Background
Medullary thyroid cancer (MTC) is a rare thyroid neuroendocrine malignancy originating from parafollicular (C) cells of the thyroid gland, accounting for <3% of all thyroid cancers.1,2 MTC can occur in either a sporadic (sMTC; 75%–80%) or a hereditary form (hMTC; 20%–25%). Currently, all mainstream guidelines in Western countries—including those from the American Thyroid Association (ATA), European Society of Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN), and British Thyroid Association (BTA)—recommend total thyroidectomy (TT) as the standard initial surgery for both sMTC and hMTC.1,3–5 Only the Japan Association of Endocrine Surgeons (JAES) guidelines allow hemithyroidectomy (HT) for unilateral sMTCs.6
Compared with HT, TT is associated with an increased risk of complications that impact quality of life, such as transient or permanent hypoparathyroidism, recurrent laryngeal nerve paralysis, and need for increased postoperative thyroxin supplementation.7 Unlike in differentiated thyroid cancer, total removal of thyroid tissue in MTC is not intended to facilitate subsequent iodine-131 therapy, but is primarily performed to prevent residual tumor tissue or recurrence in the preserved thyroid gland. For hMTC, TT is mandatory because any residual C cell harboring germline RET mutations carries a lifelong risk of carcinogenesis. However, the necessity of TT for sMTC remains controversial for several reasons: (1) the proportion of sMTCs occurring in bilateral lobes appears to be low,8,9 suggesting a limited potential for intrathyroidal spread to the contralateral lobe; (2) clinical practice patterns vary regarding the extent of thyroid surgery, leading to inconsistent adherence to guideline recommendations10; and (3) more importantly, there is a lack of high-quality evidence demonstrating that TT provides a prognostic benefit in sMTC.
In light of these controversies, there have been increasing calls in recent years to reduce the extent of surgery in selected patients with sMTC.8,11–14 However, due to the rarity of MTC, large-scale studies with sufficient patient numbers to evaluate the safety of HT in sMTC have long been lacking. To address this gap, we conducted a nationwide, multicenter, large-scale retrospective study encompassing 19 referral centers across China. Using these data, we comprehensively evaluated the safety of HT in sMTC across 5 aspects: (1) prevalence of occult foci in the contralateral lobe; (2) prevalence of contralateral lobe recurrence during follow-up; (3) biochemical response; (4) structural recurrence-free survival (SRFS); and (5) overall survival (OS). The aim of this study was to systematically evaluate the suitability of HT and identify optimal candidates for this approach in sMTC.
Patients and Methods
Study Population
A total of 1,101 patients with MTC who underwent surgery from October 1, 1998, to April 7, 2024, at 19 referral centers in China were enrolled, including 5 hospitals from Oriental Thyroid Tumor Specialist Alliance (Fudan University Shanghai Cancer Center, Changzhou Second People’s Hospital, Jiangsu Taizhou People’s Hospital, Peking University Shenzhen Hospital, and Shanghai Electric Power Hospital; n=735); 5 hospitals from Qingdao University Medical Group and Health Alliance (the Affiliated Hospital of Qingdao University, Songshan Hospital of Qingdao University, Women and Children’s Hospital of Qingdao University, Qingdao Shinan District People's Hospital, and Qingdao Shibei District People’s Hospital; n=82); 2 hospitals affiliated with Zhejiang University School of Medicine (Sir Run Run Shaw Hospital, and The First Affiliated Hospital; n=65); Shanghai Sixth People’s Hospital (n=87); the Affiliated Hospital of Jining Medical University (n=41); Renmin Hospital of Wuhan University (n=31); Zhejiang Cancer Hospital (n=19); Liaoning Cancer Hospital & Institute (n=18); the First Hospital of China Medical University (n=18); and the Second Affiliated Hospital of Dalian Medical University (n=5). This study was approved by the Ethics Review Board of contributing hospitals, and written informed consent was obtained from patients at the time of surgery.
Inclusion and Exclusion Criteria
Inclusion criteria were patients with MTC who underwent surgical resection. Patients without available medical records or who were completely lost to follow-up were excluded. We also excluded those without known genetic testing results or available tumor/normal samples for complementary genetic testing. Because the aim of this study was to compare the radicality of different surgeries, we excluded patients who underwent non–curative-intent surgery, including those receiving palliative surgery or having distant metastasis at diagnosis. Additionally, non–initially treated patients who received index surgery elsewhere but sought reoperation due to neck recurrence at our contributing hospitals were also excluded (Supplementary Figure S1, available online in the supplementary materials).
Gene Testing and Identification of Disease Heredity
Genetic testing for patients was performed using primary or metastatic tumor samples matched with peripheral blood or cancer-free normal tissues, which were confirmed to be free of cancer contamination by 2 experienced pathologists. Whole-exome or targeted sequencing using a multigene next-generation sequencing panel was conducted to profile genetic alterations on an Illumina NovaSeq 6000 system.15
Hereditary disease was identified primarily based on the presence of germline RET mutations. Family history and MEN2-related disorders (eg, pheochromocytoma, primary hyperparathyroidism, Hirschsprung disease, cutaneous lichen amyloidosis, mucosal neuroma, marfanoid body habitus) were also recorded to assist in identifying hMTC. Driver mutations were determined using the same protocol as in our previous study.16
Outcomes
This study comprised 3 endpoints: SRFS, OS, and biochemical cure. Structural recurrence was defined as the occurrence of at least one solid lesion that is radiographically/sonographically detectable during the follow-up period after curative-intent surgery. SRFS was defined as the duration from initial surgery to the first occurrence of structural disease. OS was defined as the period from diagnosis to death from any cause. Biochemical cure was identified by serum calcitonin levels at the normal range throughout the follow-up period. Notably, assays for serum calcitonin measurement varied across hospitals and changed over time. The less sensitive radioimmunoassay was primarily used at our participating hospitals before the 2010s, but has since been largely replaced by the more sensitive chemiluminescence or electrochemiluminescence immunoassays.
Variables
Variables included demographics (age at surgery, gender), tumor characteristics (tumor stage, tumor size, lymph node metastatic status, multifocality, extrathyroidal extension, desmoplasia), and treatment modalities. HT was defined as lobectomy with or without isthmusectomy, whereas TT referred to complete thyroid removal. Regarding the extent of lymph node dissection, all patients with preoperatively suspected MTC routinely underwent prophylactic central neck dissection. Prophylactic lateral neck or upper mediastinum lymph node dissection was not routinely performed, but these regions were therapeutically dissected when involvement was suspected based on imaging or confirmed by fine-needle aspiration. Desmoplasia was defined as the presence of newly formed fibrotic stroma surrounding invasive tumor cells, which is not seen in non-neoplastic thyroid parenchyma.17 Clinical data from each contributing hospital were obtained by well-trained senior physicians who were blinded to the study design. Pathologic tumor sections were independently evaluated by 2 experienced pathologists (Z. Liu, L. Zhang), who were blinded to the study design at the time of review.
Statistical Analysis
To control potential confounders and selection bias between the HT and TT groups, a sensitivity analysis was performed using propensity score matching (PSM) with the R package MatchIt (Comprehensive R Archive Network). The patients were matched 1:1 based on AJCC staging and multifocality. Standardized differences were employed to assess balance across covariates before and after matching, with a standardized difference <10% considered indicative of well-balanced covariates postmatching. Student’s t-test and Pearson’s chi-square test were used to compare continuous and categorical baseline characteristics, respectively. After PSM, OS and SRFS between the HT and TT groups were compared using Kaplan-Meier analysis with log-rank test. Univariate and multivariate Cox analyses were employed to calculate the hazards ratio (HR) and 95% confidence interval (CI) of prognostic factors, whereas univariate and multivariate logistic analyses were used to calculate odds ratio (OR) and 95% CI of risk factors for biochemical incomplete response.
All analyses were conducted using SPSS Statistics, version 22.0 (SPSS Inc.) and R version 4.1.0 (R Foundation for Statistical Computing). A 2-tailed P value <.05 was considered statistically significant.
Results
Patient Cohort and Baseline Characteristics
After the selection process (Supplementary Figure S1), a total of 797 patients with MTC receiving curative-intent index surgery at the 19 participating centers were included, with a median follow-up of 71 months (range, 2–237 months), of whom 648 were genetically confirmed as sMTC.
For the 648 patients with initially treated sMTC, the median age at initial surgery was 51 years and there were no apparent discrepancies between genders (male: 47.2%; female: 52.8%). HT was performed in 232 (35.8%) patients, none of whom had a preoperatively suspected bilateral lesion in the thyroid or lymph nodes. We found that there were no significant differences in age (P=.848) and gender (P=.877) between the HT and TT groups, whereas the TT group had significantly more advanced AJCC staging (P<.001) and a higher rate of multifocal disease (P<.001), desmoplasia (P<.001), and RETM918T-driven tumors (P=.010), thereby having a significantly lower rate of biochemical cure (52.2% vs 68.6%; P<.001) and a slightly higher rate of structural recurrence (20.2% vs 14.2%; P=.074) (Table 1).
Baseline Patient Characteristics
| Characteristic | Total n (%) |
Total Thyroidectomy n (%) |
Hemithyroidectomy n (%) |
P Value |
|---|---|---|---|---|
| Total, N | 648 | 416 | 232 | |
| Gender | .877 | |||
| Female | 342 (52.8) | 221 (53.1) | 121 (52.2) | |
| Male | 306 (47.2) | 195 (46.9) | 111 (47.8) | |
| Age at initial surgery | .848 | |||
| Median (range), y | 51 (13–87) | 51 (13–77) | 51 (24–87) | |
| T stage | <.001 | |||
| T1 | 382 (59.0) | 225 (54.1) | 157 (67.7) | |
| T2 | 138 (21.3) | 94 (22.6) | 44 (19.0) | |
| T3 | 53 (8.2) | 34 (8.2) | 19 (8.2) | |
| T4 | 75 (11.5) | 63 (15.1) | 12 (5.2) | |
| N stage | <.001 | |||
| N0 | 303 (46.8) | 165 (39.7) | 138 (59.5) | |
| N1a | 104 (16.1) | 60 (14.4) | 44 (19.0) | |
| N1b | 241 (37.1) | 191 (45.9) | 50 (21.6) | |
| AJCC staging | <.001 | |||
| I | 213 (32.9) | 109 (26.2) | 104 (44.8) | |
| II | 88 (13.6) | 54 (13.0) | 34 (14.7) | |
| III | 98 (15.1) | 57 (13.7) | 41 (17.7) | |
| IVA | 249 (38.3) | 196 (47.1) | 53 (22.8) | |
| Multifocality | <.001 | |||
| No | 547 (84.4) | 328 (78.8) | 219 (94.4) | |
| Yes | 101 (15.6) | 88 (21.2) | 13 (5.6) | |
| Tumor size | .005 | |||
| ≤2 cm | 414 (63.9) | 247 (59.4) | 167 (72.0) | |
| 2.1–4 cm | 185 (28.5) | 132 (31.7) | 53 (22.8) | |
| >4 cm | 49 (7.6) | 37 (8.9) | 12 (5.2) | |
| Extrathyroidal extension | .001 | |||
| No | 540 (83.3) | 331 (79.6) | 209 (89.1) | |
| Yes | 108 (16.7) | 85 (20.4) | 23 (9.9) | |
| Preoperative calcitonin level | .001 | |||
| ≤500 pg/mL | 219 (42.9) | 126 (37.7) | 93 (52.5) | |
| >500 pg/mL | 292 (57.1) | 208 (62.3) | 84 (47.5) | |
| Driver mutation | .010 | |||
| RETM918T | 200 (30.9) | 145 (34.9) | 55 (23.7) | |
| HRAS | 153 (23.6) | 97 (23.3) | 56 (24.1) | |
| KRAS | 27 (4.2) | 17 (4.1) | 10 (4.3) | |
| RETC634 | 53 (8.2) | 37 (8.9) | 16 (6.9) | |
| Others | 215 (33.2) | 120 (28.8) | 95 (40.9) | |
| Desmoplasiaa | <.001 | |||
| No | 240 (42.8) | 131 (37.8) | 109 (50.9) | |
| Yes | 321 (57.2) | 216 (62.2) | 105 (49.1) | |
| Biochemical cureb | <.001 | |||
| No | 246 (42.1) | 182 (47.8) | 64 (31.4) | |
| Yes | 339 (57.9) | 199 (52.2) | 140 (68.6) | |
| Structural recurrence | .074 | |||
| No | 531 (81.9) | 332 (89.8) | 199 (85.8) | |
| Yes | 117 (18.1) | 84 (20.2) | 33 (14.2) | |
| Vital status | .999 | |||
| Alive | 622 (96.0) | 399 (95.9) | 223 (96.1) | |
| Dead | 26 (4.0) | 17 (4.1) | 9 (3.9) | |
Desmoplasia was evaluated in 561 patients whose tumor sections stained with hematoxylin-eosin were available.
Biochemical response was evaluated in 585 patients who underwent regular postoperative serum calcitonin testing.
Risk of Residual Disease or Recurrence in the Contralateral Lobe
We then focused on the prevalence of bilateral disease in sMTC. To assess this more accurately, we analyzed only patients who underwent TT, because they received pathologic examination of both thyroid lobes. Among the 416 patients in the TT group, 34 (8.2%) had pathologically confirmed bilateral foci. Upon reviewing their preoperative ultrasonographic descriptions, we found that only 10 (2.4%) patients had contralateral lesions that were not detected prior to surgery, whereas only 3 (0.72%) had a maximal primary tumor size ≤2 cm (Supplementary Table S1).
We then investigated the prevalence of recurrence in the contralateral lobe among patients receiving HT. Of the 232 patients, only 4 (1.7%) experienced structural recurrence in the preserved lobe during the follow-up period, and only 1 (0.43%) had a maximal primary tumor size ≤2 cm. Altogether, these results suggested that HT conferred a very low risk of residual disease or recurrence in the contralateral lobe in sMTC, especially in patients with small tumors (≤2 cm) (Supplementary Table S1).
Prognostic Differences After PSM
We then compared prognostic differences between the 2 groups in terms of biochemical response, SRFS, and OS. Because the TT group had significantly more patients with advanced AJCC staging (Table 1), we used PSM to reduce this important confounding factor. After PSM for AJCC staging and multifocality, 230 pairs of patients were available for further analysis, with no differences in baseline characteristics between the groups. (Supplementary Table S2).
Regarding biochemical response, our results showed that HT achieved a biochemical cure rate very similar to TT (68.5% vs 67.0%; chi-square P=.744; Supplementary Table S2). After adjusting for statistically significant confounding factors in the univariate analysis, this similarity persisted in the multivariate logistic regression analysis (with TT as the reference; OR, 1.07; 95% CI, 0.62–1.82; P=.818) (Supplementary Table S3).
Regarding survival outcomes, Kaplan-Meier analyses showed nearly identical survival curves between the 2 groups for both SRFS and OS (log-rank P=.914 and .484, respectively) (Figure 1). After adjusting for statistically significant confounding factors identified in the univariate analysis, multivariate Cox regression analyses also demonstrated that HT did not increase the risk of overall mortality (with TT as the reference; HR, 0.62; 95% CI, 0.21–1.82; P=.380) or structural recurrence (HR, 1.33; 95% CI, 0.77–2.33; P=.309) (Table 2).
Kaplan-Meier survival curves illustrating (A) SRFS and (B) OS in 230 matched pairs of patients undergoing HT and TT after propensity score matching.
Abbreviations: HT, hemithyroidectomy; OS, overall survival; SRFS, structural recurrence-free survival; TT, total thyroidectomy.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2024.7088
Prognostic Factors for Mortality and Structural Recurrence: Univariable and Multivariable Cox Regression
| Overall Mortality | Structural Recurrence | |||||||
|---|---|---|---|---|---|---|---|---|
| Univariable | Multivariable | Univariable | Multivariable | |||||
| Characteristic | HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value |
| Gender | ||||||||
| Female | Ref | Ref | Ref | Ref | ||||
| Male | 1.22 (0.48–3.10) | .669 | NA | NA | 2.83 (1.65–4.84) | <.001 | 1.41 (0.81–2.44) | .226 |
| Age | ||||||||
| ≤50 y | Ref | Ref | Ref | Ref | ||||
| >50 y | 5.18 (1.49–18.06) | .010 | 9.25 (0.82–7.42) | .088 | 0.65 (0.39–1.08) | .096 | NA | NA |
| T stage | ||||||||
| T1 | Ref | Ref | Ref | Ref | ||||
| T2 | 4.23 (1.18–15.15) | .027 | 3.43 (1.91–13.00) | .698 | 1.12 (0.54–2.32) | .766 | 1.07 (0.51–2.23) | .865 |
| T3 | 7.9 (1.97–31.65) | .004 | 6.20 (1.21–31.81) | .288 | 3.17 (1.48–6.78) | .003 | 1.87 (0.82–4.26) | .134 |
| T4 | 9.59 (2.35–39.06) | .002 | 5.09 (0.973–26.56) | .054 | 7.15 (3.76–13.6) | <.001 | 1.90 (0.96–3.77) | .066 |
| N stage | ||||||||
| N0 | Ref | Ref | Ref | Ref | ||||
| N1a | 1.45 (0.26–7.94) | .669 | 0.77 (0.08–7.43) | .828 | 4.04 (1.59–10.25) | .003 | 2.61 (0.96–7.08) | .059 |
| N1b | 5.55 (1.77–17.33) | .003 | 3.41 (0.86–13.54) | .081 | 15.3 (7.19–32.57) | <.001 | 9.29 (4.05–21.28) | .051 |
| Desmoplasia | ||||||||
| No | Ref | Ref | Ref | Ref | ||||
| Yes | 0.99 (0.36–2.71) | .980 | NA | NA | 1.18 (0.54–2.6) | .673 | NA | NA |
| Multifocality | ||||||||
| No | Ref | Ref | Ref | Ref | ||||
| Yes | 0 (0–Inf) | .998 | NA | NA | 4.85 (2.65–8.88) | <.001 | 1.68 (0.93–3.04) | .087 |
| Driver mutation | ||||||||
| RETM918T | Ref | Ref | Ref | Ref | ||||
| RETC634 | 0.71 (0.08–5.91) | .749 | 0 (0–Inf) | .998 | 0.44 (0.16–1.25) | .123 | 0.72 (0.28–1.89) | .510 |
| HRAS | 0.52 (0.13–2.07) | .351 | 0.83 (0.18–3.93) | .817 | 0.29 (0.14–0.59) | .001 | 0.42 (0.18–0.96) | .093 |
| KRAS | 4.84 (1.35–17.28) | .015 | 6.18 (1.44–26.64) | .015 | 0.4 (0.09–1.66) | .205 | 0.37 (0.09–1.61) | .186 |
| Others | 0.44 (0.12–1.58) | .209 | 0.73 (0.19–2.77) | .644 | 0.26 (0.14–0.51) | <.001 | 0.52 (0.27–0.98) | .082 |
| Initial thyroid surgery | ||||||||
| TT | Ref | Ref | Ref | Ref | ||||
| HT | 0.72 (0.28–1.83) | .485 | 0.62 (0.21–1.82) | .380 | 0.97 (0.58–1.62) | .915 | 1.33 (0.77–2.33) | .309 |
Abbreviations: HR, hazard ratio; HT, hemithyroidectomy; Inf, infinite; NA, not applicable; TT, total thyroidectomy.
Given the very low risk of tumor emergence in the contralateral lobe for small sMTCs (≤2 cm) observed in these analyses, we aimed to conduct subgroup analyses for these patients, stratified by different clinicopathologic factors. Interestingly, HT resulted in comparable structural and biochemical outcomes across all subgroups, including those with well-recognized high-risk factors such as high preoperative calcitonin level, RETM918T mutation, multifocal disease, lymph node metastasis, and tumor desmoplasia (Figure 2, Supplementary Figure S2). After adjusting for confounding factors identified in the univariate analysis (data not shown), these similarities in structural recurrence and biochemical response also persisted in the subgroup multivariate analysis (Figure 3).
Kaplan-Meier survival curves illustrating SRFS in subgroups of patients with maximal sMTC tumor size ≤2 cm: (A) multifocal disease, (B) N1a stage, (C) N1b stage, (D) preoperative calcitonin level >500 pg/mL, (E) desmoplasia, and (F) RETM918T mutation.
Abbreviations: HT, hemithyroidectomy; SRFS, structural recurrence-free survival; sMTC, sporadic medullary thyroid carcinoma; TT, total thyroidectomy.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2024.7088
Forest plots summarizing (A) ORs and 95% confidence intervals for biochemical incomplete response, and (B) HRs and 95% confidence intervals for structural recurrence in subgroup analyses comparing HT versus TT.
Abbreviations: HR, hazard ratio; HT, hemithyroidectomy; OR, odds ratio; TT, total thyroidectomy.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2024.7088
Discussion
Due to the rarity of MTC, obtaining convincing answers to many clinical questions about this disease has been challenging. This nationwide multicenter cohort from China provides valuable opportunities to offer more reliable evidence for addressing these controversies. The initial surgical extent of sMTC is an important clinical controversy in thyroid surgery. Current guidelines recommend TT as the standard initial surgery for all patients with MTC, regardless of heredity, with completion thyroidectomy only exempted for some patients with incidentally confirmed sMTC after HT.1,3–5 However, a systematic review found that most of the relevant references in these guidelines were historic and of low quality.12 In early 2002, a Japanese prospective study by Miyauchi et al18 showed that HT might not compromise the biochemical cure rate for sMTC, although the sample size was small. In recent years, more updated data have supported HT as a viable option for highly selected patients with sMTC.8,9,11,14,19 However, these studies had small cohort sizes and low rates of genetic testing, and did not directly compare HT and TT, limiting the applicability of their findings. Our cohort overcame many of these shortcomings, and importantly, performed genetic testing on all patients, which is the gold standard for confirming sporadic and hereditary disease.
MTC is typically located in the lateral lobe and rarely originates from the isthmus, because the vast majority of C cells are distributed in the upper and middle thirds of the thyroid gland.20 Therefore, sMTC tends to be unicentric and confined to one lobe.21,22 In an international multicenter study, Essig et al23 found a 5.6% prevalence of bilateral disease in sMTC and concluded that this rate was high enough to support TT for all patients with sMTC. However, they appeared to overlook an important fact: most bilateral foci can be detected by preoperative ultrasound, in which case TT is indisputably mandatory. In clinical practice, clinicians are more concerned about occult contralateral lesions that are not detected by preoperative ultrasound, which may significantly influence the clinical decision regarding the surgical extent. In our cohort, postoperative pathology showed an 8.2% prevalence of overall bilateral disease, but only 2.4% involved sonographically occult contralateral foci. Additionally, only 1.5% of patients in the HT group experienced contralateral lobe recurrence during the follow-up period. Interestingly, nearly all patients with occult contralateral lesions and recurrences had a maximal primary tumor >2 cm. These results suggest that HT confers a very low risk of recurrence or residual disease in the contralateral lobe for patients with sMTC with small tumors (≤2 cm).
Biochemical response is another concern. In the past, some scholars believed that only TT could bring about a biochemical cure, though without providing direct evidence.24,25 Recent studies, however, have suggested that a high biochemical cure rate can also be achieved after HT.14,19,26 Until now, no evidence has shown that removing the normal lobe could provide additional biochemical benefits in sMTC. In this study, we made a direct comparison of biochemical responses between the HT and TT groups. Our data showed that preserving the normal lobe did not affect the biochemical cure rate, especially in patients with tumors ≤2 cm, where biochemical response were highly similar between the HT and TT groups in all subgroups. Therefore, for small sMTC (≤2 cm), HT is also biochemically adequate.
More importantly, we confirmed comparable prognosis between HT and TT in patients with sMTC, especially those with primary tumors ≤2 cm. Similar structural or biochemical outcomes were consistently observed across all subgroup analyses. The RETM918T mutation is commonly associated with tumor aggressiveness,16,27 whereas the burden of lymph node metastasis determines the likelihood of structural and biochemical cure28,29 and a preoperative calcitonin level >500 pg/mL may indicate extensive neck disease.1,30 Tumor desmoplasia is another independent risk factor for worse prognosis in sMTC, and may be a potential indicator for TT if detected in a rapid intraoperative frozen section.11 However, for small sMTCs in our cohort, the similarity in structural and biochemical outcomes between the HT and TT groups persisted in all subgroup strata, even for patients with RETM918T mutation, lymph node metastasis (including N1b stage; ie, lateral neck metastasis), high preoperative calcitonin level, and tumor desmoplasia. These findings reinforce the safety of HT for small primary tumors in sMTC.
Our study has several strengths. First, despite the rarity of this disease, this nationwide cohort represents the largest MTC cohort to date, providing a valuable opportunity to analyze clinical controversies. Second, in the past, the treatment modality for sMTC in China did not require TT for all cases, allowing a relatively large subset of patients with sMTC to undergo HT, which provides a relatively sufficient patient sample for further comparison. Nevertheless, this study also has some inevitable limitations. First, although the rarity of MTC makes it nearly impossible to conduct large-scale prospective randomized controlled trials to compare the 2 surgeries, the retrospective nature of this study is a limitation. Second, an international MTC grading system was proposed in 2022.31 However, most patients in our cohort underwent surgery prior to this, and many patients did not have additional tumor sections available for Ki-67 staining, and therefore tumor grade was not included as a covariate in our study. Third, accurate preoperative determination of sporadicity should be made through genetic testing of peripheral blood, which is not yet widely available, especially in developing countries. We do not recommend clinicians perform HT in MTC without confirming the hereditary status through genetic testing.
Conclusions
For small (≤2 cm) unilateral sMTCs, HT does not compromise prognosis and confers a very low risk of recurrence or residual disease in the contralateral lobe. It is a safe and adequate alternative to standard surgery, avoiding the additional complications associated with TT.
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