Papillary thyroid carcinoma (PTC) has an indolent behavior and a favorable prognosis (1, 2). However, 10–20% of PTC cases show aggressive features, resulting in frequent recurrence and sometimes higher mortality (3–5). The prognostication of DTC remains significantly constrained by low specificity (6), despite advancements in understanding the prognostic implications of tumor-specific genetic alterations (7). From the perspective of the prognostic field of thyroid cancer, there is a pressing need for prognosticators with high specificity and positive predictive value regarding the rate of recurrent disease after initial treatment.

The rare diffuse sclerosing variant (DSV) is among the representative aggressive subtypes of thyroid cancer that tends to occur in young patients (8–10), with a varying reported prevalence of 0.8–5.3% of PTC cases (11–16). DSV was first described in 1985 (17) and is characterized by aggressive clinico-pathological manifestations, including diffuse involvement of one or both thyroid lobes without a dominant mass, sclerosis, abundant psammoma bodies, prominent squamous metaplasia, extensive lymphatic permeation, and stromal fibrosis (18, 19). The outcomes and prognosis of DSV remain controversial (9, 10, 12–15, 20–22); however, in cases where preoperative sonography images show typical features of DSV, such as ill-defined margins, scattered microcalcifications with a snowstorm appearance, and varying echogenicity (23), radical treatment is pursued more frequently. This is due to the aggressive and highly recurrent nature of DSV, which distinguishes it from cases without these characteristics (24, 25).

To date, most studies have focused on the aggressiveness of the DSV by comparing it with conventional PTC (cPTC) (9, 18, 20–22). However, the recurrence pattern of the DSV itself remains unknown. Moreover, the relationship between recurrence and age in patients with DSV has not yet been investigated, although DSV is a prevalent and major variant of pediatric PTC (8).

To the best of our knowledge, this is the first study to perform a subgroup analysis of the DSV. In addition to confirming the well-known characteristics of the DSV compared with those of cPTC, we compared the characteristics of pediatric and adult patients with the DSV. In particular, we focused on the associations between age and recurrence rates in patients with DSV.

To the best of our knowledge, this is the first study to perform a subgroup analysis of the DSV. Treating patients with DSV is often a sobering experience for clinicians owing to the aggressive pattern of the disease and its high recurrence rate. Moreover, knowledge regarding which patient characteristics (including age, sex, maximal tumor diameter, lymph node condition, and TNM stage) should be monitored more carefully for the DSV remains largely unknown.

In the current staging system of differentiated thyroid cancer, older age is a well-established risk factor for mortality (30). Contrarily, it is also well-known that the recurrence pattern of PTC is not exactly correlated with the staging system. For instance, although pediatric patients with PTC have a relatively high recurrence rate, they also have an excellent prognosis in terms of mortality (31). Considering the low mortality rate of thyroid cancer, it is important to investigate its recurrence pattern, which is directly linked to the patients’ quality of life, requiring additional active treatment such as re-operation or repetitive radioiodine ablation, especially for aggressive subtypes such as the DSV.

In this study, our data shared similar results with previous studies. First, the DSV accounted for 0.8% of PTC cases, which is similar to the results of previous studies (11–16). Second, the DSV had a higher incidence in pediatric patients than in cPTC patients (8). Third, patients with the DSV had larger tumor sizes and lymph node metastases compared with patients with cPTC, resulting in more aggressive treatment (18, 19). Fourth, recurrence rates were higher in patients with the DSV compared with patients with cPTC. Fifth, despite its high recurrence rate, the DSV was associated with excellent survival rates (9, 18, 21, 22). Finally, the prevalence of BRAF or TERT mutations was low in patients with the DSV, which is acceptable in comparison with previous results (32–34).

Although there was a significant difference in the number of patients with cPTC (n=24,424) compared with the number of patients with DSV (n=202), no statistical matching was performed as the main purpose of this study was to perform a subgroup analysis of the DSV group.

Notably, we demonstrated that pediatric status is an independent risk factor for the recurrence of the DSV. We used only two variables for the multivariate Cox proportional hazard regression analysis owing to the limited number of events. Nevertheless, we obtained an HR of 2.82 (p=0.047) for recurrence in the pediatric patient group compared with that in the adult patient group with the DSV, even when controlling for tumor size.

It is interesting that pediatric differentiated thyroid cancer (DTC) and DSV are both known to be associated with high recurrence but with excellent survival as well. They also share similar molecular characteristics of less BRAF 600E or TERT mutations. Considering the dominance of the DSV in pediatric patients with DTC (8), we hypothesized that the reason for the distinctive characteristics of DTC in pediatric patients may be the predominance of the DSV. The present study provides an important basis for future research on this topic.

The interpretation of RCS curves requires careful attention ( Figure 3 ). It is noteworthy that the RCS curve of both the DSV and cPTC groups showed a U-shaped distribution, with the curve of the DSV tending to be located within the younger age group. In the DSV group, the RCS curve of the population whose age was not less than 55 years was not depicted owing to the low frequency and recurrence rates. Among the 202 patients with the DSV, only 13 were aged 55 years or above, and there was only 1 patient (a 57-year-old man) with recurrence (i.e., lung metastases within 10 months of the initial total thyroidectomy). The oldest patient in the DSV group was a 70-year-old woman who did not show any signs of recurrence within 36 months after the initial surgery. Therefore, we are still uncertain whether the prognosis of patients with DSV can be predicted using the current staging system, which dichotomizes patients’ age at 55 years across different types of thyroid cancer and considers older patients as having a worse prognosis.

To date, it remains unclear whether younger patients (<10–15 years of age) are at a greater risk of recurrence of DTC (31). In our study, the three youngest patients were aged <10 years (6, 7, and 9 years of age at diagnosis) and had no recurrence for at least 10 years after their initial diagnosis. The nine pediatric patients with recurrence were aged between 12 and 19 years, indicating a high recurrence rate among teenagers in the DSV group.

This study had several limitations. First, the study had a retrospective design. Second, we did not test for RET/PTC rearrangement, which is known as a major genetic alteration of the DSV. Third, all patients were treated at a single tertiary hospital, which may have caused selection bias. Fourth, we limited recurrence to structural recurrence. Clinicians often encounter cases of abnormal serum thyroglobin levels without structurally identifiable disease in clinical practice, indicating the need to be vigilant of biochemical recurrence; hence, this may have contributed to systematic bias in our study. Fifth, although we collected the data from 202 patients with the DSV, more independent risk factors can be obtained from a larger population. Variables such as tumor size, total thyroidectomy, and extracapsular invasion were only marginally insignificant in our study.

This study demonstrated that pediatric patients with DSV are at a greater risk for recurrence compared with adult patients; moreover, the pattern of recurrence risk according to age is different from that of cPTC.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Institutional Review Board of Yonsei University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

JK: Writing – original draft, Resources, Investigation, Formal analysis, Data curation. JSK: Writing – review & editing, Validation, Supervision, Software, Conceptualization. J-IB: Writing – review & editing, Validation, Supervision, Software, Formal analysis, Data curation. JKK: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Data curation, Conceptualization. S-WK: Writing – review & editing, Validation, Supervision, Data curation. JJ: Writing – review & editing, Validation, Supervision, Data curation. K-HN: Writing – review & editing, Validation, Supervision, Data curation. WC: Writing – review & editing, Validation, Supervision, Data curation.