|Year : 2020 | Volume
| Issue : 5 | Page : 1077-1081
Long-term outcomes of patients with papillary thyroid cancer who did not undergo prophylactic central neck dissection
Hui Huang1, Ligang Wu2, Wensheng Liu1, Jie Liu1, Yang Liu1, Zhengang Xu1
1 Department of Head and Neck Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
2 Department of Oncological Surgery, Cancer Hospital General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
|Date of Submission||18-Sep-2019|
|Date of Decision||01-Jan-2020|
|Date of Acceptance||26-Mar-2020|
|Date of Web Publication||29-Sep-2020|
Department of Head and Neck Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, N0. 17 Panjiayuan Road, Beijing 100021
Source of Support: None, Conflict of Interest: None
Aims: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid carcinoma (PTC) is controversial. This study reports outcomes of an observational approach in PTC patients without clinical evidence of lymph node metastasis.
Materials and Methods: Patients with PTC who had surgery (without prophylactic CND) between January 2000 and December 2008 were included in this study. Recurrence-free survival (RFS) and disease-specific survival (DSS) were calculated using the Kaplan–Meier method. Cox regression was used in multivariable models.
Results: Out of 625 patients, 486 (77.8%) were female, 144 (23%) were aged 55 years or more, 73 (11.7%) had macroscopic extrathyroidal extension, and 79 (12.7%) had pT3 or pT4 disease. Samples were collected from 12 (1.9%) patients with lymph node metastasis in the perithyroidal tissue and 2 (0.3%) patients with lymph node metastasis in the lateral neck lymph tissue for frozen section examination. After a median follow-up of 104 months, the 10-year DSS and RFS rates were 99.7% and 90.2%, respectively. The 10-year lymph node recurrence rate in the central compartment was 2.7%. pT3/4 stage was an independent predictive factor for RFS (P < 0.001, hazard ratio 1.966, 95% confidence interval 1.446–2.673).
Conclusion: The outcomes of patients with clinically negative lymph nodes in the central compartment were favorable without prophylactic CND.
Keywords: Central neck dissection, clinical N0, papillary carcinoma, thyroid neoplasms
|How to cite this article:|
Huang H, Wu L, Liu W, Liu J, Liu Y, Xu Z. Long-term outcomes of patients with papillary thyroid cancer who did not undergo prophylactic central neck dissection. J Can Res Ther 2020;16:1077-81
|How to cite this URL:|
Huang H, Wu L, Liu W, Liu J, Liu Y, Xu Z. Long-term outcomes of patients with papillary thyroid cancer who did not undergo prophylactic central neck dissection. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1077-81. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1077/296441
Hui Huang and Ligang Wu are co-first authors
| > Introduction|| |
Patients with papillary thyroid carcinoma (PTC) commonly have cervical lymph node metastasis and a high rate of occult metastasis, especially in the central compartment, with an incidence of 50%–60%.,, The impact of cervical lymph node metastasis on survival, especially disease-specific survival (DSS), remains controversial. Most investigators have concluded that lymph node metastasis has no impact on survival but is related to a high recurrence rate., Patients over 45 years of age with lateral cervical lymph node metastasis, especially clinically positive lymph node metastasis, have a high incidence of distant metastasis and disease-related mortality. The most appropriate treatments for clinically node-negative (cN0) neck, particularly in the central compartment, remain the subject of debate. At present, the impact of occult central compartment lymph node metastasis on recurrence and survival is uncertain. Central neck dissection (CND) removes occult metastatic lymph nodes, and thus, theoretically can reduce recurrence rates and improve survival outcomes. Some studies that did not support routine prophylactic CND have shown low recurrence rates after observation of cN0 neck.,,,,,, Other authors have suggested that prophylactic CND can achieve accurate risk stratification and select patients with lymph node metastasis suitable for iodine ablation therapy., In addition, the levels of thyroglobulin in patients after prophylactic CND were lower than those in patients who had only undergone thyroidectomy, and thyroglobulin was identified as a marker for detecting tumor recurrence during follow-up. The American Clinical Endocrine Association recommends prophylactic CND as the standard treatment for cN0 PTC, and the American Thyroid Society (ATA) recommends selective CND for cN0 PTC, especially for cases with extrathyroidal extension (ETE) (T3, T4). Nixon et al. reported a group of patients who did not undergo prophylactic CND, and at a median follow-up of 46 months, showed that the 5-year DSS rate was 100% and the 5-year central neck recurrence-free survival (RFS) rate was 99.1%. The recurrence of PTC is not common and can even happen 10 years after primary surgery. Mazzaferri and Kloos showed that PTC recurrence occurred in two-thirds of their cohort within the first 10 years of the study. Thus, it is necessary to extend the duration of follow-up for further observation and analysis. During the early period of our hospital, prophylactic CND was not routinely performed, and the outcomes of patients with cN0 PTC (between 1991 and 2000) after observation were reported. The present study provides an update of the outcomes among patients with cN0 PTC who did not undergo CND, with determination of the corresponding rates of recurrence and survival.
| > Materials and Methods|| |
Preoperative evaluation of patients with thyroid cancer included physical and ultrasound examinations. Chest X-ray was used to check for lung metastasis, and a few patients received enhanced computed tomography (CT) scanning. From January 2000 to December 2008, 1494 patients with PTC were treated in our hospital. Eight patients with distant metastasis, 34 patients with unifocal PTC confined in the isthmus and 409 patients with clinically positive lymph nodes were excluded. In addition, 1043 patients were cN0, of which 350 patients underwent CND and 68 patients underwent CND as well as lateral neck dissection for occult lymph node metastasis, diagnosed by intraoperative frozen section examination. The remaining 625 patients who did not undergo CND were included in this study. Data for clinicopathological factors including sex, age, tumor size, multifocality, ETE, and pTNM stage were retrospectively collected. Staging was performed according to the American Joint Committee on Cancer TNM Stage for Thyroid Cancer (8th Edition, 2017). Because this was a retrospective analysis and would not cause any harm to the patients, informed consent was not obtained from the patients, and the study was approved by the institutional ethics committee.
The principles of primary surgery were resection of at least the affected lobe and isthmus, including 59 cases with total thyroidectomy; 315 cases with resection of the ipsilateral lobe and isthmus; 177 cases with resection of the ipsilateral lobe, isthmus, and partial contralateral lobe (or nodules); 42 cases with resection of the ipsilateral lobe, isthmus, and subtotal contralateral lobe; and 32 cases with resection of less than the ipsilateral lobe (microcarcinoma was diagnosed after resection of a benign nodule). All patients were treated with levothyroxine tablets, and five patients were treated with iodine 131 ablation therapy.
All patients with the observation of the cN0 central neck were followed and retrospectively analyzed. The date of surgery was used as the start of follow-up. The follow-up data were obtained from electronic medical records or by mail/telephone calls, and 53 patients (6.5%) were lost. The median follow-up time was 104 months (range, 12–184 months). The primary end points were RFS and DSS. Other end points included lymph node recurrence rate, residual thyroid recurrence rate, and distant metastasis rate. Regional lymph node recurrence referred to histologically or cytologically confirmed lymph node metastasis in the central compartment (level VI) or lateral compartment (level II–V). The recurrence of residual thyroid referred to histological or cytological confirmation of residual thyroid after partial thyroidectomy. Distant metastasis referred to any recurrent disease outside of the thyroid and neck region (diagnosed by chest X-ray or CT scanning).
SPSS v20.0 (SPSS Inc., Chicago, IL, USA) software was used for statistical analysis. Survival data were analyzed by means of the Kaplan–Meier method, and survival curves were compared using the log-rank test on univariate analysis. Cox regression analysis was used for multivariate analysis. All statistical tests were two-sided, and a P < 0.05 was defined as statistically significant.
| > Results|| |
The median age of the included patients was 46 years (range, 14–87 years). Among all 625 patients, 486 patients (77.8%) were female, and 354 patients (56.6%) had a maximum tumor diameter ≤10 mm. Overall, 107 patients (17.1%) had tumors with ETE, of which 34 cases were microscopic ETE (5.4%) and 73 were macroscopic ETE (11.7%). Multifocal tumors were pathologically diagnosed in 123 patients (19.7%) and 69 (11.0%) cases had bilateral multifocal tumors. A total of 546 patients (87.3%) had pT1 or pT2 tumors, and 79 patients (12.7%) had pT3 or pT4 tumors. Following histopathological analysis, 12 patients (1.9%) were found to have evidence of lymph node metastasis in perithyroidal tissues and two patients (0.3%) were found to have a metastatic lymph node in the lateral compartment lymph tissues, which was removed intraoperatively for frozen section examination. A total of 611 patients had no lymph node present in the surgical specimen (pNx).
A total of ten patients died during the follow-up, of which one died from tumor distant metastasis (bone metastasis) and nine died from other causes. The 10-year DSS and RFS rates were 99.7% and 90.2%, respectively.
Tumor recurrence was observed in 39 patients (some patients with simultaneous or metachronous multiple organ recurrence). Twenty-four patients had remnant thyroid recurrence (16 of which had only remnant thyroid recurrence), and 14 patients had lymph node recurrence in the central compartment (3 of which had only lymph node recurrence in the central compartment). Fifteen patients had lymph node recurrence in the lateral compartment (6 of which had only lymph node recurrence in the lateral compartment), and four patients had distant metastasis (1 of which had only distant metastasis). The median time to recurrence was 49 months (range, 9–150 months), with 27 patients experiencing recurrence within 5 years (69.2%) and 4 patients experiencing recurrence after 10 years. The 10-year lymph node recurrence rate in the central compartment was 2.7%; the remnant thyroid recurrence rate was 5.3%; and the distant organ recurrence rate was 0.6%. Among the 14 patients with lymph node recurrence in the central compartment, three patients were diagnosed with stage pT1, 1 was diagnosed with stage pT2, 6 were diagnosed with stage pT3, and 4 were diagnosed with stage pT4. Of the 14 patients with pN1a/b disease, three had tumor recurrence (1 in the central compartment, 1 in the lateral compartment, and 1 in lateral compartment and lung). All cases of lymph node recurrence in the central and lateral compartments were salvaged successfully by surgery, and these patients survived free of disease for more than 24 months until the end of follow-up. Three patients with lung metastasis were alive after iodine ablation therapy.
Univariate analysis showed that macroscopic ETE, pT3/4 stage, and pN1a/b were significant predictive factors for RFS with the 10-year RFS rates being 78.5%, 77.9%, and 79.5%, respectively, and the 10-year RFS for patients without macroscopic ETE, pT1/2 stage, and pNx were 91.7%, 91.8%, and 90.4%, respectively [Table 1]. Multivariable analysis showed that pT3/4 stage was an independent predictive factor for FRS [P < 0.001, hazard ratio 1.966, 95% confidence interval 1.446–2.673; [Table 2] and [Figure 1].
|Table 1: Univariable analysis of factors predictive of recurrence-free survival at 10 years|
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|Table 2: Multivariable analysis of factors predictive of recurrence-free survival at 10 years|
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|Figure 1: Kaplan–Meier curve showing recurrence-free survival rates stratified by T category (pT1/2 versus pT3/4). P < 0.001 (log rank test)|
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| > Discussion|| |
Occult lymph node metastasis is common in papillary thyroid cancer, especially in the central compartment. The role of prophylactic CND in the management of papillary thyroid cancer remains controversial, and due to its excellent outcomes, low recurrence rate and mortality rate, it is not feasible to conduct a large prospective randomized clinical study. It is difficult to obtain definite conclusions from studies, as there are limitations such as a retrospective design, small sample size, and short follow-up time. Most retrospective studies showed that prophylactic CND did not improve tumor control and the disease-related death rate.,, A retrospective study by Nixon et al. showed recurrence in 11 out of 275 patients with cN0 PTC after observation of the central neck, and the 10-year DSS was 100%. We have previously reported the results from a group of patients with cN0 PTC, and the outcomes were excellent without prophylactic CND. In our previous study, the lymph node recurrence rate in the central compartment was 3% (5/172), and the 10-year DSS was 99%. In addition, Nixon et al. reported a group of patients who did not undergo prophylactic CND for which the 5-year DSS rate was 100% and the 5-year RFS and central neck RFS rates were 96.6% and 99.1%, respectively, with a median follow-up duration of 46 months. Another study showed that routine prophylactic CND did not reduce locoregional recurrence rate, but the incidence rates of temporary and permanent hypoparathyroidism were increased significantly. A prospective randomized controlled study by Viola et al. also concluded that prophylactic CND did not reduce the central neck recurrence rate or the incidence of complications, with the incidence of permanent hypoparathyroidism increasing significantly. Although the sample size was small, the characteristics of a prospective randomized controlled trial provide important insights for treatment of PTC without CND. On the other hand, some authors recommended prophylactic CND for high rates of occult lymph node metastasis (up to 30%), and at the same time, prophylactic CND helps to obtain accurate risk stratification and select patients with lymph node metastasis for radioactive iodine (RAI) ablation therapy., It has also been suggested that the level of thyroglobulin after prophylactic CND was lower than that after only thyroidectomy, facilitating follow-up. By removing occult disease, recurrence should theoretically be reduced, and outcomes improved. However, the clinical response to RAI ablation therapy for total thyroidectomy with prophylactic CND is not superior to that to total thyroidectomy alone.
In the absence of high-level evidence to prove the value of prophylactic CND, the risk of surgical complications such as recurrent laryngeal nerve injury and permanent hypoparathyroidism must be considered. CND removes lymphatic and adipose tissues from the central compartment while putting the recurrent laryngeal nerve and parathyroid gland at risk of injury. Roh et al. reported that the overall incidence rates of complications and hypocalcemia in a group that received total thyroidectomy plus central lymph node dissection were significantly higher than those in a group that received total thyroidectomy (50% vs. 12.3%; P < 0.001, 30.5% vs. 9.6%; P = 0.001). Moo et al. also reported that the rate of accidental parathyroidectomy and incidence of temporary hypocalcemia in a prophylactic central lymph node dissection group were higher than those in a group without CND (16% vs. 3%, P = 0.07; 31% vs. 5%, P = 0.001). Calò et al. concluded that CND did not improve locoregional control but increased the incidence of postoperative complications. A meta-analysis showed that although prophylactic CND reduced the locoregional lymph node recurrence rate, the incidence rates of recurrent laryngeal nerve injury and hypoparathyroidism were increased significantly. A systematic review concluded that the effect of prophylactic CND on rates of locoregional lymph node recurrence remains uncertain, but the incidence rates of permanent hypoparathyroidism are higher. However, another meta-analysis showed that CND did not significantly increase the incidence of permanent complications. The differences in complications after CND may be due to the differences in case selection and the treatment experience of surgeons. Even in high-volume cancer centers, rates of hypocalcemia and recurrent laryngeal nerve injury were higher following prophylactic CND compared with thyroidectomy alone.
In the present study, although CND was not performed, 12 patients had lymph nodes metastases found in the perithyroidal tissues (pN1a) and two patients were found to be positive for nodal disease in the lateral compartment (pN1b) following pathological examination after surgery. These patients had a relatively high recurrence rate. In most cases of recurrent disease, reoperation is effective., After long-term follow-up, only one patient died from the disease, and the 10-year DSS rate was 99.7%. Similar to the study by Nixon et al., 14 (2.71%) patients experienced recurrence in the central compartment, and resection was successful in all cases. The inconsistency between the high occult lymph node metastasis rate and the good outcomes suggests that most occult lymph node metastases will not progress to clinical disease. The clinical value of upstaging by increasing the detection of occult lymph node metastasis needs to be re-evaluated.
The sentence “consider prophylactic central neck dissection” was removed from the 2017 NCCN Guidelines  according to the results of a prospective randomized controlled study. There also has been no concrete evidence that prophylactic CND improves overall survival. Therefore, the benefits and complications of prophylactic CND should be balanced, and prophylactic CND should be performed selectively.
This study has limitations. Ultrasound diagnostic technology is constantly improving, and the experience of the ultrasonologist also varies. Even if metastatic disease is missed in the metastatic lymphadenopathy, the low recurrence rate further affirms the observation of the central neck. Iodine ablation therapy was rarely performed in this study, especially during the early period. In addition, a thyroglobulin test was not available during the early period in our hospital, and recurrence in this study refers to structural recurrence.
| > Conclusion|| |
The results of the present study showed that patients with cN0 PTC who were not treated with prophylactic CND had excellent outcomes after a long-term follow-up of 10 years.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]