Initial Lymph Node Dissection Increases Cure Rates in Patients with Medullary Thyroid Cancer

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1 Original Article Initial Lymph Node Dissection Increases Cure Rates in Patients with Medullary Thyroid Cancer David Yü Greenblatt, Diane Elson, 1 Eberhard Mack and Herbert Chen, Departments of Surgery and 1 Medicine, University of Wisconsin, Madison, Wisconsin, USA. OBJECTIVE: Medullary thyroid carcinoma (MTC) is the third most common type of thyroid cancer. MTC spreads early to local lymph nodes, and most endocrine surgeons recommend total thyroidectomy with central lymph node dissection (CLND) as the minimum initial operation. We reviewed our experience to determine if the initial operation influences clinical outcomes. METHODS: Twenty-two patients with sporadic or inherited MTC who received surgery at one academic centre between 1994 and 2004 were identified. Clinical, operative, and pathology findings were reviewed. RESULTS: Ten patients had prophylactic thyroidectomy for hereditary MTC, while 12 patients underwent therapeutic operations for sporadic MTC. The average age of the prophylactic group was 11 ± 3, and 43 ± 6 years for the therapeutic group. All patients in the prophylactic group received thyroidectomy without neck dissection. No patient in the prophylactic group had residual disease or required re-operation. In the therapeutic surgery group, three patients were treated with thyroidectomy plus CLND, and nine patients received thyroidectomy alone. The CLND group had a significantly higher cure rate as demonstrated by a lower incidence of residual disease (0% vs. 89%, p = 0.018), and re-operations (0% vs. 78%, p = 0.045). CONCLUSION: Initial CLND for MTC increases cure rates by reducing residual disease and re-operations. [Asian J Surg 2007;30(2):108 12] Key Words: lymph node dissection, medullary thyroid carcinoma, neuroendocrine tumours, thyroid neoplasms, thyroid surgery First presented at the 10 th Congress of the Asian Association of Endocrine Surgeons, Hong Kong SAR, March Introduction Medullary thyroid carcinoma (MTC) is the third most common type of thyroid cancer, accounting for approximately 2 5% of all cancers of the thyroid gland. 1 The natural history of MTC is significant for early metastasis to the central neck compartment and other local and regional lymph nodes. In advanced cases, MTC can invade local structures such as the trachea and jugular vein, and metastasize to distant organs such as the liver, lungs, and bone. 2 Approximately 75% of MTC cases are sporadic, and 25% are hereditary. Sporadic MTC usually presents as a unifocal clonal population of tumour cells, while the heritable forms are typically multifocal and bilateral. Hereditary MTC has an earlier onset and, in MEN2B, a more aggressive course. Hereditary MTC is caused by mutations in the RET proto-oncogene, located on chromosome 10. Address correspondence and reprint requests to Dr Herbert Chen, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. chen@surgery.wisc.edu Date of acceptance: 28 June Elsevier. All rights reserved. 108 ASIAN JOURNAL OF SURGERY VOL 30 NO 2 APRIL 2007

2 LYMPHADENECTOMY INCREASES CURE RATES IN MTC Total thyroidectomy is the accepted prophylactic therapy for patients with hereditary MTC. The timing of surgery depends on the patient s hereditary MTC syndrome. With an understanding of the genotype phenotype correlations in hereditary MTC, the timing and extent of surgery can be tailored to the patient s particular RET codon mutation. Some controversy exists regarding the optimal initial treatment for sporadic MTC. Historically, many general surgeons performed total thyroidectomy alone for the disease. With the understanding that MTC often has already spread to local lymph nodes at the time of presentation, most endocrine surgeons now advocate thyroidectomy and central lymph node dissection (CLND) as the minimum initial operation. Some centres routinely add modified radical neck dissection when the primary tumour is palpable or the lymph nodes are involved. Given this background, we reviewed our experience in treating MTC to determine whether or not CLND influences cure rates in patients receiving initial surgery for MTC. Patients and methods A review of the University of Wisconsin Hospital operative database identified 22 patients with sporadic or inherited MTC who received initial thyroid surgery over a 10-year period. Clinical, operative, and pathology findings were reviewed. Statistical analysis was performed by analysis of variance, and disease-free survival curves were prepared using the Kaplan Meier method (SPSS 10.0; SPSS Inc., Chicago, IL, USA). Cure was defined as the absence of clinical, radiographic or biochemical (i.e. elevated basal serum calcitonin) evidence of MTC at the time of last follow-up. Significance was defined as a p value of < Results Of the study population of 22 patients, 10 patients received prophylactic surgery for hereditary MTC, and 12 had therapeutic surgery for a thyroid nodule diagnosed preoperatively as MTC. Only patients receiving their first thyroid operation were included. The average age of the prophylactic surgery group was 11 ± 3 years, compared to 43 ± 6 years for the therapeutic group (p < 0.001). Just over half of the patients in each group were female (Table 1). Table 1. Patient characteristics Group n Age (yr) Female (%) Prophylactic ± 3 55 Therapeutic ± 6 58 p < NS NS = not significant. Prophylactic surgery for hereditary MTC Ten patients received prophylactic thyroid resection because of hereditary MTC. Importantly, no prophylactic CLNDs were done. Two patients had foci of MTC in their resected thyroid specimens. The tumours were small, measuring 3 mm and 4 mm, respectively. No patient in the prophylactic surgery group had residual disease or required a further thyroid operation. Therapeutic surgery for MTC Twelve patients had initial surgery for a thyroid nodule diagnosed as MTC. Re-operative cases were not considered in this study. Nine patients received total thyroidectomy alone, and three received thyroidectomy plus CLND. The Thyroidectomy Alone Group on average was younger, more predominantly female, and had slightly smaller tumours than the CLND Group. These differences, however, were not statistically significant (Table 2). The average follow-up time for the Thyroidectomy Alone Group was 85 ± 13 months while the CLND Group had an average follow-up time of 71 ± 34 months. However, this difference was also not statistically significant (p = 0.65). Interestingly, more extensive surgery was not associated with an increase in perioperative complications. In fact, the converse was true: there were more complications in the Thyroidectomy Alone Group than the CLND Group. The three complications in the Thyroidectomy Alone Group included unilateral vocal cord paralysis, pneumonia and transient hypocalcaemia. After an average follow-up time of 80 months, one patient in the Thyroidectomy Alone Group had died from MTC. There were no complications or deaths in the CLND Group. These differences in morbidity and mortality, however, did not reach statistical significance. Comparing treatment outcomes, the Thyroidectomy Alone Group had a significantly higher rate of MTC recurrence than the CLND Group. In the Thyroidectomy Alone Group, eight of nine patients had recurrent MTC, and ASIAN JOURNAL OF SURGERY VOL 30 NO 2 APRIL

3 GREENBLATT et al Table 2. Therapeutic surgery group: patient and tumour characteristics Operation n Age (yr) Female (%) Tumour size (cm) Thyroidectomy Alone 9 39 ± ± 0.6 Thyroidectomy + CLND 3 54 ± ± 1.7 p NS NS CLND = central lymph node dissection; NS = not significant. Table 3. Therapeutic surgery for MTC: recurrence, re-operation and cure rates Operation n Residual or recurrent MTC Re-operations Cures Thyroidectomy Alone 9 8 (89%) 7 (78%) 1 (11%) Thyroidectomy + CLND (100%) p MTC = medullary thyroid carcinoma; CLND = central lymph node dissection. Disease-free survival Time after initial surgery (mo) Figure. Kaplan Meier disease-free survival curves for patients with medullary thyroid carcinoma treated with thyroidectomy alone (dotted line) and thyroidectomy plus central lymph node dissection (solid line). seven went on to have additional surgery. One patient who had recurrent disease refused further surgical treatment. In contrast, none of the patients who received CLND had disease recurrence, and no patient required re-operation (Table 3). The difference in disease-free survival between the two groups is illustrated in the Figure, which shows divergent Kaplan Meier survival curves. The cure rate among patients who received CLND was 100%, compared to only 11% in the Thyroidectomy Alone Group. This difference was statistically significant. We defined cure as the absence of clinical, radiographic or biochemical evidence of MTC at the time of last follow-up (Table 3). Discussion MTC, which arises from calcitonin-secreting parafollicular cells of the thyroid gland, accounts for 2 5% of all cases of thyroid cancer in the United States. 1 Average 5-year survival for MTC (83%) is lower than for papillary and follicular thyroid cancer (90 94%). 3,4 The natural history of MTC is significant for early metastasis to local and regional lymph nodes, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnoses. 3 6 Unlike papillary and follicular carcinomas, MTC does not concentrate radioiodine, eliminating this as an adjuvant treatment modality. MTC also does not generally respond to external beam radiation. 7 For these reasons, complete surgical resection currently represents the only chance for cure in patients with MTC. 8 MTC occurs in sporadic and familial forms. In a Swedish population-based study, hereditary MTC accounted for 26% of all MTC cases. 9 Among patients with MTC treated at some tertiary referral centres, the proportion with hereditary MTC may be much higher, e.g. 44% in a case series from the University of California, San Francisco. 10 In recent years, genotype phenotype correlations have been used to stratify risk in hereditary MTC. Decisions regarding the timing and extent of prophylactic surgery for hereditary MTC are increasingly based on the patient s specific RET oncogene codon mutation, which may be determined with genetic testing In our series, 12 of 22 (55%) patients receiving initial thyroid surgery for MTC had a familial MTC syndrome, such 110 ASIAN JOURNAL OF SURGERY VOL 30 NO 2 APRIL 2007

4 LYMPHADENECTOMY INCREASES CURE RATES IN MTC as multiple endocrine neoplasia (MEN) Type 2. Ten of these patients with familial MTC had no signs or symptoms of carcinoma, and received prophylactic operations; the other two patients had therapeutic surgery for thyroid nodules preoperatively diagnosed as MTC. In all cases, the prophylactic surgical procedure was thyroidectomy alone, without neck dissection. Two patients in the prophylactic surgery group were found to have small MTC tumours upon histological examination of their resected thyroid specimens. No patient in the prophylactic surgery group had residual or recurrent MTC, and no patient required re-operation. The optimal surgical management strategy for the patient with a thyroid nodule diagnosed as MTC has been a subject of controversy. Historically, many general surgeons motivated, perhaps, by a desire to avoid serious operative complications such as recurrent laryngeal nerve injury and permanent hypoparathyroidism in treating a cancer with relatively low mortality performed thyroidectomy alone, without systematic cervical node dissection. This is perhaps the reason why so many of the patients in our series had thyroidectomy alone. These operations were performed earlier in the study time period, before the establishment of a section of endocrine surgery within our department. Retrospective studies have demonstrated that the majority of patients with MTC have metastasis to local lymph nodes at the time of diagnosis. In these studies, patients treated with thyroidectomy alone frequently had persistently elevated postoperative serum calcitonin levels, and also had high rates of recurrence in the cervical lymph nodes, necessitating re-operation. These data have provided the rationale for surgeons to perform systematic cervical lymphadenectomy at the time of initial thyroidectomy for MTC, and this approach is emerging as the standard of care Despite these data on the benefits of cervical lymph node dissection for MTC, a significant proportion of patients continue to receive less than optimal initial surgical treatment. A recent review of the National Cancer Institute s Surveillance, Epidemiology and End Results (SEER) database revealed that, for the time period, 15% of patients with MTC in the national database had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. 27 Our series included 12 patients who received initial surgery for a thyroid nodule preoperatively diagnosed as MTC. Nine patients had thyroidectomy alone (Thyroidectomy Alone Group), and three had thyroidectomy plus CLND (CLND Group). Despite the more extensive resection, there was no increase in perioperative morbidity in the CLND Group. However, compared to the Thyroidectomy Alone Group, the CLND Group had significantly lower rates of MTC recurrences and re-operations. The cure rate for the CLND Group was 100%, versus only 11% in the Thyroidectomy Alone Group, with cure defined as the absence of any clinical, radiographic or biochemical evidence of MTC at the time of last follow-up. While the current study is limited by its retrospective design, small sample size, and lack of standardized operative protocol, our findings are consistent with those of numerous other retrospective and prospective studies which have shown decreased MTC recurrence rates associated with systematic lymphadenectomy at the time of initial thyroidectomy. 17,18,28,29 A more extensive initial resection may reduce the need for re-operations. Reoperative thyroid surgery has been associated with increased rates of complications such as haemorrhage, permanent hypoparathyroidism and recurrent laryngeal nerve injury Summarizing our series, thyroidectomy alone was an effective prophylactic therapy for patients with hereditary MTC, as no patient had residual disease or required re-operation. Furthermore, lymphadenectomy did not increase morbidity in patients receiving initial surgery for a MTC thyroid nodule. Finally, CLND, done at the time of the initial operation, increased cure rates by decreasing residual or recurrent disease and the need for additional procedures. Therefore, we conclude that thyroidectomy plus CLND is superior to thyroidectomy alone as an initial operation for patients with a thyroid nodule diagnosed as MTC. Given that results from our institution and the SEER database 27 indicate that a significant number of patients with sporadic MTC are not treated with appropriate lymphadenectomy, increasing surgeon awareness is required. References 1. Incidence: Thyroid Cancer. Bethesda, MD: National Cancer Institute, SEER, Chen H, Roberts JR, Ball DW, et al. Effective long-term palliation of symptomatic, incurable metastatic medullary thyroid cancer by operative resection. Ann Surg 1998;227: Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A national cancer data base report on 53,856 cases of thyroid carcinoma treated in the US, Cancer 1998;83: ASIAN JOURNAL OF SURGERY VOL 30 NO 2 APRIL

5 GREENBLATT et al 4. Bhattacharyya N. A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 2003;128: Modigliani E, Vasen HM, Raue K, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The EUROMEN Study Group. J Intern Med 1995;238: Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the surveillance, epidemiology and end results (SEER) program Cancer 1997;79: Giuffrida D, Gharib H. Current diagnosis and management of medullary thyroid carcinoma. Ann Oncol 1998;9: Chen H, Kunnimalaiyaan M, Van Gompel JJ. Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1. Thyroid 2005;15: Bergholm U, Bergstrom R, Ekbom A. Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 1997; 79: Kebebew E, Ituarte PH, Siperstein AE, et al. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88: Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86: Massoll N, Mazzaferri EL. Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med 2004;24: Machens A, Ukkat J, Brauckhoff M, et al. Advances in the management of hereditary medullary thyroid cancer. J Intern Med 2005;257: Szinnai G, Meier C, Komminoth P, Zumsteg UW. Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 2003;111:E Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET protooncogene: a review and update of genotype phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 2005;15: Ogilvie JB, Kebebew E. Indication and timing of thyroid surgery for patients with hereditary medullary thyroid cancer syndromes. J Natl Compr Canc Netw 2006;4: Dralle H, Damm I, Scheumann GF, et al. Compartmentoriented microdissection of regional lymph nodes in medullary thyroid carcinoma. Surg Today 1994;24: Fleming JB, Lee JE, Bouvet M, et al. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 1999;230: Evans DB, Fleming JB, Lee JE, et al. The surgical treatment of medullary thyroid carcinoma. Semin Surg Oncol 1999;16: Udelsman R, Chen H. The current management of thyroid cancer. Adv Surg 1999;33: Kebebew E, Clark OH. Medullary thyroid cancer. Curr Treat Options Oncol 2000;1: Scollo C, Baudin E, Travagli JP, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2003;88: Kendall-Taylor P, Guidelines Working Group. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf) 2003;58: Beastall GH. Guidelines for management of thyroid cancer in adults: implications for clinical biochemistry. Ann Clin Biochem 2003;40: National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Available at: professionals/physician_gls/pdf/thyroid.pdf 26. Kouvaraki MA, Shapiro SE, Lee JE, et al. Surgical management of thyroid carcinoma. J Natl Compr Canc Netw 2005;3: Kebebew E, Greenspan FS, Clark OH, et al. Extent of disease and practice patterns for medullary thyroid cancer. J Am Coll Surg 2005;200: Gimm O, Ukkat J, Dralle H. Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma. World J Surg 1998;22:562,7; discussion Yen TW, Shapiro SE, Gagel RF, et al. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery 2003;134: 890,9; discussion Menegaux F, Turpin G, Dahman M, et al. Secondary thyroidectomy in patients with prior thyroid surgery for benign disease: a study of 203 cases. Surgery 1999;126: Reeve TS, Delbridge L, Brady P, et al. Secondary thyroidectomy: a twenty-year experience. World J Surg 1988;12: Wilson DB, Staren ED, Prinz RA. Thyroid reoperations: indications and risks. Am Surg 1998;64:674,8; discussion Chao TC, Jeng LB, Lin JD, Chen MF. Reoperative thyroid surgery. World J Surg 1997;21: ASIAN JOURNAL OF SURGERY VOL 30 NO 2 APRIL 2007

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