197). PTC-like FVPTC had a higher stage than FN-like FVPTC (p=0.0001). These significant factors persisted in multivariate analysis. Only one recurrence and one distant metastasis were identified, and both occurred in PTC-like FVPTC.

Conclusions:

FVPTC with malignant US features seems to behave in a more aggressive fashion than FVPTC without malignant US features. US can help predict the behavior of FVPTC.

Introduction

The follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common subtype of papillary thyroid carcinoma (PTC) after the classic type, constituting 9–22.5% of all PTCs (1 –3). The FVPTC was first defined by Dailey et al. in 1950 as a neoplasm having the nuclear features of classic PTCs with a predominantly follicular architecture (4). Preoperative diagnosis of FVPTC using fine-needle aspiration cytology is difficult compared with conventional PTC, as the diagnosis of malignancy depends only on the presence of the nuclear features of papillary carcinoma, which can be affected by interobserver variability.

According to recent studies, the sonographic features of FVPTC are different from those of classic PTC. The FVPTC shows more benign sonographic features, such as well-defined margins, oval shape, and the absence of calcification. However, 48–68% of FVPTCs were found to have at least one suspicious sonographic finding. FVPTCs have been found to have a lower incidence of lymph node metastasis and extrathyroidal extension, as well as higher rates of lung and bone metastasis compared with conventional PTC (5,6). In general, FVPTC is considered to have more favorable clinicopathologic features but with long-term outcomes similar to those of conventional PTC (7). Liu et al. reported that FVPTC is composed of two distinct groups on the basis of pathology: a nonencapsulated subvariant, which resembles classic papillary carcinoma, and an encapsulated form, which behaves more like a follicular neoplasm (8). We expected dichotomous sonographic FVPTC findings to be associated with a difference in clinicopathologic behavior. The purpose of this study was to examine the differences in the biologic behavior of FVPTCs with and without malignant US features.

Materials and Methods

Patients and imaging

This retrospective study was approved by our institutional review board. A total of 3292 patients underwent operation for thyroid malignancies at our institution between January 2006 and December 2008. During this period, based on pathological reports, 82 (2.54%) of 3222 PTC patients had a histological diagnosis of FVPTC. Of these, seven patients were excluded because preoperative ultrasonography (US) was not available for five of these patients, and tiny FVPTCs that were not detected on US were incidentally excised in two patients. In total, 75 patients (14 male and 61 female; age range 13–80 years; mean age 49 years) were included for statistical analysis in this study. The 75 patients with FVPTCs underwent either total thyroidectomy (n=66) or lobectomy (n=9). The sonographic findings of these nodules were retrospectively reviewed by two experienced radiologists, and clinical information and pathologic results were obtained from medical records.

All sonographic examinations were performed with an iU22 or HDI 5000 (Philips Medical Systems, Bothell, WA) equipped with a 7–12 MHz linear array transducer. The scanning protocol in all cases included both transverse and longitudinal imaging of the thyroid nodules. We divided the nodules into two groups on the basis of the criteria for suspicious malignant nodules: PTC-like and FN-like (9). A taller-than-wide shape, an infiltrative margin, marked hypoechogenicity, microcalcifications, and macrocalcifications were findings suspicious for malignant nodules (Fig. 1). PTC-like nodules were defined as having at least one accepted malignant feature, whereas FN-like nodules were solid oval nodules with no malignant features (Fig. 2).

FIG. 1.

Preoperative ultrasound of a thyroid nodule in a 40-year-old woman with a papillary thyroid carcinoma (PTC)-like FVPTC. Transverse (A) and longitudinal (B) ultrasound (US) images show a 1.2 cm spiculated hypoechoic nodule with microcalcifications in the left thyroid gland (arrows). This nodule has malignant US features. Multifocality, extrathyroidal tumor extension, and central lymph node metastasis were found on surgical pathology.

FIG. 2.

Preoperative US of a thyroid nodule in a 22-year-old woman with a follicular neoplasm (FN)-like FVPTC. Transverse (A) and longitudinal (B) US images show a 3.0 cm well-defined oval isoechoic nodule in the left thyroid gland (arrows). This nodule does not have any malignant feature on sonography. This patient does not have poor prognostic factors.

The patients' medical records were reviewed for age at the time of diagnosis, sex, and the type of surgery. Pathological reports were also reviewed for multifocality, extrathyroidal extension, TNM stage, and the presence of lymph node metastasis. Tumor recurrence and distant metastasis were established on the basis of clinical examination and imaging.

Statistical analysis

We used Fisher's exact test, the two-sample Student's t-test, the Mann–Whiney test, and the chi-square test and multiple logistic regression to analyze the clinicopathologic and radiologic data of the patients. Multiple analyses for tumor size with continuous values were performed using Partial Spearman correlation analysis. The two groups were compared in terms of age, sex, tumor size, multifocality, extrathyroidal extension, lymph node metastasis, stage, recurrence, and distant metastasis. We investigated whether some of the malignant US features have a correlation with extrathyroidal extension or lymph node metastasis. A p-value of <0.05 was considered to be statistically significant. All analyses were performed with SAS v9.1.3 (SAS Institute Inc., Cary, NC).

Results

Of the 75 FVPTCs, 42 (56%) were PTC-like and 33 (44%) were FN-like. Table 1 summarizes the clinicopathological characteristics of PTC-like and FN-like FVPTCs. The mean age in the PTC-like FVPTC group was 47.4 years (range 13–80 years) and 39.9 years (range 14–77 years) in the FN-like FVPTC group. The PTC-like group comprised nine men (21%) and 33 women (79%), and the FN-like group comprised five men (15%) and 28 women (85%). There were no significant differences in age and sex between the two groups.

Table 1.

Clinicopathologic Characteristics of Follicular Variants of Papillary Thyroid Carcinoma According to Ultrasound Features

Characteristics	PTC-like FVPTCs	FN-like FVPTCs	Total	p-Value
Number of patients	42	33	75
Sex				0.4886
Male	9 (21.4%)	5 (15.2%)	14
Female	33 (78.6%)	28 (84.8%)	61
Mean age (years)	49.4 (range 13–80)	47.4 (range 14–77)	48.6	0.5535
Mean tumor size (cm)	1.31 (range 0.4–4.5)	1.64 (range 0.4–4.5)	1.46	0.0483
Type of operation				0.137
Total thyroidectomy	39 (93%)	29 (88%)	68
Hemithyroidectomy	3 (7%)	4 (12%)	7
Lymph node dissection				0.462
None	7 (16%)	10 (30%)	17
Central neck	32 (76%)	23 (70%)	55
Central neck with lateral neck	3 (7%)	0	3
Multifocality	20 (48%)	5 (15%)	25	0.0031
Extrathyroidal extension	23 (55%)	4 (12%)	27	0.0001
Lymph node metastasis	15 (36%)	4 (12%)	19	0.0197
TNM stage				0.0001
I	15 (36%)	25 (76%)	40
II	2 (5%)	2 (5%)	4
III	19 (45%)	6 (14%)	25
IV	6 (14%)	0 (0%)	6
Distant metastasis	1 (2%)	0	1
Recurrence	1 (2%)	0	1

PTC, papillary thyroid carcinoma; FN, follicular neoplasm; FVPTC, follicular variant of papillary thyroid carcinoma.

Thyroid nodule sizes ranged from 0.4 to 4.5 cm. The mean tumor size of the PTC-like FVPTCs was significantly smaller than that of the FN-like FVPTCs (mean longest diameter, 1.3 cm vs. 1.6 cm; p=0.0483). Multifocality was observed in 48% of patients in the PTC-like group and in 15% of patients in the FN-like group (p=0.0031). Extrathyroidal extension was seen in 55% of patients in the PTC-like group and in 12% of the patients in the FN-like group (p=0.0001). For the entire cohort, more cervical lymph node metastases were found at the time of diagnosis in the PTC-like group compared with the FN-like group (36% vs. 12%; p=0.0197). Among 58 patients who underwent lymph node dissection, 43% (15/35) in the PTC-like group and 17% (4/23) in the FN-like group had lymph node metastases. The TNM tumor stage was higher in the PTC-like group than in the FN-like group (p=0.0001).

During clinical follow-up (range 9–76 months; median 48 months), all 33 patients who had FN-like FVPTCs were free of disease with no recurrence and no distant metastasis. Tumor recurrence was identified in one (2%) case of PTC-like FVPTC. Lung metastasis was detected in only one patient (2%) with PTC-like FVPTC.

Table 2 shows the results of multivariate analysis for biological behavior of PTC-like FVPTCs and FN-like FVPTCs. PTC-like FVPTCs were independently associated with tumor size (correlation coefficient −0.23995; p=0.0409), multifocality (odds ratio (OR) 5.279; 97.5% confidence interval [CI 1.67–16.59]; p=0.0044), extrathyroidal extension (OR 8.717; [97.5% CI 2.59–29.32]; p=0.0005), lymph node metastasis (OR 5.634; [97.5% CI 1.39–22.80]; p=0.0154), and a higher stage (OR 6.862; [97.5% CI 2.11–22.28]; p=0.0002). Among 42 PTC-like FVPTCs, there were tumors having one (n=17, 40.5%), two (n=9, 21.4%), three (n=12, 28.6%), or four (n=4, 9.5%) malignant US findings. Table 3 demonstrates the incidence of each malignant US feature in PTC-like FVPTCs. Among malignant US features, the presence of an infiltrative margin and marked hypoechogenicity correlated most strongly with extrathyroidal extension (OR 6.715 and 8.16 respectively). Additionally, the presence of an infiltrative margin showed the highest correlation with lymph node metastases (OR 6.765).

Table 2.

Multivariate Analysis for Biological Behavior of PTC-Like FVPTCs Compared to FN-Like FVPTCs at Ultrasound

Factors	Odds ratio	CI	p-Value
Tumor size^a	—	—	0.0409
Multifocality	5.279	[1.67–16.59]	0.0044
Extrathyroidal extension	8.717	[2.59–29.32]	0.0005
Lymph node metastasis	5.634	[1.39–22.80]	0.0154
A higher stage	6.862	[2.11–22.28]	0.0002

Correlation coefficient was −0.23995 using partial Spearman correlation analysis.

CI, confidence interval.

Table 3.

Incidence of Each Malignant Ultrasound Finding in 42 PTC-Like FVPTCs and Correlation with Each Ultrasound Finding, Extrathyroidal Extension, and Lymph Node Metastasis

		Extrathyroidal extension				Lymph node metastasis
	PTC-like FVPTC		Univariate	Multivariate			Univariate	Multivariate
US findings	n=42	n=23	p-Value	p-Value	OR [CI]	n=15	p-Value	p-Value	OR [CI]
Taller-than-wide shape	15 (35.7%)	9 (60%)	0.6112	0.7498	0.769 [0.153–3.857]	7 (46.7%)	0.2695	0.9443	1.057 [0.222–5.029]
Infiltrative margin	18 (42.9%)	13 (72.2%)	0.049	0.0421	6.715 [1.071–42.116]	11 (61.1%)	0.0029	0.018	6.765 [1.387–32.992]
Marked hypoechogenicity	30 (71.4%)	19 (63.3%)	0.0776	0.0241	8.16 [1.317–50.57]	9 (30%)	0.292	0.4953	0.585 [0.126–2.728]
Micro- or macrocalcifications	26 (61.9%)	16 (61.5%)	0.2607	0.3358	2.058 [0.473–8.944]	11 (42.3%)	0.2556	0.7579	1.284 [0.262–6.29]

US, ultrasound; OR, odds ratio.

Discussion

FVPTCs have a relatively benign appearance on sonography that is more similar to those of follicular neoplasms than PTCs (10,11). Sonographic findings of follicular neoplasms include a solid mass with inhomogeous, hypo-, or isoechoic internal echo textures (12,13), which usually do not meet suggested sonographic characteristics of classic PTC that are most commonly solid nodules with hypoechogenicity compared to the strap muscles, an irregular margin, micro- or macrocalcifications, and often a taller-than-wide orientation (9). Therefore, the US features of FN-like FVPTCs are closer to those of follicular neoplasms than PTCs.

Thus, the common sonographic features of FVPTCs are different from those of conventional PTCs. The common sonographic features of FVPTC, such as solid internal content, ovoid-to-round shape, smooth margin, isoechogenicity, and the relative frequency of a hypoechoic rim, are similar to the sonographic features of other follicular cell-derived lesions, such as nodular hyperplasia, follicular adenoma, and follicular carcinoma. Histologically, FVPTCs are composed of a follicular architecture with the nuclear features of papillary carcinomas. The sonographic similarities between FVPTCs and other follicular cell-derived lesions might be reflections of the similar histologic features of the encapsulated masses, which are composed of follicles (5,6).

In a previous study, Liu et al. (8) classified the FVPTCs into two groups based on pathology. Patients with encapsulated FVPTCs had lower rates of intratumoral fibrosis, extrathyroid extension, and positive margins compared with patients with nonencapsulated tumors. Regional lymph node metastases and distant metastases were not seen in noninvasive, encapsulated FVPTCs. Regional lymph node metastasis was seen in 65% of patients with nonencapsulated FVPTCs. There was no distant metastasis in either the encapsulated or nonencapsulated groups. Additionally, Vivero et al. (14) found that FVPTCs that are partially encapsulated or well circumscribed have a rate of lymph node metastases similar to that seen with encapsulated FVPTCs and significantly lower than that of FVPTCs with an infiltrative growth pattern.

Several recent studies reported there are different molecular characteristics between encapsulated and infiltrative FVPTC. According to Rivera et al. (15), encapsulated FVPTCs have a high rate of RAS and absence of BRAF mutations, a very similar pattern as in follicular adenomas/carcinomas, whereas infiltrative FVPTCs have a high rate of BRAF and low frequency of RAS mutations, similar to the findings observed in classical papillary carcinomas. Howitt et al. (16) suggested that partially encapsulated or well-circumscribed and encapsulated FVPTCs are biologically similar and should be distinguished from more aggressive infiltrative FVPTCs.

In contrast to previous studies, the current study was based on US, which is easy to apply preoperatively, to classify FVPTCs into infiltrative and encapsulated types, and to examine the differences in their clinicopathological behaviors.

It was recently reported that PTCs that did not have malignant US criteria had better outcomes than PTCs with positive US criteria (17). In this study, we found that malignant sonographic features correspond to poor prognostic factors for FVPTCs. Compared to FN-like FVPTC, PTC-like FVPTCs showed a higher rate of a smaller size, multifocality, extrathyroidal extension, and lymph node metastasis, as well as a higher TNM stage on univariate and multivariate regression analysis. Tumor recurrence was identified in a single patient, and lung metastasis in another patient with a PTC-like FVPTC. Liu et al. reported that infiltrative, nonencapsulated FVPTC resembles classic PTC in its invasive growth and lymph node metastasis pattern, and that encapsulated FVPTCs behave more like follicular neoplasms. On the basis of US features, FVPTCs that have malignant features seemed to have similar clinicopathologic features to classic PTCs. Encapsulated FVPTCs that have the appearance of follicular neoplasm seem to behave in an indolent fashion. FN-like FVPTCs had lower rates of LN metastases, multifocality, and extrathyroidal extension than the PTC-like FVPTCs. While the FN-like FVPTCs had less aggressive characteristics, there were four cases that showed extrathyroidal extension. These tumors were all located at the periphery of the thyroid gland or were very large tumors. In addition, four FN-like tumors had associated lymph node metastases.

Our study has several limitations in that it is a retrospective analysis with an unavoidable selection bias. FVPTCs accounted for a low percentage of PTCs in our cohort (2.53%). This is likely the result of the fact that classical type PTC accounts for the vast majority of PTC cases in Korea. The prevalence of PTC variants in Korea was previously reported as 6.7% (18,19). In addition, some pathologists do not register the type of PTC in cases that are subtle or equivocal. Therefore, such cases would not be included in this study. This retrospective US review was performed by experienced radiologists. However, interobserver variability may exist at each institution. The US features suggesting the possibility of malignancy are, however, well accepted (9,20,21).

In conclusion, FVPTCs have dichotomous US features. FVPTCs with malignant features appear to behave in a more aggressive fashion than FVPTCs without malignant features. US can help to predict the behavior of FVPTC.

Footnotes

Author Disclosure Statement

The authors declare that no competing interests exist.

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