Is unicentric familial papillary thyroid microcarcinoma different from multicentric?

Familial papillary thyroid microcarcinoma (FPTMC) appears to be more aggressive than sporadic papillary thyroid microcarcinoma (SPTMC). However, there are authors who indicate that unicentric FPTMC has a similar prognosis to SPTMC. The objective is to analyze whether unicentric FPTMC has a better prognosis than multicentric FPTMC. Type of study: National multicenter longitudinal analytical observational study. Study population: Patients with FPTMC. Study groups: Two groups were compared: Group A (unicentric FPTMC) vs. Group B (multicentric FPTMC). Study variables: It is analyzed whether between the groups there are: a) differentiating characteristics; and b) prognostic differences. Statistical analysis: Cox regression analysis and survival analysis. Ninety-four patients were included, 44% (n = 41) with unicentric FPTMC and 56% (n = 53) with multicentric FPTMC. No differences were observed between the groups according to socio-familial, clinical or histological variables. In the group B a more aggressive treatment was performed, with higher frequency of total thyroidectomy (99 vs. 78%; p = 0.003), lymph node dissection (41 vs. 15%; p = 0.005) and therapy with radioactive iodine (96 vs. 73%; p = 0.002). Tumor stage was similar in both groups (p = 0.237), with a higher number of T3 cases in the group B (24 vs. 5%; p = 0.009). After a mean follow-up of 90 ± 68.95 months, the oncological results were similar, with a similar disease persistence rate (9 vs. 5%; p = 0.337), disease recurrence rate (21 vs. 8%; p = 0.159) and disease-free survival (p = 0.075). Unicentric FPTMC should not be considered as a SPTMC due to its prognosis is similar to multicentric FPTMC.


Introduction
The incidence of familial papillary thyroid microcarcinoma (FPTMC) is increasing due in part to a better diagnosis of familial papillary thyroid carcinoma (FPTC).Thus, classically most of these tumors were diagnosed as sporadic due to a family history was not performed.However, currently screening programs in families with FPTC allow an early detection of these malignant tumors, most of them in the phase of microcarcinoma [1,2].
It must be remembered that since there is no genetic diagnostic test that allows the diagnosis of the FPTMC, it makes us suspect that several of the cases labeled as FPTMC could be really a sporadic papillary thyroid microcarcinoma (SPTMC).In this sense, the presence of multifocality is frequently associated with FPTC and FPTMC [3][4][5].Thus, for many authors, the finding of a multicentric papillary thyroid carcinoma (PTC) should suggest a familial disease [5].On this basis, unicentric FPTMC is frequently mislabelled as SPTMC, and therefore could present a good prognosis.In this way and, as a general rule, multifocality in PTC leads to higher rates of disease persistence, cervical metastatic lymph nodes and distant metastases, which implies a worse evolution and morbimortality [6,7].
On the other hand, multifocality in the sporadic form is described in around 25-30% of patients, and therefore it is not specific to the familial form [8][9][10].This aspect is important, since while in SPTMC the prognosis is favorable, in the case of the FPTMC its biological behavior is little known, but it is indicated that it has an aggressive behavior [3,4,[11][12][13][14][15]. In this sense, international guidelines such as that of the American Thyroid Association (ATA), recommends a more aggressive treatment in the FPTMC than in the SPTMC [16].
The objective of this study is to analyze whether the unicentric FPTMC has a better prognosis than the multicentric one.

Study population
Spanish multicenter longitudinal analytical observational study, where the study population consists of patients diagnosed with FPTMC.
The concept "FPTC" implies the presence of at least two first-degree relatives with a PTC with a confirmed histological diagnosis.Families with any of the following criteria are excluded: genetic syndromes with predisposition to PTC (Multiple Endocrine Neoplasia (MEN) syndrome, Cowden syndrome, Gardner syndrome, adenomatous polyposis and Carney complex) and previous exposure to ionizing radiation.
On the other hand, the concept of "FPTMC" implies the presence of a FPTC with a size equal to o less than 1 cm.

Data collection protocol
A data collection protocol was developed by the project manager, which was approved by the Endocrine Surgery Section of Spanish Society of Surgeons.The study protocol was approved by institute's committee (2021-2-13-HCUVA).
A first direct contact was made by the project manager with the different Endocrine Surgery Units to explain the project.Later, an institutional contact through the secretariat of the Spanish Society of Surgery was made to provide the documentation in order to participate in the project.
The project was developed over a period of 4 years, from 2015 to 2018.Subsequently, the follow-up was updated but without including more patients.The information provided for each case was the complete protocol and the family tree that confirmed that the tumor was a FPTMC.The information was obtained from the patients and their family histories.
All cases were evaluated by the same investigator to confirm the validity of each case.Once its validity is accepted, it is formalized and any doubt or contradiction regarding the case was consulted to resolve it.

Study groups
After the selection of the patients with FPTMC, two study groups are compared according to the finding of tumor multifocality in the histopathological analysis.a. Group A: unicentric FPTMC.b.Group B: multicentric FPTMC.

Study variables
To compare both groups a double analysis is carried out, to assess whether there are differences in terms of: 2. Oncological results and prognostic differences: Oncological results are evaluated according to the presence of disease persistence after the initial treatment and disease recurrence in patients with cure criteria.Recurrence is considered as the presence of disease (locoregional or distant metastases) after six months of complete radical treatment.This disease can be clinically evident or only biochemical (increased serum thyroglobulin with negative antithyroglobulin antibodies in patients with total thyroidectomy and treatment with I 131 ).

Statistical analysis
The data are analyzed using the statistical program SPSS® v21.0 for Windows® (SPSS, Chicago, Illinois, USA).Descriptive statistics is performed.For categorical variables, the data are expressed as frequencies and percentages, and are compared using the Pearson's Chi-square test, applying the Yates correction when the expected frequency is less than 5%.For continuous quantitative variables, the data are expressed as mean ± standard deviation and are compared using the Student t test for independent data.
For bivariate analysis of the different variables as risk factors, a Cox analysis is performed, expressing the results as Odds Ratio (OR) with a 95% confidence interval (95%CI) and p value.Multivariate analysis is performed using a binary logistic regression to evaluate the independent associations of all factors that are statistically significant in the bivariate analysis.The results are expressed as OR with a 95CI and p value.Kaplan Meier method is used to analyze disease-free survival (DFS) and overall survival, and the Log Rank test to compare survival between groups.A p value < 0.05 was considered statistically significant.

Casuistry
Eighteen Spanish Endocrine Surgery Units participated in the project, contributing a total of 94 cases of FPTMC.The group A (unicentric FPTMC) consisted of 41 patients and the group B (multicentric FPTMC) consisted of 53 patients (Fig. 1).

Socio-familial and clinical differences
No relationship was observed between unicentric and multicentric FPTMC according to socio-familial variables, clinical variables and thyroid function (Table 1).

Differences according to histophatology variables
No differences were observed between unicentric and multicentric FPTMC according to histophatology variables (Table 2).

Oncological results and prognostic differences
Oncological results were similar in both groups, although a higher (not statistically significant) disease persistence rate was observed in the multicentric FPTMC group (9 versus 5%; p = 0.337) (Table 4).
After a mean follow-up of 90 ± 68.95 months, the percentage of patients with active disease (without cure criteria) was higher in the group of patients with multicentric FPTMC (28%; n = 15) than in the group of patients with unicentric FPTMC (12%; n = 5), at the limit of statistical significance (p = 0.058).
In patients who met cure criteria after a complete initial treatment, no differences were observed in terms of disease recurrence rate or disease-free survival (Tables 4-6 and Fig. 2).

Discussion
The incidence papillary thyroid microcarcinoma is increasing all over the world.At the same time, FPTMC is increasing mainly due to screening protocols in families diagnosed with PTC [2].Nowadays, the treatment of PTMC is less aggressive regarding to surgery and I 131 therapy is being discontinued.In this sense, conservative treatment is being established in low-risk cases [1].However, FPTC is considered as a high risk carcinoma owing to its possible worse prognosis, and conservative treatment is not considered.
This more aggressive behavior of FPTC respect to sporadic PTC has been associated, among other factors, with the presence of histological factors of high aggressiveness such as multifocality.Thus, the frequency of multifocality is higher in FPTC in most series, in such a way that the finding of a multicentric tumor should suggest a familial disease [5].In this context, it has been proposed that unicentric FPTMC could be a false FPTMC and that it could be treated as a SPTMC.The data presented in this national series do not corroborate this hypothesis.Although the worst prognosis of FPTMC does not come from multifocality, other factors are involved.
In recent years, various studies have been performed about multifocality [10,[17][18][19][20][21][22][23][24], with very different results.Thus, some authors consider that multifocality [23,24] is a more aggressive form of thyroid cancer.Among them, the study by Feng et al. [10] stands out, which find that multicentric tumors have a larger size and a higher extrathyroidal extension, vascular involvement and lymph node metastases.On the contrary, other authors indicate that multicentric FPTC has no independent risk prognostic value, like the multi-institutional study by Wang et al. [18].
Our Spanish national study, focused only on FPTMC, agrees with authors such as Wang et al. [18] due to multifocality is not a prognostic risk factor.Thus, the oncological prognosis is similar between unicentric FPTMC and multicentric FPTMC, with no higher percentage of patients with disease persistence or recurrence.In this sense, unicentric FPTMC can´t be considered as a tumor with a prognosis similar to SPTMC, and therefore wouldn´t present a better prognosis.On the other hand, unicentric FPTMC is not the same as multicentric FPTMC, and we agree with Feng et al. [10] in the existence of a higher percentage of nonmicroscopic extrathyroidal extension, although we don´t confirm the presence of higher vascular or lymphatic involvement.
Since several authors indicate that multifocality is a predictor of risk of disease progression and recurrence, and that this risk increases as the number of tumor foci increases, a more aggressive treatment is proposed [10,17].Furthermore, some authors confirm this situation for microcarcinoma [10].In our study, focused on FPTMC, this differentiating aggressiveness is not confirmed.Therefore, unicentric FPTMC should be treated like multicentric FPTMC, with a treatment that is currently more aggressive than SPTMC [25][26][27][28][29][30].Most protocols propose total thyroidectomy and therapy with I 131 .
The study by Wang et al. [18] should be highlighted, which indicates that tumor multifocality have no an independent risk prognostic value in the clinical results of PTC, and therefore its indiscriminate use as an independent risk factor should be avoided, especially with regard to treatment.It should be noted that other authors have objectified the same prognostic situation and indicate that except in cases of lymph nodes involvement or macroscopic extrathyroidal extension, multifocality PTC should be treated as unicentric PTC [19,20].
The fact that multicentric FPTMC presents high frequency of extrathyroidal extension, like it is observed in our series, does not present a clear pathophysiological justification [10,19,20].In PTC > 1 cm, this situation has been associated with size, a fact that did not occur in our series.Some authors, such as Qu et al. [21], indicate that the incidence of extrathyroidal extension is associated with the number of tumor foci.Thus, PTC shows a higher incidence of extrathyroidal extension, lymph node metastases and disease recurrence in patients with a greater number of tumor foci, especially from three or more foci.Feng et al. [10] suggest that the number of tumor foci can be used to assess the risk of poor prognosis and recommend total thyroidectomy in these patients.
The prognostic value of multifocality will continue to generate debate, but in the case of FPTMC, its higher aggressiveness does not seem to be determined by multifocality.Thus, the behavior is similar in unicentric and multicentric FPTMC.The general genetic profile of thyroid cancer may need to be considered when investigating multifocality, and may clarify whether multicentric tumors arise from a single clonal origin or from several independent clonal foci [22].
Finally, it should be noted that the size of our study does not allow us to be dogmatic.Further research is required in this field and further studies are required.Given the infrequency of this pathology, it is necessary to carry out multicenter studies like the one presented in this article.One of the limitations of our study, despite being one of the largest samples described for FPTMC, is the sample size.In this sense, the KM plot in Fig. 2 shows a clear and progressive separation between two groups with p-value of 0.075, despite more aggressive treatments in the cohorts with shorter mean follow-up time (62 vs. 87 months).One would think that this could be a type II error and wonder if the multicentric group had equal follow up time, there may be

Cox analysis
Fig. 2 Kaplan-meier survival curve.Disease-free survival of familial papillary thyroid microcarcinoma more recurrences.This can only be ruled out with more and larger studies, so we encourage other groups to continue investigating and carry out more large multicenter studies.Another limitation was that the treatment strategy for these patients was similar in all involved institutes but not iqual,.

Conclusion
Although patients with multicentric FPTMC had the more aggressive disease at presentation and received more aggressive interventions, the prognosis of patients with multicentric FPTMC was not different than those with unicentric FPTMC.So, unicentric FPTMC should not be considered as a SPTMC due to its prognosis is similar to multicentric FPTMC.

Fig. 1
Fig. 1 Flow chart.Series casuistry.Flow chart of the cases under study and the lost cases

Table 1
Differences between unicentric familial papillary thyroid microcarcinoma (group A) and multicentric familial papillary thyroid microcarcinoma (group B) according to socio-familial variables, clinical variables and thyroid function

Table 2
Differences between unicentric familial papillary thyroid microcarcinoma (group A) and multicentric familial papillary thyroid microcarcinoma (group B) according to histophatologic variables

Table 3
Differences between unicentric familial papillary thyroid microcarcinoma (group A) and multicentric familial papillary thyroid microcarcinoma (group B) according to therapeutic and prognostic variables

Table 6
Risk of recurrence of familial papillary thyroid microcarcinoma