Impact of major different variants of papillary thyroid microcarcinoma on the clinicopathological characteristics: the study of 1041 cases

Papillary thyroid microcarcinoma (PTMC), defined as papillary thyroid carcinoma (PTC) 10 mm or less in diameter, has been dramatically rising in incidence during the past few decades, accounting for nearly half the increase in PTC [1‐4]. PTMC is generally regarded as an indolent disease but does pose a risk for local recurrence and distant metastasis [5, 6]. Identification of aggressive cases from favorable ones is necessary for the patient-tailored treatment of PTMC.

PTMC does not have a distinctive morphology, which means that all cellular features and growth patterns that can be found in other variants of PTC can be observed in PTMC [7, 8]. In PTC, the variant-related differences in biological behavior and prognosis are very large. Compared with the conventional variant, solid variant, diffuse sclerosing variant, and tall cell variant are recommended as the aggressive types, and follicular variant and the Warthin-like variant are considered favorable [9‐14], which has further led to variant-related changes in PTC treatment [11, 13, 15, 16]. Considering the findings of these studies, the appearance of other variants in PTMC may incur variant-relevant risk, which has a profound impact on the treatment strategies. The purpose of this study was to classify the PTMCs according to the nature of the tumor boundaries, distinct architecture, or cellular characteristics and explore the clinicopathological characteristics of different variants of PTMC. Additionally, we sought to evaluate whether different variants of PTMC can be an independent predictor for lymph mode metastasis when considering other risk factors.

This retrospective cohort review research was supported by the academic ethics board, and informed consent was obtained from all patients to allow their information to be used for the study.

There were 1041 PTMC patients enrolled in this study. The major variants of PTMC, including conventional variant (CPTMC, 471 cases, 45.2%; Fig. 1a), follicular variant (FPTMC, 454 cases, 43.6%; Fig. 1b), and encapsulated variant (EnPTMC, 82 cases, 7.9%; Fig. 1c), collectively accounted for 96.7% of the entire PTMC cohort. Other variants of PTMC (e.g., Warthin-like variant, solid variant, oncocytic variant, tall cell variant, or trabecular variant) were rare (collectively, 34 cases, 3.3%), so we only analyzed the clinicopathological characteristics of the 1007 cases with the major variants. The sex ratio was 1:3.86 (male:female, 207:800). The age range was 18–73 (mean, 46 ± 9.5) years. The size of the largest tumor was 5.7 ± 1.8 (mean ± SD) mm. The rate of fibrosis and calcification was 98.5% and 31.7%, respectively. Multifocal tumors were found in 364 cases (Table 1). Minimal ETE was seen in 200 (19.9%) patients, including 59 in vascular, 120 in fat, 8 in striated muscle, 1 in nerve, and 12 multiple minimal ETE. HT was present in 26.3% of the patients. The frequency of LNM was 26.3%; among these, 275 were N1a and 40 were N1b (Table 2). Most patients (94.6%) underwent prophylactic central neck dissection; in only 54 patients was central + lateral neck dissection performed.

The American Thyroid Association (ATA) guidelines recommend thyroidectomy without prophylactic central neck dissection is appropriate for small (T1 or T2), noninvasive, clinically node-negative (cN0) PTC [15]. In cases whose largest tumor is >10 mm, this practice successfully keeps the balance of the risk caused by the enlarged surgery extent and the benefit of reduction in recurrence. In PTMC, however, the balance is remarkably disturbed by variant-specific differences without sufficient attention. Although PTMC is a subset of PTC, variants of PTMC differ from those of PTC in two respects: clinicopathological features and variant distribution, resulting in an unbalanced extent of surgery in PTMC patients (Table 6).

Encapsulated variant is defined as a papillary carcinoma totally surrounded by a capsule. In the present study, EnPTMC showed excellent biological behavior, being the lowest in aggressive parameters (tumor size and incidence of minimal ETE and LNM) among three variants. Because several authors have reported that age less than 45 years had a higher incidence of lymph node metastasis [17, 18], the age distribution also indicated the indolent nature of EnPTMC. The previous studies of PTC grouped the encapsulated variant according to the variant inside, underlining the benign behavior of the encapsulated follicular variant of PTC (E-FPTC) [19, 20]. One study reported that E-FPTC resembled the adenoma/follicular carcinoma group of tumors in its capsular/vascular invasive pattern and its propensity for lymph node metastasis whereas E-CPTC behaved more like conventional PTC [21]. In 2016, E-FPTC was categorized as low risk by the ATA [15]. In the present study, however, there was no significant difference in any respect between the encapsulated conventional variant of PTMC (E-CPTMC) and the encapsulated follicular variant of PTMC (not shown in the table), and both were shown as indolent. Overtreatment may occur in patients with EnPTMC (especially E-CPTMC), which needs further studies to determine the optimal extent of surgery.

Follicular variant is defined as a papillary carcinoma composed entirely or almost entirely of follicles. FPTMC was entirely intermediate in all parameters between CPTMC and EnPTMC. Except for the incidence of minimal ETE, all the aggressive parameters including age, tumor size distribution, and the occurrence rate of LNM in FPTMC was analogous to that of EnPTMC, remarkably differentiated from that of CPTMC. These findings are supported by the previous studies on PTC [9, 22]. In the present study, FPTMC accounted for 43.6% of the 1041 PTMCs, whose prevalence was nearly equal to that of CPTMC. This finding was particularly worth noting because several reports mentioned that the incidence of CPTC was 2 to 4.5 times higher than that of FPTC [9, 23, 24]. One reasonable hypothesis for the decrease in proportion of follicular variant from PTMC to PTC is that, compared with CPTMCs, fewer FPTMCs enlarge in tumor size and develop into FPTC. In spite of the absence of relevant evidence, this hypothesis may have some association with the phenomenon that quite a number of PTMCs enlarged slowly or almost did not enlarge [25, 26]. In our study, the size of tumor was significantly smaller in FPTMCs than in CPTMCs (44.9% vs. 55.7%, P < 0.001). The change in variant distribution indicates the specific growth pattern on FPTMC, deserving further studies and cautious selection in surgery extent.

In our univariate and multivariate analysis, LNM was significantly associated with male gender, age less than 45 years, tumor size, minimal ETE, and multifocality, which was supported by the recent study [6, 27, 28]. Compared with CPTMC, FPTMC was an independent protective factor for LNM, again demonstrating the indolent nature of this variant.

Calcification has been reported as a significant indicator for nonprogressive disease in PTMC [29], which was in contrast to our findings. In CPTMC, calcification was positively correlated with LNM, whereas in FPTMC and EnPTMC, no significant differences in LNM were found between tumors with or without calcification. Calcification in both subtypes was correlated with the unknown growth pattern but not with the occurrence of LNM. A cautious extent of surgery should be selected whether or not calcification is observed.

To investigate whether subtypes can be confirmed intraoperatively, differences in variant identification were compared between intraoperative frozen sections and postoperative paraffin sections. In intraoperative frozen sections, all the variants, except for the oncocytic variant, can be identified correctly according to the distinctive morphological characters, meaning that for almost all PTMCs, variants can be confirmed intraoperatively and thus used for the decision as to surgery extent.

There are three limitations in the present study. To clarify whether cases had LNM, we excluded the cases with no lymph node resected, which led to a slight rise in the rate of LNM. This issue was minimized by the rare occurrence of this situation. Also, the lower rate of LNM indicated that use of lymphadenectomy should be cautious in PTMC. The effect of surgery extent on data was another issue, being minimized by preoperative US of every patient. Because of color aberration, the oncocytic variant may be confused with other variants in frozen sections. As this variant does not have any prognostic implications in PTC [8] and was rare in PTMC, this limitation may not be important.

The present study establishes the three major variants in PTMC and their aggressive order: CPTMC ≫ FPTMC > EnPTMC. For reasons of distinct clinicopathological features and variant distribution, variant identification has important clinical significance in determination of lymphadenectomy, having an effect on individual treatments in PTMC. Patients with variant-relevant risk and other predictors, including male gender, age less than 45 years, tumor size, minimal ETE, calcification, and multifocality, are recommended to undergo prophylactic lymph node dissection.