Prognostic Evaluation of Patients With Multicentric Papillary Thyroid Microcarcinoma

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1 Volume 110 Number 8 August 2011 Formosan Medical Association Taipei, Taiwan ISSN Resveratrol for prophylaxis of ischemic stroke Microglia and chronic pain ART in HIV-1-discordant couples in Taiwan Prognostic evaluation of patients with multicentric papillary thyroid microcarcinoma J Formos Med Assoc 2011;110(8): Contents lists available at ScienceDirect Journal of the Formosan Medical Association Journal homepage: Journal of the Formosan Medical Association Original Article Prognostic Evaluation of Patients With Multicentric Papillary Thyroid Microcarcinoma Sheng-Fong Kuo, 1 Tzu-Chieh Chao, 2 Hung-Yu Chang, 3 Chuen Hsueh, 4 Chung-Han Yang, 5 Jen-Der Lin 3 * Background/Purpose: Patients with papillary thyroid microcarcinoma (PTMC) often have an excellent prognosis. We hypothesize that patients with multicentric PTMC are associated with good clinical outcome, although multicentricity in papillary thyroid carcinoma may be associated with poor prognosis. Methods: Retrospective analysis of multicentric PTMC cases in one medical center enrolled from 1987 to 2008 was conducted. At the end of follow-up, patients were classified as recurrence-free or recurrence or persistent disease. The tumor node metastasis (TNM) staging system was used, and (T1, N0, M0) was regarded as early clinical stage, whereas (T3 4, any N, any M) or (any T, N1, or M1) was regarded as advanced clinical stage. Results: There were 61 patients with a median age of 45 years. After a median follow-up period of 7.3 years (range: years), the overall cause-specific survival rate was 98.36%. The patients with tumor diameters < 0.5 cm were all recurrence-free. Advanced clinical stage, especially distant metastasis, was highly associated with recurrence or persistent disease. Conclusion: Our results demonstrate excellent prognosis in multicentric PTMC patients. No patients with tumor diameter < 0.5 cm had recurrence or persistent disease. Tumor size is an important risk factor in patients with multicentric PTMC. Key Words: microcarcinoma, multicentric tumor, papillary thyroid cancer, prognosis, tumor size Although multicentricity is not a classical risk factor of papillary thyroid carcinoma (PTC), 1 3 multicentricity is frequently associated with an increased risk of recurrence, distant metastasis and mortality in PTC patients. 4 7 To date, there are no reports specifically on the clinical features and prognosis in patients with multicentric papillary thyroid microcarcinoma (PTMC). Accordingly, 2011 Elsevier & Formosan Medical Association Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Chang Gung University, 2 Department of General Surgery, 3 Division of Endocrinology and Metabolism, Department of Internal Medicine, 4 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, and 5 Department of Internal Medicine, Landseed Hospital, Taoyuan, Taiwan. Received: December 8, 2009 Revised: May 4, 2010 Accepted: July 17, 2010 *Correspondence to: Dr Jen-Der Lin, Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, 5, Fu-Shin Street, Kweishan County, Taoyuan Hsien, Taiwan. einjd@adm.cgmh.org.tw J Formos Med Assoc 2011 Vol 110 No 8 511

2 S.F. Kuo, et al we retrospectively evaluated 61 patients with multicentric PTMC from 325 PTMC patients treated at Chang Gung Medical Center in Taiwan, to show their clinical manifestations and prognosis. 8 Patients and Methods Patients Between January 1987 and December 2008, 325 patients were diagnosed with PTMC and received follow-up treatment for > 2 years after surgery at Chang Gung Medical Center, Taiwan. Among these, 61 had multicentric PTMC based on the final histopathological analyses of 325 PTMC patients. Multicentric PTMC was defined as the occurrence of at least two papillary cancer lesions in the thyroid, either within one lobe or in both. The diameter of each lesion was 1.0 cm based on the final pathologic records. Initial survey and primary therapy Most of the 61 patients underwent preoperative thyroid ultrasonography and fine needle aspiration cytology (FNAC) due to palpable thyroid nodules. All 61 patients received surgery, and frozen sections were obtained from most of them during surgery. In this paper, the term total thyroidectomy refers to near total or total thyroidectomy with or without central compartment and selective bilateral neck lymph node dissection; non-total thyroidectomy refers to subtotal thyroidectomy or lobectomy. Follow-up After surgery, most patients received long-term thyroid hormone suppressive therapy. Postoperative investigation usually consisted of thyroid ultrasonography, MBq (2 5 mci) radioactive 131 I whole-body diagnostic scanning, serumstimulated thyroglobulin (Tg), anti-tg antibody test, and thyroid function. Postoperative investigation was performed 1 month after surgery and at 6 12-month intervals thereafter. Serum Tg levels were measured with an immunoradiometric assay kit (CIS Bio International, Gif-sur-Yvette, France). Large-dose 131 I therapy was performed when recurrent lesions were suspected. Surgery was performed whenever recurrent localized lesions were confirmed based on thyroid ultrasonography with FNAC. Outcome assessment At the end of follow-up, patients were classified as recurrence-free or recurrence or persistent disease based on the treatment outcome. Recurrencefree was defined as absence of distant metastasis and no local recurrence based on physical and noninvasive imaging (e.g. thyroid ultrasonography, chest X-ray, 131 I scan, computed tomography, magnetic resonance imaging, and positron emission tomography) at clinical follow-up. Recurrence was defined as distant metastasis or local tumor recurrence during clinical follow-up, and persistent disease as distant metastasis at diagnosis and throughout follow-up. Tumor staging and risk stratification Tumors were staged according to the International Union against Cancer (UICC) tumor node metastasis (TNM) criteria (6 th edition). 3 In this study, patients with confined intrathyroid PTMC (T1, N0, M0) were regarded as early clinical stage, and extra-thyroid extension PTMC (T3 4, any N, any M) or those with lymph node metastasis, soft tissue involvement, or distant metastasis (any T, N1, or M1) were regarded as advanced clinical stage. Statistical analysis Metric data were presented as median and range, and were analyzed by Mann Whitney test. The χ 2 or Fisher s exact test was used for categorical data. The association between tumor size and recurrence or persistent disease was explored by a receiver-operating-characteristic (ROC) curve. Besides, tumor size was dichotomized based on the best cut-off level chosen by ROC curve and the Yuden Index. Recurrence-free survival was analyzed by the Cox proportional-hazards model. Multivariate logistic regression was used to examine factors associated with recurrence or persistent 512 J Formos Med Assoc 2011 Vol 110 No 8

3 Multicentric papillary thyroid microcarcinoma disease of multicentric PTMC. Potential confounders, collinearity and interaction between factors were evaluated for building the final model. Statistical significance was set at a two-sided p value of All analyses were conducted with the use of statistical software (Stata, version 10.1; StataCorp, College Station, TX, USA). Results Clinical presentations Based on the final histopathology from 325 PTMC patients, there were 61 multicentric and 264 unifocal PTMC patients. Of the 61 multicentric PTMC patients, there were 46 women and 15 men with a median age of 45 years (range: years). After a median follow-up period of 7.3 years (range: years), one of the 61 patients died of metastatic thyroid cancer 5.33 years after diagnosis. Twenty-seven patients presented with asymptomatic thyroid nodules and underwent surgery because malignancy or suspected malignancy was detected by thyroid ultrasonography and FNAC; 21 patients underwent surgery due to the presence of a large goiter; nine patients underwent surgery as a result of hyperthyroidism; and four patients underwent thyroid surgery because metastatic lesions were suspected to originate from the thyroid gland. Table 1 shows a comparison of the clinical characteristics between multicentric (n = 61) and unifocal (n = 264) PTMC patients. Forty of the 61 multicentric PTMC patients presented with tumor in both lobes (65.6%), whereas the other 21 patients had PTMC confined to only one lobe (34.4%). Accordingly, multicentricity was observed in 61 of 325 PTMC patients (18.8%), and the involvement of both lobes was detected in 40 of 325 PTMC patients (12.3%). Of the 61 multicentric PTMC patients, 50 underwent preoperative thyroid ultrasonography and FNAC, and PTC was detected in 17 of these (34%); 49 were examined by frozen sections during surgery, and PTC was detected in 43 of 49 patients (87.8%). Sixteen of 61 patients were diagnosed with PTC incidentally based on final pathology (26.2%). Table 1. Comparison of the clinical characteristics of multicentric and unifocal papillary thyroid microcarcinoma patients a Multicentric (n = 61) Unifocal (n = 264) p Sex, female 46 (75.4) 229 (86.7) Age (yr) 45 (18 72) 41 (15 80) Follow-up period (yr) 7.3 ( ) 8.9 ( ) Hyperthyroidism 9 (14.8) 74 (28.0) Identified by FNAC 17 (34.0) (n = 50) 49 (23.7) (n = 207) Diagnosed by frozen sections 43 (87.8) (n = 49) 125 (70.2) (n = 178) Diagnosed incidentally by final 16 (26.2) 133 (50.4) pathology (incidental finding) Tumor size (cm) 0.7 ( ) 0.5 ( ) Tumor size 0.7 cm 34 (55.7) 100 (37.9) Postoperative 131 I accumulated 75 (0 1,050) 30 (0 1,035) < dose (mci) Total thyroidectomy 52 (85.3) 132 (50.0) < mo postoperative Tg b (ng/ml) 6.9 (0 31,993) (n = 50) 3.0 (0 249) (n = 125) Postsurgical relapse c 10 (16.4) 9 (3.4) Disease specific mortality 1 (1.6) 1 (0.4) a Data are presented as n (%) for categorical variables and median (range) for continuous variables; b Post total-thyroidectomy stimulated thyroglobulin; c including cases with recurrence or persistent disease. FNAC = fine needle aspiration cytology; Tg = thyroglobulin. J Formos Med Assoc 2011 Vol 110 No 8 513

4 S.F. Kuo, et al Table 2. Comparison of the clinical data of recurrence-free and recurrence or persistent disease multicentric papillary thyroid microcarcinoma patients a Recurrence-free Recurrence or persistent (n = 51) disease (n = 10) p Sex, female 42 (82) 4 (40) Age (yr) 45 (18 72) 48 (24 72) Follow-up period (yr) 7.3 ( ) 8.1 ( ) Both lobes involved 34 (67) 6 (60) Hyperthyroidism 7 (14) 2 (20) TNM stage < T1, N0, M0 41 (80) 2 (20) T3 4, N0, M0 1 (2) 0 T1, N1, M0 6 (12) 3 (30) T3 4, N1, M0 3 (6) 1 (10) T1, N0, M1 0 3 (30) T3 4, N1, M1 0 1 (10) Advanced clinical stage 10 (20) 8 (80) < Tumor size (cm) 0.6 ( ) 0.95 ( ) Tumor size 0.7 cm 25 (49) 9 (90) Postoperative 131 I accumulated dose (mci) 60 (0 445) 435 (90 1,050) < Total thyroidectomy 42 (82) 10 (100) mo postoperative Tg b (ng/ml) 4.95 (0 35.4) (n = 40) 186.1( ) (n = 10) a Data are presented as n (%) for categorical variables and medians (ranges) for continuous variables; b Post-total thyroidectomy stimulated thyroglobulin. Advanced clinical stage: (T3 4, any N, any M) or (any T, N1, or M1). TNM = tumor node metastasis. Outcome and prognosis Fifty-two of the 61 multicentric PTMC patients received total thyroidectomy (85.2%), including nine that underwent secondary operation for complete thyroidectomy; the other nine patients underwent non-total thyroidectomy (14.8%), including seven undergoing subtotal thyroidectomy and two undergoing lobectomy. The diameter of each thyroid lesion in the 61 patients was 1.0 cm. Fifty-three of the 61 patients (86.9%) were administered at least 1.1 GBq (30 mci) 131 I during postoperative follow-up. Two patients had permanent hypoparathyroidism after total thyroidectomy; however, there were no other serious complications related to surgery and 131 I therapy. Of the 61 multicentric PTMC patients, 51 (83.6%) were recurrence-free and 10 (16.4%) had recurrence or persistent disease at clinical followup, including six with recurrence and four with persistent disease. Table 2 shows a comparison of the clinical characteristics of 51 recurrence-free and 10 recurrence or persistent disease patients. The data shows that larger tumor diameter, higher postoperative serum stimulated Tg level and advanced clinical stage were associated with recurrence or persistent disease. The area under the ROC curve of tumor size predicting recurrence or persistent disease was 0.72 (95% confidence interval: ). There was no recurrence or persistent disease for tumor diameter < 0.5 cm (sensitivity 100%, specificity 35.3%), and the best cut-off level was 0.7 cm (sensitivity 90.0%, specificity 51.0%). Patients with tumor size < 0.7 cm were designated as the small tumor group and the remainder as the large tumor group. The Figure shows the Kaplan Meier recurrence-free survival curves between patients with different tumor size and clinical stages (excluding 4 patients with persistent disease). Patients with advanced clinical stage and large tumor size had higher recurrent rate. Table 3, which summarizes the results of the multivariate logistic regression, reveals the factors 514 J Formos Med Assoc 2011 Vol 110 No 8

5 Multicentric papillary thyroid microcarcinoma Kaplan Meier recurrence-free survival curve Early clinical stage & small tumor size (n = 18) Advanced clinical stage & small tumor size (n = 8) Early clinical stage & large tumor size (n = 25) Survival Advanced clinical stage & large tumor size (n = 6) Time (mo) Figure. Kaplan Meier recurrence-free survival curves between patients with different tumor size and clinical stages. Solid line: early clinical stage and small tumor size; dotted line: advanced clinical stage and small tumor size; long dashed line: early clinical stage and large tumor size; short dashed line: advanced clinical stage and large tumor size. Table 3. associated with recurrence or persistent disease. The results indicated that advanced clinical stage and large tumor size were significantly and independently associated with recurrence or persistent disease of multicentric PTMC. Discussion Factors predicting recurrence or persistent disease in patients with multicentric papillary thyroid carcinoma Variables OR (95% CI) a p Clinical stage 45.2 ( ) (early vs. advanced) Tumor size ( ) a Logistic regression. Early clinical stage: (T1, N0, M0); advanced clinical stage: (T3 4, any N, any M) or (any T, N1, or M1). OR = odds ratio; CI = confidence interval. Although PTMC patients usually have an excellent prognosis, 9 13 the clinical behavior and prognosis of multicentric PTMC patients is not well known. This study revealed an excellent cause-specific survival rate of 98.4% for multicentric PTMC patients after a median follow-up period of 7.3 years. Based on the results of this study, patients with multicentric PTMC have larger tumor diameter and higher rate of recurrence or persistent disease than those with unifocal PTMC, although their prognosis is excellent. The frequency of multicentricity in PTMC is reported to be 15 32% ,14,15 Both thyroid lobes are involved in 10 19% of PTMC patients. 11,12 Our results are similar to previous studies, in which multicentricity was observed in 18.8% of patients, and both lobes were involved in 12.3% of cases. Neck ultrasonography is a sensitive and cost-effective method for the detection of thyroid cancer, and it increases the frequency of preoperative diagnosis of thyroid microcarcinomas Both ultrasonography with FNAC and frozen sections during surgery are helpful in identifying multicentricity of thyroid cancer in PTMC patients, which might avoid secondary operation for these patients, although the diagnostic rate of FNAC is low ( %) for PTMC patients, because it is not easy to perform a successful FNAC on thyroid microcarcinoma. Although there have been no reports specifically on the prognostic factors in patients with multicentric PTMC, previous studies on PTMC patients have indicated that tumor size, postoperative Tg level, presence of lymph node metastases at diagnosis, sex, and extent of surgery are prognostic factors. 10,12,14,15,20,21 Based on the ROC curve in the present study, multicentric PTMC patients with tumor diameter < 0.5 cm tended to J Formos Med Assoc 2011 Vol 110 No 8 515

6 S.F. Kuo, et al be recurrence-free. From the results of multivariate logistic regression, advanced clinical stage and larger tumor size were independently associated with recurrence or persistent disease. Tumor size was a more important risk factor than clinical stage in the present study. As the tumor size increased, the prognosis became poorer. Additionally, advanced clinical stage in the present study included lymph node metastasis. Although lymph node metastasis increased risks of tumor recurrence, it did not influence survival rate in previous studies. 22,23 Four patients had persistent disease in the present study, and all of them underwent thyroid surgery because metastatic lesions originated from the thyroid; these patients actually had the poorest clinical outcome, and one of them died of metastatic thyroid cancer. Whether multicentric tumors originate from different unrelated clones or from one focus with intrathyroid spreading is unclear. Results from studies such as those involving polymerase chain reactions with the human androgen receptor gene or BRAF gene imply that noncontiguous tumor foci originate from independent precursors, 24,25 whereas another study has shown that multicentric papillary lesions arise from the same clone. 26 To date, it is unknown whether the clinical presentations and prognosis differ between these two disease subgroups in multicentric PTC or PTMC patients. There were some limitations in this retrospective study. Because 14.8% of multicentric PTMC cases had non-total thyroidectomy, it might have been difficult to identify recurrence by serum Tg levels and 131 I scans. We determined recurrence based mainly on physical and imaging studies (e.g. thyroid ultrasonography, chest X-ray, 131 I scan, computed tomography, magnetic resonance imaging, and positron emission tomography) other than serum Tg levels, and thus recurrence might have been under-reported as a result. In conclusion, multicentric PTMC patients might have an excellent prognosis. Patients with tumor diameter < 0.5 cm tend to be recurrencefree. Tumor size is an important independent prognostic factor in multicentric PTMC patients. References 1. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104: Hay ID, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through Surgery 1993;114: Sobin LH, Wittekind CH. UICC: TNM Classification of Malignant Tumors, 6 th edition. New York: Wiley Liss, 2002: Katoh R, Sasaki J, Kurihara H, et al. Multiple thyroid involvement (intraglandular metastasis) in papillary thyroid carcinoma. A clinicopathologic study of 105 consecutive patients. Cancer 1992;70: Loh KC, Greenspan FS, Gee L, et al. Pathological tumornode-metastasis (ptnm) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab 1997;82: Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97: Ringel MD, Ladenson PW. Controversies in the follow-up and management of well-differentiated thyroid cancer. Endocr Relat Cancer 2004;11: Lin JD, Kuo SF, Chao TC, et al. Incidental and nonincidental papillary thyroid microcarcinoma. Ann Surg Oncol 2008;15: Baudin E, Travagli JP, Ropers J, et al. Microcarcinoma of the thyroid gland. The Gustave Roussy Institute experience. Cancer 1998;83: Chow SM, Law SC, Chan JK, et al. Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality. Cancer 2003;98: Hay ID, Grant CS, Van Heerden JA, et al. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-years period. Surgery 1992;112: Roti E, Rossi R, Trasforini G, et al. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. J Clin Endocrinol Metab 2006;91: Sakorafas GH, Giotakis J, Stafyla V. Papillary thyroid microcarcinoma: a surgical perspective. Cancer treat rev 2005;31: Pelizzo MR, Boschin IM, Toniato A, et al. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients. Eur J Surg Oncol 2006;32: Küçük NÖ, Tari P, Tokmak E, et al. Treatment for microcarcinoma of the thyroid clinical experience. Clin Nucl Med 2007;32: Lin JD, Huang BY, Chao TC, et al. Diagnosis of occult thyroid carcinoma by thyroid ultrasonography with fine needle aspiration cytology. Acta Cytol 1997;41: J Formos Med Assoc 2011 Vol 110 No 8

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