Current management of medullary thyroid cancer

Medullary thyroid cancer accounts for 5%-10% of all thyroid cancers. The majority of medullary thyroid cancers are sporadic, but 20% of cases are a result of a germline mutation in the ret proto-oncogene. Hereditary medullary thyroid cancer can be seen as part of the multiple endocrine neoplasia syndrome type 2A or 2B or as part of familial medullary thyroid cancer. This article discusses the current methods available for the diagnosis and evaluation of a patient with suspected medullary thyroid cancer. The management of medullary thyroid cancer is predominantly surgical excision, consisting of a total thyroidectomy and lymph node dissection. The extent and timing of surgical excision are discussed. Systemic therapeutic options are limited for medullary thyroid cancer, but several therapeutic targets show promise for the development of new therapies in the future.     

甲状腺髓样癌临床病理分析

目的:探讨甲状腺髓样癌(MTC)的临床病理特点、免疫表型及电镜诊断特点。方法:回顾性分析10例甲状腺髓样癌的临床资料,采用免疫组化、组织化学方法研究其病理形态特点,结合文献分析甲状腺髓样癌的电镜诊断特点。结果:散发型甲状腺髓样癌8例,家族型甲状腺髓样癌2例,6例淋巴结转移;9例肿瘤间质刚果红染色( );免疫组化:癌组织中降钙素( )10例、铬粒素A( )10例、突触素( )7例,1例见甲状腺球蛋白阳性细胞,CD44V6在髓样癌中的阳性表达率为60%;电镜下见癌细胞胞质内有大小不一的神经内分泌颗粒。结论:MTC具有多分化肿瘤的特点,可产生多种神经内分泌物质;其诊断依赖于组织病理学、免疫组化和组织化学,电镜在MTC的诊断中有重要价值;降钙素(CT)是其特异性标记物;CD44V6的高表达与MTC的颈部淋巴结转移密切相关。     

Prognostic impact of nuclear DNA content in medullary thyroid carcinoma; a retrospective pilot study

The prognostic significance of DNA content in medullary thyroid carcinoma was studied retrospectively in 16 patients. Five patients died within 3 years of medullary thyroid carcinoma and 11 patients survived for at least 10 years. Clinical data and tumour morphology were studied. DNA measurements on tumour cells in histologic sections were performed with slide cytophotometric technique. The tumours of the survivors had in all but two cases a DNA content comparable to that of normal cells, whereas the tumours of the non-survivors and two of the survivors had higher DNA content. The results indicate that DNA measurements in medullary thyroid carcinoma might be of use in addition to clinical and morphologic data and that further studies are warranted.     

甲状腺髓样癌的预后因素分析

目的　评估影响甲状腺髓样癌预后的因素。方法　采用统计学单、多因素分析研究本院初治 5 3例甲状腺髓样癌的预后因素。结果　总的 5年、10年、15年生存率各自为 6 6 %、5 9.9%和 5 3.2 %。单因素分析示 :原发灶累及双侧 ,原发灶 >4cm ,病灶外侵甲状腺包膜 ,无腹泻症状 ,远处转移 ,手术彻底程度影响预后。多因素示 :手术彻底程度是影响甲状腺髓样癌生存的独立预后因素。结论　手术彻底程度是影响甲状腺髓样癌生存的独立预后因素。     

Neck management in medullary thyroid carcinoma

Aims

The aims of this study were to retrospectively evaluate incidence and patterns of lymph node metastases, surgical treatment and prognostic factors of medullary thyroid carcinoma.

Methods

Out of a group of 70 MTC patients data of 67 patients were collected. Sixty-two of these patients underwent surgery. Apart from thyroidectomy, 16 patients underwent a bilateral neck dissection, 21 a unilateral neck dissection and 29 a paratracheal dissection or node-picking operation. Thirty-six patients were irradiated, of which 31 postoperatively and five with palliative intent.

Results

Lymph node metastases were found in 91% of the ipsilateral neck dissection specimens, 91% of the paratracheal dissections and 63% of the contralateral dissections. Of the 12 elective neck dissections, 5 were tumor positive. Level VI was positive in 91% of the cases where a dissection was done, whereas preoperatively only 16% were scored tumor positive. During follow-up 22 of the 67 patients developed one or more locoregional recurrences (in total 28 recurrences). The most important factors that were correlated with a worse prognosis of survival were late stage of disease (stage III and IV) (p = 0.0014), high number of positive lymph nodes (p = 0.0023) and incomplete surgical resection (p = 0.0002).

Conclusions

The high rate of locoregional recurrences in this study are a strong argument for a more aggressive approach to the primary and neck. A routine central and ipsilateral selective neck dissection of levels II–V should be considered in all MTC patients based on the high incidence of metastases and the relative low morbidity of a unilateral neck dissection. Patients referred after thyroidectomy alone with elevated (stimulated) calcitonin levels should be re-operated, performing an elective or therapeutic central and unilateral neck dissection.     

Systemic treatment and management approaches for medullary thyroid cancer

Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.     

甲状腺髓样癌的辅助治疗

目的 评价放射治疗、化学治疗和放射性核素186Re对晚期甲状腺髓样癌的疗效。方法 回顾性分析本院1960年6月～2000年7月间接受放疗、化疗或放射性核素治疗的甲状腺髓样癌患者疗效。结果 放射治疗对术后肉眼残留者3年局控率为33．3％(3／9例)，对镜下残留者3年局控率达63．6％(7／11例)，单用放射治疗无效(3例)。化学治疗疗效不明显(11例)。放射性核素186Re对晚期甲状腺髓样癌肿瘤灶有抑制生长作用。结论 放射治疗对术后镜下残留、肉眼残留者不失为手术治疗的有益补充，能明显提高局控率。放射性核素186Re的治疗价值有待研究。     

遗传型甲状腺髓样癌肿瘤休眠现象与RET基因突变

甲状腺髓样癌(medullary thyroid carcinoma,MTC)属于甲状腺癌中恶性程度较高的一类,其10年生存率约为50%.我们报告2例来自同一家系休眠时间超过20年的遗传型甲状腺髓样癌,同时提取其外周血基因组DNA,对RET原癌基因进行检测,探讨其肿瘤休眠现象发生的可能机制.     

核素靶向治疗在转移性甲状腺髓样癌治疗中的价值

目的 评价放射性同位素^90Y标记的奥曲肽（^90Y-DOTATOC）及^131I标记的间碘苄胍（^131I-MIBG）在治疗转移性甲状腺髓样癌中的价值。方法 12例经病理学检查证实的转移性甲状腺髓样癌患者均进行了^131In-奥曲肽和^131I-MIBG或^123I-MIBG联合显像。根据显像结果,分别选择奥曲肽显像阳性或MIBG显像阳性的患者行^90Y-DOTATOC或^131I-MIBG内照射靶向治疗。内照射靶向治疗方案为：静脉滴注3．33GBq ^90Y．DOTATOC,治疗间期为6周;或11．1GBq ^131I-MIBG,治疗间期3个月以上。结果 12例患者联合显像均为阳性,其中奥曲肽显像阳性8例,MIBG显像阳性6例。根据联合显像结果,筛选出4例采用^90Y-DOTATOC治疗,5例采用^131I-MIBG治疗。经过3-5个疗程的治疗,随访15～36个月,9例核素治疗的患者中,3例部分缓解,6例病情稳定,有效率为33．3％（3／9）,反应率为100％（9／9）,未见明显副作用。结论 核素标记的奥曲肽及MIBG靶向治疗转移性甲状腺髓样癌安全有效,可作为改善患者预后的一种方法。     

Ultrasound Score to Select Subcentimeter-sized Thyroid Nodules Requiring Ultrasound-guided Fine Needle Aspiration Biopsy in Eastern China

Ultrasound-guided fine needle aspiration biopsy (FNAB) is a costly diagnostic item with a low yield inidentifying the tiny proportion of nodules that actually represent malignant disease. Our aim through this studywas to obtain an ultrasound (US) score for selecting subcentimeter-sized thyroid nodules requiring FNAB ineastern China. Some 248 patients for a total of 270 thyroid nodules less than 1 cm in diameter underwent FNABand subsequent surgery from January 2006 to March 2012 at our hospital. The clinicopathological and US datafrom all the nodules were analyzed retrospectively. An US score was developed on the basis of independentpredictive factors for malignancy. Irregular shape, hypoechogenicity, no well-defined margin, presence ofcalcifications and ratio between antero-posterior and transversal diameters (AP/TR) ≥1 were independentpredictive factors for malignancy on logistic regression analysis. US score were statistically significant, with ≤2favoring benignancy with an 80.3% sensitivity and a 72.7% specificity. US score is useful for differentiatingbetween malignant and benign subcentimeter-sized thyroid nodules. We suggest FNAB for nodules when theUS score is higher than 2.     

Total thyroidectomy alone versus ipsilateral versus bilateral prophylactic central neck dissection in clinically node-negative differentiated thyroid carcinoma. A retrospective multicenter study

Background

Central neck dissection (CND) remains controversial in clinically node-negative differentiated thyroid carcinoma (DTC) patients. The aim of this multicenter retrospective study was to determine the rate of central neck metastases, the morbidity and the rate of recurrence in patients treated with total thyroidectomy (TT) alone or in combination with bilateral or ipsilateral CND.

胰高糖素样肽-1受体激动剂对人甲状腺髓样癌细胞生长和能量代谢的影响

背景与目的：胰高糖素样肽-1(glucagon like peptide-1,GLP-1)受体激动剂是一种新型降糖药。在研发过程中,发现其可增加啮齿类动物患甲状腺C细胞肿瘤的风险。因此,该药物对人类甲状腺的影响引人关注。本研究旨在探讨GLP-1受体激动剂对人甲状腺髓样癌(medullary thyroid cancer,MTC)细胞增殖、降钙素的分泌和能量代谢的影响。方法：体外培养人MTC细胞系(TT)。分别以0、1、10和100 nmol/L艾塞那肽和利拉鲁肽处理细胞24、48和72 h后,采用细胞计数试剂盒(cell counting kit-8,CCK-8)检测GLP-1受体激动剂艾塞那肽和利拉鲁肽处理后细胞增殖情况;采用降钙素试剂盒测定细胞培养上清液中降钙素水平的变化;采用Seahorse能量代谢分析仪检测细胞糖酵解及线粒体呼吸的变化。结果：实验组细胞增殖率与对照组相比,差异无统计学意义(P>0.05),降钙素的量与对照组相比,差异无统计学意义(P>0.05),不同浓度艾塞那肽和利拉鲁肽处理细胞24 h后,与对照组相比,实验组艾塞那肽和利拉鲁肽对MTC细胞能量代谢并无明显影响(P>0.05),随着艾塞那肽和利拉鲁肽处理时间延长,TT细胞糖酵解和线粒体呼吸并无明显改变(P>0.05)。结论：GLP-1受体激动剂对人MTC发生、发展无明显促进作用,未来仍需大规模临床数据进一步证实GLP-1受体激动剂的安全性。     

超声对低分化和未分化甲状腺癌的诊断价值

目的 探讨超声对低分化甲状腺癌(PDTC)和未分化(间变性)甲状腺癌(UTC)的诊断价值.方法 应用彩色多普勒超声对22例PDTC和UTC的甲状腺形态、大小、回声、边界、内部砂粒、血流分布等声像图表现及其内部血流状况进行观察,并与手术、活组织病理检查病理结果对照;扫查颈部及气管食管沟区淋巴结.根据甲状腺双叶或单叶弥漫性病变及局部淋巴结的超声表现,结合临床表现,判断甲状腺病变的性质.结果 术前或活组织病理检查前超声检出甲状腺单叶肿物16例,左甲9例,右甲7例.双叶肿物6例.超声提示UTC 2例,甲状旁腺癌1例,慢性淋巴细胞性甲状腺炎1例,其余提示甲状腺恶性肿瘤.结论 超声检查可提高PDTC和UTC的检出率和诊断率.     

Medullary thyroid cancer and pseudocirrhosis: case report and literature review

Pseudocirrhosis is a rare form of liver disease that can cause clinical symptoms and radiographic signs of cirrhosis; however, its histologic features suggest a distinct pathologic process. In the setting of cancer, hepatic metastases and systemic chemotherapy are suspected causes of pseudocirrhosis. Here, we present a patient with medullary thyroid carcinoma metastatic to the liver who developed pseudocirrhosis while on maintenance sunitinib after receiving 5-fluorouracil, leucovorin, and oxaliplatin (folfox) in combination with sunitinib. Cirrhotic change in liver morphology was accompanied by diffusely infiltrative carcinomatous disease resembling the primary tumor. We discuss the diagnosis of pseudocirrhosis in this case and review the literature regarding pseudocirrhosis in cancer.     

Parity and risk of thyroid cancer: a nested case-control study of a nationwide Swedish cohort

The association between parity and risk of thyroid cancer was examined in a case-control study nested within a cohort of Swedish women born 1925–60. A total of 1,409 cases of thyroid cancer were compared with 7,019 agematched controls. Odds ratios (OR) and 95 percent confidence intervals (CI) were calculated as estimates of relative risk. A weak association was found between parity and risk of thyroid cancer (OR for ever-parous women cf nulliparous was 1.1, CI=1.0–1.3). For the subset of papillary cancers, there was a significantly increased risk (OR for ever-parous cf nulliparous = 1.3, CI=1.0–1.6), and among women diagnosed at the age of 50 or older, there was a positive linear trend with increasing number of livebirths. Women during the first year after a livebirth had an increased risk of thyroid cancer compared with women who delivered 10 or more years before; this association was most prominent among uniparous women (OR=2.5, CI=1.1–5.9). An increased risk was also apparent for age over 20 years at livebirth (among uniparous women) and age over 25 years at last livebirth (among multiparous women). A negligible effect of parity on thyroid cancer risk was seen, but each livebirth may have a short-term and age-dependent promoting effect.Authors are with the Department of Cancer Epidemiology, University Hospital, Uppsala, Sweden (M.R. Galanti, M. Lambe, A. Ebbora, R. Sparda B. Pettersson): Department of Social Medicine, University Hospital, Uppsala, Sweden (M. Lambe); Department of Epidemiology, Harvard School of Public Health, Boston, USA (A. Ekbom). Address correspondence to Dr M. Rosaria Galanti, Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden. This work was supported in part by grant n. 3136-B92-02XBB from the Swedish Cancer Society.     

Gamma knife radiosurgery for metastatic brain tumors from thyroid cancer

Objective We report our experience using gamma knife radiosurgery (GKR) for brain metastasis from thyroid cancer, which is extremely rare. Methods Between 1995 and 2007, 9 patients with 26 metastatic brain tumor(s) from thyroid cancer underwent GKR. The mean patient age was 58 years (range: 10–78). Seven patients had metastases from papillary thyroid cancer, and two from medullary thyroid cancer. Five patients had solitary tumors, and four patients had multiple metastases. Three patients who had multiple metastases also underwent whole brain radiation therapy (WBRT). The mean tumor volume was 2.4 cc (range: 0.03–14.0). A median margin dose of 18.0 Gy (range: 12–20) was delivered to the tumor margin. Results Tumor control was obtained in 25 out of 26 tumors (96%). The median progression-free period after GKR was 12 months (range: 4–53). The overall median survival after GKR was 33 months (range: 5–54). There were no procedure-related complications and six patients are still living 5–54 months after GKR. Conclusions Radiosurgery is an effective and minimally invasive strategy for management of brain metastases form thyroid cancer.     

甲状腺髓样癌的放射治疗新进展

甲状腺髓样癌（MTC）是一种源自甲状腺滤泡旁C细胞的神经内分泌肿瘤。 甲状腺髓样癌的初始治疗通常是手术。临床分期较晚的患者,尽管进行了积极的手术治疗,但局部复发风险仍很高。随着辐射技术的改进,足够的放疗剂量可以有效地照射到高危区域,同时最小化周围关键组织结构的受照剂量。因此放射治疗应该是局部晚期甲状腺髓样癌的治疗选择,以提高局部区域控制。     

Pituitary metastasis from medullary carcinoma of thyroid: case report and review of literature

Pituitary is a rare site for metastases from thyroid cancer. Most reported cases have been of papillary and follicular carcinoma. Metastases from medullary thyroid carcinoma have not been reported. We report a case of intrapituitary metastasis from medullary carcinoma thyroid in a 38-year-old male, who had been operated for pituitary adenoma 5 years earlier. At the time of presentation in Nov 2006, he had visual field defects and a painless thyroid nodule. Further evaluation revealed medullary carcinoma thyroid, cervical and mediastinal lymphadenopathy, elevated serum calcitonin levels, and lobulated pituitary tumor. After surgical excision of thyroid and lymph node clearance, he underwent craniotomy and subfrontal excision of pituitary tumor. All the tumors were of identical histology, i.e., medullary carcinoma thyroid. Pituitary tumor was positive for calcitonin.