PTMc is the most frequently incidentally discovered thyroid neoplasm because of its indolent and asymptomatic course (14). Prognosis of incidental PTMc is excellent, with recurrence rate of 0.5% and mortality as low as 0% (15). In this direction, it has been observed that PTMc show an alternative rearrangement gene expression pattern compared to PTC. Therefore that specific microenvironment is responsible for the different phenotypic and clinical expression (16)(17). Consequently American Thyroid Association (ATA) guidelines and the 8th AJCC/TNM system, suggest less aggressive therapeutical approaches (18, 19). It has even been proposed active surveillance of low-risk PTMc as the best first-line treatment, particularly in elderly (20) (21).
There are some clinical characteristics that modify the indolent evolution of PTMc, conferring those patients a higher risk. These modifiers are youth (under 19 years), multifocality, microscopic features of aggressiveness (tall cell, blood vessel permeation), incidental diagnosis in patients with clinical metastases (6). Some authors have proposed a subdivision according to size, with a cut-off point of 7mm, as this seems to be related with tumorigenic behavior (22). Three different subtypes of PTMc have been identified: type I (incidentally detected PTMc with no symptoms, harmless the life expectancy), type II (accompanied by small lymph node metastasis and/or minimal invasion with no progression) and type III (high-risk for presenting data on aggressiveness) (23). Recent studies have shown a growing prevalence of PTC over the last decades (1). Our local thyroid cancer registry of the Community of Navarre (Spain) is consistent with this trend. It demonstrated an increase of TC diagnosis in both sexes, as a result of a gradual rise of T1a papillary carcinoma probably due to a higher diagnosis of microcarcinomas over the years (24).
Frequency of incidentally PTMc found in surgical series differs depending on the cohort reviewed, ranging from 2–40% (25). Interpretation of this inter-study variability could be explained by geographical factors (environmental features, diet, medical healthcare access) and underlying pathology of the subjects that leads them to surgery. The first study that proved a grater incidental thyroid cancer risk in patients referred to surgery was carried out by Smith et al. (26), with an overall prevalence of 15.6%. PTMc prevalence in our cohort was 9.3% (167/1802), which places us near the lower limit of other series (27)(28)(26)(29). A possible explanation of this results could be that there are no environmental exposures that increase risk of PTMc in our region. Exclusion criteria were strict because the main objective was to include only patients with truly incidentally discovered PTMc and avoid selection vias. Therefore, all patients with a suspicion of thyroid carcinoma confirmed by histologic examination were not included.
Our analysis found a higher prevalence of occult PTMc in MNG, followed by other benign pathologies such as CLT and finally GD. Leading indication for surgery in our center was MNG, probably due to the relatively high prevalence in our environment, which is at endemic levels (30). Moreover, thyroid nodules are the most frequent thyroid disease. The term of MNG is currently used when there are several nodules in the thyroid gland. Overall, 10.5% of the MNG operated (147/1406) had an occult microcarcinoma, similar to the 12% risk described by Fama et al (25) and 14% of Taşova et al (31), but lower than the 29.2% of the cohort of Ajarma et al (32). This percentage is comparable to pre-surgery probability of malignancy of nodules, ranging from 7–15%, depending on age, sex, radiation history or family history (18).
Opposite to our findings, other authors have reported a greater prevalence of cancer in patients with underlying thyroiditis. Nevertheless, relationship between thyroid autoimmunity and cancer remains controversial. Some studies have demonstrated that there is a link between lymphocytic infiltration of the thyroid parenchyma and PTC, an histologic feature described in Hashimoto's disease (33). The pathophysiological mechanism responsible is not fully understood, however Virchow in 1863 had speculated the link between chronic inflammation and neoplastic transformation of normal tissue (34). Some of trigged mechanisms proposed for carcinogenesis are stimulation due to the action of TSH, expression of specific proto-oncogenes and chemokines produced by tissue-infiltrating lymphocytes (35). Autoimmune role of antibodies and chronic lymphocyte infiltration may predispose for dysplastic evolution of the follicular epithelium, creating a pre-neoplastic area progressing toward the existence of a tumor (36). Hashimoto’s thyroiditis has been reported that only increases the risk of PTC in euthyroid individuals and in those that partially preserve the function (37). High TSH levels leads to cellular hypertrophy and hyperplasia by a constitutive activation of this pathway, tiggering genetic abnormalities. In this direction, Fiore E. et al (38), showed that risk of malignancy is associated with increased in TSH values. Microenvironment and molecular investigation of thyroid cancer is crucial because it may explain why the same histological subtype have different behavior. Research have found that PTC is less frequent and aggressive in GD as compared to CLT and non-autoimmune thyroid disease (39). Nevertheless, it has been considered that cancer and autoimmunity were extremes of immune-responses (40).
Our cohort reported one of the lowest prevalence of PTMc in CLT (3/46=6.5%), compared to other series. Slijepcevic et al (29) show a different distribution of incidental PTMc in relation to the benign thyroid disease to undergoing surgery, with the highest prevalence in Hashimoto thyroiditis (22.7%). Bircan et al (41) noted around 39%. Notably, the indication for CLT surgery is the lowest of all in our cohort. This may be due to the strict inclusion criteria. Probably, areas of thyroiditis in the parenchyma may form nodules with an ultrasound appearance that mimics nodules with intermediate or high suspicion (42)(43). This pre-surgical suspicion could lead to perform cytological studies by fine needle aspiration biopsy (FNAB) and, if malignancy is confirmed by histological analysis of the specimen, these subjects would be excluded.
The current study found the lowest risk in GD, with a frequency of PTMc around 4.9% (17/349). Prevalence reported range from 0.5–15%, with many cohorts submitting rates below 5%. Dǎnilǎ R. et al. (44), in a retrospective study performed on a consecutive 92 patients operated with GD, conclude that the 2.2% prevalence of incidental thyroid microcarcinoma was similar to other benign disease. Lower distribution of PTMc in autoimmune disorders compared to MNG, suggest that thyroid autoimmunity does not affect tumorigenesis (45).
Age was not found to affect the risk of malignancy. Our results are in concordance with Luo et al. (46) who reported that age was not a very strong independent factor for predicting malignancy (OR 0.97, 95%CI 0.960–0.987, p < 0.001) due to an odds ratio approached to 1. Consequently, age is not helpful for predicting malignancy. However, it seems to influence on progression and prognosis of PTMc (21).
In our study we did not find sex as a risk factor to predict PTMc, with a male prevalence of 11.1% (36/323) compared to 17.3% (131/759) in females. Slijepcevic N. et al. (29), did not report gender differences in his cohort of 2,466 patients. Roti E. et al. (47), corroborated this same theory. This phenomenon does not seem to occur in cancers of a larger size, since the overall higher prevalence of papillary PTC in women suggests a role in promoting malignancy transformation attributable to estrogen stimulation (48). At the onset of puberty, the prevalence of PTC increases only in females, decreasing again after menopause, possibly due to the growth-promoting effect mediated by membrane-bound estrogen receptors (49).
Rising prevalence of PTMc in our cohort over decades (24), is a fact that is consistent with other series (14). Leenhardt L. et al. (50), described an increase of 8.1% and 6.2% per year in women and men, due to papillary type with an epidemic tumors measuring less than 1 centimeter (43% of total operated cancers). Rego-Iraeta A. et al. (51), support these results. This Spanish descriptive epidemiological study found that this rise exclusive of PTMc. Besides PTMc, they do not identify significant variations in tumor size over time. One possible explanation that may have influenced in this increasing incidence in the population of Navarre is the change in the iodization situation. There has been a progressive change in recent decades from an iodine-deficient to an iodine-sufficient community, although the association between increased iodine intake and thyroid cancer is controversial. Another factor to take into is that the number of pathologic slides from each surgical specimen has increased over the years, contributing to the detection of PTMC specimens. Overexposure to ionizing radiation sources through the decades may also contribute to this effect.
In conclusion, we found a prevalence of 9.3% of incidental PTMc, that is comparable to rates of other European cohorts. Age and gender are not independent predictors for PTMc, with a higher prevalence of incidental PTMc in MNG followed by CLT and lastly in GD. Surgical findings of PTMc in total thyroidectomy for benign disease has increased significantly over the years, particularly in the 2017-2020 period.