Introduction
Thyroid cancer (TC) is the most common cancer of the endocrine glands. Papillary thyroid carcinoma (PTC) constitutes the most common subtype of TC (85–90%) and generally has a good prognosis with disease-free, 5-year survival (DFS) at 87.5% and cancer-specific mortality after 5 years at 0.8%. In differentiated papillary thyroid carcinoma, the 10-year survival rate ranges between 85 and 95% [
1‐
5]. The current treatment for PTC consists of total thyroidectomy complemented by postoperative radioactive iodine and thyroxine suppression. For papillary thyroid microcarcinomas (PTMC, ≤10 mm), hemithyroidectomy alone is considered sufficient [
6,
7].
In recent decades, a rapid increase in TC incidence has been reported worldwide and, in some countries, TC is the fastest growing form of all cancers, especially in women [
5,
8‐
10]. Incidence is steadily increasing. However, mortality rate is relatively unchanged, and the prognosis is still good for differentiated thyroid carcinoma [
1,
6,
10]. Small PTC (≤20 mm in size) and especially papillary thyroid microcarcinomas (PTMC ≤ 10 mm) are responsible for the majority of the incidence rate increment [
5,
6]. One etiologically established risk factor is ionizing radiation, but this alone cannot explain the increasing incidence of PTC [
6,
11]. Another contributing factor is believed to be the widespread use of ultrasound examinations of the neck and fine-needle aspiration cytology (FNAC) of lesions found in the thyroid gland. FNAC leads to increased diagnosis, but also makes it possible to diagnose patients at an early stage [
7,
10,
12]. Other contributing factors like genetic mutations (for example BRAF) and geographic differences in iodine supply can affect the incidence of various TC types [
6].
Small PTCs are classified as low-risk or extremely low-risk tumors with favorable prognosis. Yet, a few of these can be more aggressive, causing lateral lymph node metastases, distant metastases or even death, possibly requiring another treatment strategy [
6,
7,
12,
13]. These findings indicate that there is a difference in biological aggressiveness within this group of tumors. Known histological features that are associated with a worse prognosis are multifocality, bilateral foci, vascular invasion, extrathyroidal extension and/or lymph node metastases. Regional lymph node metastases are a predictor for recurrence and patients with lymph node metastases have an increased risk of death from differentiated papillary thyroid cancer, especially if the tumor size is >4 cm [
12,
14,
15]. Age has classically been considered a strong predictive factor in carcinoma death, but is now more often considered in conjunction with other variables [
6,
16]. Therefore, decisions regarding treatment can be very difficult for physician and patient alike, especially in lesions below 1 cm without aggressive features. In such cases, active surveillance can be used as a treatment method in order to avoid the side effects of possibly unnecessary surgery [
12,
13,
17].
Thus, there is a great clinical need to establish factors related to invasiveness in small PTCs and to characterize the demographic as well as histological and molecular differences between the low- and high-risk forms of PTC. The aim of this study is to analyze small PTC with and without lymph node metastases, which is a marker for aggressiveness, using the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) [
1], with the aim of discovering potential demographic differences between these groups.
Discussion
In this observational study from a validated national quality registry, we found some regional differences in the incidence of small PTCs. We plan to investigate the reasons for this in a future study. Environmental factors might contribute as well as a combination of tumor-promoting elements. This retrospective, demographic register study cannot distinguish whether these incidence differences are due to environmental causes or whether, at least in part, they are influenced by differences in diagnostic work-up and the frequency of thyroid surgery performed in different regions of Sweden.
Stockholm region had the lowest N0 to N1 disease ratio (2.18), which might indicate a difference in the distribution of patients with N0 and N1 disease in Stockholm region compared with the other regions, which we speculate due to Stockholm region being the capital region with younger inhabitants compared with the other regions, and as showed before, the N1 disease had an earlier younger age peak.
The incidence difference between N0 and N1a status may also to a small part be influenced by some local variations in the application of the National Guidelines for Thyroid Cancer but we have to believe and do expect that centers follow the guidelines. These, however, were the same for the entire study period and included the recommendation for (a) central lymph node dissection in cases with a preoperatively known TC and/or clinically noted central metastases during surgery, and (b) lateral node dissection if metastases were proven in the lateral compartment. Less extensive surgical applications in various localities depending on, for example, old age or comorbidity and the surgeon’s decision, can also contribute to some minor extent. According to the National Guidelines during the study period, there was no recommendation for re-interventive, central lymph node surgery within a two-stage surgical procedure if the TC was preoperatively unknown and the tumor was small.
However, the geographic differences in the N1b group are unlikely to be affected by these circumstances and are more likely to represent the aggressive tumors that are more amenable to metastasis unless adequate lymph node work-up, and appropriate node surgery is undertaken and well-adopted in all geographic regions alike.
Even though a formal sub-analysis of the causes of these regional discrepancies was not possible on SQRTPA register data and was not within the main scope of this demographic descriptive study, these findings, in our opinion, warrant further studies comparing geographic, environmental and tumor-promoting factors comparing the data with the Swedish Cancer Register as well as using modern geographic and environment analyzing software, and we plan to do this in a follow-up study.
We found an association between the tumor size and increasing lymph node metastases (N1 disease group) in small PTCs, indicating (as expected) that a larger tumor is generally more aggressive and thus increases the risk for lymph node metastases. This is in accordance with the literature [
3,
6,
21]. However, when analyzing the N1a and N1b groups separately, tumor size was significantly smaller in the N1b group, indicating a possibly different mechanism for lateral lymph node engagement than that of central node metastases, the latter more predicted by tumor size. A comparison between patients with both central and lateral lymph node metastases vs patients with only lateral metastases would be interesting but, unfortunately, is impossible to obtain from the register. Further studies are warranted to determine whether this is related to a different tumor biology of certain small PTCs, such as mutations (e.g., BRAF) or different growth factors within the tumor stroma, multifocality and the topical location (polarity and laterality) of the tumor within the thyroid gland or a combination of all these factors that facilitate the development of lateral metastases in the setting of a small PTC [
12,
22]. We have initiated such studies on the cohort on both stromal markers and BRAF mutations, but data remain to be evaluated. BRAF mutations alone cannot be held responsible for tumor aggressiveness according to our preliminary data, though. One can also, of course, speculate if a selection bias may contribute in some cases as lateral lymph node metastases occasionally occur in the absence of a primary tumor in the thyroid though meticulous histopathological examination as well as an incidental PTMC might have been noted on histopathology not being related to the lateral lymph node metastasis.
Our finding that approximately 7% of patients with PTMC and thus tumor size <10 mm without local invasion show lateral lymph node metastases at the time of primary surgery enlightens the need of a thorough preoperative lymph node evaluation and also stresses the importance of concomitant lymph node evaluation when applying a watchful waiting and in some cases avoidance of FNAC in small PTCs as new international as well as national guidelines advocate.
Male gender is a known negative predictive factor in overall PTC prognosis [
3] and was also observed to be correlated with N1b disease subgroup in our study in which the proportion of females was significantly lower. However, the N1b group is relatively small and a larger cohort would be of value to confirm these results. This is also needed to establish whether there is an effect in relation to recurrent disease and mortality.
In terms of age, we found a statistical difference between the N0 and N1 groups as a whole, and in the female subgroup specifically, when analyzing the subgroups separately. A probable reason for this would be that many cases in which the small PTC was found consist of patients who underwent surgery for nodular goiter with preoperatively unknown cancer; a disease clearly dominated by postmenopausal women. In these cases, no routine lymph node dissection was carried out in the absence of enlarged or suspicious lymph nodes, so most of this group fall into the N0 group. According to earlier Swedish data presented by Lundgren et al. [
3], the incidence peak for thyroid cancer (all TC types included) among women was at 55–65 years. This was similar for men, whereas we noted a peak for almost all categories at 41–50 years of age for T1 PTC. The time period in that study ranged from 1958 to 1987. This difference in age peak could possibly be explained by the development of better diagnostic methods, which produce earlier diagnosis. It could also indicate that the incidence age has indeed moved to a younger demographic distribution.
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