DOI: https://doi.org/10.21203/rs.3.rs-1862286/v1
Purpose: Medullary thyroid carcinoma (MTC) patients with distant metastasis frequently present a relatively poor survival prognosis. Our main purpose was developing anomogram model to predict distant metastasis in MTC patients.
Methods: This was a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER) database. Data of 852 MTC patientsdiagnosed from 2004 to 2015who undergone total thyroidectomy and neck lymph nodes dissection was included in our study. The log‐rank test was used to compare the differences of Kaplan-Meier curves of cancer-specific survival (CSS) in different groups. Independent risk factors were screened byunivariate and multivariate logistic regression analysissuccessively, which were used to develop a nomogram model predicting for distant metastasis risk.
Results: CSS differed by different M stage, lymph node ratio (LNR) and age groups. Five clinical parametersincluding age>55 years, N1 stage, tumor size>40 mm, gross extra-thyroidal extension (ETE) and LNR>0.3were significantfor distant metastasis in MTC patients, which wereselectedto develop a nomogram. This model had satisfied discrimination with the AUC and C-index of 0.874, and C-index was confirmed to be 0.861 through bootstrapping validation. A decision curve analysis was subsequently made to evaluate the feasibility of this nomogram for predicting distant metastasis.
Conclusions: Age, N stage, tumor size, gross ETE and LNR were extracted to develop a nomogram model for predicting the risk of distant metastasis in MTC. The model is of great significance for clinicians to timely identify patients with high risk of distant metastasis and make further clinical decisions.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignant tumor arises from parafollicular C-cells.About 75% MTC are sporadic and the remaining 25% are hereditary.1,2Germline mutations of the RET proto-oncogene cause virtually all hereditary MTC, where as somatic RET mutations have been described in approximately 50% sporadic MTC samples.3 Although it accounts for less than 5% of thyroid cancer, it causes approximately 13%-14% of thyroid cancer-related deaths.2–6Distant metastasis is a poor prognostic factor in MTC patients.5,7,8However, about 10%-15% of MTC patients had distant metastases at the time of initial diagnosis.2,9,10The most common metastatic sites of MTC are the lung, bone and liver.11–16 According to previous studies, the 10-year survival rate of MTC patients is greater than 80%.10,17However, in the presence of distant metastases, the 10-year disease-specific survival rate drops to 44%,4 and the overall survival (OS) rate drops to 40%.2
Targeted therapy has brought great hope to patients with advanced progressive MTC over the past decade. Selpercatinib and pralsetinib, two RET-specific inhibitors recently approved by the FDA for the treatment of RET-mutant MTC, have been shown to be effective and well tolerated.18,19MTC patients with distant metastases are expected to improve survival through targeted therapy. Therefore, it is critical to timely and effective identification of MTC patients at high risk of distant metastasis.
According to American Thyroid Association Guidelines, contrast-enhanced CT of the neck and chest, three-phase contrast-enhanced CT or contrast-enhanced MRI of the liver, and axial MRI and bone scintigraphy are recommended in MTC patients with suspected distant metastases.3However, the sensitivity of these imaging techniques inlocalizing metastatic disease is below 80%,3and these systemic imaging techniques are expensive to repeat during postoperative monitoring.
Currently, there are very rare models for predicting distant metastasis of MTC. Therefore, it is of great clinical significance and economic benefit to construct a simple and convenient clinical model for predicting the distant metastasis in MTC. We designed a retrospective study base on the SEER database, which mainly aimed at constructing and validating a nomogram to predict distant metastasis for MTC patients.
The data we analyzed were generated from the SEER database using the SEER∗Stat software (version 8.3.9.2; National Cancer Institute, USA). The SEER database was last updated in November 2020, and the last follow-up date for the updated data was late 2018.
Inclusion criteria were the following: (1) Patients diagnosed with primary cancer from 2004 to 2015. (2) According to the International Classification of Diseases (ICD) for Oncology-3, patients histological codes were codes 8345/3 and 8510/3, Primary site code C73.9. (3) All included patients were undergone total thyroidectomy and neck lymph nodes dissection. Data such as year of diagnosis, sex, age of diagnosis, race (white, black, other), marital status at diagnosis (married, single, divorced/separated/widowed), primary site, histologic type, combined summary stage, clinical TNM stage, tumor size, tumor extension, CS site-specific factor 1 (multifocality), surgery of primary site, scope of regional lymph node surgery, regional nodes examined, regional nodes positive, survival months, cause of death, and vital survival status were collected from the SEER database. Exclusion criteria included: (1) Patients with more than one kind of primary malignant cancer. (2) Patients aged < 18 years or > 90 years. (3) Patients with survival time less than 1 month. (4) Patients without regional lymph nodes examined. (5) Patients with unknown or missing clinical information. Finally, data of 852 patients were selected from the SEER database based on the inclusion and exclusion criteria.
In this study, N stage and M stage of all cases were performed according to the 8th Edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system.20 Referring to previous study by A. Kotwal et al., we used 55 years as the age cut-off point.10Tumor expansion classification includes with or without gross extra-thyroidal extension(ETE). Based on the regional nodes examinedand regional nodes positiveof each case, we calculated the lymph node ratio (LNR), which represented the proportion of metastatic lymph nodes resected. The continuous variable of the LNR was analyzed by X-tile software,21and the best cut-off value was 0.3 (Supplementary Materials Fig. 1), which was grouped as binary variables.
Statistical analyses were conducted using the SPSS software (version 23.0; IBM corporation) and R (Version 4.1.3; https://cloud.r-project.org/) software. Continuous variables were presented as mean ± standard deviation or median with interquartile range, as appropriate. Categorical variables were presented as number and percentage. The χ2test or Fisher’sexact test was used for categorical variables. The log-rank test was used to compare the differences of Kaplan-Meier curves of cancer-specific survival (CSS) in different groups, and the life table method was used to calculate the cumulative CSS rate. Univariate logistic regression analysis was used to screen potential risk factors for distant metastasis. Subsequently, independent risk factors were further screened by multivariate logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were also reported for each risk factor. All tests were 2-sided, and a P value < 0.05 was considered statistically significant.
All independent risk factors were applied to develop a nomogram model predicting for distant metastasis risk. The Harrell’s concordance index (C-index), receiver operating characteristic curve (ROC) and the calibration curve of MTC patients were formulated to evaluate the exact predictive performance of the nomogram model. The Bootstrap method (1,000 bootstrap resamples) was used to conduct internal verification of the nomogram model. Decision curve analysis (DCA) was also performed to determine the clinical utility of the predictive model.
Ethical Approval
The SEER database is public, does not contain any personally identifiable information, and therefore does not require ethical approval. Our request for access to SEER Data has been approved from the National Cancer Institute, USA (reference number 23459-Nov2020).
Clinical parameters of MTC patients
The mean age of all included MTC patients was 51.55 ± 15.30 years, of whom 492 (57.7%) were female, 360 (42.3%) were male. The tumors median size was 23.00 (12.00, 35.00) mm; 143(16.8%) were with gross ETE, 709(83.2%) were without gross ETE; 582 (68.3%) were unifocal tumor, 270 (31.7%) were multifocal tumor; 445 (52.2%) had regional lymph node metastasis, 407 (47.8%) had no regional lymph node metastasis; 56 (6.57%) had distant metastasis, 796 (93.43%) had no distant metastasis; the median regional nodes examined was 14.00 (5.00, 34.00), and the median regional nodes positive was 1.00 (0, 8.00).The median follow-up time for all MTC patients was 85.00 (52.00, 120.75) months. Their basic clinical parameters of the MTC patients were summarized in Table 1.
Cancer-specific survival curves of for different M stage, LNR and age groups
A total of 807 MTC patients were included in the analysis of the CSS. CSS differed by different M stage, LNR and age groups (Figure 1). Overall, the CSS of MTC patients with distant metastases were significantly lower than those without distant metastasis (χ2=225.147, P<0.001). The 5-, and 10-year cumulative CSS of MTC patients without distant metastases were 93% (91%-95%) and 87% (83%-91%), while they were reduced to 44% (30%-58%) and 22% (6%-38%) with distant metastases. MTC patients with LNR>0.3 or age>55 years both had lower CSS (χ2=93.977, P<0.001; χ2 =42.948, P<0.001; respectively).
Selection of risk factors for distant metastasis
Analyses were performed using univariate and multivariate logistic regression to identify clinical parameters affecting distant metastasis. In univariate analyses, age>55years, male sex, N1 stage, large tumor size, gross ETE and LNR>0.3 were significant (P<0.05) factors (Table 2). When the multivariable analysis was performed, age>55 years (OR=2.576, 95%CI:1.403-4.732, P=0.002), N1 stage (OR=5.527, 95%CI:1.495-20.433, P=0.01), tumor size >40mm (OR=5.060, 95%CI: 2.161-11.848, P<0.001), gross ETE (OR=2.941, 95%CI:1.580-5.474, P=0.001) and LNR>0.3 (OR=2.075, 95%CI:1.030-4.181, P=0.041) were identified as predictors of distant metastasis (Table 2).
Development and validation of the nomograms for distant metastasis
Based on the result of multivariate logistic regression, five variables including age, N stage, tumor size, gross ETE and LNR were finally extracted to build the nomogram model for predicting the risk of distant metastasis in MTC (Figure 2). According to the plotted ROC curve (Figure 3A), the AUC of the nomogram was 0.874. The C-index for the nomogram model was 0.874 (95%CI: 0.839-0.910), and was confirmed to be 0.861 through bootstrapping validation, which showed that the nomogram model had a high accuracy prediction. The calibration curve demonstrated good consistency between the predicted result and the actual distant metastasis state of the MTC (Figure 3B).
Decision curve analysis for clinicalutility
As can be seen in the DCA for the distant metastasis nomogram (Figure 3C), the net benefit (NB) of the decision curve of the model is higher than that of the two invalid lines within the range of threshold probability between 1%-42%.
MTC is a rare carcinoma which is more aggressive than differentiated thyroid carcinoma (DTC). MTC cells do not concentrate radioactive iodine and are not sensitive to thyrotropin-suppressive therapy, which is different from DTC. Although the proportion of MTC in thyroid cancer had declined in recent years, it caused a disproportionately high rate of thyroid-related death.2-6The survival rate for the MTC is significantly lower than of DTC.10,17According to our results, 6.6% (56/852) of MTC patients had distant metastases, and the 5- and 10-year cumulative CSS rate of these patients were 44% and 22%, respectively. The decrease of distant metastasis might be related to the early diagnosis of MTC in recent years. The cumulative survival rate obtained in our study was lower than previous studies, this reason might be explained by selection bias.
Several studies have already identified survival prognostic factors for MTC, includingage, primary tumor size, initial stage, extrathyroidal extension, lymph node metastasis and initial distant metastasis.2,3,5,8,10,11However, distant metastasis is the strongest predictor of OS and progression-free survival.8The most common metastatic sites of MTC are the lung, bone and liver.11-16 Lung metastases general present as multiple micronodular in most patients.11 For bone metastases, the lesions are mostly multifocal and preferentially occur in the spine, pelvis and ribs, and the most common morphologies of bone metastases are osteolytic and osteogenic.22,23Moreover, liver metastases are often multiple, and disseminated throughout the parenchyma.24,25The most common causes of death from distant metastases are complications from the progression of distant metastases, chemotherapy-related complications, and airway obstruction from tracheal invasion.11
The recent application of RET-specific inhibitors (selpercatinib and pralsetinib) has provided an effective and promising option for systemic treatment in RET-mutant MTC patients with metastatic and progressive diseases.18,19 However, the high cost of imaging techniques screening for distant metastases reduces the initiative for monitoring, and these techniques still have the possibility of false negatives, which may delay the timing of treatment in patients with advanced MTC. It is of great clinical significance to evaluate the independent risk factors for distant metastasis and further establishment a clinical prediction model in MTC.
According to the 8th edition of the AJCC staging system,the TNM classification lacks important prognostic factors such as gradations of age in patients with MTC.20 In addition, the lymph node metastases classifications for MTC in this staging system are just according to the location of nodes, regardless of the number or the rate of lymph nodes metastases.5,26-29
Increased age was associated with higher disease specific mortality and worse survival in MTC patients.2,10,30-32 The cut-off value analyzed by X-tile software for the relationship between age and the CSS was 67 years (Supplementary Materials Figure 2).21While, referring to previous study by A. Kotwal et al., the cut-off value for age was 55 years.10In univariate logistic regression analyses, age>55 and>67 years were all statistically significantfor distant metastasis (OR=2.815, 95%CI: 1.609-4.928, P<0.001; OR=2.002, 95%CI: 1.075-3.728, P=0.029, respectively). According to the calculated OR values, we selected 55 years as the preferred cut-off value for age.
In our study, the optimal cut-off value for the relationship between LNR and the CSS was 0.3. Previous studies found that highermetastatic lymph node ratio predict poorer survival in MTC.5,28,29 The cut-off values for the metastatic lymph node ratio previously selected were 0.1 and 0.5.28,33Different from previous studies, our study was based on all adult MTC patients who underwent total thyroidectomy and neck lymph nodes dissection. Therefore, 0.3, as our cut-off value, is more clinically applicable than previous studies.In addition to predicting survival, the lymph node ratio can potentially predict recurrence and distant metastases in MTC.10,34We came to similar conclusion, LNR>0.3 (OR=2.075, 95%CI:1.030-4.181, P=0.041) was a significant predictor of distant metastasis.
Our study also confirmed that N1 stage (OR=5.527, 95%CI: 1.495-20.433, P=0.010) and gross ETE (OR = 2.941, 95%CI: 1.580-5.474, P=0.001) were found to be independent predictors of distant metastases, which was consistent with the literature reports.10,15,26Tumor size>40 mm (OR=5.060, 95%CI: 2.161-11.848, P<0.001) was an independent risk factor for distant metastasis in our study. A. Kotwal et al. found that tumor size could significantly predict distant metastasis in univariate analysis, but it lost significance in multivariate analysis,10 further research is needed to confirm.
Univariate analysis in our study showed thatmale sex (OR=2.622, 95%CI: 1.491-4.612, P=0.001) was a potential risk factor for distant metastasis in MTC, but it lost significance in the subsequent multivariate analysis,which was similar to the finding of A. Kotwal et al.10
We developed the nomogram for distant metastasis based on the five independent predictors mentioned above, including age, N1 stage, tumor size, gross ETE and LNR. To our knowledge, this is a very rare nomogram with good predictive performances to predicted distant metastasis of MTC patients who undergone total thyroidectomy and neck lymphnodes dissection.In this model, the C-index and AUC values of the nomogram prediction model were both 0.874, and the C-index value of bootstrapping validation was 0.861, indicated that the model had good predictive ability. The calibration curve suggested that the actual probability of distant metastasis corresponded closely with the predicted probability of distant metastasis in MTC patients.
The predictive model can help clinicians to screen patients at high risk of distant metastasis in MTC. Through the implementation of close postoperative monitoring of these people, timely treatment if necessary, and ultimately improve the poor prognosis of these patients.
The limitation of our study was its retrospective design, small sample size and lacking external validation. Moreover, there was a lack of evaluation of genetic status, calcitonin in our study. Despite these limitations, we verified that age>55 years and LNR>0.3 were significant predictors of poor CSS and distant metastasis, and N1 stage, tumor size>40 mm andgross ETE were significant predictors of distant metastasis. We further established a nomogram model for predicting distant metastasis in MTC patients. For these MTC patients at high risk of distant metastasis, we recommend close monitoring of whole-body imaging procedures after surgery.
Overall, the survival prognosis of MTC patients with distant metastasis is poor. Based on the SEER database, we found that age>55 years and LNR>0.3 could predict poor CSS in MTC patients. More importantly, we had successfully developed a visual nomogram model to predict distant metastasis in MTC patients who undergone total thyroidectomy and neck lymph nodes dissection. The model is of great significance for clinicians to timely identify patients with high risk of distant metastasis and make further clinical decisions.
Author Contributions
Zhufeng Chen, Yaqian Mao, Tingting You, Gang Chen contributed to this study. Zhufeng Chen and Gang Chen contributed to the conception and design of this study. Zhufeng Chen collected data. Yaqian Mao and Tingting You performed the statistical analysis.Zhufeng Chen, Yaqian Mao and Tingting You drafted and wrote the manuscript.Chen Gang supervised the entire study.All authors read and approved the final manuscript.
Funding information
Startup Fund for scientific research of Fujian Medical University, Grant number:2020QH1174
Data availability statement
The data set generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflict of interest
There are no conflicts of interest.
Table 1. Comparison of main clinical parameters of the MTC patients with and without distant metastases
|
Total (n=852) |
With DM (n1=56) |
Without DM (n2=796) |
pvalue |
Age (years) |
|
|
|
< .001 |
≤55 |
521(61.2%) |
21(37.5%) |
500(62.8%) |
|
>55 |
331(38.8%) |
35(62.5%) |
296(37.2%) |
|
Sex |
|
|
|
.001 |
Female |
492(57.7%) |
20(35.7%) |
472(59.3%) |
|
Male |
360(42.3%) |
36(64.3%) |
324(40.7%) |
|
Marital status |
|
|
|
.509 |
Married |
579(68.0%) |
36(64.3%) |
543(68.2%) |
|
Single |
164(19.2%) |
14(25.0%) |
150(18.8%) |
|
Divorced / Separated / Widowed |
109(12.8%) |
6(10.7%) |
103(12.9%) |
|
Race |
|
|
|
.496 |
White |
719(84.4%) |
45(80.4%) |
674(84.7%) |
|
Black |
74(8.7%) |
7(12.5%) |
67(8.4%) |
|
Other |
59(6.9%) |
4(7.1%) |
55(6.9%) |
|
Combined Summary Stage |
|
|
|
< .001 |
Localized |
395(46.4%) |
0(0%) |
395(49.6%) |
|
Regional |
379(44.5%) |
0(0%) |
379(47.6%) |
|
Distant |
78(9.2%) |
56(100%) |
22(2.8%) |
|
N Stage |
|
|
|
< .001 |
N0 |
407(47.8%) |
3(5.4%) |
404(50.8%) |
|
N1 |
445(52.2%) |
53(94.6%) |
392(49.2%) |
|
Tumor size (mm) |
|
|
|
< .001 |
≤20 |
381(44.7%) |
8(14.3%) |
373(46.9%) |
|
21-40 |
316(37.1%) |
18(32.1%) |
298(37.4%) |
|
>40 |
155(18.2%) |
30(53.6%) |
125(15.7%) |
|
Gross ETE |
|
|
|
< .001 |
No |
709(83.2%) |
24(42.9%) |
685(86.1%) |
|
Yes |
143(16.8%) |
32(57.1%) |
111(13.9%) |
|
Multifocality |
|
|
|
.063 |
Unifocal |
582(68.3%) |
32(57.1%) |
550(69.1%) |
|
Multifocal |
270(31.7%) |
24(42.9%) |
246(30.9%) |
|
LNR |
|
|
|
< .001 |
≤0.3 |
602(70.7%) |
16(28.6%) |
586(73.6%) |
|
>0.3 |
250(29.3%) |
40(71.4%) |
210(26.4%) |
Abbreviations: MTC,Medullary thyroid carcinoma; DM, distant metastasis;Gross ETE, Gross extra-thyroidal extension; LNR, lymph node ratio.
Table2. Univariate and multivariate logistic regression analysis of distant metastasis in the MTC patients
|
Univariate analysis |
Multivariate analysis |
||||
OR |
95%CI |
pvalue |
OR |
95%CI |
p value |
|
Age (years) |
|
|
|
|
|
|
≤55 |
Ref |
|
|
Ref |
|
|
>55 |
2.815 |
1.609-4.928 |
< .001 |
2.576 |
1.403-4.732 |
.002 |
Sex |
|
|
|
|
|
|
Female |
Ref |
|
|
|
|
|
Male |
2.622 |
1.491-4.612 |
.001 |
— |
— |
— |
Marital status |
|
|
|
|
|
|
Married |
Ref |
|
|
|
|
|
Single |
1.408 |
0.740-2.679 |
.297 |
— |
— |
— |
Divorced / Separated / Widowed |
0.879 |
0.361-2.139 |
.776 |
— |
— |
— |
Race |
|
|
|
|
|
|
White |
Ref |
|
|
|
|
|
Black |
1.565 |
0.679-3.607 |
.293 |
— |
— |
— |
Other |
1.089 |
0.378-3.141 |
.874 |
— |
— |
— |
Combined Summary Stage |
|
|
|
|
|
|
Localized |
Ref |
|
|
|
|
|
Regional |
1.000 |
— |
1.000 |
— |
— |
— |
Distant |
4112116802 |
— |
.991 |
— |
— |
— |
N Stage |
|
|
|
|
|
|
N0 |
Ref |
|
|
Ref |
|
|
N1 |
18.207 |
5.643-58.749 |
< .001 |
5.527 |
1.495-20.433 |
.010 |
Tumor size (mm) |
|
|
|
|
|
|
≤20 |
Ref |
|
|
Ref |
|
|
21-40 |
2.816 |
1.208-6.567 |
.017 |
2.113 |
0.876-5.097 |
.096 |
>40 |
11.190 |
4.999-25.048 |
< .001 |
5.060 |
2.161-11.848 |
< .001 |
Gross ETE |
|
|
|
|
|
|
No |
Ref |
|
|
Ref |
|
|
Yes |
8.228 |
4.672-14.491 |
< .001 |
2.941 |
1.580-5.474 |
.001 |
Multifocality |
|
|
|
|
|
|
Unifocal |
Ref |
|
|
|
|
|
Multifocal |
1.677 |
0.967-2.907 |
.066 |
— |
— |
— |
LNR |
|
|
|
|
|
|
≤0.3 |
Ref |
|
|
Ref |
|
|
>0.3 |
6.976 |
3.826-12.722 |
< .001 |
2.075 |
1.030-4.181 |
.041 |
Abbreviations: MTC, Medullary thyroid carcinoma; Gross ETE, Gross extra-thyroidal extension; LNR,lymph node ratio.