Elective Central Compartment Neck Dissection in Patients With Papillary Thyroid Carcinoma Recurrence

Transcription

1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Elective Central Compartment Neck in atients With apillary Thyroid Carcinoma Recurrence Omer Trivizki, MD; Moran Amit, MD; Dan M. Fliss, MD; Ziv Gil, MD, hd Objectives/Hypothesis: To investigate the role of elective central compartment neck dissection (CND) in patients with recurrent papillary thyroid carcinoma in the jugular chain lymph nodes. Study Design: Retrospective medical record review and analysis of survival outcomes. Methods: The study was conducted at Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University. Fifty-one patients who had prior thyroidectomy underwent therapeutic lateral neck dissection (LND) without radiological evidence of central neck metastases. Therapeutic LND without elective CND was performed in 17 patients, and 34 patients had elective CND. The clinical variables were similar in both groups. The median follow-up was 44 months. Disease-free survival and overall survival were the main outcome measures. Results: The recurrence rate in the central neck was 9% (n 5 3/34) in patients undergoing CND and 12% (n 5 2/17) in patients without CND. The overall recurrence rate was 18% (6/34) in patients with CND and 36% (6/17) in patients without CND ( ). The 5-year disease-free survival rate was 82% and 65% in patients with or without CND, respectively ( ). Long-term thyroglobulin levels and complication rates were similar in both groups. Conclusions: The lack of significant disease-free survival advantage demonstrates the need for a prospective evaluation of the common practice of this disease. Key Words: Thyroid, papillary, neck dissection, lymph node metastases, paratracheal. Level of Evidence: 4. Laryngoscope, 123: , 2013 INTRODUCTION The incidence of thyroid carcinoma has increased in the last decade, mostly due to widespread use of imaging modalities, although with no concomitantly significant impact on survival. 1 Surgery continues to be the routine management of carcinomas originating in the thyroid From the Department of Otolaryngology (O.T., M.A., Z.G.), Rambam Medical Center, Rappaport School of Medicine, the Technion, Israel Institute of Technology, Haifa, Israel, Laboratory for Applied Cancer Research (O.T., M.A., Z.G.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, Department of Otolaryngology Head and Neck Surgery Unit (D.M.F.), Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Editor s Note: This Manuscript was accepted for publication December 17, Dr. Trivizki has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The study was performed in partial fulfillment of the MD thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University (O.T.). This research was supported by the Legacy Heritage Biomedical Science artnership rogram of the Israel Science Foundation (No. 1680=08), the Israel Cancer Association (grant donated by Ellen and Emanuel Kronitz in memory of Dr. Leon Kronitz, No ), the Israeli Ministry of Health (No ), the Weizmann Institute Sourasky Medical Center Joint Grant, the Tel Aviv Sourasky Intramural Grant, the ICRF Barbara S. Goodman Endowed Research Career Development Award ( BGC), and a grant from the US Israel Binational Science Foundation (No ) to Dr. Ziv Gil. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Ziv Gil, MD, Department of Otolaryngology, Rambam Medical Center, Rappaport School of Medicine, the Technion, Israel Institute of Technology, Haifa, Israel. ziv@baseofskull.org DOI: /lary gland. Well-differentiated thyroid carcinomas (WDTCs), including papillary thyroid carcinoma (TC), require resection of the primary tumor and clearance of clinically evident nodal metastases. The primary echelons for malignant tumors of the thyroid are the paratracheal and superior mediastinum lymph nodes (levels VI and VII). It is generally accepted that palpable neck disease or radiological evidence of nodal metastases in TC will necessitate therapeutic neck dissection; however, there is no level 1 evidence supporting the rationale for performing prophylactic neck dissection in TC. We approached the question of whether an elective central compartment neck dissection (CND) should be performed in patients who had prior thyroidectomy and presented with jugular chain metastases, by investigating specific outcome measures, including disease-free survival, recurrence rate, and morbidity, in two groups of patients: those undergoing therapeutic lateral neck dissection (LND) and elective CND and those undergoing LND alone. This is the first study to compare the early outcomes of patients undergoing an elective CND in the presence of clinically positive jugular chain nodes. MATERIALS AND METHODS This retrospective study is based on a review of the hospital and outpatient clinical records of the 464 patients who underwent neck dissection for WDTCs in our institution between 2000 and Of these, 51 (11%) patients who had prior thyroidectomy without central or lateral neck dissection had clinically positive jugular chain metastases (N1b1) without

2 evidence of central neck metastases (N1a2). All patients underwent preoperative central compartment evaluation by ultrasound. The patients with clinical or radiological evidence of neck metastases in level VI VII (paratracheal and superior mediastinum nodes) or thyroid bed were excluded. Clinically positive nodes were defined as abnormal by ultrasound. In all patients, clinically positive nodes were evaluated by fine-needle aspiration prior to surgery. All patients underwent a standardized selective neck dissection involving levels II IV or II V (LND) as described by the American Head and Neck Society. 2 Analysis of the data revealed that one surgeon routinely performed all the elective CND, whereas two other surgeons routinely chose not to perform an elective procedure. The type of neck dissection was prespecified in all patients before the operation. Elective CND was performed in 34 of 51 patients. One patient had bilateral jugular chain metastases, and one patient had bilateral elective CND. The follow-up interval ranged from 8 to 226 months, with a median of 44 months. None of the patients died of thyroid cancer. All patients had postoperative treatment with radioactive iodine (I 131 ). The median ablative dose used was 150 mci. An additional dose of I 131 ( mci) was given when any remaining uptake was found 1 year after the first treatment. All patients received postoperative hormone supplement (thyroxine), with a mean dose of 1116 lg/week, aiming to keep a thyrotropin (TSH) level of <0.1 mu/ml. Total calcium serum levels were measured before and after the operation. Follow-up included radioactive scanning 12 months after the initial I 131 treatment and periodic neck ultrasound examinations. Thyroglobulin (TG), anti-tg antibody, and TSH levels were monitored every 3 months. Twelve patients (24%) had disease recurrence, and four (8%) of them had distant metastases. The demographic and clinical data of the cohort and its subgroups are listed in Table I. Specimen dissection and tissue sampling were carried out in accordance with the current guidelines for the histopathological assessment of head and neck cancer. 3 The levels of neck dissection specimens were identified, marked, and submitted for pathological analysis. The lymph nodes were evaluated for metastasis by pathologists specializing in head and neck cancer. All identified nodes were submitted by the pathologist for further histological analysis. Lymph nodes were defined as aggregates of encapsulated lymphoid tissue of any size that had a peripheral sinus. Each lymph nodes was sectioned every 2 mm, put in different cassettes, and embedded in paraffin. Sectioning was performed at 200 -lm intervals. Clinical, demographic, and tumor variables were analyzed using nonparametric qualitative and quantitative tests (JM statistical software; SAS Institute Inc., Cary, NC). Fisher exact test (StatCalc 2.0; University of Louisiana, Lafayette, LA) was used when the number of events was <10. Two-tailed calculations were performed in all statistical analyses. Disease-free survival rate was calculated using the Kaplan-Meier method (JM statistical software; SAS Institute Inc.). The study was approved by the institutional review board committee ( TLV). RESULTS The clinical and demographic characteristics of 51 patients who underwent 53 therapeutic selective neck dissections of levels II IV (n 5 48) or II V (n 5 5) were analyzed. Therapeutic LNDs without elective CNDs were performed in 17 patients, and therapeutic LNDs with elective CNDs were performed in 34 patients. The main clinical and demographic characteristics of each group are listed in Table I. All patients had undergone Variable TABLE I. Clinical and Demographic Characteristics of the atients. Entire cohort, n (%) 17 (33) 34 (67) Age, mean 6 SD (range), yr (18 70) Sex, n (%) (17 77) Male 11 (65) 17 (50).38 Female 6 (35) 17 (50) Family history of TC, n (%) 1 (6) 1 (3).9 Irradiation exposure, n (%) 1 (6) 1 (3).9 Neck dissection laterality, n (%) Unilateral 16 (94) 33 (97).9 Bilateral 1 (6) 1 (3) Total of I 131 treatments, n (%) T stage at initial presentation, n (%) 1 10 (59) 15 (44) (0) 2 (6) 3 5 (29) 11 (32) 4a 2 (12) 5 (15) 4b 0 (0) 1 (3) rimary tumor multifocality, n (%) 4 (24) 14 (41).2 rimary tumor location, n.2 Isthmus 7 3 Lateral lobes Upper pole 1 rimary tumor 5 (29) 13 (38).4 extracapsular invasion, n (%) Overall TNM stage, n (%) I 7 (41) 14 (41).9 III 9 (53) 17 (50) Iva 1 (6) 3 (9) Follow-up time, mean 6 SD (range), mo Number of resected nodes, median (range) II V 24 (2 45) 22 (1 63).7 VI 5 (2 17) Number of positive nodes II V, n (%) 0 5 (29) 7 (21) (12) 5 (15) >2 10 (59) 22 (64) Number of positive nodes VI, n (%) 0 10 (29) 1 6 (18) >2 18 (53) Thyroid-stimulating hormone, n (%), mu/ml < (76) 28 (82) (18) 3 (9) >5 1 (6) 3 (9) Thyroid hormone supplement, mean 6 SD, lg TC 5 papillary thyroid carcinoma; SD 5 standard deviation

3 TABLE II. Recurrence Rates. TABLE III. Thyroglobulin Level. Variable, n (%), n (%) Recurrence site Central neck 2 (12) 3 (9).73 Lateral neck 6 (36) 2 (6).006 Thyroid bed 1 (6) 0 (0).15 Metastases 1 (6) 3 (9).71 Total * 6 (36) 6 (18).16 *Some patients had recurrence in multiple sites. prior thyroidectomy, and there was no difference in the age, gender, iodine treatment, initial tumor multifocality, location or extra capsular invasion, total number of dissected nodes, TNM classification, stage, or TSH suppression between the two groups (Table I). Thyroid hormone supplement dosage was higher in the group that did not have elective CND dissection ( 5.02). Twelve patients had disease recurrence; eight (67%) were in the lateral neck, five (42%) were in the central compartment region, and four (33%) were distant metastases. The overall recurrence rate was 18% (6/34) for the group with elective CNDs compared with 35% (6/17) for the group without elective CNDs ( 5.16). Table II shows the recurrence subsites in the two groups. The rate of disease recurrence in the central neck compartment (level VI VII) was 9% (n 5 3) in those undergoing elective CNDs compared to 12% (n 5 2) in the group without elective CNDs ( 5.73). Figure 1 depicts the Kaplan-Meier analyses of the two groups. The 5-year disease-free survival rate of patients who had LND and elective CND was 82% compared to 65% in those who had LND alone. The difference in early disease-free survival between the two groups did not reach a level of significance ( 5.69). We also evaluated the TG levels for both groups to obtain objective data on postoperative recurrence. Thyroglobulin level <2.5 lg/ml, n (%) 12 (71) 29 (85).2 >2.5 lg/ml, n (%) 5 (29) 5 (15) Mean6SD, lg/ml ositive anti-tg Ab, n (%) 1 (6) 2 (6) 1 SD 5 standard deviation. The distribution of TG levels among patients who had no evidence of recurrence were similar regardless of whether or not an elective CND had been performed (Table III). Overall complication rate was 12% (6/51), and two (33%) patients had RLN paralysis, three (50%) had hypocalcemia, and one (17%) had bleeding that required revision surgery (Table IV). The distribution of complication rates was similar regardless of whether or not an elective CND had been performed ( 5.3). DISCUSSION The generally accepted therapeutic management for TC with clinical evidence of nodal metastases is total thyroidectomy and neck dissection, with the intent to remove all of the involved lymphatic tissue. The type, grade, site, and stage of the primary tumor determine the risk of cervical metastases and therefore the form of neck treatment. 4 In head and neck squamous cell carcinoma, when the risk for positive neck nodes exceeds 20%, elective neck dissection is indicated not only for treatment, but also for evaluation of the need for adjuvant therapy. 5 However, because there is minimal impact of neck metastases on survival of patients with TC, elective neck dissection is not routinely recommended in this population. 6 Because of a lack of level 1 evidence, there is an ongoing debate on whether patients with TC should undergo elective neck dissection. 4 Fig. 1. Kaplan-Meier analysis. The graph shows the disease-free survival of patients undergoing therapeutic lateral neck dissection (tlnd), with elective central compartment neck dissection (ecnd) (black line) or without ecnd (dotted line). The 5-year disease-free survival rate was 82% in the group with ecnd and 65% in those without ecnd ( 5.69). 1566

4 Type of Complication TABLE IV. Complications., n (%) Lateral and, n (%) ermanent recurrent 0 (0) 2 (6).19 laryngeal nerve paralysis ermanent hypocalcemia 1 (6) 2 (6).99 Bleeding 0 (0) 1 (3).62 Total 1 (6) 5 (15).33 Moreover, it is unknown whether patients who had prior thyroidectomy undergoing therapeutic LND also require an elective CND. 7,8 reoperative ultrasound can detect nonpalpable nodal metastases in one-third of the patients with TC. 9,10 An elective CND will detect occult nodal metastases in 40% to 60% of the remaining patients, and an elective LND will detect positive nodes in 40%. 11 Contralateral occult paratracheal nodes are present in 10% to 25% of patients. 12,13 Furthermore, the risk of central compartment metastases is even higher when there are jugular chain metastases. 14 Hence, the overall risk of occult nodal metastases in patients with TC is over 80%. 11 Based on these numbers alone, some surgeons recommended prophylactic CND (ipsilateral or bilateral) in patients with TC with clinically positive jugular nodes. 7 However, there is no level 1 evidence showing a clinical advantage of elective CND in this population. Another unanswered question is: Which population should undergo an elective CND (i.e., young patients who have a high risk of nodal metastases or older patients who have a low risk of neck metastases)? ositive neck nodes in the former group have no impact on survival, but they are associated with worse outcome in the latter group. 15,16 In addition, there is no consensus as to which type of elective neck dissection should be performed, LND with a 40% risk of positive nodes in level II IV or CND with a 60% incidence of nodal metastases in level VI VII. The answers to these questions should be based on the potential benefit weighed against the potential morbidity of the surgical outcome. We assessed whether an elective CND offers an advantage to patients with positive jugular chain metastases by investigating the early tumor-free survival, recurrence rate, and complications. The clinical, demographic, and pathological variables were similar in the groups with or without CND, and both groups also received the same adjuvant radioiodine treatment dose and had a similar degree of TSH suppression. Overall, the difference in the disease-free survival (Kaplan-Meier analysis) among the subgroups was not statistically significant. The early recurrence rate in the central compartment was the same (9% 12%) in both groups. These data are supported by TG levels that were identical in both groups. The rate of neck metastases in the current study was similar to that reported in the literature, and as expected, the highest risk of recurrence was found in the lateral neck. 8,17 Taken together, these data demonstrate that prophylactic CND does not influence the early outcome of this population, and that the risk of locoregional recurrence and distant metastases remains similar whether or not CND was performed. 8 Shah et al. evaluated the recurrence rates in patients with well-differentiated thyroid carcinoma who underwent a therapeutic LND, CND, or both and found no differences in the rate of recurrence among the three groups. 8 The implications of their study and ours are that although central compartment metastases are common in this population, they have minimal clinical impact on the patient s outcome. The rationale for prophylactic CND is based on suspicion of a high incidence of occult nodal metastasis. However, we found similar rates of nodal recurrence in this area regardless of CNDs. One explanation for this observation is that the adjuvant radioiodine treatment efficiently cleared all microscopic residual cancer cells in the central neck compartment. 18 Another possibility is that TC cells survive but do not progress to clinically evident disease in the metastatic environments, a phenomenon known as metastatic dormancy. 19 Regarding complication, some will argue that there is no increased risk in adding CND when performing therapeutic LND. The incidence rates of hypoparathyroidism and vocal cord paralysis are well established and not negligible following central compartment reoperation. 20 Although the rates are acceptable given that these patients are reoperated, in the presence of jugular chain metastasis and no thyroid tissue, performing elective CND puts the patient at increased risk for hypoparathyroidism and vocal cord paralysis. We are aware of several limitations of our study. In addition to its retrospective design, the small number of patients in our cohort limits our ability to draw firm conclusions from the data. Although more than 14 items were entered into our database, it is still difficult to precisely delineate which factors influenced the risk of tumor recurrence. Other parameters, such as the type of radiologic evaluation during follow-up and the quality of neck dissection, are difficult to quantify. These important variables can potentially affect the rate of locoregional recurrence. During the postoperative follow-up, the mean TG levels were almost half among patients undergoing elective CND compared to those not submitted to CND ( and lg/ml, respectively). Although this difference was not statistically significant ( 5.63), it is conceivable that our ability to distinguish between small differences in TG level was limited by the sample size. The retrospective nature of the study may also have the potential of selection bias, because surgeons often tailor their treatment based on clinical node involvement both preoperatively and intraoperatively. 8 This does not apply to our study, however, because the surgeons decide whether to perform CND in a regular routine based on their preferences, regardless of clinical or demographic parameters. We are aware that the follow-up of the patients in our cohort is relatively short. Approximately 80% of all recurrences in TC occur within the first 5 years after initial treatment. 21 Our overall 5-year disease-free survival rate was 65% in 1567

5 patients undergoing LND alone and 82% in those undergoing LND and an elective CND. An identical 5-year disease-specific survival rate was reported by the Toronto group on a similar group of patients. 8 In their study, the median length of follow-up was 104 months. Although it is likely that our results represent a lower estimation of overall recurrence rate, we believe that our main finding that elective CND does not change disease-free survival, will remain valid when an updated evaluation of our data will be available in several years. A final decision on the performance of an elective neck dissection in TC will have to wait for the availability of level 1 evidence. CONCLUSION The current study shows for the first time that neither the early tumor recurrence rate nor the diseasespecific survival is influenced by an elective central compartment neck dissection in patients with positive jugular chain nodes. The absence of significant diseasefree survival advantage along with the known risk of complications demonstrate the need for a prospective evaluation of the common practice of this disease. ACKNOWLEDGMENTS The authors thank Esther Eshkol for editorial assistance. BIBLIOGRAHY 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin 2010;60: Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg 2008;134: Yorkshire Cancer Network. Guidelines for the Examination and Reporting of Head and Neck Cancer Specimens, Leeds, UK: Yorkshire Cancer Network; 2007: Gil Z, Fliss DM. Contemporary management of head and neck cancers. Isr Med Assoc J 2009;11: Shah J, Gil Z. Current concepts in management of oral cancer surgery. Oral Oncol 2009;45: Tuttle RM, Ball DW, Byrd D, et al.; National Comprehensive Cancer Network. Thyroid carcinoma. J Natl Compr Canc Netw 2010;8: Khafif A, Ben-Yosef R, Abergel A, Kesler A, Landsberg R, Fliss DM. Elective paratracheal neck dissection for lateral metastases from papillary carcinoma of the thyroid: is it indicated? Head Neck 2008;30: Shah MD, Hall FT, Eski SJ, Witterick IJ, Walfish G, Freeman JL. Clinical course of thyroid carcinoma after neck dissection. Laryngoscope 2003;113: Stulak JM, Grant CS, Farley DR, et al. Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Arch Surg 2006;141: ; discussion Kouvaraki MA, Shapiro SE, Fornage BD, et al. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 2003;134: ; discussion Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003; 237: Sadowski BM, Snyder SK, Lairmore TC. Routine bilateral central lymph node clearance for papillary thyroid cancer. Surgery 2009;146: ; discussion Roh JL, Kim JM, ark CI. Central lymph node metastasis of unilateral papillary thyroid carcinoma: patterns and factors predictive of nodal metastasis, morbidity, and recurrence. Ann Surg Oncol 2011;18: Goropoulos A, Karamoshos K, Christodoulou A, et al. Value of the cervical compartments in the surgical treatment of papillary thyroid carcinoma. World J Surg 2004;28: Shaha AR, Shah J, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 1996;3: Hughes CJ, Shaha AR, Shah J, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck 1996;18: Shaha AR, Shah J, Loree TR. atterns of nodal and distant metastasis based on histologic varieties in differentiated carcinoma of the thyroid. Am J Surg 1996;172: Sacks W, Fung CH, Chang JT, Waxman A, Braunstein GD. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April Thyroid 2010;20: Ringel MD. Metastatic dormancy and progression in thyroid cancer: targeting cells in the metastatic frontier. Thyroid 2011;21: Roh JL, Kim JM, ark CI. Central compartment reoperation for recurrent/persistent differentiated thyroid cancer: patterns of recurrence, morbidity, and prediction of postoperative hypocalcemia. Ann Surg Oncol 2011;18: Hay ID, Thompson GB, Grant CS, et al. apillary thyroid carcinoma managed at the Mayo Clinic during six decades ( ): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002;26: