GRAPHICAL ABSTRACT

INTRODUCTION

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that originates from parafollicular C cells of the thyroid. MTC is rare, accounting for only 1% to 2% of thyroid cancers; however, it is responsible for up to 15% of thyroid cancer-related deaths [1,2]. Unlike other differentiated thyroid carcinomas (DTCs) originating from follicular cells, which have a sodium iodine symporter, MTC cells do not uptake iodine. Therefore, definitive surgical resection is the only curative therapy for MTC [3,4]. For definitive surgical resection, early detection and curative surgery by a high-volume surgeon are crucial. We previously reported that surgeon volume was associated with the long-term oncologic outcomes of patients with MTC [5]. Several studies have also reported the impact of detection routes on clinical outcomes in all types of thyroid cancer [6-8]. However, data specifically addressing MTC, which has fundamental differences in natural history, treatment, and prognosis from other DTCs, are lacking. Therefore, this study aimed to evaluate the impact of early detection on the clinical outcomes of MTC. We hypothesized that the prognosis of patients with MTC diagnosed early while asymptomatic would be better than that of patients diagnosed late due to symptoms.

METHODS

Study design and population

This retrospective study was approved by the Institutional Review Board of Samsung Medical Center (approval number: 2024-04-020) and was conducted according to the tenets of the Declaration of Helsinki. The need for informed consent was waived owing to the retrospective nature of the study.

In total, 247 patients diagnosed with MTC and treated at Samsung Medical Center in Seoul, Korea between 1995 and 2019 were evaluated. Among them, 103 patients were excluded: 57 patients who underwent primary operation at another hospital, 29 patients who had incomplete follow-up data, and 17 patients with familial MTC detected through genetic testing as part of family screening for proband cases. Thus, 144 patients were included in the final analysis. Clinicopathological information was collected from electronic medical records (EMRs). The cause of death and date of death were obtained from the EMR or the Korean National Statistical Office database. The detection methods were classified into asymptomatic and symptomatic presentations.

Study outcome

The primary outcome of interest was cancer-specific survival (CSS), defined as the time from the date of initial surgery until cancer-specific death or the last censoring event. The secondary outcomes of interest included were the initial treatment response and final clinical outcomes.

Definition of initial treatment response

Initial treatment response for the first-year clinical outcome was used as previously suggested [9,10]. Treatment response was determined according to the nadir serum calcitonin and carcinoembryonic antigen (CEA) levels and imaging results within the first year after initial surgery. Treatment response was classified as excellent, biochemical incomplete, or structural incomplete. Excellent response was defined as undetectable calcitonin and normal CEA levels without structural evidence of disease. Biochemical incomplete response was defined as detectable calcitonin or abnormal CEA levels without structural evidence of disease. Structural incomplete response was defined as persistent or recurrent structural disease. Undetectable calcitonin levels were determined as less than 7.7 pg/mL according to the functional sensitivity value of our institution.

Definition of final clinical outcomes

The final clinical outcomes were determined based on the latest follow-up clinical data. They were divided into three categories of (1) no evidence of disease (NED), (2) biochemical evidence only, and (3) structurally identifiable. NED was defined as no identified structural disease with undetectable calcitonin level and normal range of CEA level. Biochemical evidence only was defined as no identified structural disease but detectable calcitonin or CEA levels above the normal range. Structurally identifiable was defined as identification of any structural disease through structural or functional imaging studies.

Statistical analysis

Continuous variables are described as the mean±standard deviation or median (interquartile range [IQR]) and were compared between groups using the t test or Mann–Whitney test. Meanwhile, categorical variables are presented as numbers with percentages and were compared using the chi-square test or Fisher’s exact test. CSS rates were estimated using the Kaplan–Meier method and compared between groups using the log-rank test. All statistical analyses were conducted using SPSS version 27.0 for Windows software program (IBM Co., Armonk, NY, USA). P<0.05 was considered statistically significant.

RESULTS

Patient characteristics

The mean age at initial surgery was 51.4±13.2 years, and 92 patients (63.9%) were female. The baseline demographic and clinicopathological characteristics of the 144 patients with MTC are described in Table 1. Among the 144 patients, 104 (72.2%) and 40 (27.8%) patients were diagnosed with MTC through the asymptomatic detection and symptomatic presentation, respectively. In the asymptomatic group, MTC was mostly detected during routine health check-ups: ultrasonography in 91 patients (87.5%), an increase in serum calcitonin or CEA levels in 10 patients (9.6%), and incidentally through other imaging studies, such as positron emission tomography or computed tomography, in the remaining three patients (2.9%). Meanwhile, in the symptomatic group, the patients were diagnosed based on symptoms of palpable neck mass, voice changes, and pain. RET germ-line mutations were detected in 16/97 (16.5%) patients who underwent gene testing.

The median primary tumor size was 1.8 (0.8–2.4) cm. A total of 143 (99.3%) patients underwent total thyroidectomy, with 138 (95.8%) undergoing central node dissection and 83 (57.6%) undergoing lateral node dissection, respectively. Cervical lymph node metastasis was found in 72 (50.0%) patients. With respect to the American Joint Committee on Cancer/tumor, node, metastasis (TNM) 8th stage, 57 (39.6%) patients had stage I disease; 16 (11.1%) patients, stage II disease; 16 (11.1%) patients, stage III disease; and 52 (36.1%) patients, stage IV disease. Data on preoperative serum calcitonin levels were available in 139/144 patients; the median level was 378.0 pg/mL (IQR, 97.0 to 1,150.0). Data on postoperative serum calcitonin levels were available in all patients; the median level was 5.0 pg/mL (IQR, 2.2 to 33.8). Data on preoperative serum CEA levels were available in 92/144 patients; the median level was 8.8 ng/mL (IQR, 2.5 to 29.5). Data on postoperative serum CEA levels were available in 132/144 patients; the median level was 1.4 ng/mL (IQR, 0.8 to 2.6). The median follow-up duration was 120.0 months (IQR, 74.0 to 175.5).

Between-group comparison of baseline characteristics

The symptomatic group was significantly older (P=0.026) and exhibited a higher prevalence of RET germ-line mutations (P=0.009). Additionally, the symptomatic group demonstrated a significantly larger primary tumor size (P<0.001), a higher frequency of lateral neck lymph node metastasis (P=0.006), more advanced TNM staging (P<0.001), and elevated pre- and postoperative serum calcitonin levels (P<0.001 for both). However, there was no significant between-group difference in sex, surgical extent, and preoperative CEA levels (Table 2).

Between-group comparison of initial treatment responses and final clinical outcomes

Initial treatment response was significantly different between the two groups (P<0.001). In the asymptomatic group, 74 patients (71.2%) had an excellent response, 28 patients (26.9%) had biochemical incomplete response, and two patients (1.9%) had structural incomplete response. The symptomatic group had a poorer response to initial therapy, with only 16 patients (40.0%) achieving excellent response, 15 patients (37.5%) having biochemical response, and nine patients (22.5%) having structural incomplete response. The final clinical outcomes were also significantly different between the two groups (P<0.001). In the asymptomatic group, 70 patients (67.3%) achieved NED, 26 patients (25.0%) had biochemical evidence only, and eight patients (7.7%) had structurally identifiable response. Meanwhile, the symptomatic group showed a poorer status at the final follow-up examination, with 12 patients (30.0%) achieving NED, 10 patients (25.0%) having biochemical evidence only, and 18 patients (45.0%) showing structurally identifiable response. These significant differences between the two groups persisted even after excluding microcarcinomas of 1 cm or less from the analysis (Table 3).

Between-group comparison of cancer-specific survival

The Kaplan–Meier curves of CSS according to the diagnostic route are shown in Fig. 1. The symptomatic group showed significantly poorer survival outcomes than did the asymptomatic group (log-rank P=0.023).

DISCUSSION

In the present study, we examined the impact of early detection on the clinical outcomes of MTC. We investigated 144 patients with MTC, and diagnostic route was divided into two categories as asymptomatic and symptomatic. The results of our study show that in comparison to symptomatic detection, early MTC detection in asymptomatic patients results in significantly better initial treatment response, final clinical outcomes, and CSS.

The presence of lymph node and distant metastases at initial diagnosis is associated with significantly worse prognosis and survival rate in MTC [11,12]. Therefore, early detection is crucial to ensure complete surgical resection. Consistent with previous findings, our study found that the symptomatic diagnostic route in MTC was significantly associated with a larger primary tumor size, more frequent lateral neck lymph node metastasis, more advanced TNM staging, and higher pre- and postoperative serum calcitonin levels (P<0.001). A 2023 retrospective multicenter cohort study of patients with MTC in Israel suggested that an accurate preoperative diagnosis of MTC might enable guideline-concordant surgical treatment and ultimately yield an overall survival benefit [13]. Despite this, early detection and accurate preoperative diagnosis of MTC are difficult for several reasons. First, the existing ultrasonographic risk stratification systems are mainly focused on papillary thyroid carcinoma (PTC) and cannot be applied in MTC [14,15]. Second, fine-needle aspiration cytology has low diagnostic sensitivity for MTC [16]. In a 2015 meta-analysis by Trimboli et al. [17] that included 641 cases from 15 studies, the rate of readings as suspicious for or consistent with MTC was only 56.4% (95% confidence interval, 52.6% to 60.1%). Third, the usefulness of routine measurement of serum calcitonin concentration in patients with thyroid nodules is still debated despite the proven usefulness of calcitonin levels in early diagnosis, prediction of disease extent, and prognostic prediction [18].

In addition, there have been concerns regarding the overdiagnosis and overtreatment of thyroid cancer. The development and widespread use of ultrasonography has increased the diagnosis of thyroid cancer. Further, the indolent nature and favorable prognosis of PTC, which accounts for the majority of thyroid cancers, has led to controversy about overdiagnosis and overtreatment [19-21]. Thus, the concept of active surveillance for papillary thyroid microcarcinoma (micro-PTC) has been suggested [22]. However, it is important to note that medullary thyroid microcarcinoma (micro-MTC) is a distinct entity from micro-PTC. Micro-MTC has an aggressive nature. Kim et al. [23] conducted a meta-analysis of 15 studies and compared the clinicopathological significance and prognosis of micro-MTC with those of macro-MTC. They found that the aggressive features of micro-MTC, such as multifocality and distant metastasis, are similar to those of macro-MTC; therefore, treatment of microMTC should be approached with a similar focus as that of macro-MTC. In 2023, Wu et al. [24] studied 56 patients with microMTC and found that central lymph node metastasis, local invasion, and overall survival rates were similar to those of macroMTC. In 2023, Kesby et al. [25] studied the natural history and outcomes of sporadic micro-MTC. They reported that most sporadic micro-MTCs were detected incidentally, but 12% (5/64) of their patients developed recurrence and 7% (3/64) died of MTC. They concluded that tumor size was not significantly associated with the outcomes of micro-MTC. The clinical outcomes of micro-MTC in the current study were similar to those of previous studies. Among the 50 patients with micro-MTC, 14 patients (28.0%) had stage III/IV disease, and two patients died of MTC. Notably, even in the symptomatic group, five patients (12.5%) had micro-MTC, all of whom presented with a palpable mass in the neck, and four of whom had stage 4A disease (Supplemental Tables S1-S3). Collectively, the current and previous findings suggest that early detection is critical, considering the aggressive nature and poor prognosis of micro-MTC.

The strength of this study is that it enrolled a relatively large number of patients with MTC over a 25-year period. Previous studies have identified several factors that affect the clinical outcomes of MTC, including age, sex, primary tumor size, extrathyroidal extension, metastasis, pre/postoperative calcitonin level, initial surgical extent, and surgeon volume [5,11,26-28]. In addition, aside from existing prognostic factors, there have been no direct comparisons of clinical outcomes between early detection (asymptomatic) and late detection (symptomatic) groups in MTC. However, this study also has some limitations. First, it was conducted in a single tertiary referral center. Therefore, there was a potential selection bias that patients with more advanced stages were enrolled. Second, this was a retrospective study. Third, additional clinical information such as Ki-67 index, mitotic count, and necrosis was not available; therefore, tumor grading could not be assessed because most pathological tissues were old. Multicenter prospective studies are needed to validate the findings.

In conclusion, compared to symptomatic detection, early detection in asymptomatic patients results in significantly better initial treatment response, final clinical outcomes, and CSS in MTC.

Supplementary Material

Article information

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

The authors would like to express their gratitude to all the staff at the Thyroid Center of Samsung Medical Center for their support and assistance.

AUTHOR CONTRIBUTIONS

Conception or design: J.H.Y., J.H.C. Acquisition, analysis, or interpretation of data: J.H.Y., D.E.L., B.R.K., T.H.K., S.W.K., J.H.C. Drafting the work or revising: J.H.Y., J.H.C. Final approval of the manuscript: J.H.Y., J.H.C.

Fig. 1.

Comparison of cancer-specific survival between the asymptomatic and symptomatic groups. The symptomatic group has significantly poorer survival outcomes than the asymptomatic group (log-rank P=0.023).

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