Latent Subclinical Medullary Thyroid Carcinoma: Diagnosis and Treatment

n = 11), palpable metastatic lymph node ( n = 6), distant metastases ( n = 4). In nine cases the diagnosis was made by both fine-needle aspiration cytology and serum CT measurement. In the four other cases the initial cytology was incorrect, but the diagnosis was revised on the basis of elevated basal CT values. In 11 patients (group 2) presenting with nodular thyroid disease, SMTC was not clinically detectable. SMTC was preoperatively suspected by elevated CT levels: basal CT > 10 pg/ml and pentagastrin-stimulated CT peak > 100 pg/ml. One patient in group 1 with distant metastases was not operated on. All of the other 12 patients underwent total thyroidectomy and extensive lymph node dissection. The mean size of the tumors was 27 mm. Lymph node involvement was found in nine patients. After surgery, CT levels returned to normal in five patients but remained elevated in five others; the two remaining patients died of distant metastases. All 11 patients in group 2 underwent total thyroidectomy and central neck dissection. None of the 11 patients had nodal extension. All 11 patients are biochemically cured. It was concluded that routine measurement of basal serum CT in those with nodular thyroid disease allows early, preoperative diagnosis of subclinical SMTC and improves the results of surgery.     

Medullary Carcinoma of the Thyroid Gland

Medullary thyroid carcinoma (MTC) is an uncommon thyroid tumor that has attracted a great deal of interest because of its frequent presentation as a familial tumor and its primary involvement in the type II multiple endocrine neoplasia (MEN) syndromes MEN-IIA and MEN-IIB and familial medullary thyroid carcinoma (FMTC). The MTC tumor cells secrete the polypeptide hormone calcitonin, which serves as an excellent tumor marker, useful for defining the presence of disease, preoperatively or following thyroidectomy. The discovery that mutations in the RET proto-oncogene are associated with MEN-II syndromes was highly significant in that it demonstrated a clear correlation between genotype and phenotype; and most importantly it provided a mechanism whereby family members at risk could be identified by direct DNA analysis. Virtually all patients with MEN-IIA, MEN-IIB, and FMTC develop MTC; therefore there is a clear rationale for performing thyroidectomy as soon as a RET mutation has been identified. Because MTC appears to be much more aggressive in patients with MEN-IIB, thyroidectomy is performed during the first year of life in this setting, whereas in patients with MEN-IIA, where the tumor appears to be more indolent, the procedure can be safety delayed until age 5 years. Reoperative neck exploration in patients with evidence of persistent or recurrent MTC has been effective in a significant number of patients, although the success of the operation requires careful patient selection and preoperative assessment. MTC, as expressed in the MEN-II syndromes, is an excellent model to evaluate the usefulness of interventional therapy in patients demonstrated to have a genetic predisposition for cancer.     

Provocative Agents and the Diagnosis of Medullary Carcinoma of the Thyroid Gland

Twenty-six patients with known or suspected medullary thyroid carcinoma (MTC) and 21 normal control subjects were tested intravenously on four separate days with calcium gluconate (CG), 2 mg Ca⁺⁺/kg/1 min.; pentagastrin (P), 0.5 ug/kg/ 5 sec.; calcium chloride (CC), 3 mg Ca⁺⁺/kg/10 min.; and a combination of calcium gluconate and pentagastrin (CG + P). Calcitonin (CT) levels were determined by radioimmunoassay on plasma collected before and immediately following each test infusion. In none of the 21 control subjects was there a clear increase in CT above 200 pg/ml following any of the four provocative tests. Conversely, in all 26 patients with known or suspected MTC, plasma CT levels were markedly increased (>300 pg/ml) following the combined infusion of CG + P. The peak CT response was greater with CG + P than with a) CG alone (22 of 24 patients, p < 0.002), b) P alone (25 of 26 patients, p < 0.002), or c) CC alone (17 of 17 patients, p < 0.002). Of 12 MTC patients with undetectable basal calcitonin levels, all had peak responses greater than 300 pg/ml following CG + P, whereas such responses occurred less often following CG alone (8 of 12) or P alone (8 of 12). The results demonstrate that the combined administration of pentagastrin and calcium gluconate constitutes a more effective and reliable stimulus for CT secretion from MTC cells than the use of either agent alone, and appears the most useful single screening test for the detection of occult MTC.     

Medullary Thyroid Carcinoma: Relationship of Method of Diagnosis to Pathologic Staging

Medullary thyroid carcinoma (MTC) develops in virtually all patients affected with multiple endocrine neoplasia type II (MEN II), a disease inherited as an autosomal dominant trait. The thyroid tumor cells secrete calcitonin (CT) and the detection of elevated plasma levels (>300 pg/ml) of this hormone in MEN II kindred members strongly suggests the presence of MTC even though it may not be evident clinically. Intravenously administered calcium ion (Ca⁺⁺) and pentagastrin (Pg) are potent CT secretagogues which are of particular value in establishing the early diagnosis of MTC. In evaluating seven kindreds with MEN II, we detected 90 patients with MTC. Depending on the method of diagnosis, they could be divided into three categories: Group 1; patients with no clinical evidence of MTC whose undetectable basal plasma calcitonin levels became elevated following intravenous Ca⁺⁺ or Pg, Group II; patients with no clinical evidence of MTC who had elevated basal plasma CT levels, and Group III; patients with clinically evident MTC. At the time of diagnosis of MTC, the patients in Group I were younger (20.5 ± 1.9 years) than the patients in Group II (32.5 ± 4.7 years, p < 0.005) and Group III (34.3 ± 2.0, p < 0.00005). The incidence of residual MTC, as indicated by an elevated plasma CT level following provocative testing postoperatively, was less frequent in patients diagnosed biochemically ([6/34]; Group I, 4/26 and Group II, 2/8) than in those diagnosed clinically (Group III, 15/26, p < 0.002). Furthermore, regional nodes were involved less often in patients diagnosed biochemically ([5/28]; Group I, 2/22 and Group II, 3/6) than in those diagnosed clinically (Group III, 15/24, p < 0.02). Distant metastases were only evident in Group III patients. Patients with MEN II who had the diagnosis of MTC established biochemically rather than clinically, had a more favorable pathological stage of disease at the time of thyroidectomy. This was especially true if the biochemical diagnosis had been by provocative testing.     

甲状腺髓样癌的外科治疗

虽然甲状腺癌是人体内分泌系统中最常见的恶性肿瘤，但甲状腺髓样癌并不多见，约占甲状腺癌的3％～10％。我科2005年共收治甲状腺癌患者542例，甲状腺髓样癌仅18例，占3．3％。甲状腺髓样癌是来自于甲状腺滤泡旁细胞（亦称C细胞）的一种恶性肿瘤。甲状腺滤泡旁细胞为神经内分泌细胞，亦属APUD（amine precursor uptake and dccarboxylation）系的细胞，即胺前身摄取和脱羟细胞，该细胞的主要特征为分泌降钙素及多种物质包括癌胚抗原（CEA），并产生淀粉样物。     

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.     

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。     

Long-term Outcome of Reoperations for Medullary Thyroid Carcinoma

Background Most patients with medullary thyroid carcinoma (MTC) have persistent disease after primary surgery, as evidenced by calcitonin elevation. Previous reports showed that reoperation on selected patients yields immediate calcitonin normalization in one-third of patients. Long-term follow-up data are needed to assess the outcome in such patients. This report aims to provide 8– to 10–year follow-up on reoperations for persistent or recurrent MTC. Methods An Internal Review Board (IRB) approved database on patients treated for MTC has been prospectively maintained. This database was reviewed to report follow-up data on calcitonin levels and survival. Results Between 1992 and 2006, 148 patients underwent reoperations for recurrent or persistent MTC (55 patients had 59 reoperations for palliation, and 93 patients had 105 reoperations for cure). Of the 93 patients operated on for cure (44 with hereditary MTC, 49 with the sporadic form), 8–10-year follow-up data were available on 56. Four patients died of disease (4.3% of 93). Two died of unrelated causes, and were excluded from calcitonin outcome analysis. Fourteen patients of 54 (26.0%) have unstimulated calcitonin levels of < 10 pg/ml at 8–10 years. Eleven additional patients (20.4%) have levels < 100 pg/ml. None of these 25 patients (46.4%) have radiologic recurrence. Conclusions Previous reports demonstrated the low morbidity of reoperation for MTC in experienced hands, and success was determined by lowering of calcitonin levels. Follow-up data demonstrate that at least one third of such patients have long-term eradication of their disease following reoperation, as evidenced by biochemical and imaging studies.     

Medullary Thyroid Carcinoma: Ethical Issues for the Surgeon

Medullary thyroid cancer is a disease with an established genetic inheritance pattern for which evidence-based guidelines recommend genetic testing and subsequent management of affected patients and their family members. The perceived stigma of genetic testing, coupled with issues involving confidentiality and disclosure, create potential conflict and confusion. In some cases, there is a need for genetic testing and prophylactic surgery in children, augmenting the need for a judicious approach that balances respect for individual autonomy and parental rights with the best interest of the child. We provide an overview of the ethical issues facing surgeons caring for patients with familial medullary thyroid carcinoma, and recommend interventions and resources to assist in decision making in these difficult situations.     

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.     

Genotype-Phenotype Based Surgical Concept of Hereditary Medullary Thyroid Carcinoma

Background Since DNA tests have enabled reliable identification of asymptomatic RET (rearranged during transfection) gene carriers, myriads of publications have appeared on genotype-phenotype relationships. A comprehensive appraisal of this body of evidence using evidence-based methodology is pending. Methods This study was based on systematic evaluation of the literature using evidence-based criteria. Results (1) There is a distinct age-related progression of hereditary medullary thyroid carcinoma (MTC) in carriers of RET mutations (grade C). (2) Among the high-risk RET mutations, those in codon 634 cause higher penetrance rates of the multiple endocrine neoplasia 2A phenotype (MTC, pheochromocytoma, and parathyroid hyperplasia/adenoma) than mutations in codons 609, 611, 618, and 620, irrespective of the amino acid substituting for cysteine (grade C). (3) DNA-based screening is superior to calcitonin-based screening in asymptomatic RET carriers (grade C). (4) Using a worst-case scenario, i.e., considering the earliest finding of MTC in asymptomatic RET carriers, pre-emptive thyroidectomy should be performed before that time (grade C) to be truly prophylactic. Specifically, for carriers of highest-risk mutations (codon 918): within the first year of life; for carriers of high-risk mutations (codon 609, 611, 618, 620, 630, and 634): before the age of 5 years; and for carriers of least-high risk mutations (codon 768, 790, 791, 804, and 891): before the age of 5-10 years. Strict adherence to these grade C recommendations can result in undertreatment of the former (codon 634) and overtreatment of the latter. Conclusions These genotype-phenotype correlations provide a solid foundation on which to base surgical concepts, leaving little room for randomized controlled clinical trials.     

Medullary Thyroid Carcinoma: Long-Term Outcomes of Surgical Treatment

Background

Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths.

Methods

We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009.

Results

We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort.

Conclusions

A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.     

Clinical Analysis of Familial Nonmedullary Thyroid Carcinoma

Objective

To analyze the clinical characteristics of familial nonmedullary thyroid carcinoma (FNMTC), in order to provide evidence for early diagnosis and treatment.

Methods

We retrospectively investigated the inpatients between September 2006 and September 2013 in the First Bethune Hospital of Jilin University, in which 78 patients with FNMTC from 31 families were analyzed by a comparison with 3445 control cases from the patients with sporadic nonmedullary thyroid carcinoma (SNMTC).

Results

There was no significant difference in gender, age, and tumor size between FNMTC and SNMTC patients. However, the characteristics of disease in multifoci, neck lymph node metastasis, invasion to the surrounding tissues, and coexistence with Hashimoto disease in two types of cancer patients show significant difference. They are: multifoci: 71.8 % (56/78) in FNMTC versus 46.3 % (1595/3445) in SNMTC; neck lymph node metastasis: 52.6 % (41/78) in FNMTC versus 33.3 % (1148/3445) in SNMTC; surrounding tissue invasion: 64.1 % (50/78) in FNMTC versus 48.5 % (1670/3445) in SNMTC; coexistence with Hashimoto disease: 30.8 % (24/78) in FNMTC versus 20.0 % (689/3445) in SNMTC.

Conclusion

Lymph node metastasis, multifoci, invasion to the surrounding tissues, and combination with chronic lymphocytic thyroiditis are the main features of FNMTC, which suggests the extent of the operation for FNMTC patients should be amplified properly.

     

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.     

Medullary Thyroid Carcinoma Metastasis to the Breast and Axillary Lymph Nodes

Breast metastases of medullary thyroid carcinoma (MTC) are extremely rare, and only a few cases have been reported in the literature so far. Here, we report a case of metastatic MTC to the breast and axillary lymph nodes (LN). The case illustrates that (1) metastatic MTC of the breast could be clinically and pathologically misdiagnosed as primary breast cancer, such as invasive lobular carcinoma with axillary LN involvement; (2) unlike other metastatic breast cancer patients, who have very poor prognoses, our patient survived for more than 5 years after the breast and axillary surgery; and (3) metastasis of MTC to the breast is accompanied by axillary LN metastasis, which requires thorough axillary LN dissection, as in most primary breast cancers.     

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。