PDF
Citation
Print
INTRODUCTION
Medullary thyroid carcinoma (MTC), which accounts for 2% to 4% of thyroid cancers, arises from calcitonin-secreting C cells and is responsible for up to 13.4% of deaths related to thyroid cancer [1]. Studies have shown that the 5- and 10-year overall survival (OS) rates for MTC patients range from 70%–94% and 57%–90%, respectively [2-8], while the 5- and 10-year recurrence-free survival (RFS) rates vary between 83%–86% and 65%–66% [4,5]. Distant metastasis, which was initially detected in 7%–23% of MTC patients, is a well-established strong predictor of disease-specific mortality [4,9]. Previous studies have identified several risk factors for recurrence and mortality in MTC patients, including age at diagnosis, specific types of the rearranged during transfection (RET) mutation, lymph node status, tumor stage, and postoperative biochemical remission (BCR) status [4,10].
However, advances in preoperative diagnostics, incorporating genetic, biochemical, radiological, and cytological examinations, have facilitated the early-stage detection of MTC, leading to diagnoses at earlier tumor stages [11,12]. This progress, along with evolving guidelines and clinical practices such as increased surgical extents, has changed the clinicopathological characteristics and prognosis of MTC over time [13-16]. Given these temporal changes, there is a critical need for updated information on the long-term outcomes of MTC and the identification of prognostic factors to guide tailored management. Although retrospective analyses of MTC patients from our center have been conducted, covering the period from 1982 to 2012 [4,17], a decade has since passed, necessitating a comprehensive reassessment. This reassessment includes data from newly diagnosed patients and extend the follow-up data for existing patients over subsequent years. Therefore, the objective of this study was to evaluate the long-term outcomes of surgically treated MTC patients over more than three decades, analyzing their characteristics and identifying prognostic factors related to recurrence and survival.
METHODS
Patient selection and data collection
A retrospective review was conducted on 226 MTC patients diagnosed and followed from 1980 to 2020 at Seoul National University Hospital. The study excluded cases with incomplete medical records (n=40), resulting in a total of 226 patients included for analysis. Data were collected on patient and disease characteristics, including RET mutation testing, surgical extents, histopathology, and clinical outcomes such as recurrences and deaths. Additionally, information on the survival status of patients, duration of survival, and cause of death up to December 31, 2019, was obtained from the registered data of Korea Statistics [18]. The causes of death were categorized as either death from all causes, defined as patient death for any reason, or MTC-specific death, defined as patient death related to MTC. To assess changes in clinical characteristics and long-term outcomes over time, patients were grouped by their year of diagnosis. The year 2009/2010 was selected as the reference point for dividing the patient cohorts into different time periods, coinciding with the publication of the American Thyroid Association (ATA) guidelines in 2009 and 2015 [15,16], which may have significantly influenced clinical practice for managing MTC. Patients were then grouped into 10-year intervals based on their year of diagnosis (Supplemental Table S1). Our observations indicated that the clinical characteristics were similar between the periods 1980–2009 and 2010–2020, supporting this grouping approach. The study was conducted in accordance with the Declaration of Helsinki and received approval from the Institutional Review Board of Seoul National University Hospital (No. 2012-081-1181), with a waiver for individual consent for the retrospective analysis.
Definitions and outcomes of interest
Initial distant metastasis was defined as the detection of structural metastasis to distant organs beyond the neck, based on imaging findings at the time of the initial diagnosis of primary MTC. Recurrence was identified through the detection of structural recurrence, pathologically confirmed via reoperation, or through evidence of metastasis to distant organs outside the neck on imaging. Persistent disease was indicated by evidence of metastasis at the time of surgery that persisted postoperatively, or by evidence of ongoing structural disease within 6 months following surgery. For the postoperative status, patients were classified based on their serum calcitonin levels and the presence of structural disease on imaging studies conducted within 6 months of surgery. BCR was characterized by a serum calcitonin level of <10 pg/mL with no evidence of structural disease, while biochemical disease (BCD) was indicated by a serum calcitonin level of ≥10 pg/mL, also with no evidence of structural disease. At the last follow-up, patients were categorized into one of the following statuses: BCR, BCD, stable disease (SD), progressive disease (PD), or death due to MTC. SD was defined as a recurrence of the disease with a serum calcitonin level of ≥10 pg/mL and structural disease, but without significant changes in the disease status during the last follow-up. PD was defined as a recurrence of the disease with an observed increase in size or extent during the last follow-up. Death due to MTC was defined as a death resulting from the progression of MTC.
Long-term oncologic outcomes, including disease-specific survival (DSS) and RFS, were analyzed. DSS was defined as the time from surgery to death from MTC, and RFS was defined as the time from surgery to clinically evident recurrence. Prognostic factors for DSS and RFS of MTC patients, as well as OS, defined as the time from surgery to death from any cause, and distant metastasis-free survival (DMFS), defined as the time from surgery to clinically evident distant metastasis, were analyzed.
RET mutation and screening
Medical and family histories, along with RET proto-oncogene mutation analysis, were reviewed to determine whether the disease was sporadic or hereditary. Genetic testing for RET proto-oncogene mutations (exons 8, 10, 11, 13, 14, 15, 16) was performed only in selected patients. Patients who tested positive for RET mutations or those who exhibited clinical suspicion for multiple endocrine neoplasia type 2 (MEN2) syndromes—either through a family history of MTC or the presence of MEN2 phenotypes—were classified as having hereditary MTC. Conversely, those who tested negative were classified as having sporadic MTC. Among the patients tested for RET mutations, those with detected mutations were labeled RET-positive, while those without detected mutations were labeled RET-negative. RET-positive patients were further categorized as either screened or non-screened, depending on whether MTC was identified during screening examinations prompted by positive RET results. RET mutations were classified as moderate, high, or highest risk, according to the guidelines set forth by the ATA [16].
Statistical analysis
Data were presented as mean±standard deviation or as percentages (n%) for descriptive statistics. For continuous variables, either the Student t test or the Mann-Whitney U test was employed. Categorical variables were analyzed using the Pearson chi-square test or logistic regression analysis. Kaplan–Meier survival analysis was utilized to estimate the DSS and RFS rates, with the log-rank test comparing these rates between groups. To compare the long-term oncologic outcomes between RET-negative patients and those not screened but RET-positive, 1:1 propensity-score matching was conducted to adjust for significant variables such as age and sex. This matching was executed using the MatchIt package (R Foundation for Statistical Computing, Vienna, Austria). The Cox proportional hazard regression model was then applied to identify prognostic factors for recurrence and disease-specific death. In all analyses, a P value of less than 0.05 was considered to indicate statistical significance. All data were analyzed using R software version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Clinical characteristics and long-term oncologic outcomes over time
The clinical characteristics of all MTC patients, categorized by the year of diagnosis, are summarized in Table 1. Between 1980 and 2020, a total of 226 patients were diagnosed with MTC. The cohort included 62 (27%) men and 164 (73%) women, with a mean age of 48.1±15.5 years. When comparing the two groups by diagnosis period (1980–2009 vs. 2010–2020) patients diagnosed in the latter period were older, although the sex distribution was similar (P=0.669). Furthermore, 24% of cases were hereditary, although no significant differences were observed between the groups (P=0.719). RET mutation testing was conducted more frequently in the later period (39% vs. 80%, P<0.001), but the prevalence of RET mutations did not differ significantly between the groups (18% vs. 23%, P=0.524). Surgical interventions were more extensive in the 2010–2020 group, including greater surgical extent (P=0.003) and more extensive lymph node dissection (P<0.001). Pathological findings revealed that the mean tumor size was larger in the earlier group (2.3 cm vs. 2.0 cm, P=0.003), and lymph node metastasis status was worse in 1980–2009 than in 2010–2020, but with marginal statistical significance (P=0.072). There were also more combined carcinomas, especially papillary thyroid carcinomas, in the 2010–2020 group (P<0.006). There were no significant differences in extrathyroidal extension and resection margin status between the two groups (P>0.050). Eight cases (4%) exhibited initial distant metastasis, with no significant difference between the two groups (P=0.151) (Table 1).
Table 1.
Clinical Characteristics of Medullary Thyroid Carcinoma Patients by Year of Diagnosis
| Characteristic | Total (n=226) | 1980–2009 (n=120) | 2010–2020 (n=106) | P value |
|---|---|---|---|---|
| Female sex | 144 (64) | 78 (65) | 66 (62) | 0.669 |
| Age, yr | 48.1±15.5 | 44.9±14.8 | 51.7±15.5 | <0.001 |
| Hereditary | 53 (24) | 27 (23) | 26 (25) | 0.719 |
| RET mutation, positive/tested | 46 (20)/132 (58) | 22 (18)/47 (39) | 24 (23)/85 (80) | 0.524/<0.001 |
| Operation | ||||
| Surgical extent, less than TT/TT | 17 (8)/209 (92) | 15 (13)/105 (88) | 2 (2)/104 (98) | 0.003 |
| Lymph node extenta, CND/LND/none | 88 (42)/83 (40)/39 (19) | 26 (25)/45 (42)/35 (33) | 62 (58)/38 (36)/4 (4) | <0.001 |
| Pathology | ||||
| Tumor size in greatest length, cm | 2.1±1.8 | 2.3±1.5 | 2.0±2.0 | 0.003 |
| Tumor size, <2 cm/≥2 cm | 111 (49)/85 (38) | 43 (36)/52 (43) | 68 (64)/33 (31) | 0.003 |
| ETE, none/microscopic/gross | 129 (68)/41 (22)/19 (10) | 62 (69)/19 (21)/9 (10) | 67 (68)/22 (22)/10 (10) | 0.981 |
| Lymph node metastasisb, none/CN/LN | 64 (28)/42 (19)/56 (25) | 20 (17)/16 (13)/29 (24) | 44 (42)/26 (25)/27 (25) | 0.072 |
| Resection margin positive status | 12 (6) | 7 (8) | 5 (5) | 0.805 |
| Combined pathology, PTC/FTC | 28 (14)/2 (1) | 8 (8)/1 (1) | 20 (19)/1 (1) | 0.006 |
| Initial distant metastasis | 8 (4) | 2 (2) | 6 (6) | 0.151 |
| Postoperative neck radiotherapy | 41 (18) | 22 (18) | 19 (18) | 0.994 |
| Recurrence outcomes | ||||
| Follow-up period, mo | 70.5 (36.0–134.5) | 74.5 (37.75–158.3) | 64.5 (34.5–119.3) | <0.001 |
| Recurrence/persistence | 92 (41)/8 (4) | 65 (54)/2 (2) | 27 (25)/6 (6) | <0.001 |
| Cumulative recurrence rate at 5/10/20/30 years, % | 28.9/43.9/59.8/67.9 | 32.6/50.9/65.4/72.3 | 23.8/33.2/-/- | 0.031 |
| Sites of recurrencec | ||||
| LN/mediastinum/distant organs | 83 (89)/25 (27)/69 (74) | 60 (91)/18 (27)/44 (67) | 23 (85)/7 (26)/25 (93) | 0.265 |
| Single/multiple | 44 (44)/56 (56) | 33 (49)/35 (51) | 11 (34)/21 (66) | 0.186 |
| Final disease status, BCR/BCD/CD | 113 (50)/40 (18)/41 (18) | 50 (42)/26 (22)/22 (18) | 63 (59)/14 (13)/19 (18) | 0.139 |
| Survival outcomes | ||||
| Follow-up period, mo | 116.0 (57.8–170.0) | 157.5 (72.8–227.3) | 89.5 (48.3–132.8) | <0.001 |
| Mortality, MTC-specific/all causes | 32 (14)/43 (19) | 22 (18)/31 (26) | 10 (9)/12 (11) | 0.016/0.005 |
| Cumulative disease specific death rate at 5/10/20/30 years, % | 7.3/10.6/25.7/31.9 | 7.8/10.1/25.5/31.7 | 7.3/11.5/-/- | 0.995 |
Values are expressed as number (%), mean±standard deviation, or median (interquartile range).
RET, rearranged during transfection; TT, total thyroidectomy; CND, central node dissection; LND, lateral node dissection; ETE, extrathyroidal extension; CN, central node; LN, lateral node; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; BCR, biochemical remission; BCD, biochemical disease; CD, clinical disease; MTC, medullary thyroid carcinoma.
a Available information for 210 patients (106 patients in the 1980–2009 period and 104 patients in the 2010–2020 period);
b Available information for 166 patients (67 patients in the 1980–2009 period and 99 patients in the 2010–2020 period);
c Percentages are relative to only 93 recurrent patients (66 patients in the 1980–2009 period and 27 patients in the 2010–2020 period). Data includes cases with recurrence at multiple sites, with each site counted separately, which may have resulted in duplicate counts. Specific recurrences to distant organs are summarized in Supplemental Table S2.
Survival analysis of all MTC patients revealed 5-, 10-, 20-, and 30-year RFS rates of 71.1%, 56.1%, 40.2%, and 32.1%, respectively, along with 5-, 10-, 20-, and 30-year DSS rates of 92.7%, 89.4%, 74.3%, and 68.1%, respectively (Supplemental Fig. S1). The period from 1980–2009 saw more recurrences than the 2010–2020 period (54% vs. 25%, P<0.001), with 5- and 10-year RFS rates of 66.2% and 48.2% for the earlier period, and 75.5% and 61.2% for the latter period (Table 1). The sites of recurrence, including distant sites, did not differ significantly (Supplemental Table S2). Additionally, there were more deaths attributed to MTC in the 1980–2009 period than in the 2010–2020 period (18% vs. 9%, P=0.016). The RFS rate showed a significant difference between the two periods (P=0.031), but the DSS rate did not (P=0.995) (Fig. 1).
Clinical characteristics according to last follow-up status
When grouped by last follow-up status, 113 patients (50.0%) were in the BCR group, 64 patients (28.3%) were in the BCD or SD group, and 49 patients (21.7%) had PD or died due to MTC. The period from 2010 to 2020 saw a higher proportion of MTC patients with a better last follow-up status (BCR > BCD or SD > PD or death due to MTC) compared to the period from 1980 to 2009 (P<0.001). The male sex ratio and age were higher in patients with PD and those who died due to MTC than in the BCR and BCD or SD groups. Although the extent of surgery did not significantly differ between the groups, the extent of lymph node dissection increased with the severity of the disease status. The prevalence of lymph node metastasis and distant metastasis at diagnosis was higher as the disease status worsened. Poorer pathology findings, including larger tumor size, extrathyroidal extension, and resection margins, were also more commonly associated with advanced disease status. Recurrence and death were more frequent among patients with advanced disease status (Supplemental Table S3).
Prognostic factors for recurrence and survival
The multivariate analyses using the Cox proportional hazards model to identify prognostic factors for OS, DSS, RFS, and DMFS are summarized in Table 2. The univariate and multivariate analyses for each OS, DSS, RFS, and DMFS are summarized in Supplemental Tables S4-S7, respectively.
Table 2.
Multivariate Survival Analysisa Using a Cox Proportional Hazards Model to Identify Prognostic Factors in Medullary Thyroid Carcinoma
OS, overall survival; DSS, disease-specific survival; RFS, recurrence-free survival; DMFS, distant metastasis-free survival; HR, hazard ratio; CI, confidence interval.
a Adjusted for age, sex, hereditary/sporadic, tumor size, resection margin, lymph node metastasis, and initial distant metastasis (summarized data of multivariate analysis of model 2 in Supplemental Tables S4-S7).
Multivariate analysis identified extrathyroidal extension as the strongest independent prognostic factor for both DSS and RFS. For DSS, the hazard ratios (HRs) were 10.500 (95% confidence interval [CI], 1.977 to 55.774; P=0.006) for microscopic extension and 7.942 (95% CI, 1.217 to 51.809; P=0.030) for gross extension. For RFS, the HRs were 4.960 (95% CI, 2.495 to 9.857; P<0.001) for microscopic extension and 3.448 (95% CI, 1.491 to 7.973; P=0.004) for gross extension. Additionally, extrathyroidal extension was associated with increased tumor size, lymph node metastasis, and initial distant metastasis (P<0.001) (Supplemental Table S8).
Age >55 years (HR, 6.447; 95% CI, 1.848 to 22.483; P=0.003) and tumor size ≥2 cm (HR, 5.166; 95% CI, 1.053 to 25.343; P=0.043) were also significant prognostic factors for DSS. Hereditary disease (HR, 1.966; 95% CI, 1.058 to 3.651; P=0.030) and lymph node metastasis (HR, 2.691; 95% CI, 1.088 to 6.657; P=0.032 for central nodes; HR, 4.020; 95% CI, 1.635 to 9.885; P=0.002 for lateral and mediastinal nodes) were also significant prognostic factors for RFS (Table 2).
Survival graphs for each of the prognostic factors for DSS and RFS are shown in Figs. 2, 3, while survival graphs for each of the prognostic factors for OS and DMFS are shown in Supplemental Figs. S2, S3.
Fig. 2.
Survival graphs according to risk factors for disease-specific survival in patients with medullary thyroid carcinoma. (A) Disease-specific survival by age. (B) Disease-specific survival by sporadic versus hereditary disease. (C) Disease-specific survival by tumor size. (D) Disease-specific survival by lymph node (LN) dissection extent. (E) Disease-specific survival by the presence of extrathyroidal extension. (F) Disease-specific survival by the presence of LN metastasis. CND, central node dissection; LND, lateral node dissection; CN, central node.
Fig. 3.
Survival graphs according to risk factors for recurrence-free survival in patients with medullary thyroid carcinoma. (A) Recurrence-free survival by age. (B) Recurrence-free survival by sporadic versus hereditary disease. (C) Recurrence-free survival by tumor size. (D) Recurrence-free survival by lymph node (LN) dissection extent. (E) Recurrence-free survival by the presence of extrathyroidal extension. (F) Recurrence-free survival by the presence of LN metastasis. CND, central node dissection; LND, lateral node dissection; CN, central node.
Genetic characteristics of MTC patients and clinical characteristics and survival of RET mutation-tested patients
Of the one MTC patients, 173 (77%) were clinically sporadic, and 53 (24%) were clinically hereditary, with no significant difference between the two time periods (P=0.719). RET mutation tests were conducted on 132 patients, with 86 (65%) testing RET-negative and 46 (35%) testing RET-positive. The proportion of RET-positive results among those tested was higher in the 1980–2009 group than in the 2010–2020 group (35% vs. 25%, P=0.032). Among the RET-positive patients, 27 (59%) were classified as moderate risk, 15 (33%) as high risk, and three (9%) as highest risk according to the ATA risk classification, with no significant difference in the distribution of ATA risks between the year groups (P=0.318) (Supplemental Table S9).
RET-positive patients were categorized based on whether MTC was identified through screening due to a family history of MEN2 or not. There were 32 non-screened RET-positive patients and 14 screened RET-positive patients. The RET-negative patients were significantly older than both the non-screened RET-positive patients (52.3 vs. 39.3, P<0.001) and the screened RET-positive patients (52.3 vs. 25.2, P<0.001). Additionally, the non-screened RET-positive patients were significantly older than their screened counterparts (39.3 vs. 25.2, P=0.004). The screened RET-positive patients had, on average, significantly smaller tumors than both the RET-negative patients (0.8 cm vs. 1.8 cm, P<0.001) and non-screened RET-positive patients (0.8 cm vs. 2.5 cm, P<0.001). The recurrence rate was significantly lower in the RET-negative patients than in non-screened RET-positive patients (31% vs. 81%, P<0.001), but similar to that of the screened RET-positive patients (31% vs. 7%, P=0.126) (Table 3). There were no significant differences in recurrence sites, including distant recurrence sites (Supplemental Table S10). The survival graphs indicated no significant difference in DSS rates between the RET-negative and non-screened RET-positive patients (P=0.159). However, there was a significant difference in RFS rates between these two groups (P<0.001) (Supplemental Fig. S4).
Table 3.
Clinical Characteristics between RET-Negative and Non-Screened RET-Positive Patients before and after Propensity-Score Matching
| Characteristic |
Before propensity-score matching |
After propensity-score matching |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| RET-negative (n=86) | RET-positive (non-screened) (n=32) | P valuea | RET-positive (screened) (n=14) | P valueb | P valuec | RET-negative (n=86) | RET-positive (non-screened) (n=32) | P value | |
| Sex | |||||||||
| Male | 28 (33) | 12 (38) | 0.614 | 7 (50) | 0.204 | 0.428 | 12 (38) | 12 (38) | >0.999 |
| Female | 58 (67) | 20 (63) | 7 (50) | 20 (63) | 20 (63) | ||||
| Age, yr | 52.3±11.8 | 39.3±13.2 | <0.001 | 25.2±16.9 | <0.001 | 0.004 | 42.4±10.2 | 39.3±13.2 | 0.216 |
| Follow-up duration, yr | 103 (61–149) | 149 (104–307) | <0.001 | 139 (59–188) | 0.201 | 0.054 | 128 (87–156) | 149 (104–307) | 0.055 |
| Medullary thyroid cancer | |||||||||
| Basal calcitonin, pg/mLd | 1,369±2,950 | 1,469±1,214 | 0.036 | 3,742±12,860 | 0.504 | 0.521 | 2,385±4,396 | 1,469±1,214 | 0.569 |
| Tumor size, cme | 1.8±1.5 | 2.5±1.4 | 0.351 | 0.8±0.6 | <0.001 | <0.001 | 2.4±2.0 | 2.5±1.4 | 0.340 |
| Tumor size >2 cm | 31/84 (37) | 15/26 (58) | 0.099 | 3/14 (21) | 0.411 | 0.062 | 15/30 (50) | 15/26 (58) | 0.759 |
| Extrathyroidal extension | 27/82 (63) | 8/25 (32) | 0.931 | 1/13 (8) | 0.064 | 0.095 | 11/30 (37) | 8/25 (32) | 0.717 |
| Lymph node metastasis | 43/77 (56) | 17/22 (77) | 0.070 | 6/14 (55) | 0.935 | 0.181 | 19/28 (68) | 17/22 (77) | 0.462 |
| Distant metastasis at diagnosis | 3/86 (4) | 0/32 (0) | 0.562 | 0/14 (0) | 0.478 | >0.999 | 2/32 (6) | 0/32 (0) | 0.492 |
| Recur | 26/83 (31) | 26/32 (81) | <0.001 | 1/14 (7) | 0.062 | 0.126 | 14/32 (44) | 26/32 (81) | 0.005 |
| Cumulative recurrence rate at 5/10/20/30 years, % | 21.9/31.4 /44.1/44.1 | 48.9/78.0 /92.7/92.7 | <0.001 | 0.0/90.0/90.0/90.0 | 0.063 | 0.126 | 38.0/52.5/52.5/52.5 | 48.9/78.0/92.7/92.7 | 0.040 |
| Cumulative disease-specific death rate at 5/10/20/30 years, % | 4.1/9.5/19.6/19.6 | 0.0/0.0/4.8/4.8 | 0.159 | 0.0/0.0/0.0/0.0 | 0.250 | 0.504 | 3.4/11.9/11.9/11.9 | 0.0/0.0/4.8/4.8 | 0.250 |
Values are expressed as number (%), mean±standard deviation, or median (interquartile range).
RET, rearranged during transfection.
After 1:1 propensity-score matching of the RET-negative and non-screened RET-positive patients, the clinical characteristics were similar in terms of sex, age, basal calcitonin level, tumor size, extrathyroidal extension, lymph node involvement, distant metastasis at diagnosis, recurrence sites, and disease-specific death (P>0.050). However, there was a significant difference in the recurrence rate (44% vs. 81%, P=0.005) (Table 3). Survival graphs indicated no significant difference in the DSS rate (P=0.249), but a significant difference in the RFS rate (P=0.040) was noted, even after propensity-score matching of RET-negative and non-screened RET-positive patients (Fig. 4).
DISCUSSION
This long-term follow-up study showed that the patients treated in 2010–2020 had significantly improved RFS but no meaningful difference in DSS compared to those treated in 1980–2009. Despite decreases, the recurrence rate remained remarkably high, at 23.8% at 5 years and 33.2% at 10 years. Notably, MTC-related mortality remained unchanged over 40 years, at 7.3%–7.8% at 5 years and 10.1%–11.5% at 10 years. The risk factors for recurrence or mortality varied somewhat, with older age being associated only with mortality, and lymph node metastases or RET proto-oncogene mutations being associated only with recurrence. Extrathyroidal extension and larger tumor size increased both risks, but the association between tumor size and recurrence was not statistically significant.
The reasons for the observed decrease in recurrence rates without a corresponding decrease in mortality remain unclear. This trend was significant across different time periods and between hereditary and non-hereditary cases. The risk factors for DSS included age, extrathyroidal extension, and tumor size greater than 2 cm. In contrast, RFS was associated with extrathyroidal extension and lymph node metastasis. From 1980 to 2009, tumors were generally larger, whereas from 2010 to 2020, the average age of patients was higher, with similar rates of extrathyroidal extension in both periods. The contrasting trends in age and tumor size may account for the minimal changes in DSS observed between these periods. The increased frequency of lymph node dissection during 2010–2020 likely improved RFS by reducing lymph node recurrence, but did not significantly affect DSS, as lymph node metastasis has a weak association with DSS. These findings underscore the importance of early detection at a younger age or before significant tumor growth and extrathyroidal extension to reduce mortality. Additionally, lymph node dissection plays a crucial role in lowering the recurrence rate.
The presence of metastatic lymph nodes during initial surgery is widely recognized as a negative prognostic indicator for achieving complete remission [6,19]. Our study also found that lymph node metastasis at diagnosis was a strong prognostic factor for both recurrence and distant metastasis. However, lymph node dissection itself was not an independent prognostic factor for recurrence and death. Nonetheless, the observed decrease in lymph node metastasis rates after 2010, alongside an increase in lymph node dissection, suggests the importance of this procedure in reducing lymph node recurrence at initial surgery, despite no change in the rates of distant metastases compared to previous years. The increase in lymph node dissection during the 2010–2020 period, likely in response to ATA guideline recommendations [15,16], may have contributed to improved prognosis by removing small or occult lymph node metastases that could otherwise lead to recurrence if left untreated. Survival curves, according to the extent of lymph node dissection, highlighted a superior prognosis among patients undergoing central node dissection (CND). CND may facilitate the removal of clinically undetected micro-metastases during surgery, consequently reducing lymph node recurrence rates. Hence, guidelines advocate for prophylactic CND even in clinically node-negative cases due to the heightened prevalence of occult disease [16,20]. In advanced stages of disease, the benefits of extensive nodal dissection remain debatable since it does not guarantee cure or prolonged survival and may lead to increased morbidity and complications [21]. Thus, the extent of lymph node dissection must be tailored according to the presurgical evaluation [22,23]. Additionally, for those with lymph node metastasis, close follow-up is crucial for detecting any recurrence, enabling timely and appropriate management of recurrent disease.
Extrathyroidal extension has emerged as the most potent prognostic factor for both RFS and DSS, with no significant differences observed between the two time periods studied. It is associated with increasing age, larger tumor size, the extent of lymph node metastasis, and the presence of initial distant metastasis. Given that extrathyroidal extension correlates with advanced disease characteristics, our findings underscore the need for earlier detection of MTC to improve prognosis. However, since extrathyroidal extension independently increases the risk of both recurrence and death, more rigorous follow-up and management are crucial for MTC patients with either microscopic or gross extrathyroidal extension, even if they do not exhibit other advanced disease characteristics. While some previous studies have identified extrathyroidal extension as a risk factor for recurrence and death [4,24,25], others have not [26]. Due to these conflicting results, further research is necessary to confirm our findings regarding the prognostic significance of extrathyroidal extension for recurrence and death.
Similar to trends observed in differentiated thyroid cancer [27-29], the tumor size in greatest length decreased over time when comparing the 1980–2009 and 2010–2020 groups. This trend may be attributed to the early detection of MTC due to advances in imaging techniques, increased screening, and enhanced follow-up in recent years, aligning with previous reports [30-32]. Throughout the study period, clinical diagnostic tools for MTC, including serum calcitonin measurements, neck ultrasonography, and RET genetic testing, continued to evolve [33]. These changes in standard diagnostic procedures could have influenced the detection rates of initial MTCs or recurrent diseases. It is noteworthy that the mean age in the 2010–2020 group was older, despite expectations of more common early detection over time. Although this trend has been observed in other recent studies, the reasons for the increased incidence of older patients remain unclear [34,35]. Possible explanations may include the demographic shift towards an aging population and increased life expectancy due to better healthcare. Additionally, the gradual advancement of MTC, which may result in delayed symptom onset and diagnosis among older patients, along with alterations in thyroid tissue induced by environmental factors or the natural aging process, could also contribute to the development of MTC in older individuals. Nevertheless, further research is needed to fully understand these factors.
The extent of surgery and lymph node dissection was greater in the 2010–2020 group than in the 1980–2009 group. This increase can likely be attributed to changes in surgical practices and the influence of new guidelines published over the years, particularly after the 2009 MTC management guidelines were released by the ATA [15]. Both the early diagnosis and a comprehensive surgical approach, which includes at least a total thyroidectomy and central neck lymph node dissection, are known to significantly improve outcomes for MTC patients [30,36]. These practices may have contributed to the observed decrease in recurrence rates in patients diagnosed with MTC in more recent years. However, our multivariate analysis indicated that the extent of surgery was not an independent predictor of recurrence or death, suggesting that other factors may have played a more significant role in influencing our results.
The genetic landscape of MTC, particularly the role of RET mutations, continues to be a significant focus of both research and clinical interest. Our analysis revealed differential outcomes between RET-negative and RET-positive patients, with RET-negative patients exhibiting higher recurrence rates. This highlights the critical role of genetic profiling in guiding risk assessment and treatment decisions in MTC. The integration of RET mutation testing for family members of MTC patients allows clinicians to identify individuals at risk, providing the opportunity for prophylactic surgeries before the onset of overt clinical disease [37]. Furthermore, the genetic signature within a specific lineage offers prognostic insights into the potential aggressiveness of the disease [16]. Testing for the RET proto-oncogene has increased over time, as documented in our results. This increase was particularly notable following the 2009 ATA guidelines, which recommended RET mutation genetic testing for patients with MTC [15]. However, the proportion of those undergoing RET gene testing still does not meet the 100% recommendation. Possible reasons for this include patients’ reluctance to undergo genetic testing, the high costs and lack of insurance coverage, and issues with the accessibility, convenience, and efficiency of the test.
The implementation of RET gene mutation screening has led to the earlier identification of patients with hereditary MTC, resulting in a higher frequency of early-stage hereditary MTC [38]. Consequently, we observed potential differences in outcomes between screened and non-screened RET-positive patients, necessitating a separate analysis. To accurately assess whether the RET proto-oncogene mutation is associated with recurrence or disease-specific death, we excluded screened patients from the comparative analysis between RET-positive and RET-negative patients. Additionally, we employed propensity-score matching to adjust for age and sex, which are recognized as significant variables. After matching, no significant differences were observed between RET-negative and non-screened RET-positive patients in terms of disease-specific outcomes. However, RET-positive status in non-screened patients was associated with a higher recurrence rate than in RET-negative patients. This finding contrasts with previous studies suggesting the RET mutation does not impact long-term outcomes [26,39]. It is noteworthy, however, that those previous studies did not exclude screened patients from their analyses. Therefore, more research specifically focusing on non-screened RET-positive MTC patients is essential to validate our findings.
This study has several limitations worth noting. As a retrospective analysis, it is subject to the inherent variability in patient management practices over three decades. This variability includes changes in clinical protocols and the evolving quality of data, which occasionally resulted in missing information. Additionally, there was a lack of standardized systematic follow-up evaluations for all patients. Furthermore, the single-center study design limits the robustness and generalizability of the findings. Despite these limitations, our study provides valuable insights into the evolving landscape of MTC management and the factors influencing long-term outcomes. By identifying key prognostic factors and highlighting the impact of surgical interventions and genetic characteristics, our findings contribute to the ongoing efforts to optimize personalized approaches for MTC patients. Although the study included a large cohort, considering the rarity of MTC, further multi-center studies with larger sample sizes are essential to validate and extend these outcomes.
In conclusion, extrathyroidal extension emerged as a strong prognostic factor for both RFS and DSS in MTC. Additionally, hereditary disease and lymph node metastasis significantly impacted RFS, while older age and larger tumor size were associated with decreased DSS. Non-screened RET-positive patients demonstrated higher recurrence rates than RET-negative patients. These findings underscore the importance of early cancer detection, as well as rigorous follow-up and management for MTC patients with adverse prognostic factors. Moreover, despite the stable mortality rate, the observed decline in recurrence over the past decade highlights the need to identify individuals at high risk of MTC-related death to ensure timely and appropriate diagnosis and treatment.
XML Download