Biological behavior of familial papillary thyroid microcarcinoma: Spanish multicenter study

The incidence of papillary thyroid microcarcinoma (PTMC) has increased in recent decades. This is largely due to the high-resolution ultrasonography and thyroid pathology screening in many countries [1]. Since this tumor generally has an excellent prognosis, several groups, especially in Asia, have proposed conservative treatment with active surveillance [2, 3].

Familial papillary thyroid microcarcinoma (FPTMC) accounts for approximately 5 to 10% of all diagnosed cases of PTMC [4‐6]. However, its frequency is increasing due to screening programs in families with familial papillary thyroid carcinoma (FPTC) [4].

While sporadic papillary thyroid microcarcinoma (SPTMC) has a favorable prognosis, the biological behavior of FPTMC is little known and could have a probably more aggressive course [6, 7]. In this sense, it is described that FPTMC can present a high rate of multifocality, vascular involvement, and lymph node metastasis [8‐12]. However, there are few and short series in order to recommend a more aggressive treatment [6, 7, 9‐12].

There are currently only 5 studies that analyze FPTMC [6, 7, 9‐11], and two of them have a high risk of bias according to the Newcastle–Ottawa scale [7, 10]. Furthermore, some case series are very small, such as that of Lupoli G. et al. [7] with only 7 cases and Capezzone M. et al. [11] with 43 cases. On the other hand, the most numerous series have a very short follow-up. In this sense, the series of 217 cases presented by Cao J. et al. [10] has only a mean follow-up of 34 months.

Despite this lack of consistent evidence, there are guidelines such as the 2015 American Thyroid Association (ATA) that recommends a more aggressive management of the FPTC [13]. For this reason, active surveillance is not considered in FPTMC [2, 3] and the minimal surgery that is recommended is total thyroidectomy. Even authors such as Lee et al. [6] recommend associating a central neck dissection.

The objective of this study is to analyze the recurrence rate of FPTMC and the factors related to recurrence in a national multicenter study.

PTMC is considered an indolent tumor because active surveillance achieves good results avoiding the morbidity associated with surgery [2, 3]. However, FPTMC appears to be more aggressive [4, 6‐12]. On the other hand, since the outcomes are linked to an adequate initial treatment [14, 15], although the treatment could associate a greater morbidity, the more aggressive tumors should be treated more aggressively [14].

The recurrence rate of SPTMC is relatively low, below 4% in majority of studies and generally less than 2% [15, 16]. On the contrary, the reported recurrence rate in FPTMC is more variable. The first problem in this regard is the scarcity of studies reporting on this pathology, the second is the low number of patients included in these studies, and the third is that these studies are all retrospective [6‐12]. In this manner, the recurrence rate is above 2%, ranging between 2.1% [9] and 42.8% [7], although the study that provides such a high rate analyzes only 7 patients. The Spanish multicenter study also shows a high recurrence rate for FPTMC, specifically13.8%. This is an important data taking into account the mean follow-up longer than 6 years. Therefore, despite the heterogeneity of the data, patients with FPTMC, unlike SPTMC [17, 18], should not be considered for conservative treatment like active surveillance due to the high recurrence rate [2, 3].

When risk factors for recurrence of FPTMC are analyzed, one of the main prognostic factors is tumor size, so for every millimeter the risk of recurrence is practically twofold compared to the previous size. Although it is difficult to establish a cut-off point, in our series a size less than 4–5 mm reduces the risk of recurrence. These small tumors are the most indolent and with best prognosis [19]. Another aspect already known is the presence of histological variants of PTC with a poor prognosis, such as diffuse sclerosing variant [20]. It has not been observed in published studies that FPTC presents a higher incidence of more aggressive histological variants compared to sporadic carcinoma [4, 8, 10]. Finally, it should be noted that the assessment of the risk of recurrence of the ATA is highly predictive of the risk of FPTMC recurrence [21].

A more in-depth analysis of the data presented in this Spanish national study above FPTMC shows a high percentage of cases with tumor multifocality (56%), bilaterality (30%), and vascular invasion (7.5%). In other words, FPTMC has histological factors of poor prognosis in a high percentage of cases, a fact already indicated by other authors [11, 12]. There are several studies that show the high frequency of multifocality and bilaterality of FPTMC; even the finding of a multifocal tumor should suggest a familial disease [22]. It is necessary to remember that multifocality leads to higher rates of persistent local disease, cervical lymph node metastasis, and distant metastases, circumstances that cause a worse evolution and an increase of morbimortality [23, 24].

A controversial issue is the change in the 8th edition of TNM staging system compared to the previous edition in order to assess recurrence and survival differences. The 8th edition seems more predictive of mortality than the 7th edition [25], but in pathologies such as PTMC the application of the 8th edition is limited because mortality is practically zero, so it would require studies with large sample size and a very long follow-up in order to show differences. Thus, in this multicenter national study, the 8th edition practically does not differentiate and more than 97% of the cases are T1a and stage I, with a recurrence rate higher than 13%, so in this tumor the application of the 7th edition of TNM staging system is more discriminating. However, only in studies with large sample size such as the one presented by Yang et al. [25], which includes 39,032 microcarcinomas from the “National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER),” the 8th edition has been shown to be more useful in order to assess survival. In our series, as it shows in Table 4, the application of the 8th edition is very homogeneous and does not allow defining the patients according to the recurrence and survival. For this reason, it is very difficult to perform a survival analysis in a relatively rare disease with a low mortality rate, and therefore, no study will probably be able to demonstrate differences in overall survival. On the contrary, DFS is a much more suitable variable to study diseases with these characteristics [26].

In conclusion, we can say that FPTMC is associated with a high recurrence rate, specifically higher than 13%, and presents poor prognostic histological parameters such as multifocality and vascular invasion. Although there are no studies that demonstrate the existence of a treatment more effective for FPTMC than for SPTMC, and therefore there is no evidence to support a more aggressive treatment, FPTMC should not be included in active surveillance protocols and the treatment should be surgical.

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