Prognostic Factors for Sporadic Medullary Thyroid Carcinoma

Introduction Medullary thyroid carcinoma (MTC) originates from the thyroid parafollicular cells and accounts for 3% to 10% of all thyroid malignancies. Approximately 84% of cases are sporadic. The aim of this study was to evaluate the outcomes of treatment for sporadic medullary thyroid carcinoma (SMTC) and define the prognostic factors for overall survival. Methods The records of 32 SMTC patients treated at Ankara Oncology Education and Research Hospital between September 1993 and April 2003 were retrospectively evaluated. The effects of age, gender, tumor localization, extent of the primary surgical resection, tumor size, capsule invasion, lymph node metastasis, extranodal extension, tumor stage, local recurrence, and distant metastasis on the overall survival rate were evaluated by univariate and multivariate analyses. Results There were 32 patients (19 females, 13 males) with a median age of 45 years (21–76 years). Altogether, 22 patients had undergone complete resection and 10 patients incomplete resection. The median follow-up was 48 months (9–111 months), and the overall 5-year survival rate was 51%. Based on the univariate analysis, the extent of primary surgical resection, pathologic tumor size, capsule invasion, lymph node invasion, extranodal extension, tumor stage, local recurrence, and distant metastasis were factors that significantly affected survival. In the multivariate analysis, however, only the extent of the primary surgical resection, capsule invasion, and distant metastasis were found to be statistically significant factors. Conclusions The extent of the primary surgical resection significantly influences the survival of patients with SMTC. Capsule invasion and distant metastasis were additional factors affecting the prognosis.     

Evidence-based Approach to the Management of Sporadic Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare malignancy of the thyroid C cells. It occurs in hereditary (25% of cases) and sporadic (75%) forms. Sporadic MTCs frequently metastasize to cervical lymph nodes. Thorough surgical extirpation of the primary tumor and nodal metastases by compartment-oriented resection has been the mainstay of treatment (level IV evidence). Surgical resection of residual and recurrent disease is effective in reducing calcitonin levels and controlling complications of central neck disease (level IV evidence). Radioactive iodine, external beam radiation therapy, and conventional chemotherapy have not been effective. Newer systemic treatments, with agents that target abnormal RET proteins hold promise and are being tested in clinical trials for patients with metastatic disease.     

Single Center Experience in Primary Surgery for Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare disease, and most studies are either based on small numbers or multicenter studies with their inherent difficulties. Since 1995, a total of 440 patients with MTC underwent surgery in our clinic. A primary operation was performed in 188 patients (43% of 440). In 60 patients, the primary operation was performed because of a germline RET mutation (prophylactic surgery). Most (84%, 158/188) of the patients had pathologic calcitonin levels. Notably, MTC was found in almost 10% (3/30) of patients with normal calcitonin levels. However, all patients with lymph node metastases (LNMs) had elevated calcitonin levels. Total thyroidectomy (TTx) was performed in all patients. Lymph node dissection (LND) was performed at various extensions: one-compartment LND in 35% (66/188), three-compartment LND in 31% (58/188), and four-compartment LND in 29% (22/188). In general, lymph node dissection increased the likelihood of complications. LNM and distant metastases (DM) correlated with the extent of the primary tumor (pT category). The presence of LNM ranged from 17% (pT1 tumor) to 100% (pT4 tumor), whereas the presence of DM ranged from 0% (pT1 tumor) to 81% (pT4 tumor). Biochemical cure (normal calcitonin levels) was obtained in 72% (137/188) of patients. All 60 patients undergoing prophylactic surgery (tumor stage pT0/pT1) were biochemically cured. In contrast, only 60% (77/128) of the remaining patients were cured. The data suggest that primary surgery should be scheduled as soon as possible to treat patients at a node-negative stage. In the case of normal basal and elevated stimulated calcitonin levels, TTx and cervicocentral LND is recommended. If the basal calcitonin level is elevated, LND should include the cervicolateral compartment.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14–17, 2004.     

Occult Contralateral Carcinoma in Patients with Unilateral Papillary Thyroid Microcarcinoma

Background  

The optimal resection extent for papillary thyroid microcarcinoma (PTMC) confined within a unilateral lobe remains controversial.     

Long-Term Outcome After Surgery for Medullary Thyroid Carcinoma: A Single-Center Experience

Background

Medullary thyroid carcinoma (MTC) is a rare C cells-derived tumor, with a hardly predictable long-term prognosis. This study was aimed to evaluate the predictive factors of cure and survival after surgery for MTC in a monocentric series.

Methods

A retrospective analysis of the long-term outcomes was assessed in 255 MTC patients operated between 1980 and 2015 at Padua University hospital.

Results

Sporadic MTC occurred in 65.1% and hereditary MTC in 34.9% of patients. At a median follow-up of 93 months (range 7–430), the cure rate was 56.8%. The overall 10-year survival was 84.4%, and MTC-related death rate was 15.3%. Patients who died because of MTC had a median age of 61 years (range 21–84) and were at stages III–IV in all cases; deaths occurred in 18% of sporadic MTC, 6% of MEN2a and 66.7% of MEN2b patients. None of the patients at stages I–II died because of the disease, but 17.7% had persistent/recurrent disease. Based on univariate analysis, age, gender, genetic variant, extent and year of surgery, tumor size, lymph-nodal metastases and tumor stage significantly affected cure and survival rates. At multivariate analysis, only patient- and tumor-related features (age, lymph-nodal status and stage) remained significant independent prognostic factors.

Conclusions

Radical surgery is the only chance of definitive cure in MTC, but it is possible only at early stage; in advanced stages, even extensive surgery could not grant cure and prolonged survival. Stage, nodal metastases and age remain the main predictive factors for cure and survival.

     

Regulatory T Cells in Peripheral Blood, Lymph Node, and Thyroid Tissue in Patients with Medullary Thyroid Carcinoma

Background  

Immunological response of the human body is controlled by the suppressive characteristics of regulatory T cells (Tregs). In various diseases a change in the number of Tregs is evident. For example, whereas Tregs are reduced in auto-immunological processes, an increase of Tregs is found with various malignant tumors. Regarding medullary thyroid carcinoma (MTC) no such studies have been performed to date.     

甲状腺髓样癌26例临床分析

目的探讨甲状腺髓样癌临床特点、诊断、手术原则和术后处理。方法回顾性分析26例甲状腺髓样癌的临床资料,其中散发性24例,家族性2例。均行手术治疗,7例术后行60Co放疗。结果26例中随访22例(84.6%),平均随访(62.7±26.1)月;失访4例。死亡5例,死于肺转移3例,死因不明2例。术后随访5年者17例,5年生存率为70.6%(12/17),术后复发4例。结论甲状腺髓样癌术前诊断困难,大部分病人仅以甲状腺肿块就诊,手术应以患侧甲状腺叶加峡部切除为主,对术前B超示双侧甲状腺肿块病人可行甲状腺全切术或近全切除术,有淋巴结转移者加行同侧颈淋巴结清扫术。     

Prognostic Significance of Disseminated Tumor Cells in the Connective Tissue of Patients with Medullary Thyroid Carcinoma

Introduction Disseminated tumor cells in the connective tissue (CT-DTCs) do not have any connection to a primary tumor or the lymph nodes. They are identified quite often in patients with medullary thyroid carcinoma (MTC), but nothing is known regarding their prognostic significance. Methods Among 450 patients with MTC, 69 (15%) were identified as having CT-DTCs. A case-control group of patients without CT-DTCs was selected. The two groups were matched concerning TNM classification, age, heredity, and sex. Because many patients with CT-DTCs had extrathyroidal tumor extension (pT4 category), distant metastases (M1 category), or both, only 35 matched pairs could be identified. The TNM classification in both groups was as follows: pT1, n = 8; pT2, n = 15; pT3, n = 4; pT4, n = 8; pN0, n = 4; pN1, n = 31; M0, n = 30; M1, n = 5. The mean age was 46.8 ± 17.0 years in the CT-DTC group and 44.4 ± 15.0 years in the case-control group (NS). Results In both groups, 23 patients had sporadic MTC, and 12 patients had hereditary MTC. Neither mean basal preoperative nor postoperative calcitonin levels differed significantly between the two groups. In contrast, none of the patients with CT-DTCs was biochemically cured (normal calcitonin level after pentagastrin stimulation) compared to eight patients without CT-DTCs (P < 0.005). The two groups did not differ concerning other parameters (basal calcitonin level >3000 pg/ml, more than 10 lymph node metastases, more than two involved locoregional lymph node compartments, mediastinal lymph node metastases) that have been reported to correlate with the lack of or almost (<10%) lack of biochemical cure. Conclusions In patients with MTC, disseminated tumor cells in the connective tissue correlate with advanced tumor stages and appear to be of prognostic significance.     

甲状腺髓样癌35例治疗体会

目的总结甲状腺髓样癌(medullary thyroid carcinoma,MTC)临床特征及治疗方法。方法回顾分析1997年1月~2005年12月经治的35例MTC的临床及病理资料。结果35例均予手术切除原发灶并加行颈淋巴结清扫术,术后放疗5例,化疗7例。所有病例均经病理证实为MTC,淋巴结转移率为51.4%。32例术后随访2~10年,5年生存率为87.5%。结论MTC治疗应以根治性切除为原则,切除范围应比其他类型的甲状腺癌积极,术后可以辅以多种非手术治疗。     

Thyroid Venous Catheterization in the Early Diagnosis of Familial Medullary Thyroid Carcinoma

In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520±635 pg/ml) and C (6322±2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.     

Excellent Prognosis of Patients with Nonhereditary Medullary Thyroid Carcinoma with Ultrasonographic Findings of Follicular Tumor or Benign Nodule

Background  Medullary thyroid carcinoma (MTC) accounts for only 1.4% of all thyroid malignancies in Japan. Generally, MTC shows ultrasonographic findings typical of thyroid carcinoma. However, in our experience, some MTC may be diagnosed as a follicular tumor or a benign nodule on ultrasonography because ultrasonographic findings of malignancy are lacking. In this study we investigated differences in biological behavior between these two types of MTC. Methods  Seventy-seven patients with nonhereditary MTC who underwent surgery in our department between 1988 and 2007 were enrolled in this study. Of these patients, 54 were diagnosed as having thyroid carcinoma (malignant, or M-type) but the remaining 23 were diagnosed as having follicular tumor or benign nodule (benign, or B-type) on ultrasonography. Results  Clinically apparent lateral node metastasis, extrathyroid extension, and extranodal tumor extension were observed in 37%, 17%, and 11% of M-type patients, respectively, but none of the B-type patients showed any of these features. All B-type patients but only 59% of M-type patients were biochemically cured. Lymph node metastasis was pathologically confirmed in 38 and 65% of B-type and M-type patients, respectively. Eight patients showed recurrence and three have died of carcinoma to date; all of these patients were M-type patients. Conclusions  B-type MTC is highly indolent and shows an excellent prognosis. However, thyroidectomy and lymph node dissection for B-type MTC should be the same as for M-type MTC because 38% of B-type MTC showed pathologic node metastasis.     

结节性甲状腺肿并存甲状腺癌的治疗

目的:探讨结节性甲状腺肿并存甲状腺癌时的临床特征、治疗和预后。方法:回顾性分析1991年1月～2000年12月经手术治疗的结节性甲状腺肿合并有甲状腺癌的临床资料。结果:同期中,共手术治疗结节性甲状腺肿3955例中,内25例合并甲状腺癌(0.63%)。男6例,女19例,年龄12～65(36.8±13.1)岁。12例为微小的甲状腺乳头状癌,12例为乳头状甲状腺癌,1例为滤泡状甲状腺癌。有颈淋巴结转移者4例,3例位于颈侧,1例位于气管前。术前和术中诊断出甲状腺癌者占32%,术后病理检查时发现的为68%。术后随访10个月～10年,2例因颈淋巴结肿大而再次手术治疗,1例为甲状腺癌淋巴结转移,1例为淋巴结反应性增生。结论:结节性甲状腺肿合并甲状腺癌者预后较好。一方面,不应简单地认为结节性甲状腺肿是良性病变,而忽略同时存在恶性结节的可能性;另一方面,也不应过分强调甲状腺癌存在于结节性甲状腺肿中的可能性而随意放宽手术指征,或扩大手术范围。     

Survival Implications of Cervical Lymphadenectomy in Patients with Medullary Thyroid Cancer

Background

The relationship between extent of cervical lymphadenectomy along with the number of involved lymph nodes (LNs) removed and overall survival has not been well documented in patients with medullary thyroid carcinoma (MTC). This study investigates whether the overall number of LNs removed and the number of metastatic LNs are independent prognostic factors for overall survival.

Methods

Data from patients with MTC in the Surveillance, Epidemiology, and End Results (SEER) registry database were examined. After categorizing the study population based on the number of overall LNs examined and the number of metastatic LNs, survival estimates were compared. The total number of examined LNs and their histopathological status were analyzed for their prognostic value in estimating overall survival.

Results

593 patients were included in this study. Those with all negative LNs had the best overall survival; those with LNs examined and at least one positive LN had worst overall survival (p < 0.0001). The total number of examined LNs for both groups with negative and positive LNs was not associated with improved survival outcome (p = 0.41). In node-positive patients, each additional positive LN was significantly associated with an increase in overall mortality [hazard ratio (HR) = 1.05, 95% confidence interval (CI) = 1.02–1.08].

Conclusions

Cervical LN metastases conferred an independent risk for worse survival rate in MTC. Cervical lymphadenectomy is important for staging and regional disease control, however the extent of lymph node dissection, the overall number of lymph nodes removed along with removal of an increased number of involved lymph nodes do not confer a survival advantage. Future prospective studies are needed.