- Email: [email protected]
Extent of Disease and Practice Patterns for Medullary Thyroid Cancer
Extent of Disease and Practice Patterns for Medullary Thyroid Cancer Electron Kebebew, MD, FACS, Francis S Greenspan, MD, FACP, Orlo H Clark, MD, FACS, Kenneth A Woeber, MD, FRCPE, Jocelyn Grunwell, PhD There have been significant improvements in the management of medullary thyroid cancer (MTC), and consensus treatment guidelines have been established by numerous international and national societies. It is unclear if the advances in diagnosis and treatment of MTC have led to earlier diagnosis and more complete initial treatment of patients with MTC. STUDY DESIGN: Patients with MTC (n ⫽ 1,070) were identified in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 12 population-based cancer registries between 1973 and 2000. Four equal-time quartiles (group I ⫽ 1973 to 1979, group II ⫽ 1980 to 1986, group III ⫽ 1987 to 1993, and group IV ⫽ 1994 to 2000) were compared for changes in demographics, extent of disease, and treatment. RESULTS: Mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p ⫽ 0.044), but there was no significant trend toward smaller tumor size. The number of patients having total or near total thyroidectomy increased significantly in the latter two quartiles (p ⬍ 0.001) but not the number of patients having cervical lymph node dissection. Unfortunately, 15% of patients in group IV still had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. There were no significant differences in age, gender, rate of lymph node or distant metastasis, SEER stage, TNM stage, and cause-specific mortality among the four time groups and annually. CONCLUSIONS: There was no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in the survival of patients with MTC during a 28-year period. A high proportion of patients continue to receive less than optimal initial surgical treatment. (J Am Coll Surg 2005;200:890–896. © 2005 by the American College of Surgeons) BACKGROUND:
Medullary thyroid cancer (MTC) accounts for only 3% to 8% of all thyroid cancer, but is responsible for up to 14% of all thyroid cancer deaths.1 Our knowledge of the unique biochemical, genetic, and clinical features of MTC have advanced significantly over the last five decades.2-8 MTC occurs in a hereditary form (multiple endocrine neoplasia type 2 or familial MTC) in about 25% of patients, and is
transmitted in an autosomal dominant pattern of inheritance.9 Measurement of basal and stimulated serum calcitonin (a tumor marker for MTC) levels was instrumental for screening patients at risk for hereditary MTC in the past and currently remains indispensable for followup of patients with MTC after initial surgical treatment.1,6,10 Identification of the RET protooncogene, the gene responsible for hereditary MTC, has been effectively used to determine gene carrier status in affected families and has replaced biochemical screening.3,4,7,8 Commercially available genetic analysis for germline RET mutations in exons 10, 11, 13, 14, 15, and 16 identify more than 95% of hereditary MTC patients.2 Screening for germline RET mutations is now recommended for individuals at risk for MTC and all patients diagnosed with MTC.2 Before genetic and biochemical testing was available, patients with MTC usually presented with advanced disease, and the associated mortality rate was 15% to 20%.2,11 When screening with calcitonin testing
Competing Interests Declared: None. Supported in part by the Harold Amos Faculty Development Program of the Robert Wood Johnson Foundation, Hellman Family Grant, and the University of California Cancer Research Committee. Presented in part at the 76th Annual Meeting of the American Thyroid Association, Vancouver, Canada, 2004. Received December 1, 2004; Revised December 15, 2004; Accepted December 15, 2004. From the Department of Surgery (Kebebew, Clark, Grunwell), the Comprehensive Cancer Center (Kebebew, Clark), and the Division of Endocrinology (Greenspan, Woeber), University of California, San Francisco, San Francisco, CA. Correspondence address: Electron Kebebew, MD, University of California, San Francisco, Department of Surgery, Box 1674, UCSF/Mount Zion Medical Center, San Francisco, CA 94143-1674.
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became widely available, MTC-associated mortality decreased to less than 5%.2,9 Implementation of fine needle aspiration biopsy has also led to accurate preoperative diagnosis of most MTC, allowing selection of the appropriate initial extent of surgical resection. Studies in patients with MTC have also shown that total or near total thyroidectomy and central neck node dissection are necessary because MTC is commonly bilateral and multicentric (especially in hereditary cases), frequently spreads to lymph nodes in the central neck, and is associated with a reduced risk of persistent or recurrent MTC.9,10,12-17 These procedures also result in longer survival time than less extensive surgical treatment. Most single institution studies suggest that the advances in managing MTC have led to earlier diagnosis, more complete initial treatment, and better survival of patients.1-3,9,12,15,16,18 It is unclear if these advances have been universally applied to patients with MTC or have changed the epidemiology of MTC. Because MTC is rare, cooperative groups have established guidelines for screening, diagnosing, and treating patients.19-23 But the effect of these efforts on the outcomes of patients with MTC is unclear. In this study, we analyzed the population-based cancer registry of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program to determine if the advances and consensus guidelines on the diagnosis and treatment of MTC have translated into earlier and complete initial treatment of patients with MTC. METHODS Study design
A retrospective cohort design was used to analyze the SEER data from January 1, 1973, to December 31, 2000. The study was exempted from review by the University of California, San Francisco Committee on Human Research.
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information on demographics, extent of disease, treatment, and survival. Variable definitions
Medullary thyroid cancer patients were selected from the SEER database for public use (SEER 12 Registry Database).24 Cancers diagnosed at autopsy or by death certificate only were excluded from the analysis. The cutoff date for followup was December 31, 2000. Classification of stage of disease at diagnosis, tumor size, treatment, and race/ethnicity followed SEER definitions. Stage was defined as local (confined to the thyroid gland), regional (extension into adjacent tissue or lymph node involvement), distant (metastatic), and unstaged. The SEER stages were also recoded into the TNM staging system (Table 1).25 Four equal-time quartiles (group I ⫽ 1973 to 1979, group II ⫽ 1980 to 1986, group III ⫽ 1987 to 1993, and group IV ⫽ 1994 to 2000) and annual rates were compared for changes in patient demographics, extent of disease, and treatment. Data analysis
We used the SEER Stat 5.0.20 software to abstract MTC cases into the StatView 4.51 statistical software (SAS Inc) by ICD-0 to 3 code for Site and Histology (C739 and 8510). Data are reported as mean ⫾ standard deviation (SD) or number (percentage). Student’s t-tests or analysis of variance for multiple group comparisons were used if normality could be assumed; otherwise, Wilcoxon rank-sum, Kruskal-Wallis, or Spearman rank corTable 1. Tumor Node Metastasis (TNM) Stage for Medullary Thyroid Cancer25 Stage
I II III
Data source and setting
The SEER cancer registries collect data on approximately 26% of the US population.24 The SEER 12 Registry Database consists of patients diagnosed from 1973 through 2000 in Connecticut, New Mexico, Hawaii, Iowa, and Utah; the metropolitan areas of Atlanta, Detroit, San Francisco-Oakland, and Seattle-Puget Sound; and patients diagnosed from 1992 through 2000 in the Los Angeles, San Jose-Monterey metropolitan areas and the Alaska Native region. The SEER database includes
Trends in Medullary Thyroid Cancer
IV A B C
TNM stage
T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 N1a M0 T2 N1a M0 T3 N1a M0 T4a N0-1a M0, T1-4a N1b M0 T4b Any N M0 Any T Any N M1
T1 is tumor size ⱕ2 cm. T2 is tumor size between 2 cm and 4 cm. T3 is tumor size ⬎ 4cm. T4a is tumor of any size with invasion outside of the thyroid capsule into the adjacent soft tissue, trachea, larynx, esophagus, or recurrent laryngeal nerve. T4b is tumor of any size invading the prevertebral fascia or encasing the vessels (carotid and mediastinal). N1a is metastasis to central neck nodes and N1b is metastasis to lateral neck or upper mediastinal lymph nodes. M1 is metastasis to distant sites.
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relation tests were used. The Pearson chi-square test was used for categorical data. For survival analysis, the logrank test was used to compare the Kaplan-Meier events. We studied the following specific variables: age, gender, race/ethnicity, era of diagnosis (time quartile and annual rates), tumor size, extent of disease (local, regional, and distant), overall recoded TNM stage, and surgical treatment. The observed differences were assumed to be statistically significant if the probability of chance occurrence was less than 0.05.
thyroidectomy. Seventeen percent of patients in group IV had less than total or near total thyroidectomy even if their tumors were TNM stages II or III. Information on lymph node dissection was collected beginning in 1988, so only groups III and IV could be compared. The number of patients having lymph node dissection only increased by 5.7% (p ⫽ 0.207), and 41% of patients in group IV had no cervical lymph node dissection (Fig. 4). Overall, 31% of patients with stage II or III disease did not have a lymph node dissection.
RESULTS A total of 1,070 cases of MTC were reported from 1973 to 2000 to the SEER program, and the number of MTC patients ranged from 16 to 70 per year (Table 2). The average age at diagnosis was 50.3 years. Most patients with MTC were Caucasian (87.0%) and women (59.7%). According to the SEER staging system, 49.1% of patients had an intrathyroidal tumor; 32.6% had extrathyroidal invasion, regional lymph node metastasis, or both; and 13.6% had distant metastasis (Table 2). The majority of patients (91.4%) had surgical resection of their primary tumor, 13.4% had external beam radiation, and 3.9% had radioisotope treatment (Table 2). Mean followup was 96.1 months (median ⫽ 72.0 months). The cause-specific mortality was 19.4% at 10 years and 27.7% at 20 years. The number of Asian patients increased significantly in the latter two quartiles (groups III and IV versus groups I and II, p ⫽ 0.024), but there were no other significant increases among the other racial groups. Because information on tumor size was collected beginning in 1988, only groups III and IV could be compared. We found no significant difference between these two time quartiles. The annual mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p ⫽ 0.044), but there was no significant trend toward smaller tumor size during this time period (Fig. 1). Age, gender, rate of lymph node or distant metastasis, SEER stage, overall TNM stage, and cause-specific mortality did not differ significantly among the four time groups or annually (Table 3 and Fig. 2). Because information on the site-specific surgery was collected beginning in 1983, only groups II to IV could be compared (Fig. 3). The number of patients having total or near total thyroidectomy increased by 14.6% (group III versus IV, p ⬍ 0.001). Surprisingly, 15% of patients in group IV had less than total or near total
DISCUSSION The impact of the advances in the treatment of patients with MTC and implementation of consensus treatment guidelines on the epidemiology of MTC is unknown. Although most observational, single-institution studies suggest that advances in fine needle aspiration cytology and biochemical and genetic screening have resulted in earlier diagnosis of MTC and improved outcomes, such studies do not measure changes in the epidemiology of MTC. We believe our study using the population-based SEER database provides important information on the trends of extent of disease and pattern of care in patients with MTC on a national level.3,4,9,15,18,26 The large sample size, which is representative of the US population, and the long study period provide useful information. We found that despite significant advances in the diagnosis and screening of MTC, patients are not being diagnosed earlier or treated at a lower stage of disease. Although there is a trend toward the use of total or near total thyroidectomy, a significant proportion of patients unfortunately continue to receive less than optimal initial treatment. Mean age at diagnosis and gender distribution in our study are similar to those reported in other smaller cohort studies.9,12,17 The increase in the number of Asian patients diagnosed with MTC is probably because of the addition of cancer registry data from the Los Angeles and San Jose-Monterey regions to the SEER database. Although the SEER database does not have data on all MTC patients in the US, it is the only comprehensive source of population-based data on demographics, primary tumor site, morphology, stage at diagnosis, first course of treatment, and followup for cancer patients in the US.24 So we believe it is a useful source for analyzing changes in extent of disease at diagnosis and initial treatment of MTC in the US. Screening for germline RET protooncogene muta-
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Table 2. Summary of Demographic, Extent of Disease, and Treatment Data for 1,070 Cases of Medullary Thyroid Cancer, 1973 to 2000 Demographics
Age at diagnosis, mean ⫾ SD, y Women Race Caucasian African American Other* Unknown Era of diagnosis Group I (1973–1979) Group II (1980–1986) Group III (1987–1993) Group IV (1994–2000)
50.3 ⫾ 18.6 639 (59.7) 931 (87.0) 61 (5.7) 69 (6.4) 9 (0.8) 197 (18.4) 207 (19.3) 277 (25.9) 389 (36.4)
Pathology
Diagnostic confirmation Positive histology Positive cytology Clinical Radiographic Laboratory marker Unknown Tumor size, mean ⫾ SD, cm SEER extent of disease Local Regional Distant Unstaged Recoded TNM stage† Stage I Stage I/II Stage II Stage III Stage III/IV Stage IV Unknown
1,048 (97.9) 14 (1.3) 1 (0.1) 2 (0.2) 1 (0.1) 4 (0.4) 2.8 ⫾ 2.5 525 (49.1) 349 (32.6) 145 (13.5) 51 (4.8) 127 (11.9) 243 (22.7) 146 (13.6) 138 (12.9) 132 (12.3) 233 (21.8) 51 (4.8)
Treatment
Surgical resection Yes No Unknown Radiation treatment External beam Radioisotope Unspecified None Unknown
978 (91.4) 54 (5.0) 38 (3.6) 143 (13.4) 42 (3.9) 11 (1.0) 866 (80.9) 8 (0.7)
Data shown are number (%) unless otherwise specified. *Other refers to 6 Native Americans and 63 Asian and Pacific Islanders. † TNM stage recoded according to new American Joint Commission on Cancer staging system (Table 1). Some cases could not be distinguished because tumor size information was only collected beginning in 1988.
Figure 1. Medullary thyroid cancer tumor size (in mm) and year of diagnosis. Although there was a significant difference in tumor size in 1988 as compared with 1989 through 2000, there was no significant trend toward smaller tumor size at the time of diagnosis. * indicates significant difference in size between 1989, 1996, and 1999 as compared with 2000. Values represent mean ⫾ standard deviation.
tion can result in earlier diagnosis of MTC, sometimes even before MTC develops.27 We found that there is no significant trend toward the diagnosis of earlier-stage MTC in the US population during a 28-year period. The SEER database does not classify cases of sporadic and hereditary MTC separately and does not include data on the use of chemotherapy. Cases in which patients have prophylactic total thyroidectomy based on a positive germline RET mutation may not have developed MTC, and such patients may not have been reported to the SEER program. The number of patients receiving prophylactic treatment represents a small proportion of patients with MTC. In addition, 15% of the study cohort were younger than 20 years old and likely Table 3. Extent of Disease in 1,070 Medullary Thyroid Cancer Cases over Four Time Quartiles and Annually p Value Variables
Age Gender Race/ethnicity* Tumor size SEER stage Local/regional/distant Recoded TNM stage
Quartile
Annually
0.668 0.202 0.003 0.630
0.886 0.787 0.024 0.287
0.695 0.966
0.670 0.670
*Race/ethnicity was the only significant variable (significance: p ⬍ 0.05). SEER, Surveillance, Epidemiology, and End Results.
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Figure 2. Cause-specific mortality in 1,070 patients with MTC among the four time quartiles. There was no significant difference in mortality.
represent patients with hereditary MTC. It is possible that it might be too early to find a trend toward less aggressive MTC in the SEER database given that genetic screening has been in clinical use for less than 10 years. Regardless of these limitations, no survival difference was observed when comparing the outcomes of patients with MTC over 3 decades. There is a general consensus that patients with clini-
cally evident MTC should be treated by total or near total thyroidectomy with at least a central neck lymph node dissection.2,20-23 It was surprising to find that 15% of patients had less than total or near total thyroidectomy, and 41% of patients had no cervical lymph node dissection, sometimes even with stages II and III MTC. Although these findings are based on data from a smaller subset of patients than in the entire cohort, information
Figure 3. Extent of thyroidectomy in patients with medullary thyroid cancer in groups II to IV. Data on extent of thyroidectomy were collected beginning in 1983. NOS, not otherwise specified.
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Figure 4. Initial lymph node dissection in patients with MTC in groups III and IV. Information on lymph node dissection was collected beginning in 1988. The extent of lymph node dissections was modified radical neck dissection (n ⫽ 28), radical neck dissection (n ⫽ 12), regional NOS (n ⫽ 48), selective (n ⫽ 21), and neck dissection type NOS (n ⫽ 71). NOS, not otherwise specified.
on the type and extent of thyroidectomy was collected beginning in 1983, and for regional lymph node dissection, in 1988. Because MTC does not trap radioiodine, it is unclear why 3.9% of patients with MTC received radioisotope treatment. This might be because some investigators believe that radioiodine could have a bystander effect on MTC by ablating the adjacent follicular thyroid cells, or it might be because of the use of radiolabeled anti-CEA antibody therapy in patients with MTC metastases.28-30 In summary, despite significant advances in the management of MTC, there is no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in survival over a 28-year period. A significant proportion of patients with MTC continue to receive less than optimal initial surgical treatment. Health-care provider knowledge about the optimal treatment of patients with MTC needs to be improved. Author Contributions
Study conception and design: Kebebew Acquisition of data: Kebebew, Grunwell Analysis and interpretation of data: Kebebew, Grunwell Drafting of manuscript: Kebebew Critical revision: Greenspan, Clark, Woeber Statistical expertise: Kebebew Obtaining funding: Kebebew Supervision: Kebebew
Acknowledgment: We would like to thank Tida Violante, MPH, Dr PH, for reviewing our article and for the helpful suggestions.
REFERENCES 1. Kebebew E, Clark OH. Medullary thyroid cancer. Curr Treat Options Oncol 2000;1:359–367. 2. 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;86:5658–5671. 3. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988;318:478–484. 4. Wells SA Jr, Chi DD, Toshima K, et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220:237–247; discussion 247–250. 5. Block MA, Horn RC Jr, Miller JM, et al. Familial medullary carcinoma of the thyroid. Ann Surg 1967;166:403–412. 6. Jackson CE, Tashjian AH Jr, Block MA. Diagnostic dependability of calcitonin assay in family studies for medullary thyroid carcinoma. J Lab Clin Med 1971;78:817–818. 7. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458–460. 8. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375–376. 9. Kebebew E, Ituarte PH, Siperstein AE, et al. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88:1139–1148. 10. Kebebew E, Kikuchi S, Duh QY, Clark OH. Long-term results of reoperation and localizing studies in patients with persistent
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15. 16. 17. 18.
19. 20.
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or recurrent medullary thyroid cancer. Arch Surg 2000; 135:895–901. Brandi M, Gagel R, Angeli A, et al. 2001 guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metal 2001;86:5658–5671. Brierley J, Tsang R, Simpson WJ, et al. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996;6:305–310. Machens A, Holzhausen HJ, Lautenschlager C, et al. Enhancement of lymph node metastasis distant metastasis of thyroid carcinoma. Cancer 2003;98:712–719. Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg 1999;229:880–887; discussion 887–888. Samaan NA, Schultz PN, Hickey RC. Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 1988;67:801–805. Weber T, Schilling T, Frank-Raue K, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery 2001;130:1044–1049. Dolan SJ, Russell CF. Medullary thyroid carcinoma in Northern Ireland, 1967–1997. Ann R Coll Surg Engl 2000;82:156–161. Dralle H, Gimm O, Simon D, et al. Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 1998;22:744–750; discussion 750–751. Harris PE. The management of thyroid cancer in adults: a review of new guidelines. Clin Med 2002;2:144–146. Beastall GH. Guidelines for management of thyroid cancer in adults: implications for clinical biochemistry. Ann Clin Biochem 2003;40:435–438.
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21. Kendall-Taylor P. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf ) 2003;58:400–402. 22. Singer PA, Cooper DS, Daniels GH, et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 1996; 156:2165–2172. 23. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Available at www.nccn.org/professionals/ physician_gls/PDF/thyroid.pdf. Accessed September 9, 2003. 24. National Cancer Institute. Surveillance, epidemiology and end results. Available at http://www.seer.cancer.gov/publicdata/. Accessed September 9, 2003. 25. Greene F, Page D, Fleming I, et al. In: Greene F, ed. Thyroid. AJCC cancer staging manual, 6th ed. Springer-Verlag, New York; 2002: 77. 26. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003;349:1517–1525. 27. Kebebew E, Tresler PA, Siperstein AE, et al. Normal thyroid pathology in patients undergoing thyroidectomy for finding a RETgene germline mutation: a report of three cases and review of the literature. Thyroid 1999;9:127–131. 28. Juweid ME, Hajjar G, Stein R, et al. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. J Nucl Med 2000;41:93–103. 29. Juweid M, Sharkey RM, Behr T, et al. Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen. J Clin Oncol 1996;14:1209–1217. 30. Nieuwenhuijzen Kruseman AC, Bussemaker JK, Frolich M. Radioiodine in the treatment of hereditary medullary carcinoma of the thyroid. J Clin Endocrinol Metab 1984;59:491– 494.
Medullary thyroid cancer (MTC) accounts for only 3% to 8% of all thyroid cancer, but is responsible for up to 14% of all thyroid cancer deaths.1 Our knowledge of the unique biochemical, genetic, and clinical features of MTC have advanced significantly over the last five decades.2-8 MTC occurs in a hereditary form (multiple endocrine neoplasia type 2 or familial MTC) in about 25% of patients, and is
transmitted in an autosomal dominant pattern of inheritance.9 Measurement of basal and stimulated serum calcitonin (a tumor marker for MTC) levels was instrumental for screening patients at risk for hereditary MTC in the past and currently remains indispensable for followup of patients with MTC after initial surgical treatment.1,6,10 Identification of the RET protooncogene, the gene responsible for hereditary MTC, has been effectively used to determine gene carrier status in affected families and has replaced biochemical screening.3,4,7,8 Commercially available genetic analysis for germline RET mutations in exons 10, 11, 13, 14, 15, and 16 identify more than 95% of hereditary MTC patients.2 Screening for germline RET mutations is now recommended for individuals at risk for MTC and all patients diagnosed with MTC.2 Before genetic and biochemical testing was available, patients with MTC usually presented with advanced disease, and the associated mortality rate was 15% to 20%.2,11 When screening with calcitonin testing
Competing Interests Declared: None. Supported in part by the Harold Amos Faculty Development Program of the Robert Wood Johnson Foundation, Hellman Family Grant, and the University of California Cancer Research Committee. Presented in part at the 76th Annual Meeting of the American Thyroid Association, Vancouver, Canada, 2004. Received December 1, 2004; Revised December 15, 2004; Accepted December 15, 2004. From the Department of Surgery (Kebebew, Clark, Grunwell), the Comprehensive Cancer Center (Kebebew, Clark), and the Division of Endocrinology (Greenspan, Woeber), University of California, San Francisco, San Francisco, CA. Correspondence address: Electron Kebebew, MD, University of California, San Francisco, Department of Surgery, Box 1674, UCSF/Mount Zion Medical Center, San Francisco, CA 94143-1674.
© 2005 by the American College of Surgeons Published by Elsevier Inc.
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became widely available, MTC-associated mortality decreased to less than 5%.2,9 Implementation of fine needle aspiration biopsy has also led to accurate preoperative diagnosis of most MTC, allowing selection of the appropriate initial extent of surgical resection. Studies in patients with MTC have also shown that total or near total thyroidectomy and central neck node dissection are necessary because MTC is commonly bilateral and multicentric (especially in hereditary cases), frequently spreads to lymph nodes in the central neck, and is associated with a reduced risk of persistent or recurrent MTC.9,10,12-17 These procedures also result in longer survival time than less extensive surgical treatment. Most single institution studies suggest that the advances in managing MTC have led to earlier diagnosis, more complete initial treatment, and better survival of patients.1-3,9,12,15,16,18 It is unclear if these advances have been universally applied to patients with MTC or have changed the epidemiology of MTC. Because MTC is rare, cooperative groups have established guidelines for screening, diagnosing, and treating patients.19-23 But the effect of these efforts on the outcomes of patients with MTC is unclear. In this study, we analyzed the population-based cancer registry of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program to determine if the advances and consensus guidelines on the diagnosis and treatment of MTC have translated into earlier and complete initial treatment of patients with MTC. METHODS Study design
A retrospective cohort design was used to analyze the SEER data from January 1, 1973, to December 31, 2000. The study was exempted from review by the University of California, San Francisco Committee on Human Research.
Kebebew et al
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information on demographics, extent of disease, treatment, and survival. Variable definitions
Medullary thyroid cancer patients were selected from the SEER database for public use (SEER 12 Registry Database).24 Cancers diagnosed at autopsy or by death certificate only were excluded from the analysis. The cutoff date for followup was December 31, 2000. Classification of stage of disease at diagnosis, tumor size, treatment, and race/ethnicity followed SEER definitions. Stage was defined as local (confined to the thyroid gland), regional (extension into adjacent tissue or lymph node involvement), distant (metastatic), and unstaged. The SEER stages were also recoded into the TNM staging system (Table 1).25 Four equal-time quartiles (group I ⫽ 1973 to 1979, group II ⫽ 1980 to 1986, group III ⫽ 1987 to 1993, and group IV ⫽ 1994 to 2000) and annual rates were compared for changes in patient demographics, extent of disease, and treatment. Data analysis
We used the SEER Stat 5.0.20 software to abstract MTC cases into the StatView 4.51 statistical software (SAS Inc) by ICD-0 to 3 code for Site and Histology (C739 and 8510). Data are reported as mean ⫾ standard deviation (SD) or number (percentage). Student’s t-tests or analysis of variance for multiple group comparisons were used if normality could be assumed; otherwise, Wilcoxon rank-sum, Kruskal-Wallis, or Spearman rank corTable 1. Tumor Node Metastasis (TNM) Stage for Medullary Thyroid Cancer25 Stage
I II III
Data source and setting
The SEER cancer registries collect data on approximately 26% of the US population.24 The SEER 12 Registry Database consists of patients diagnosed from 1973 through 2000 in Connecticut, New Mexico, Hawaii, Iowa, and Utah; the metropolitan areas of Atlanta, Detroit, San Francisco-Oakland, and Seattle-Puget Sound; and patients diagnosed from 1992 through 2000 in the Los Angeles, San Jose-Monterey metropolitan areas and the Alaska Native region. The SEER database includes
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TNM stage
T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 N1a M0 T2 N1a M0 T3 N1a M0 T4a N0-1a M0, T1-4a N1b M0 T4b Any N M0 Any T Any N M1
T1 is tumor size ⱕ2 cm. T2 is tumor size between 2 cm and 4 cm. T3 is tumor size ⬎ 4cm. T4a is tumor of any size with invasion outside of the thyroid capsule into the adjacent soft tissue, trachea, larynx, esophagus, or recurrent laryngeal nerve. T4b is tumor of any size invading the prevertebral fascia or encasing the vessels (carotid and mediastinal). N1a is metastasis to central neck nodes and N1b is metastasis to lateral neck or upper mediastinal lymph nodes. M1 is metastasis to distant sites.
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relation tests were used. The Pearson chi-square test was used for categorical data. For survival analysis, the logrank test was used to compare the Kaplan-Meier events. We studied the following specific variables: age, gender, race/ethnicity, era of diagnosis (time quartile and annual rates), tumor size, extent of disease (local, regional, and distant), overall recoded TNM stage, and surgical treatment. The observed differences were assumed to be statistically significant if the probability of chance occurrence was less than 0.05.
thyroidectomy. Seventeen percent of patients in group IV had less than total or near total thyroidectomy even if their tumors were TNM stages II or III. Information on lymph node dissection was collected beginning in 1988, so only groups III and IV could be compared. The number of patients having lymph node dissection only increased by 5.7% (p ⫽ 0.207), and 41% of patients in group IV had no cervical lymph node dissection (Fig. 4). Overall, 31% of patients with stage II or III disease did not have a lymph node dissection.
RESULTS A total of 1,070 cases of MTC were reported from 1973 to 2000 to the SEER program, and the number of MTC patients ranged from 16 to 70 per year (Table 2). The average age at diagnosis was 50.3 years. Most patients with MTC were Caucasian (87.0%) and women (59.7%). According to the SEER staging system, 49.1% of patients had an intrathyroidal tumor; 32.6% had extrathyroidal invasion, regional lymph node metastasis, or both; and 13.6% had distant metastasis (Table 2). The majority of patients (91.4%) had surgical resection of their primary tumor, 13.4% had external beam radiation, and 3.9% had radioisotope treatment (Table 2). Mean followup was 96.1 months (median ⫽ 72.0 months). The cause-specific mortality was 19.4% at 10 years and 27.7% at 20 years. The number of Asian patients increased significantly in the latter two quartiles (groups III and IV versus groups I and II, p ⫽ 0.024), but there were no other significant increases among the other racial groups. Because information on tumor size was collected beginning in 1988, only groups III and IV could be compared. We found no significant difference between these two time quartiles. The annual mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p ⫽ 0.044), but there was no significant trend toward smaller tumor size during this time period (Fig. 1). Age, gender, rate of lymph node or distant metastasis, SEER stage, overall TNM stage, and cause-specific mortality did not differ significantly among the four time groups or annually (Table 3 and Fig. 2). Because information on the site-specific surgery was collected beginning in 1983, only groups II to IV could be compared (Fig. 3). The number of patients having total or near total thyroidectomy increased by 14.6% (group III versus IV, p ⬍ 0.001). Surprisingly, 15% of patients in group IV had less than total or near total
DISCUSSION The impact of the advances in the treatment of patients with MTC and implementation of consensus treatment guidelines on the epidemiology of MTC is unknown. Although most observational, single-institution studies suggest that advances in fine needle aspiration cytology and biochemical and genetic screening have resulted in earlier diagnosis of MTC and improved outcomes, such studies do not measure changes in the epidemiology of MTC. We believe our study using the population-based SEER database provides important information on the trends of extent of disease and pattern of care in patients with MTC on a national level.3,4,9,15,18,26 The large sample size, which is representative of the US population, and the long study period provide useful information. We found that despite significant advances in the diagnosis and screening of MTC, patients are not being diagnosed earlier or treated at a lower stage of disease. Although there is a trend toward the use of total or near total thyroidectomy, a significant proportion of patients unfortunately continue to receive less than optimal initial treatment. Mean age at diagnosis and gender distribution in our study are similar to those reported in other smaller cohort studies.9,12,17 The increase in the number of Asian patients diagnosed with MTC is probably because of the addition of cancer registry data from the Los Angeles and San Jose-Monterey regions to the SEER database. Although the SEER database does not have data on all MTC patients in the US, it is the only comprehensive source of population-based data on demographics, primary tumor site, morphology, stage at diagnosis, first course of treatment, and followup for cancer patients in the US.24 So we believe it is a useful source for analyzing changes in extent of disease at diagnosis and initial treatment of MTC in the US. Screening for germline RET protooncogene muta-
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Table 2. Summary of Demographic, Extent of Disease, and Treatment Data for 1,070 Cases of Medullary Thyroid Cancer, 1973 to 2000 Demographics
Age at diagnosis, mean ⫾ SD, y Women Race Caucasian African American Other* Unknown Era of diagnosis Group I (1973–1979) Group II (1980–1986) Group III (1987–1993) Group IV (1994–2000)
50.3 ⫾ 18.6 639 (59.7) 931 (87.0) 61 (5.7) 69 (6.4) 9 (0.8) 197 (18.4) 207 (19.3) 277 (25.9) 389 (36.4)
Pathology
Diagnostic confirmation Positive histology Positive cytology Clinical Radiographic Laboratory marker Unknown Tumor size, mean ⫾ SD, cm SEER extent of disease Local Regional Distant Unstaged Recoded TNM stage† Stage I Stage I/II Stage II Stage III Stage III/IV Stage IV Unknown
1,048 (97.9) 14 (1.3) 1 (0.1) 2 (0.2) 1 (0.1) 4 (0.4) 2.8 ⫾ 2.5 525 (49.1) 349 (32.6) 145 (13.5) 51 (4.8) 127 (11.9) 243 (22.7) 146 (13.6) 138 (12.9) 132 (12.3) 233 (21.8) 51 (4.8)
Treatment
Surgical resection Yes No Unknown Radiation treatment External beam Radioisotope Unspecified None Unknown
978 (91.4) 54 (5.0) 38 (3.6) 143 (13.4) 42 (3.9) 11 (1.0) 866 (80.9) 8 (0.7)
Data shown are number (%) unless otherwise specified. *Other refers to 6 Native Americans and 63 Asian and Pacific Islanders. † TNM stage recoded according to new American Joint Commission on Cancer staging system (Table 1). Some cases could not be distinguished because tumor size information was only collected beginning in 1988.
Figure 1. Medullary thyroid cancer tumor size (in mm) and year of diagnosis. Although there was a significant difference in tumor size in 1988 as compared with 1989 through 2000, there was no significant trend toward smaller tumor size at the time of diagnosis. * indicates significant difference in size between 1989, 1996, and 1999 as compared with 2000. Values represent mean ⫾ standard deviation.
tion can result in earlier diagnosis of MTC, sometimes even before MTC develops.27 We found that there is no significant trend toward the diagnosis of earlier-stage MTC in the US population during a 28-year period. The SEER database does not classify cases of sporadic and hereditary MTC separately and does not include data on the use of chemotherapy. Cases in which patients have prophylactic total thyroidectomy based on a positive germline RET mutation may not have developed MTC, and such patients may not have been reported to the SEER program. The number of patients receiving prophylactic treatment represents a small proportion of patients with MTC. In addition, 15% of the study cohort were younger than 20 years old and likely Table 3. Extent of Disease in 1,070 Medullary Thyroid Cancer Cases over Four Time Quartiles and Annually p Value Variables
Age Gender Race/ethnicity* Tumor size SEER stage Local/regional/distant Recoded TNM stage
Quartile
Annually
0.668 0.202 0.003 0.630
0.886 0.787 0.024 0.287
0.695 0.966
0.670 0.670
*Race/ethnicity was the only significant variable (significance: p ⬍ 0.05). SEER, Surveillance, Epidemiology, and End Results.
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Figure 2. Cause-specific mortality in 1,070 patients with MTC among the four time quartiles. There was no significant difference in mortality.
represent patients with hereditary MTC. It is possible that it might be too early to find a trend toward less aggressive MTC in the SEER database given that genetic screening has been in clinical use for less than 10 years. Regardless of these limitations, no survival difference was observed when comparing the outcomes of patients with MTC over 3 decades. There is a general consensus that patients with clini-
cally evident MTC should be treated by total or near total thyroidectomy with at least a central neck lymph node dissection.2,20-23 It was surprising to find that 15% of patients had less than total or near total thyroidectomy, and 41% of patients had no cervical lymph node dissection, sometimes even with stages II and III MTC. Although these findings are based on data from a smaller subset of patients than in the entire cohort, information
Figure 3. Extent of thyroidectomy in patients with medullary thyroid cancer in groups II to IV. Data on extent of thyroidectomy were collected beginning in 1983. NOS, not otherwise specified.
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Figure 4. Initial lymph node dissection in patients with MTC in groups III and IV. Information on lymph node dissection was collected beginning in 1988. The extent of lymph node dissections was modified radical neck dissection (n ⫽ 28), radical neck dissection (n ⫽ 12), regional NOS (n ⫽ 48), selective (n ⫽ 21), and neck dissection type NOS (n ⫽ 71). NOS, not otherwise specified.
on the type and extent of thyroidectomy was collected beginning in 1983, and for regional lymph node dissection, in 1988. Because MTC does not trap radioiodine, it is unclear why 3.9% of patients with MTC received radioisotope treatment. This might be because some investigators believe that radioiodine could have a bystander effect on MTC by ablating the adjacent follicular thyroid cells, or it might be because of the use of radiolabeled anti-CEA antibody therapy in patients with MTC metastases.28-30 In summary, despite significant advances in the management of MTC, there is no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in survival over a 28-year period. A significant proportion of patients with MTC continue to receive less than optimal initial surgical treatment. Health-care provider knowledge about the optimal treatment of patients with MTC needs to be improved. Author Contributions
Study conception and design: Kebebew Acquisition of data: Kebebew, Grunwell Analysis and interpretation of data: Kebebew, Grunwell Drafting of manuscript: Kebebew Critical revision: Greenspan, Clark, Woeber Statistical expertise: Kebebew Obtaining funding: Kebebew Supervision: Kebebew
Acknowledgment: We would like to thank Tida Violante, MPH, Dr PH, for reviewing our article and for the helpful suggestions.
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