Clinicopathological characteristics and prognosis of medullary thyroid microcarcinoma: a tumor with a similar prognosis to macrocarcinoma

The incidence of thyroid cancer has been gradually increasing worldwide. Nearly 600,000 new cases of thyroid cancer are reported annually, ranking 11th among all cases of cancer and accounting for approximately 3% of them [1, 2]. Further, thyroid cancer results in more than 40,000 deaths per year, accounting for approximately 0.4% of all tumor-related deaths [1, 2]. According to the 5th edition of the World Health Organization Classification of Endocrine and Neuroendocrine Tumors, thyroid neoplasms can be classified as developmental abnormalities, follicular cell-derived neoplasms, thyroid C cell-derived carcinoma, mixed medullary and follicular cell-derived carcinomas, and several other unusual neoplasms that occur in the thyroid [3]. Papillary thyroid carcinoma is the main subtype of follicular cell-derived neoplasms, while C cell-derived tumor refer to medullary thyroid carcinoma (MTC). Compared with papillary thyroid carcinoma, MTC has shown no obvious increase in the incidence rate. It accounts for only 1%–2% of all thyroid cancers but 8.6% of thyroid cancer-related deaths [4, 5]. Surgery is the main treatment modality for both sporadic and hereditary MTC and involves total thyroidectomy and central lymph node dissection. Some patients also require lateral lymph node dissection. Further, indicators such as calcitonin and carcinoembryonic antigen (CEA) can be used to monitor the disease in patients with MTC. Although radioactive iodine treatment is ineffective for MTC, new therapies, such as tyrosine kinase inhibitors, are promising [6, 7].

According to the eighth edition of the Cancer Staging Manual by the American Joint Committee on Cancer, tumor size plays an important role in the T staging of thyroid carcinoma [8, 9]. Tumors with a maximum diameter ≤ 1 cm and limited to the thyroid gland are staged as T1a. Meanwhile, a tumor with a maximum diameter less than or equal to 1 cm is defined as microcarcinoma [10‐12]. In papillary thyroid carcinoma, the clinical characteristics, treatment strategies, and prognosis of microcarcinoma (≤ 1 cm) and macrocarcinoma (> 1 cm) differ significantly. Hemithyroidectomy is a widely used surgical procedure in papillary thyroid microcarcinoma. However, it is unclear if the clinicopathological characteristics and prognosis of MTC microcarcinoma and macrocarcinoma also differ. There is a lack of effective clinical evidence to support the formulation of treatment plans and evaluation of prognosis for patients with medullary thyroid microcarcinoma (MTMC). It remains to be determined whether MTMC has unique clinical characteristics and requires special treatment. Therefore, in the present study, we summarized the data from a large tertiary hospital to clarify the clinical characteristics and prognosis of MTMC.

Based on the inclusion and exclusion criteria, a total of 198 patients were included in this study. The general information of all patients is presented in Table 1. All patients underwent radical surgery and 23 of them had complications. The detailed information of complications is presented in Table 2. Based on the postoperative pathological results, all patients were divided into two groups: micro- (tumor ≤ 1 cm) (n = 56) and macro- (tumor > 1 cm) (n = 142) MTC groups. The general characteristics and operative information of both groups are presented in Table 3. The pathological results of both groups are compared in Table 4.

Compared with the micro group, the macro group had a higher CEA level, longer operation time, more patients with lateral lymph node metastasis, and more patients who underwent lateral compartment lymph node dissection. It is worth mentioning that the number of patients with central lymph node metastasis was not significantly different between the two groups. Patients in the macro group had more positive central lymph nodes and higher tumor, nodes and metastases (TNM) staging. However, there was no significant difference in the number of patients with bilateral tumors, multifocal tumors, capsular invasion, extrathyroidal invasion, and high-N staging between the two groups.

As of December 2022, 178 (89.9%) patients were followed up, with a median follow-up time of 61 (35, 105) months, and the other 20 (10.1%) patients were lost to follow-up. Of the patients who were followed up, 116 (65.2%) survived without tumors, 42 (23.6%) survived with tumors, and 20 (11.2%) died. The cumulative OS rates of the micro and macro groups are presented and compared in Fig. 1. The 5-, 10-, and 15-year cumulative OS rates of MTMC were 97.5%, 93.6%, and 93.6%, respectively. For macrocarcinoma, the rates were 87.7%, 82.5%, and 72.7%, respectively. There was no significant difference in the OS rate of the two groups (log rank, p = 0.083). The cumulative DFS rates of the micro and macro groups are presented and compared in Figs. 2. The 5-, 10-, and 15-year cumulative DFS rates of MTMC were 80.9%, 60.4%, and 60.4%, respectively. For macrocarcinoma, the rates were 64.9%, 55.7%, and 38.2%, respectively. The DFS rate was significantly better in the micro group (log rank, p = 0.032).

The present study summarizes the clinical characteristics and prognosis of patients with MTMC. We found that, although patients with MTMC had less lateral lymph node metastasis and better DFS, the local invasion, central lymph node metastasis, and OS rates were not superior to those in macrocarcinoma. Therefore, we suggest that the same treatment strategies and surgical approaches should be adopted for MTMC and macrocarcinoma.

Over the past decades, the incidence of thyroid carcinoma has increased by more than 300% [14]. Although the growth rate of MTC is not evident, the proportion of MTMC has increased [15]. Therefore, greater attention is being paid to this disease. Owing to the unique endocrine function of the thyroid gland, it is important to pay attention to the quality of life of patients during treatment. In selected papillary thyroid carcinomas, such as microcarcinoma, hemithyroidectomy may be as effective as total thyroidectomy. Whether similar management is applicable in MTC has also been investigated. Some early studies with small sample sizes had questioned whether the extent of radical surgery required for MTMC is same as that for macrocarcinoma [16‐18]. Raffel et al. [16] retrospectively studied 15 patients with small sporadic MTC and concluded that total thyroidectomy and lymph node dissection were not mandatory for selected patients. Hamy et al. [17] performed a prospective multicenter study on 43 patients with sporadic MTMC. They found that lymph node metastasis was uncommon, and they questioned the significance of systematic central neck dissection in MTMC. However, the present study indicated that the invasiveness of MTMC was similar to that of macrocarcinoma. The two groups of tumors with different sizes were similar in terms of capsular invasion, extrathyroidal invasion, central lymph node metastasis, and N staging. This may be related to the strong invasiveness of MTC. Even if the tumor diameter is small, it is prone to local invasion and lymphatic metastasis.

The aggressive nature of MTMC has been further confirmed by several different studies. Kazaure et al. [15] used the Surveillance, Epidemiology, and End Results database to report on 310 patients with MTMC and found a 10-year OS rate of 91.6%. They recommended thyroidectomy and central compartment lymph node dissection for preoperatively diagnosed MTMC. Kim et al. [19] performed a meta-analysis of 15 studies and compared the clinical features of MTMC with those of macrocarcinoma. They observed that MTMC has aggressive features and accordingly suggested a similar treatment strategy for MTMC and macrocarcinoma. Li et al. [20] retrospectively compared the clinical and ultrasonographic characteristics of MTMC and papillary thyroid microcarcinoma and found that MTMC was more likely to have lymph node metastasis. Machens et al. [21] studied 233 patients with MTMC and found that lymph node metastases were common. In a recent study, Kesby et al. [22] studied 42 patients with MTMC, of which five (12%) had lymph node metastases; during a median follow-up of 6.6 years, five (12%) had recurrence, and three (7%) died. In summary, studies of MTMC have led to very different conclusions from those of papillary thyroid microcarcinoma.

Indications for lymph node dissection in patients with MTMC have not clearly established [4]. There was even guideline that indicated central compartment lymph node dissection as unnecessary in MTMC [23]. Lymph node metastasis is associated with MTC prognosis. Regardless of the tumor size, the central and ipsilateral lymph node metastasis rates of MTC can be as high as 50% to 75% [4]. Therefore, although controversial, total thyroidectomy and central compartment lymph node dissection remain mainstream surgical procedures for MTC. In our study, there was no difference between MTMC and macrocarcinoma in terms of local invasion or central lymph node metastasis. This finding supports the aforementioned perspective. Extrathyroidal invasion can easily lead to lymph node metastasis [15, 24‐26]. This may be the reason for similar central lymph node metastases in MTMC and macrocarcinoma. MTMC therefore requires the same extent of surgery as macrocarcinoma. A recent systematic review revealed that there remains a lack of evidence on surgical procedures less invasive than total thyroidectomy and lymph node dissection for MTMC [27]. In the present study, the operative time of MTMC was shorter than that of macrocarcinoma. Because there were more patients underwent lateral lymph node dissection in the macro group. However, the postoperative complication rates between micro and macro groups were similar. It indicated that as long as the surgery was performed with precision, even lateral lymph node dissection would not significantly increase the incidence of complications.

Although controversial, the management approaches for papillary thyroid microcarcinoma are becoming more conservative [10]. The indolent biological nature of microcarcinoma may not have a significant effect on patient prognosis. However, it is unclear whether a similar strategy can be applied to MTMC and whether MTMC and macrocarcinoma should be treated differently. A meta-analysis showed that the DFS rate of MTMC was better than that of macrocarcinoma [19], which is consistent with the present findings. However, no significant difference was observed in the OS or local invasion between both lesions. According to our data, there were fewer lateral metastases in MTMC, which may be the reason for the better DFS of MTMC. Because lymph node metastasis is an important cause of tumor recurrence. On the other hand, the OS may be more closely related to the invasiveness of the tumor. This could explain the lack of a significant difference in the OS rates of the two groups. For this reason, it is necessary to implement the same treatment strategies for MTMC and macrocarcinoma.

This study had some limitations. First, owing to its retrospective nature, registration information and patient volume could not be planned beforehand. Second, the sample size of this single-center study was limited, with a low incidence of MTC. Third, 20 patients (10.1%) who were lost to follow-up had a high possibility of death, which may have affected the results on patient prognosis. In future, multicenter, prospective, controlled clinical trials should be performed to obtain more robust data.

The present study summarized the clinicopathological characteristics and prognosis of MTMC and compared them with those of macrocarcinoma. MTMC showed local invasion, central lymph node metastasis, and OS rates similar to those of macrocarcinoma; however, MTMC had better lateral lymph node metastasis and DFS rates. Based on the data from this study, the same treatment strategies are recommended for MTMC and macrocarcinoma.