Edited by: Paolo Miccoli, University of Pisa, Italy
Reviewed by: Yuqian Luo, Nanjing Drum Tower Hospital, China; Nelson Wohllk, University of Chile, Chile
*Correspondence: Tae Hyuk Kim,
†These authors have contributed equally to this work and share first authorship
This article was submitted to Thyroid Endocrinology, a section of the journal Frontiers in Endocrinology
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Serum calcitonin level is a useful biomarker for predicting primary tumor size, the extent of lymph node, and distant metastasis in patients with medullary thyroid carcinoma (MTC). However, the association between preoperative serum calcitonin levels and long-term oncologic outcomes has not yet been established. The aims of this study were to determine the preoperative serum calcitonin cut-off value for predicting disease recurrence and to evaluate its prognostic value.
Patients with MTC (
The overall disease-free survival rate was 75.7%. The preoperative serum calcitonin cut-off value that predicted structural recurrence was 309 pg/mL. Preoperative serum calcitonin levels of > 309 pg/mL were the strongest independent predictor of disease recurrence (hazard ratio (HR) 5.33, 95% confidence interval (85% CI) 1.67–16.96;
The preoperative serum calcitonin cut-off value is useful in clinical practice. It is also the best predictive factor for disease-free survival. Preoperative serum calcitonin levels may help determine the optimal postoperative follow-up strategy for patients with MTC.
Medullary thyroid carcinomas are a subtype of neuroendocrine tumors that are derived from the parafollicular cells of the thyroid gland, and secrete several hormones and peptides including calcitonin and carcinoembryonic antigen (
Tumor markers play an important role in screening for early malignancy, diagnosis, prognosis, and surveillance following curative surgery (
The aims of this study were to determine the preoperative serum calcitonin cut-off value for predicting structural recurrence and to evaluate its usefulness as a prognostic biomarker for recurrence in patients with medullary thyroid carcinoma.
The medical records of 246 patients with medullary thyroid carcinoma who were treated at the Samsung Medical Center, Seoul, Korea between 1995 and 2019 were retrospectively reviewed. Patients were excluded if preoperative serum calcitonin levels were unavailable (
The primary outcome of this study was to determine the preoperative serum calcitonin cut-off value for predicting structural recurrence. Structural recurrence was defined as a newly identified structural disease in the thyroid bed or neck lymph nodes or distant metastasis. A diagnosis of structural disease in the thyroid bed and/or neck lymph nodes by imaging studies was confirmed cytologically or pathologically. Distant metastases were detected by chest and/or abdominopelvic computed tomography, magnetic resonance imaging, whole-body bone scintigraphy, and 19-fluorodeoxyglucose positron emission tomography (PET) and/or were pathologically confirmed. The secondary outcomes were factors associated with disease-free survival, which was defined as the time from initial surgery to the date of first structural recurrence or last follow-up.
The preoperative serum calcitonin levels were all measured by immunoradiometric assay: MEDGENIX CT-U.S.-IRMA kit (BioSource Europe S.A., Belgium) from 1995 to 2005, DSL-7700 ACTIVE IRMA kit (Diagnostic Systems Laboratories, Inc., Webster, TX) from 2005 to 2007. Since then it was replaced by current immunoradiometric assay (CT-US-IRMA, DIAsource ImmunoAssays SA, Louvain-la-Neuve, Belgium). All samples were measured in duplicate. The intra- and interassay coefficients of variation were 2.4%–3.4% and 3.6%–5.4%, respectively. The detection limit was 0.9 pg/mL.
Continuous variables were presented as means ± standard deviation or medians (interquartile range) and analyzed using the Student’s
The clinicopathological features of all patients with medullary thyroid carcinoma (
Baseline characteristics.
Characteristics | Patients ( |
---|---|
|
49.4 ± 14.5 |
|
|
female | 112 (65.1) |
male | 60 (34.9) |
|
|
sporadic | 139 (82.2) |
hereditary (MEN2A) | 30 (17.8) |
|
|
total thyroidectomy | 167 (98.8) |
subtotal/near total thyroidectomy | 2 (1.2) |
|
|
yes | 162 (95.9) |
no | 7 (4.1) |
|
|
≤2.0 | 118 (69.8) |
>2.0 and ≤4.0 | 38 (22.5) |
>4.0 | 13 (7.7) |
|
|
none/micro | 151 (89.3) |
gross | 18 (10.7) |
|
|
negative | 162 (95.9) |
positive | 7 (4.1) |
|
|
no | 98 (58.0) |
yes | 71 (42.0) |
|
|
no | 107 (63.3) |
yes | 62 (36.7) |
|
|
≤309 | 75 (44.4) |
>309 | 94 (55.6) |
|
84 (39.5-127.5) |
SD, standard deviation; MEN2A, multiple endocrine neoplasia type 2A; CND, central lymph node dissection; LNM, lymph node metastasis; IQR, interquartile range.
Clinicopathological characteristics were evaluated according to preoperative serum calcitonin levels (
Clinicopathological characteristics according to preoperative serum calcitonin levels.
Characteristics | Calcitonin level (pg/mL) |
|
|
---|---|---|---|
≤ 309 | > 309 | ||
|
50.2 (12.1) | 48.7 (16.2) | 0.528 |
|
|||
female | 55 (73.3) | 55 (58.5) | 0.045 |
male | 20 (26.7) | 39 (41.5) | |
|
|||
sporadic | 65 (86.7) | 74 (78.7) | 0.179 |
hereditary (MEN2A) | 10 (13.3) | 20 (21.3) | |
|
|||
total thyroidectomy | 73 (97.3) | 94 (100.0) | 0.195 |
Subtotal/near total thyroidectomy | 2 (2.7) | 0 (0.0) | |
|
|||
Yes | 71 (94.7) | 91 (96.8) | 0.701 |
No | 4 (5.3) | 3 (3.2) | |
|
|||
≤2.0 | 70 (93.3) | 48 (51.1) | <0.001 |
>2.0 and ≤4.0 | 4 (5.3) | 34 (36.2) | |
>4 | 1 (1.3) | 12 (12.8) | |
|
|||
none/micro | 72 (96.0) | 79 (84.0) | 0.012 |
gross | 3 (4.0) | 15 (16.0) | |
|
|||
negative | 74 (98.7) | 88 (93.6) | 0.134 |
Positive | 1 (1.3) | 6 (6.4) | |
|
|||
no | 61 (81.3) | 37 (39.4) | <0.001 |
yes | 14 (18.7) | 57 (60.6) | |
|
|||
no | 68 (90.7) | 39 (41.5) | <0.001 |
yes | 7 (9.3) | 55 (58.5) | |
|
96 (58–123) | 80 (30.5-150.5) | 0.953 |
SD, standard deviation; MEN2A, multiple endocrine neoplasia type 2A; CND, central lymph node dissection; LNM, lymph node metastasis; IQR, interquartile range.
Maximally selected log-rank statistics were applied to establish a preoperative serum calcitonin cut-off value of prognostic significance. The highest log-rank statistic coincided with a preoperative serum calcitonin level of 309 pg/mL (
The maximum of the standardized log-rank statistics for preoperative serum calcitonin cut-off value.
Kaplan–Meier curves of disease-free survival according to the preoperative serum calcitonin cut-off value (309 pg/mL) (
Disease-free survival and cancer-specific survival according to the preoperative serum calcitonin cut-off value of 309 pg/mL.
Calcitonin | No of patients | No of recurrences (%) | Disease-free survival (%) | |||
---|---|---|---|---|---|---|
5-year | 10-year | 15-year | 20-year | |||
≤309 pg/mL | 75 | 4 (5.3) | 95.5 | 92.9 | – | – |
>309 pg/mL | 94 | 37 (39.4) | 69.7 | 52.9 | 38.3 | 30.7 |
all | 169 | 41 (24.3) | 81.5 | 71.2 | 62.3 | 57.1 |
|
|
|
|
|||
|
|
|
|
|||
≤309 pg/mL | 72 | 0 (0.0) | – | – | – | – |
>309 pg/mL | 93 | 7 (7.5) | 95.6 | 90.2 | 90.2 | 70.3 |
all | 165 | 7 (4.2) | 97.6 | 94.6 | 94.6 | 77.6 |
*Cancer-specific survival was calculated after the exclusion of four patients deaths from other causes.
Clinical characteristics, including preoperative serum calcitonin level (≤ 309 or > 309 pg/mL), age at diagnosis, sex, extent of surgery, tumor type, primary tumor size, central and lateral neck lymph node metastasis, extrathyroidal extension, and resection margin, were analyzed as independent variables in multivariable Cox regression analysis (
Multivariable analysis of disease-free survival.
Characteristics | Unadjusted | Adjusted | ||
---|---|---|---|---|
HR (95% CI) |
|
HR (95% CI) |
|
|
|
0.98 (0.96-1.00) | 0.104 | ||
|
||||
male | 1 (reference) | |||
female | 0.61 (0.33-1.13) | 0.118 | ||
|
||||
Subtotal/near total thyroidectomy | 1 (reference) | |||
total thyroidectomy | non-estimable | – | ||
|
||||
no | 1 (reference) | |||
yes | 3.61 (0.48-27.02) | 0.211 | ||
|
||||
sporadic | 1 (reference) | |||
hereditary | 0.55 (0.21-1.40) | 0.207 | ||
|
(<0.001) | (0.022) | ||
≤2.0 | 1 (reference) | 1 (reference) | ||
>2.0 and ≤4.0 | 1.85 (0.90-3.82) | 0.095 | 0.53 (0.23-1.18) | 0.119 |
>4.0 | 5.90 (2.71-12.84) | <0.001 | 1.78 (0.78-4.09) | 0.177 |
|
||||
no | 1 (reference) | 1 (reference) | ||
yes | 5.30 (2.54-11.03) | <0.001 | 1.42 (0.52-3.86) | 0.497 |
|
||||
no | 1 (reference) | 1 (reference) | ||
yes | 7.35 (3.47-15.59) | <0.001 | 3.70 (1.61-8.51) | 0.002 |
|
||||
none/micro | 1 (reference) | 1 (reference) | ||
Gross | 4.72 (2.33-9.55) | <0.001 | 1.50 (0.64-3.54) | 0.353 |
|
||||
negative | 1 (reference) | 1 (reference) | ||
positive | 8.78 (3.82-20.18) | <0.001 | 3.57 (1.44-8.88) | 0.006 |
|
||||
≤309 | 1 (reference) | 1 (reference) | ||
>309 | 9.53 (3.39-26.84) | <0.001 | 5.33 (1.67-16.96) | 0.005 |
*Non-estimable because all recurred patients underwent total thyroidectomy. CND, central lymph node dissection; LN, lymph node; HR, hazard ratio; 95% CI, 95% confidential interval.
Herein, we examined the relationship between preoperative serum calcitonin levels and the prognosis of patients with medullary thyroid carcinoma. We defined a specific preoperative serum calcitonin cut-off value of 309 pg/mL for predicting structural recurrence. We also showed that preoperative serum calcitonin levels are an accurate predictor of clinical outcomes in patients with medullary thyroid carcinoma.
Cancer biomarkers have shown potential applications in cancer detection and management (
Predicting biochemical cure is important, because postoperative biochemical cure is associated with a favorable outcome (
Previous studies (
We also postulated that preoperative serum calcitonin levels would play an important role in predicting cancer-specific survival. A preoperative serum calcitonin cut-off value of 309 pg/mL was closely correlated with cancer-specific survival. There were no cancer-specific deaths in patients with preoperative serum calcitonin levels of < 309 pg/mL. The 5-, 10-, and 20-year cancer-specific survival rates in patients with preoperative serum calcitonin levels of > 309 pg/mL were 95.6%, 90.2%, and 70.3%, respectively. However, further multivariable analysis to identify factors affecting cancer-specific survival was not performed because only a small number of patients died from medullary thyroid carcinoma.
Postoperative biochemical remission of serum calcitonin and post-operative calcitonin doubling time were known as an important factors for oncologic outcome (
The strength of this study lies in its relatively large number of patients with medullary thyroid carcinoma who were recruited from a single tertiary hospital. The optimal cut-off value for preoperative serum calcitonin levels was determined using maximally selected log-rank statistics, which is an appropriate statistical methodology for assessment of biomarker in survival endpoints (
In conclusion, this study defined a preoperative serum calcitonin level of 309 pg/mL as a useful threshold for predicting disease recurrence. It also has clinical implications for long-term cancer-specific survival.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The study design was approved by the Institutional Review Board of Samsung Medical Center (approval number: 2020-07-007). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
HP, SYP, and THK conceptualized and designed the study. HP, SYP, and S-YW analyzed the data and made the figures. HP drafted the manuscript. JP, JHCho, and MKC, data curation. SWK, JHChu, and JYC acquired and interpreted the data, and revised the manuscript. THK coordinated, and critically reviewed the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
This research was supported by a CRP-achievement grant (OTA1810531) from Samsung Medical Center. The funding source had no role in the collection, management, analysis, and interpretation of the data; design and conduct of the study; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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