The Long-Term Cure of Patients With Hereditary Medullary Thyroid Carcinoma

40 years of follow-up in a single center

Background: The cure rate of patients with hereditary medullary thyroid carcionoma (MTC) can be decisively improved by screening for elevated calcitonin (Ctn) levels and RET gene mutations in patients from families affected by multiple endocrine neoplasia type 2 (MEN2), followed by prophylactic thyroidectomy in persons with mutated RET genes. In this long-term observational study, we investigated whether postoperative cures are indeed maintained decades after the procedure.

Methods: From 1979 to 2021, 277 patients with MEN2 who underwent thyroidectomy were observed postoperatively for 14.4 ± 10.3 years (mean, standard deviation). They were classified as either cured or not cured depending on the last measured serum Ctn level (cured, Ctn < 10 pg/mL or < 2 pg/mL; not cured, Ctn ≥ 10 pg/mL). Depending on their RET mutation status, they were categorized as moderate, high, or highest risk (121, 130, and 26 patients, respectively).

Results: 154 patients (55.6%) obtained a long-term cure (Ctn <10 pg/mL). The median age at surgery was 27, 14, and 4 years in patients at moderate, high, and highest risk. All 52 patients who had undergone prophylactic thyroidectomy before the age of 6 years, 9 years, or 6 months had a Ctn level below 2 pg/mL and were cured at the end of the follow-up period. In a multivariable analysis, prognostic factors for a long-term cure were a lower tumor stage and, by tendency, classification as belonging to the moderate as opposed to the highest-risk group.

Conclusion: In patients receiving an early diagnosis of MEN2 via family screening, prophylactic thyroidectomy taking into account the RET mutation risk group can achieve a long-term cure of MTC with undetectable serum Ctn levels.

Medullary thyroid carcinoma (MTC) is the malignant degeneration of thyroid C cells, with an incidence of 0.19/100 000 and a prevalence of 3.8/100 000 (1). MTCs release calcitonin (Ctn), which is used as a sensitive and specific tumor marker (2, 3). A quarter of MTC cases are familial as a result of a mutation in the RET proto-oncogene in the context of the tumor syndrome multiple endocrine neoplasia type 2 (MEN2), which is inherited in an autosomal dominant manner (4). The only curative treatment for MTC is surgical removal of the thyroid gland (5). Since the introduction of serum calcitonin determination in 1971 (6), efforts have been made to diagnose MEN2A early on in affected families via annual screening and to operate accordingly (7). This approach was hampered by the need to annually repeat the testing of children. It was not until the discovery in 1993 that mutations in the RET proto-oncogene cause MEN2 (8) that it became possible to prospectively screen RET mutation carriers in MEN2 families and introduce a new concept of removal of a seemingly healthy thyroid gland in RET mutation carriers before carcinoma could develop: that is to say, prophylactic (no histologically detectable carcinoma, thereby preventing a potential carcinoma) or early (a small, localized carcinoma may be present and removal is associated with cure) thyroidectomy. Early studies on children operated in this way showed a favorable outcome in terms of the normalization of postoperative Ctn level depending on the age of the patients at the time of surgery and the type and location of the mutation on the RET gene (9, 10, 11, 12, 13). RET mutations are categorized into three risk groups (highest, high, and moderate risk) based on the age at which MTC develops, and the recommended age for prophylactic thyroidectomy is based on this categorization: In highest-risk cases, thyroidectomy is recommended as early as possible in the first year of life; in the high-risk group, it is recommended in the fifth year of life or earlier if serum Ctn levels rise; and in the moderate-risk group, it is recommended after the fifth year of life based on elevated serum Ctn levels (5). MEN2 patients have a 70% (moderate-risk group) to 100% (high- and highest-risk group) risk of developing MTC by the age of 70 years. These findings were included in the 2001 MEN guidelines (14), the 2015 ATA MTC guidelines (5), and the 2019 ESMO guidelines (15) and were then used as the standard treatment for hereditary MTC (16, 17, 18, 19, 20, 21). In this context, it was found that postoperative serum Ctn is an excellent prognostic marker for cure or recurrence. Although patients with serum Ctn < 10 pg/mL were initially considered to be biochemically cured, 0.5–24% showed a biochemical recurrence defined as Ctn levels that rose again to above 10 pg/mL during follow-up (9, 12, 19, 20, 22, 23, 24). Given that the sensitivity of the biochemical marker Ctn is significantly better than that of imaging, tumor localization can generally only be determined at serum Ctn levels of > 150 pg/mL.

The definition of postoperative cure as measured by Ctn has varied over the course of recent decades, but was generally < 10 pg/mL. Meanwhile, more sensitive Ctn assays were developed around 20 years ago that better capture the normal range, meaning that the previously common definition of cured (Ctn < 10 pg/mL) needs to be reconsidered. A small proportion of patients that were initially considered to be cured developed detectable serum Ctn over time with the new assays (25, 26, 27). Due to the slow growth of MTCs and the fact that recurrences can develop even decades later (28), patients that have undergone prophylactic/early thyroidectomy require long-term follow-up.

The aim of this observational study was to evaluate which characteristics of the disease course are associated with long-term cure, as measured by Ctn level at the end of the study. This was investigated in a series of 277 MEN2 patients that underwent thyroidectomy and received long-term care at a single center.

Patients and methods

A retrospective analysis evaluated the medical records of 357 patients with hereditary MTC or a familial risk for MEN2 (Figure). Using a data collection form, demographic, clinical, imaging, biochemical, genetic, and surgical data were collected. Patients were examined, diagnosed, and treated by the authors (FR and KFR) at regular intervals (6–12 months) between 1979 and 2021 at the endocrinology outpatient department of the Heidelberg University Hospital, Germany, and from 1996, at an endocrinology practice in Heidelberg. Treatment was carried out in line with state-of-the-art diagnosis and treatment at the respective time (5, 14, 15). The study was approved by the Heidelberg University ethics committee (No. S-003/2015).

Figure

Study population with MEN2: selection process MEN2, multiple endocrine neoplasia type 2

All biochemical and imaging tests were the standard methods used at the time. The primary endpoint was serum Ctn level at the last visit, whereby patients with ≥ 10 pg/mL were classified as not cured and compared to cured patients (< 10 pg/mL). The endpoint used, cure (Ctn < 10 pg/mL), was selected in order to enable a comparison with the vast majority of published studies. For further analysis, the two groups with serum Ctn levels of < 10 pg/mL and < 2 pg/mL were compared with each other. Ctn determination was carried out from 2000 onwards with the chemiluminescence assay from the Nichols Institute (analytical sensitivity of 1 pg/mL, reference range M < 6.5 pg/mL F < 4.1 pg/mL), from 2004 with the Diasorin assay (sensitivity of 1 pg/mL, reference range M < 9.8 pg/mL, F < 4.0 pg/mL), and from 2012 onwards with the Roche assay (sensitivity of 0.5 pg/mL, reference range M < 9.5 pg/mL, F < 6.4 pg/mL). For the definition of cure at the end of the study (Ctn < 2 pg/mL), only Ctn measurements from chemiluminescent assays with an analytical sensitivity of ≤ 1 pg/mL were used. If available, preoperative Ctn levels as well as postoperative Ctn levels (2–6 months postoperatively) were included in the analyses. Only MEN2 patients with a known germline mutation in the RET proto-oncogene were included in the study. A total of 80 patients were excluded for various reasons (Figure). The remaining 277 patients underwent thyroidectomy, some involving central and lateral lymph node extirpation. Based on histology, either medullary thyroid carcinoma, C-cell hyperplasia (CCH), or normal findings were documented. Postoperative staging was carried out in line with the American Joint Committee on Cancer (29) and the 2015 American Thyroid Association (ATA) guidelines (5). Patients with C-cell hyperplasia or normal findings were classified as stage 0. The 277 patients that had undergone thyroidectomy were assigned to three risk groups according to their RET mutation (5): highest risk (HST; codon 918), high risk (H; codon 634, 883), moderate risk (MOD; all other mutations except codon 918, 634, and 883). In family screening, a distinction was made between index patients and patients that were already symptomatic or had an elevated serum Ctn level at first screening (primary screening) and asymptomatic RET mutation carriers who only had an elevated Ctn level in follow-up investigations (secondary screening) or had reached the recommended age limit for surgery.

Statistics

Continuous data are given as mean (x), standard deviation (± SD), median (M), and range (minimum, maximum), and categorical variables as absolute and relative frequency. The data were compared separately for each RET mutation risk group. Continuous data were analyzed using Student’s t-test and non-parametric data using Wilcoxon’s rank-sum test for unpaired groups. Categorical data were compared using the Chi-squared test. Multivariable logistic regression analysis was used to assess the dependence of cure rate on age at surgery, sex, surgical method, ATA RET mutation risk group, and tumor stage.

Results

Cured patients (Ctn < 10 pg/mL)

Of the 277 patients that underwent surgery, 154 (55.6%) had a Ctn level of < 10 pg/mL (M, 1.0 pg/mL) after a median follow-up period of 15 years (range, 1–47 years) and were considered cured (Table 1). The age of cured patients at the time of surgery was 17 years (M, range, 0.5–69 years). The preoperative Ctn level was available for 114 cured patients and was 23 pg/mL (M, range 1–2000), of which 70.2% (n = 80) were elevated above normal levels (≥ 10 pg/mL). All underwent total thyroidectomy, with 54% undergoing additional lymph node dissection; in the majority of cases, this was performed in a single surgical procedure. Lymph node metastases (stage III) were found in only 14 patients (9%). A total of 82% of those affected were in tumor stage 0 or 1. In 29%, only C-cell hyperplasia or normal histology was found. Of those currently cured (n = 154), a Ctn was available for 83 patients 2–6 months postoperatively: this was < 10 pg/mL in 81 (97.6%), while only two had slightly elevated postoperative serum Ctn levels (13 pg/mL and 24 pg/mL), which normalized by the end of the study (< 2 pg/mL, 1.9 pg/mL). All other patients had normal serum Ctn levels at all postoperative measurement time points.

Table 1

Patients with hereditary MTC classified on the basis of cured (Ctn < 10 pg/mL) and not cured (Ctn = 10 pg/mL)

Comparison of cured with not cured patients (Ctn ≥ 10 pg/mL)

A total of 123 patients had a current Ctn level of ≥ 10 pg/mL following a comparable median follow-up period of 14 years (range, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48) and were thus not cured (Table 1). They were on average 13 years older at the time of surgery compared to the cured patients (M 30 years), had higher preoperative serum Ctn levels (M 952 pg/mL), were predominantly the index patient in their family, or were diagnosed in primary screening (93%). Not cured patients more frequently underwent lymph node dissection (80%) and were more likely to require reoperation. An advanced tumor stage (stages III and IV) was found in 91% of cases. A total of 64 patients (52%) had or developed distant metastases, while 20 (16.2%) died due to MTC during the follow-up period. Of the 123 currently not cured patients, 68 had a 2- to 6-month postoperative serum Ctn level, while 15 patients initially had normal Ctn levels (2–8 pg/mL); these had risen to the pathological range by the end of the study.

A multivariable analysis of the recorded parameters (Table 2) showed a poorer cure rate for advanced tumor stages (odds ratio 65.005; 95% confidence interval: [23,61; 178,97] and a trend toward a worse outcome in the highest compared to the moderate RET mutation risk group (OR 3.940; [0.74; 21.07]). Sex, age at of surgery, and surgical method had no effect on cure rate (Table 2).

Table 2

Multivariable analysis of parameters as risk factors in relation to the cure of patients with hereditary MTC

Comparison of RET mutation risk groups

After classifying patients into the three mutation risk groups (MOD: n = 21, H: n = 130, HST: n = 26), the age dependence of tumor development was seen in both the cured and in the not cured group (Table 3). In the moderate risk group, the median age of cured patients at the time of surgery was 27 years, in the high risk group 14 years, and in the highest risk group 4.3 years. Not cured patients were 14, 14, and 11 years older than the corresponding patients in the cured group. The remaining factors behaved similarly in the mutation groups compared to the overall group. All patients younger than 6 years in the moderate group, younger than 9 years in the high-risk group, and younger than 0.5 years in the highest-risk group achieved long-term cure. The same was true for all those with a preoperative serum Ctn level of < 13 pg/mL.

Table 3

Patients with hereditary MTC classified according to ATA RET mutation risk groups (moderate, high, highest) and cured (Ctn < 10pg/mL) or not cured (Ctn = 10 pg/mL)

Cured patients and patients with Ctn < 2 pg/mL

Of the 154 patients with a Ctn of < 10 pg/mL, the majority (n = 136) had a Ctn of < 2.0 pg/mL at the end of the study; only 18 had serum Ctn levels between 2 and 10 pg/mL, of which 61% were diagnosed with primary tumors stage II–IV, while in the group with a Ctn of < 2 pg/mL, only 12% were diagnosed with stage II–IV (Table 4). Age at the time of surgery in the group with serum Ctn levels of < 2 pg/mL was also significantly younger (median of 17 years) than in the comparison group (median of 37 years) with serum Ctn levels of 2–10 pg/mL. Of the 154 patients, 2- to 6-month postoperative Ctn values were available for 83; the serum Ctn levels were initially below 2 pg/mL in 75 patients and between 2 and 10 pg/mL in six patients; Ctn values were also undetectably low at last measurement.

Table 4

Patients with hereditary MTC classified according to postoperative Ctn (< 2 pg/mL versus 2–10 pg/mL)

Discussion

The long-term results presented here show that lifelong cure from MTC is possible in the case of early prophylactic thyroidectomy in carriers of RET gene mutations, as measured by Ctn. Following a median follow-up period of 15 years, a normalization of serum Ctn level (< 10 pg/mL) that persisted postoperatively was observed in 154 (56%) of the 277 MEN2 patients. This shows that the concept of early treatment based on molecular genetic testing is also effective in the long term.

This extensive analysis broadens the previous data in the literature, given that it is based on the largest number of cured patients and the longest follow-up (with one exception [25]). All studies published between 1999 and 2022 define cure on the basis of postoperative serum Ctn level (Table 5). Even when taking a stricter and more specific definition as a basis (Ctn < 2 pg/mL), 136 (49%) of the patients are considered to have achieved long-term cure. All patients that achieved this postoperative Ctn level of < 2 pg/mL after 2–6 months were also always in the undetectable range in the long-term follow-up.

Table 5

Studies on prophylactic thyroidectomy in patients with MEN2: long-term follow-up of cured patients

Among the not cured at the end of the study, 22% initially experienced a normalization of their serum Ctn postoperatively (but not values of < 2 pg/mL), which, however, rose above 10 pg/mL during the course of the study, consistent with biochemical recurrence. The results of this study suggest that patients with undetectably low serum Ctn levels at 15 years are not expected to experience a recurrence, meaning that a lifelong cure of MTC can be assumed among RET mutation carriers who undergo early surgery. Nowadays, cure should be defined as an undetectably low serum Ctn level, measured with a sensitive assay (30, 31).

In the multivariable analysis of our data, the more favorable tumor stage is the strongest prognostic factor for cure. Our data show that the cured patients predominantly had CCH or stage I disease. Only 9% of the cured group had lymph node metastasis, which could be removed by lymph node dissection. Many studies emphasize the significance of lymph node status for outcome and prognosis (32, 33).

The highest compared to the moderate RET mutation risk group tended to be associated with a lower cure rate in the multivariable analysis of our data. In the highest risk group, MEN2B patients with the M918T RET mutation, MTC can develop very early on—as early on as in the first months of life. However, very early diagnosis is hampered by the frequent de novo mutations and the fact that clinical symptoms are often not yet present (34).

This study has a number of limitations: It was conducted retrospectively over 42 years and, for ethical reasons, had no control group. Over the course of the observation period, the diagnostic and therapeutic approach changed to some extent, and various surgeons and pathologists were involved. RET mutation analysis has only been available since 1994. Over time, the Ctn assay has been improved, gaining higher sensitivity and specificity. Only around half of the patients had their Ctn level determined in the 6 months following surgery, which explains why the cure rates based on these early postoperative Ctn levels are subject to a certain degree of uncertainty. The more precise surgical methods have contributed to the better outcomes (35).

The patients were treated over the entire period by the two authors FR and KF-R, who themselves made a substantial contribution to the further development of the diagnostic methods and guidelines—this may have led to bias.

Conclusion

Thus, this study shows that the concept of early treatment of hereditary MTC based on molecular genetic testing is also effective in the long term. Long-term cure is documented by an undetectable serum Ctn level. Molecular genetic RET analysis for risk stratification of the age of MTC onset, combined with Ctn screening to biochemically determine the early phase of MTC development, enables a personalized approach with a curative treatment goal.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 18 April 2024, revised version accepted on 9 August 2024.

Corresponding author
Prof. Dr. med. Friedhelm Raue

Endokrinologische Praxis

Brückenstrasse 21

69120 Heidelberg, Germany

Cite this as:
Raue F, Bruckner T, Frank-Raue K: The Long-term cure of patients with hereditary medullary thyroid carcinoma: 40 years of follow-up in a single center. Dtsch Arztebl Int 2024; 121: 657–64. DOI: 10.3238/arztebl.m2024.0174

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