Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy with an indolent clinical course [1,2]. Classical PTC accounts for 55% to 65% of the cases; while, more than 10 different variants have been identified [3]. Among these, follicular variant is a common subtype, accounting for about 15% to 30% of all PTCs, and its incidence has increased in recent times [4-7]. The other, relatively rare subtypes include tall cell (TCV), columnar cell (CCV), diffuse sclerosing (DSV), cribriform-morular (CMV), solid (SV), hobnail (HV), and Warthin-like variants [8,9]. The prevalence of these variants differs between regions, countries, and patient populations [9]. The incidence of TCV ranges from 4% to 16%, and it does not constitute a common pathological entity when a strict pathologic definition is applied [5,7,10,11]. The other variants are rarer, accounting for 1% to 3% of PTC [10-21]. Owing to their rarity, most studies on PTC variants largely consist of case reports with few large-sample analyses or multicenter cross-sectional studies [9].

Rare variants have distinct clinical, pathological, and prognostic characteristics [8]. Certain variants have more aggressive or, conversely, more favorable tumor behaviors than classic PTCs; therefore, they contribute to risk stratification [8]. According to the American Thyroid Association (ATA) initial risk stratification, PTCs are classified into three major groups based on their biological behaviors: (1) aggressive variants with unfavorable outcomes, including TCV, CCV, and HV; (2) variants with less favorable outcomes but controversy exists regarding their mortality rate, including SV and DSV; and (3) other variants [8]. However, the prognostic implications of these PTC variants remain controversial [8]. For example, a Korean single-centered study, conducted on 144 patients with aggressive variants of PTC, revealed that patients with TCV did not exhibit worse clinical outcomes when compared to those with classic PTC, diagnosed with similar clinicopathological factors [10]. CCV was associated with poorer clinical outcomes after propensity score matching [10]. Additionally, some studies suggest that SV and DSV could be classified as a high-risk pathological entity due to their propensity for recurrence [14,15,22-26]. A large, multicentered study in France revealed that patients with DSV were at a nine times higher risk of recurrence than patients with other variants of PTC, despite aggressive surgical interventions that required more frequent follow-ups [15]. Nevertheless, these variants usually occur in young patients and are highly responsive to treatment, with a lower mortality rate. Therefore, there is a lack of clarity regarding the pathological subtypes that require more aggressive treatment and careful surveillance.

In this multicentered study conducted in Korea, we aimed to evaluate the clinicopathologic characteristics and biological behaviors of patients with rare variants of PTC using a large, multicenter cohort of thyroid cancer patients. Additionally, we elucidated the prognostic factors associated with recurrence-free survival (RFS) in PTC patients with rare variants.

Our retrospective investigation is the first large, multicenter study in Korea that evaluated the clinicopathological characteristics and RFS of the rare variants of PTC. Out of the 5,496 patients included in the study, only 63 patients exhibited rare variants of PTC, accounting for 1.1% of all PTC cases. TCV was the most frequent variant with an incidence of 0.9%. We determined that some PTC patients with rare variants exhibited aggressive features; 12.7% each demonstrated gross ETE and lateral neck LN metastasis. Based on the ATA classification and US features, we classified all tumors into high or intermediate suspicion categories, with most belonging to the former category. During the follow-up period, locoregional recurrence occurred in 6.3% of the patients. The 5-year RFS rates for variants with favorable, less favorable, and aggressive outcomes were 100%, 71.4%, and 95.9%, respectively. Additionally, DSV emerged as an independent risk factor associated with a shorter RFS.

The pathological definitions of these variants of PTC have changed over time, thus varying the incidences of these tumors accordingly [9,27]. We defined TCV as a tumor with more than 50% tall cells that are ≥3 times as tall as wide. This rigorous definition may have contributed to a lower incidence of TCV compared to that previously reported [5,7,10,11]. A recent World Health Organization classification defined that tall cells should account for more than 30% of all tumor cells for the diagnosis of TCV. However, evidence shows that a tumor with more than 50% tall cells significantly and independently affects prognosis, whereas that with 30% to 49% tall cells does not [28]. Standardizing diagnostic criteria and accurately diagnosing rare variants of PTC are important to determine the patients who require extensive therapies, including a completion thyroidectomy followed by RAI ablation and aggressive surveillance.

This retrospective study was designed to examine the incidence and biological behaviors of rare variants of PTC, based on the pathology reports of patients with PTC. All pathology slides were reviewed by institutional pathologists to better represent clinical practice, and the incidence of rare variants varied from 0% to 5.6% for all PTCs in each institution. The uncommon variants may be easily overlooked by inexperienced pathologists, and these variants of PTC might be underdiagnosed by general pathologists, who tend to classify rare variants as classical PTC. This might be an explanation for the wide range of incidence of rare variants in this study and previous studies [29-31]. The incidence of TCV has been reported to range from 1.3% to 13% of all PTCs [29]. When carefully scrutinized for the diagnosis of TCV by endocrine pathologists, the proportion of TCV has been observed to increase [29]. The proportions of TCV diagnosed at a single institution in Korea were 4.9% and 6.8% of all PTCs in 2013 and in 2020, respectively [30,31], when all pathology slides were reviewed by an expert.

In the present study, most of the rare variants of PTC exhibited typical malignant features on US: solid hypoechoic nodules with irregular/microlobulated margins and microcalcifications. Little information exists on the imaging features of these rare variants of PTC due to their rareness [32,33]. In a retrospective study of eight patients with 10 TCVs, TCV appeared as markedly hypoechoic nodules with microlobulated margins, microcalcifications, and ETE [34]. SVs also were diagnosed as high or intermediate suspicion nodules on US [32,35]. Yun et al. [36], in their study of 17 DSV cases, described the characteristic US features that included diffuse and scattered microcalcifications with heterogeneous hypoechogenicity. On the contrary, CMVs that have indolent tumors did not exhibit malignant features on US [37]. Therefore, US features can be considered as indicators of tumor aggressiveness. Further research may help determine if US features can effectively predict prognosis in these variants of PTC. In this study, we found it difficult to assign specific characteristics for each variant and determine their prognostic implications due to a high proportion of patients with TCV and a wide overlap of US features among the variants.

Using ATA classification, the 5-year RFS rates for variants with favorable, less favorable, and aggressive outcomes were 100%, 71.4%, and 95.9%, respectively. In our study, the variants with less favorable outcomes had a significantly shorter RFS than those with aggressive outcomes. One possible explanation for our findings is the proportion of variants included in our analysis. None of our patients exhibited CCV and HV, which have been reported to be associated with recurrence, metastasis, and disease-specific death [10,38]. Another possibility is that we evaluated only for RFS, and not for disease-specific survival. Although DSV has more aggressive pathological features and are treated more aggressively than classical PTC, most studies revealed that it did not depict any adverse effects or a higher mortality rate [13,14]. However, a systematic review of DSV demonstrated that it was associated with worse overall survival [39]. Evaluating the long-term outcomes with a larger cohort may help explain the prognostic significance of each pathological variant.

Consistent with previous studies, our data indicated that DSV occurs at a younger age with a high incidence of cervical LN metastasis [22,24]. Additionally, a higher prevalence of underlying Hashimoto’s thyroiditis and a higher female-to-male ratio are unique clinical features of DSV [13]. Abundant lymphocytic infiltration is a characteristic of DSV, and the molecular profile of DSV may be a possible explanation for its pathological difference from classical PTC [40]. RET/PTC rearrangements are common in DSV, whereas BRAF mutations are observed in DSV at a lower frequency compared to classical PTC [41,42]. Our analysis of the Cox proportional hazards model revealed that DSV is a significant prognostic factor for RFS among patients with rare variants of PTC. It is noteworthy that all recurrences were locoregional and that the preoperative US features were not helpful in predicting recurrence. This suggests that close monitoring of the operation bed and lateral neck LNs is of importance during the follow-up after initial therapy for patients with DSV.

The present study has several limitations. First, this study is retrospective by design and involves a relatively small number of PTC patients with rare variants due to their inherent rareness and short period of data collection. This retrospective multicenter study was conducted after reviewing all pathology slides reported as PTC in each institution. We reviewed patients diagnosed with PTC over a year to allow more institutions to participate, and actually reviewed all pathology slides for 5,496 PTC cases. We also intend to evaluate the prognosis of patients with a follow-up period of 5 years or longer in patients diagnosed with a rare variant of PTC in 2012. Second, we failed to conduct centralized pathological examinations in this multicentered study, and there may have been discrepancies among the pathologists’ interpretation of the diagnosis criteria. Third, the median follow-up duration of 7 years was relatively short to evaluate the recurrence. Additionally, no disease-specific death occurred during this period. Further studies using cohorts with longer data collection periods will yield more definitive results. However, this is the first multicenter cohort study to evaluate the clinicopathological characteristics and biological behaviors of rare variants of PTC in Korea.

In conclusion, our multicentered Korean cohort revealed that rare variants of PTC accounted for 1.1% of all PTCs with TCV being the most frequent variant. Locoregional recurrences occurred in four patients, and DSV was the only variant that emerged as a significant prognostic factor for RFS. These findings suggest that pathological variant should be taken into consideration while determining the follow-up and treatment strategies in patients with PTC. Further studies conducted on a larger scale are needed to verify the incidence, clinicopathological characteristics, and biologic behaviors.