Abstract
Medullary thyroid carcinoma (MTC) accounts up to 10% of all thyroid cancers, but is responsible for a disproportionate number of deaths. While surgery is the only curative treatment for MTC, indications for lateral neck lymph node (LLN) dissection are controversial. We performed a retrospective review to describe clinical outcomes in 93 MTC patients from July 1995 to March 2015. We analyzed their clinicopathologic factors, and cut‐off values of tumor size and calcitonin levels were calculated using a receiver operating characteristic curve. Using the instances of lymph node metastases, the tumor size cut‐off value was 0.95 cm (area under curve, AUC = 0.697) in patients with ipsilateral central lymph node (CLN) metastases, 2.25 cm (AUC = 0.793) in contralateral CLN metastases, and 1.75 cm (AUC = 0.753) in ipsilateral LLN metastases. The cut‐off values of preoperative calcitonin levels were 226.6 pg/mL (AUC = 0.746) in ipsilateral CLN, 755.0 pg/mL (AUC = 0.840) in contralateral CLN metastases, and 237.0 pg/mL (AUC = 0.775) in ipsilateral LLN metastases. This study supports the notion that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin level, and tumor size to help individualize the extent of surgery.
Keywords: calcitonin, carcinoma, lymph nodes, medullary, thyroid
1. INTRODUCTION
Medullary thyroid cancer (MTC) accounts for 5% of all thyroid cancers, but represents 13.4% of deaths attributed to thyroid cancer.1 Surgery is the only curative treatment for MTC. However, after surgery, persistently elevated calcitonin levels are found in more than half of MTC patients who present with clinical disease.2, 3, 4 At present, there are significant differences in survival between patients who achieve complete remission and those with biochemically persistent disease postoperatively.5
Several studies suggest that recurrence and survival rates depend upon the adequacy of the initial surgery and that neoplastic foci present in the neck should be removed.4, 6, 7 High recurrence rates have been reported in neck lymph nodes,2, 3, 4 and meticulous lymph node dissection has been reported to result in a higher biochemical cure rate.8, 9 Thyroidectomy with central neck lymph node (CLN) dissection is recommended for almost all MTC patients; however, the indications for lateral neck lymph node (LLN) dissection remain controversial.10, 11, 12, 13
Previous reports suggested that preoperative basal calcitonin levels may be not only a good indicator of remission but also guide surgical planning.14 The objective of this study was to evaluate the biomarker of lymph node metastasis about MTC, including assessment of basal calcitonin levels in an effort to provide individualized management and planning of neck lymph node dissections based on tumor size and preoperative calcitonin levels.
2. METHODS
2.1. Patients and treatment
A total of 93 patients (66 females and 27 males) underwent primary operations for MTC between July 1995 and March 2015 at the Samsung Medical Center. Primary surgery included total thyroidectomy and/or central lymph node dissection (CND, level VI) and/or LLN dissection (LND, level IIa, III, IV, and Va).15, 16
Preoperative and postoperative serum calcitonin levels were measured using an immunoradiometric assay (CT‐U.S.‐IRMA, DIAsource ImmunoAssays S.A., Louvain‐la‐Neuve, Belgium). Patients were divided into two groups based on postoperative calcitonin level, a normal calcitonin (≤13 pg/mL) group (normal group) and a persistent hypercalcitoninemia group (persistent group). Between 4 weeks and 3 to 6 months after surgery, assessment of the surgical resection completeness included determination of basal calcitonin. Calcitonin was deemed normal (biochemical cure) when the basal calcitonin level was within the normal range.
The two groups (normal and persistent groups) were analyzed using pathologic reports to evaluate tumor size, multifocality, tumor site, perithyroidal extension (extracapsular invasion), the presence of nodal metastasis, and the number of metastatic lymph nodes. In cases of multiple tumors, the largest tumor was used for data analysis. Neck lymph nodes were categorized as right or left in relation to the midline. In cases of bilateral thyroid involvement, contralateral lymph nodes were defined as those contralateral to the largest tumor.
2.2. Research methods
Operative reports and electronic medical records were also reviewed to evaluate recurrent laryngeal nerve injury and symptoms of voice change. Laryngeal examination was performed in the postoperative period and regularly thereafter if laryngeal nerve palsy was observed. Serum calcium and phosphorus and parathyroid hormone were periodically measured until levels normalized. Laryngeal nerve palsy and hypoparathyroidism were considered definitive or permanent when persisting for more than 6 months after surgery.
2.3. Statistical analysis
IBM SPSS Statistics 20.0 software was used for univariate analyses (Student t test, χ 2 test, Fisher's exact test, and Mann‐Whitney U test), multivariate analyses (Cox regression analysis), and receiver operating characteristic (ROC) curve for cut‐off values. Statistical significance was defined as a P value < .05. This study was approved by the Hospital Institutional Review Board (2018AN0170).
3. RESULTS
3.1. Clinicopathological characteristics of patients
The mean follow‐up duration was 63.1 months (median 45.8 months, range 0.5‐208.2 months). The clinical characteristics of normal and persistent groups are reported in Table 1. The mean age at diagnosis was 48.4 years in the normal group and 47.3 years in the persistent group (P = .843). Male patients were significantly more common in the persistent than the normal group (54.2% vs 20.3%, P = .002). Multiple and bilateral tumors were also found more in the persistent group, but without statistical significance (multiple, 20.8% vs 8.6%, P = .113; bilateral, 16.7% vs 14.5%, P = .124). More patients (75.0%, 18/24) in the persistent group underwent LND compared to the normal group (37.7%, 26/69, P = .015), and the persistent group showed more advanced T (P < .001) and N stages (P < .001). The median level of preoperative calcitonin in the persistent group was 1059 pg/mL (range 37‐12 800 pg/mL), which was higher than 177 pg/mL (range 3‐41 400 pg/mL) of the normal group (P = .345) (Table 1).
Table 1.
Clinicopathological characteristics of all MTC patients
| Normal group (N = 69) | Persistent group (N = 24) | P value | ||
|---|---|---|---|---|
| Age (years) | <45 years | 23 (33.3%) | 9 (37.5%) | .711 |
| ≥45 years | 46 (66.7%) | 15 (62.5%) | ||
| Gender | Male | 14 (20.3%) | 13 (54.2%) | .002 |
| Type | Hereditary | 8 (20.0%) | 2 (10%) | .327 |
| Sporadic | 32 (80.0%) | 18 (90.0%) | ||
| Unknown | 29 | 4 | ||
| Tumor site | Right | 32 (46.4%) | 16 (66.7%) | .124 |
| Left | 27 (39.1%) | 4 (16.7%) | ||
| Bilateral | 10 (14.5%) | 4 (16.7%) | ||
| No. of tumors | Single | 63 (91.3%) | 19 (79.2%) | .113 |
| Multiple | 6 (8.6%) | 5 (20.8%) | ||
| Type of operation | TT | 6 (8.7%) | 2 (8.3%) | .015 |
| TT + CND | 34 (49.3%) | 4 (16.7%) | ||
| TT + CND + LND | 29 (42.0%) | 18 (75.0%) | ||
| Extent | Capsular invasion | 6 (8.7%) | 10 (41.7%) | <.001 |
| Tumor size | Median (range) | 1.1 (0.3‐6.5) | 2.4 (0.2‐5.7) | <.001 |
| T stage | T1a | 32 (46.4%) | 5 (20.8%) | .006 |
| T1b | 22 (31.9%) | 5 (20.8%) | ||
| T2 | 13 (18.8%) | 9 (37.5%) | ||
| T3 | 2 (2.9%) | 2 (8.3%) | ||
| T4a | ‐ | 2 (8.3%) | ||
| T4b | ‐ | 1 (4.2%) | ||
| N stage | N0 | 48 (69.6%) | 4 (16.7%) | <.001 |
| N1a | 7 (10.1%) | 2 (8.3%) | ||
| N1b | 9 (13.0%) | 16 (66.7%) | ||
| Nx | 5 (7.2%) | 2 (8.3%) | ||
| No. of examined LNs | Median (range) | 13.5 (2‐68) | 23 (0‐106) | .071 |
| No. of metastatic LNs | Median (range) | 0 (0‐9) | 10.0 (0‐39) | <.001 |
| Preoperative calcitonin | Median (range) | 177 (3‐41 400) | 1059 (37‐12 800) | .345 |
Abbreviations: CND, central neck lymph node dissection; LND, lateral neck dissection; LN, lymph node; RL, right lobectomy; TT, total thyroidectomy.
In the normal group, two patients (2.9%) had disease recurrence, but there were no instances of death. However, in the persistent group, 16 patients (66.7%) had recurrence and two patients died. Persistent hypercalcitoninemia was a significant prognostic factor of disease‐free survival (HR 17.7, 95% CI 4.0‐77.8, P < .001).
3.2. Central lymph node metastases vs lateral neck lymph node metastases
A total of 85 patients underwent CND, and CLN metastases were identified in 33 patients (38.8%). CLN metastases were identified more frequently in the persistent group compared to the normal group (18 out of 22 patients, 81.8% vs 16 out of 63 patients, 25.3%, P < .001). There were also 47 patients who underwent prophylactic or curative LND, and LLNs metastases were identified in 25 patients (53.2%). LLN metastases were more common in the persistent than in the normal group (16 out of 18 patients, 88.9% vs 9 out of 29 patients, 32.1%, P < .001) (Table 1).
Of the 25 patients with ipsilateral LLN metastases, 24 patients (96.0%) had ipsilateral CLN metastases. Additionally, of the 19 patients without ipsilateral CLN metastases, 18 patients (94.7%) had no ipsilateral LLN metastasis (P < .001, Table 2). All 13 patients with contralateral CLN metastases had ipsilateral LLN metastases. None of the 18 patients without ipsilateral LLN metastases had contralateral CLN metastasis (P < .001, Table 3).
Table 2.
The correlation of ipsilateral central lymph node metastases and ipsilateral lateral neck lymph node metastases (χ 2 test)
| P < .001 | Ipsilateral lateral neck lymph nodes | Total | ||
|---|---|---|---|---|
| Metastasis | No metastasis | |||
| Ipsilateral CLN | Metastasis | 24 | 3 | 27 |
| No metastasis | 1 | 18 | 19 | |
| Total | 25 | 21 | 46 | |
Table 3.
The correlation of contralateral central lymph node metastases and ipsilateral lateral neck lymph node metastases (χ 2 test)
| P < .001 | Ipsilateral lateral neck lymph nodes | Total | ||
|---|---|---|---|---|
| Metastasis | No metastasis | |||
| Contralateral CLN | Metastasis | 13 | 0 | 13 |
| No metastasis | 8 | 18 | 26 | |
| Total | 21 | 18 | 39 | |
3.3. Tumor size and lymph node metastases
Using the extent of lymph node metastases, the tumor size cut‐off value was calculated using the ROC curve (Table 4). The cut‐off value of patients with ipsilateral CLN metastases was 0.95 cm (sensitivity 94.1%, specificity 46.2%; area under curve [AUC] = 0.697). The cut‐off value of patients with contralateral CLN metastases was 2.25 cm (sensitivity 71.4%, specificity 79.6%; AUC = 0.793). The cut‐off value of patients with ipsilateral LLN metastases was 1.75 cm (sensitivity 69.2%, specificity 71.4%; AUC = 0.753).
Table 4.
The cut‐off value of pathologic tumor size in lymph node metastases
| Cut‐off (cm) | AUCa | Sensitivity | Specificity | |
|---|---|---|---|---|
| Ipsilateral central LN (N = 86) | 0.95 | 0.697 | 94.1% | 46.2% |
| Contralateral central LN (N = 63) | 2.25 | 0.793 | 71.4% | 79.6% |
| Ipsilateral lateral LN (N = 46) | 1.75 | 0.753 | 69.2% | 71.4% |
| Contralateral lateral LN (N = 4) | ‐ | 0.250 |
0.7 ≤ AUC < 0.8: acceptable discrimination.
0.8 ≤ AUC < 0.9: excellent discrimination.
AUC (area under the ROC curve) ≤ 0.5: no discrimination.
3.4. Preoperative basal calcitonin level and lymph node metastases
There was a significant correlation between preoperative calcitonin and number of metastasis. The spearman correlation coefficient (rho) is 0.505 (P < .001). Based on the ROC curve, the cut‐off value of preoperative calcitonin levels was calculated by the site CLN and LLN (Table 5). The cut‐off value of patients with ipsilateral CLN metastases was 226.6 pg/mL (sensitivity 86.7%, specificity 64.0%; AUC = 0.746). The cut‐off value of patients with contralateral CLN metastases was 755.0 pg/mL (sensitivity 84.6%, specificity 79.1%; AUC = 0.840). The cut‐off value of patients with ipsilateral LLN metastases was 237.0 pg/mL (sensitivity 95.7%, specificity 52.4%; AUC = 0.775). The cut‐off value of contralateral LLN metastases was 296.0 pg/mL, (sensitivity 33.3%, specificity 100%; AUC = 0.333).
Table 5.
The cut‐off value of preoperative calcitonin levels in lymph node metastases
| Cut‐off (pg/mL) | AUCa | Sensitivity | Specificity | |
|---|---|---|---|---|
| Ipsilateral central LN (N = 86) | 226.6 | 0.746 | 86.7% | 64.0% |
| Contralateral central LN (N = 63) | 755.0 | 0.840 | 84.6% | 79.1% |
| Ipsilateral lateral LN (N = 46) | 237.0 | 0.775 | 95.7% | 52.4% |
| Contralateral lateral LN (N = 4) | 296.0 | 0.333 | 100.0% | 33.3% |
0.7 ≤ AUC < 0.8: acceptable discrimination.
0.8 ≤ AUC < 0.9: excellent discrimination.
AUC (area under the ROC curve) ≤ 0.5: no discrimination.
Transient hypocalcemia occurred in 21.5% of patients, and permanent hypocalcemia occurred in 6.5% of patients. Vocal cord palsy occurred in six patients (5.5%), and five of those patients had advanced tumors with recurrent laryngeal nerve invasion. The other patient recovered from vocal cord palsy.
4. DISCUSSION
Surgery is a potentially curative treatment for MTC.4, 6, 8 However, after surgery, persistently elevated calcitonin levels are found in more than half of MTC patients who present with clinical disease and high recurrence rates have been reported in the neck lymph nodes.2, 3, 4 Although most MTC patients with metastases to regional lymph nodes are not biochemically cured despite aggressive surgery, including bilateral neck dissection, meticulous lymph node dissection may result in a higher biochemical cure rate8, 9 and decrease the risk of local recurrence.17, 18 Therefore, surgery should be planned to remove all tumor in the neck while maintaining an acceptable morbidity.
Total thyroidectomy and CND is recommended for almost all MTC patients, but there is still controversy regarding the treatment of MTC, especially with regard to the extent of thyroidectomy and lymphadenectomy. According to National Comprehensive Cancer Network guidelines, in tumors with a diameter ≥ 1 cm or bilateral thyroid disease, a prophylactic LND is considered if there is high volume or gross disease in the adjacent central neck.19 The 2015 ATA guidelines recommend that patients with lymph node metastases visible by ultrasonography (US) in the lateral neck compartments should undergo a total thyroidectomy with CND and LND13 while prophylactic LND is recognized as a minority view. In this set of recommendations, the results of preoperative neck ultrasound and biopsy strongly influence the extent of surgery.
Additional imaging procedures as contrast‐enhanced CT/MRI are recommended in patients with extensive neck disease and suspicious regional or distant metastases. For patients with differentiated thyroid carcinoma and suspicion of tumor recurrence, the meta‐analysis showed a higher sensitivity and a similar specificity for 2‐[18F]‐fluoro‐2‐deoxy‐d‐glucose (FDG) positron emission tomography/CT (FDG‐PET/CT) compared with conventional imaging.20 However, FDG‐PET/CT and 18F‐dihydroxyphenylalanine F‐DOPA‐PET/CT (F‐DOPA‐PET/CT) are less sensitive in detecting metastases, compared to other imaging procedures for patients with MTC. Therefore, FDG‐PET/CT or F‐DOPA‐PET/CT is not recommended for current guideline.13, 21
The clinical decision for prophylactic LND is challenging and involves considering the natural course of disease, sensitivity of imaging to detect disease in the neck and at distant sites, and assessments of outcomes including surgical morbidity. Preoperative US has been supported to evaluate lymph node metastases in MTC patients.22 Although in the setting of an experienced clinician or ultrasonographer, the limitations and insufficiency of US may alter operative strategies.21 The M.D. Anderson group reported a 44% (27 of 61 patients) false‐negative rate, which occurs more frequently when disease is found in the central (32%) compared to lateral (14%) neck compartment.22 In addition, the false‐negative rate is even higher in reoperation (49%) than primary operations (36%).
In patients with persistent or recurrent MTC localized to the neck, the majority of reoperations will not be biochemically free of disease and there is a high risk of surgical morbidity.13, 23 LND could be beneficial at the time of initial surgical treatment because of the high frequency of residual MTC in the LLNs.
The occurrence of cancer in the ipsilateral nodes is high in MTC and ranges from 32% to 80% in previous reports.8, 24, 25 Lymph node involvement is present in 10% to 30% of tumors smaller than 1 cm8, 26, 27 and is more frequently found in patients with larger tumors. Furthermore, contralateral lymph node metastases were found on histology review in 44% of patients with a palpable unilateral MTC, but only in 25% of patients with a tumor less than 1 cm.8 In this study, the significant tumor size cut‐off value was 1.75 cm in cases of ipsilateral LLN and 2.25 cm contralateral CLN.
Serum calcitonin is a sensitive and determinative marker for both preoperative diagnosis and postsurgical follow‐up of MTC.28, 29, 30, 31 Preoperative basal calcitonin levels may be a better indicator of nodal metastasis. Stratified basal calcitonin serum levels were correlated with the histopathologic extent of disease in a previous study, and nodal metastasis was noted with basal calcitonin levels of 10 to 40 pg/mL (normal range, <10 pg/mL).14 In a previous study, lymph node metastases were present in the ipsilateral central and lateral neck, contralateral central neck, contralateral lateral neck, and upper mediastinum when basal calcitonin levels were beyond threshold levels of 20, 50, 200, and 500 pg/mL, respectively.32 Our study is similar to these reports; lymph node metastases were present in the ipsilateral central and lateral neck, contralateral central neck when basal calcitonin levels were beyond thresholds of 226.6 pg/mL, 237.0 pg/mL, and 755.0 pg/mL, respectively. These results support that ipsilateral LLN metastases occur before contralateral CLN metastases. It may be related to the fact that cervical lymphatic flow is directed toward the ipsilateral lower jugular lymph nodes and the venous angle, thus lymphatic tumor cells seem to spread through the contralateral central compartment to the contralateral lateral compartment.32
In the setting of established MTC, the optimal extent of preoperative LN metastatic screening is unclear. Our study supports that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases.
Although there was no evidence of LLN metastasis at the preoperative imaging work‐up, if contralateral CLN metastases are identified by preoperative fine‐needle aspiration or intraoperative frozen biopsy, ipsilateral LLN dissection should be considered in addition to total thyroidectomy with CND. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin levels, and tumor size to maximally individualize surgery.
CONFLICT OF INTEREST
All the authors declare no conflict of interest.
Bae SY, Jung SP, Choe J‐H, Kim JS, Kim JH. Prediction of lateral neck lymph node metastasis according to preoperative calcitonin level and tumor size for medullary thyroid carcinoma. Kaohsiung J Med Sci. 2019;35 772–777. 10.1002/kjm2.12122
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