Clinical and pathological data of patients with stage T1 MTC treated at Tianjin Cancer Hospital and Sichuan Cancer Hospital from November 2006 to November 2021 were retrospectively analyzed, and data of eligible cases were collected, sorted, and statistically analyzed according to inclusion and exclusion criteria. Inclusion criteria: (1) postoperative pathological findings confirmed MTC; (2) all patients were newly diagnosed and initially treated, and had no previous history of thyroid surgery; (3) color Doppler ultrasound indicated that the maximum diameter of cancer nodules was less than 2.0 cm, with or without cervical lymph node metastasis; (4) no extraocular invasion of cancer nodules was found by preoperative color Doppler ultrasound and intraoperatively; (5) all surgeons had more than 10 years of experience in thyroid surgery; (6) the scope of surgery at least included the removal of the affected glandular lobe and isthmus, with or without the dissection of the neck lymph node; (7) complete clinical and pathological data of patients and long-term follow-up. Exclusion criteria: (1) postoperative pathology indicated papillary carcinoma, follicular carcinoma, or mixed carcinoma of other pathological types; (2) other malignant tumors in the past; (3) refusal to be studied; (4) lost to follow-up.

Lymph nodes in the central cervical region were dissected (zones VI and VII): upper boundary—lower margin of the hyoid; lower boundary—superior sternal fossa; outer boundary—lateral margins of the carotid sheath; bottom boundary—prevertebral fascia. Lymph nodes in the lateral cervical region were dissected in areas II–V: upper boundary—mastoid plane; lower boundary—supraclavicular fossa; inner boundary—sternocleidomastoid medial border; outer boundary—trapephalus anterior border; bottom boundary—prevertebral fascia.

All patients were followed up at the outpatient clinic after surgery, and the examination items mainly included blood tests (thyroid function, serum calcitonin, carcinoembryonic antigen) and imaging examinations (neck color Doppler ultrasound, chest thin layer computed tomography). Blood tests and color Doppler ultrasonography of the neck were performed every three months for the first year after surgery and then every six months. Thin-section computed tomography of the chest was performed semiannually or annually as needed. Total thyroidectomy and central or lateral cervical lymph node dissection were performed for patients with significantly elevated serum calcitonin in a short period of time or with definite recurrent lesions confirmed by color Doppler ultrasound. Multidisciplinary treatment should be made for patients with distant metastasis such as lung metastasis.

We used the tumor diameters of 0.5 cm and 1.0 cm as the cut-off points for two groups. OS and PFS were the main outcome events. Classification variables using frequency and percentage were described, using the χ2 test or Fisher’s exact test for comparison. Continuous variables were described using mean ± standard deviation. The Shapiro–Wilk test was used to verify normal distribution, and the independent sample t-test was used for comparison between groups. Survival was estimated by the Kaplan–Meier curve and compared with the log-rank test. Univariate analysis of different disease characteristics was carried out with the Cox hazards model. Disease characteristics with p ≤ 0.20 were included in multivariate prognostic hazard ratio analysis to determine independent risk factors. Bilateral p < 0.05 indicated statistical significance. All analyses were performed with SPSS software version 25.0 (SSPS, Inc., Chicago, Illinois, US).

Since 1988, when the World Health Organization defined thyroid cancer with the largest tumor diameter ≤1.0 cm as microcarcinoma, extensive research on thyroid micro-carcinoma has been carried out worldwide. As early as 1998, Beressi N. et al. reported that the proportion of sporadic micro MTC in all sporadic MTC increased rapidly, among which the proportion was 3.6% before 1984, 14.3% in 1984–1989, and 22.0% in 1990–1996 (10). Kazaure H.S. et al. analyzed 310 cases of medullary thyroid micro-carcinomas detected between 1988 and 2007 and found that the proportion of micro MTC increased by 39.0% (11). Similarly, Machens et al. found that the incidence of micro MTC increased from 19.0% to 39.0% between 2011 and 2015, and Kwon H et al. reported similar findings (12, 13). Our study showed that T1 MTC accounted for 1.33% of the total MTC from 2006 to 2010, 12.26% from 2011 to 2015, and 26.25% from 2016 to 2021, and morbidity also showed the same trend. It can be seen that the incidence of patients with small-sized MTC continues to rise.

Overall, the incidence of MTC in thyroid cancer is consistently below 5%, with a 5-year relative survival rate of about 93.0% for stage I–III patients and 28% for stage IV patients (14–17). Kim S.J. reported a 95.0% OS rate after 71 months of follow-up in patients with minimal MTC (18). Beressi N. reported a 10-year survival rate of 93.9% ± 4.4% for micro MTC (10). Kazaure H.S. et al. reported that overall 10-year survival rates were 96.0%, 87%, and 50% for patients with focal lesions, regional metastases, and distant metastases in minimal MTC, respectively (11). However, Saltiki K.’s study showed that in patients with tumor sizes of 0.1–1.0 cm and 1.1–1.5 cm, the probability of no disease progression at 10 years was 96.6% and 81.3%, respectively, and suggested that tumor size may only be clinically significant in patients with MTC of 1.0 cm (19). In this study, survival analysis of patients with stage T1 MTC was conducted with tumor diameters of 0.5 cm and 1.0 cm as the cut-off points. The results showed that the 5-year, 10-year, and 15-year OS rates of T1a patients with T1 MTC were all 100.00%, and PFS rates were 98.11%, 96.23%, and 96.23%, respectively. Meanwhile, the 5-year, 10-year, and 15-year OS rates of stage T1b patients were 95.59%, 95.59%, and 94.12%. The PFS rates of stage T1b patients were 88.24%, 85.29%, and 85.29%.

Thus, it is highly effective to use a 1.0 cm tumor diameter as the cut-off point. Although it is not significant for the OS of patients, it is critical for the PFS of the disease. It can be seen that the PFS of patients with T1a is significantly higher than that of patients with T1b (p = 0.010). When the tumor diameter of 0.5 cm was used as the cut-off point, we did not obtain valuable information on disease survival, but we believe that this may be related to the small number of patients with a tumor diameter of less than 0.5 cm. Generally, the prognosis of MTC at this stage is still good, and patients with s-MTC still have high OS and PFS rates.

Although the idea of TT and bilateral central cervical lymph node dissection for MTC patients has long been accepted by most surgeons, an increasing number of patients with early MTC are hoping to retain a normal thyroid gland. We may have overstated the benefits of TT for patients with early MTC and overlooked the potential risks of surgical complications and lifelong levothyroxine tablets, especially in poor populations. Raffel A. et al. performed a second surgery on an s-MTC patient who was found by chance in postoperative pathology and who was more likely to develop temporary and permanent hypoparathyroidism after surgery (5.6%; 3.5–8.8%), vocal cord paralysis (3.8–8.5%; 2.8–8.4%), and transient Horner syndrome (3.8–5.6%) (20). Follow-up results showed a 100% biochemical cure rate within 1.5–10.0 years after Sub-TT. Therefore, it is suggested that TT and neck dissection should not be mandatory for patients with sporadic and isolated T1 MTC as long as the genetic background is excluded (20). Three different reports by Miyauchi A., Randle R.W., and Shabina R. analyzed a total of 927 cases of sporadic s-MTC, and all concluded that unilateral thyroidectomy was acceptable for sporadic isolated s-MTC patients with normal contra-lateral thyroid and no RET mutation detected in the reproductive cell line. Dis-ease-specific survival rates did not change (21–23).

Our team has also reached similar conclusions in previous studies on surgical selection and prognosis of unilateral sporadic medullary thyroid carcinoma, i.e., that patients with total thyroidectomy have little benefit in terms of biochemical cure/OS (24). Hamy A. and Zhang D. even argued that sporadic minimal MTC was almost 100% located in the thyroid gland, lymph node metastasis was rare, calcitonin could hardly be detected after surgery, and the value of central cervical dissection was questionable (16, 25). After a follow-up of 233 patients with MTC for 7 to 445 months, Ito et al. also considered it controversial to perform TT and lymph node dissection for all MTCS with lesions confined to the thyroid, especially for T1a (26). Interestingly, studies from the Korean NHIS database showed that a total of 34.6% of patients with MTC underwent adeno lobectomy alone, and this proportion did not change significantly between 2004 and 2016 (17). Similarly, our results also showed that TT had no significant effect on OS in T1a and T1b MTC patients, but it did significantly affect PFS (p = 0.028). Patients who underwent TT had a lower PFS rate ( Figure 1B ), which we believe is related to cervical lymph node metastasis. TT was performed for the included T1 patients mainly because most of them had already developed cervical lymph node metastasis or even distant metastasis when the disease was discovered. Therefore, even after TT, they still had a lower PFS rate, which was consistent with the lower PFS rate for the later TNM stage ( Figure 2D ). In addition, after TT, patients need to take levothyroxine tablets for lifelong replacement therapy, and the long-term potential risk of cardiovascular dis-ease and the economic burden should be considered before surgery.

Compared with differentiated thyroid carcinoma, MTC appears to be more prone to cervical lymph node metastasis and distant metastasis and may be associated with many other factors in addition to tumor diameters, such as male sex, calcitonin, and carcinoembryonic antigen levels, RET mutations, bilateral carcinoma, multifocal carcinoma, neoplasmic thyroid extracapsular invasion, marginal burrs, morphological irregularities, calcification, and blood supply (26–31). The level of calcitonin before and after surgery and the doubling time of calcitonin after surgery is now widely believed to be associated with the prognosis of MTC and determines whether the surgeon decides to perform elective lateral cervical lymph node dissection at the time of initial surgery (32). For disease progression, postoperative calcitonin has been shown to be a more important predictor than tumor size (19). Due to the limitations of hospital testing levels, the cancer centers involved in this study did not carry out the detection of calcitonin levels 15 years ago. Meanwhile, since most of the small medullary thyroid carcinomas were accidentally found during the pathological examination after surgery, the level of calcitonin was not routinely detected before surgery.

For advanced MTC patients with unresectable tumor recurrence or distant metastasis, patients with RET mutation or fusion will likely receive RET inhibitor therapy and other measures (33, 34). Bilateral carcinoma also appears to be a factor in poor prognosis. Bilateral cancers tend to be more prone to cervical lymph node and blood route metastasis than unilateral cancers. The results of this study were further confirmed in stage T1 MTC, where bilateral carcinoma had significantly lower PFS ( Figure 2C ). Multifocal carcinoma and nodular blood supply may be other factors affecting the PFS rate of s-MTC. Although the results of our study were negative, this may be due to the small number of patients analyzed ( Figure 3 ). Cervical lymph node metastasis is another prognostic factor, and the later the stage of lymph node metastasis, the higher the recurrence rate. In particular, stage N1b patients had a significantly higher recurrence rate than those without cervical lymph node metastasis (13). Finally, the adhesion hyperplasia found in the tumor during the histopathological examination may also indicate that MTC has high invasive and metastatic potential. If adhesion hyperplasia is absent or only slightly visible, the risk of metastasis may be considered low (35, 36).