Kalzitoninbestimmung zur Frühdiagnose des medullären Schilddrüsenkarzinoms

Calcitonin is considered to be a sensitive marker for medullary thyroid cancer (MTC) therefore early detection and surgical treatment may help to improve the clinical prognosis of MTC. Routine calcitonin measurement has therefore been recommended in the diagnostic evaluation of patients with nodular thyroid disease. In the case of elevated serum calcitonin (>20 pg/ml) stimulation testing is recommended to improve the predictive power for MTC particularly in patients with small nodules. Serum calcitonin measurement cannot reliably discriminate between micro-MTC (<10 mm) and C cell hyperplasia. In patients with stimulated calcitonin levels exceeding 100 pg/ml thyroidectomy is recommended because of a high inherent risk of MTC. Highly elevated basal and stimulated serum calcitonin levels are strongly suggestive of MTC with practical implications for surgical management.     

甲状腺结节患者常规行血清降钙素检查对早期发现甲状腺髓样癌的临床价值

目的:探讨甲状腺结节患者血清降钙素(Ct)检测对甲状腺髓样癌(MTC)的诊断价值。方法:回顾性分析2016年10月—2017年8月1922例因甲状腺结节就诊于郑州大学第一附属医院甲状腺外科并行手术治疗的患者资料。所有患者术前均常规行血清Ct检测,术后均有明确的常规病理结果。分析Ct水平与MTC的关系、用受试者工作特征曲线分析Ct对MTC的诊断效能。结果:在1922例甲状腺结节患者中,新发现的MTC患者有12例(0.62%)。在术前血清Ct值为10~100pg/mL的155例、100~500pg/mL的12例和500pg/mL的10例中,术后确诊为MTC的分别为1例(0.65%)、1例(8.33%)和9例(90.00%)。在血清Ct500pg/mL的9例MTC患者中,有8例(88.89%)出现了不同程度的颈部淋巴结转移。血清Ct诊断MTC的截断值为258.5pg/mL,敏感性为90.91%,特异性为96.99%。结论:术前常规检测血清Ct有助于MTC的早期诊断,对患者接受彻底的手术治疗,避免二次手术有十分重要的意义。     

血清降钙素在甲状腺髓样癌全程管理中意义与应用

降钙素（Ctn）是一种参与骨钙代谢的多肽类激素,主要由甲状腺滤泡旁细胞分泌。甲状腺髓样癌（MTC）起源于甲状腺滤泡旁细胞,可大量分泌Ctn。Ctn是MTC最敏感的血清学标记物之一,对于MTC的诊断、术前和术后的评估和管理均有重要意义：（1）对甲状腺结节病人进行Ctn筛查可早期诊断MTC,有助于改善预后。（2）术前Ctn水平与肿瘤恶性程度有关,可辅助决定手术范围。（3）术后随访中监测Ctn可用于预测复发风险,早期发现并处理转移病灶。随着对MTC认识的增加和检测技术的改善,Ctn在各国相关临床指南中的地位也逐渐提升。然而,目前Ctn的检测仍缺乏明确的截断值,Ctn检测的假阳性率较高,并且尚缺乏Ctn筛查的卫生经济学获益证据。对细针穿刺针洗脱液进行Ctn检测可一定程度上提升诊断的准确率,有望成为新的临床切入点。相信通过未来更多研究,Ctn检测在MTC全程管理中的应用框架将日益完善。     

血清降钙素在甲状腺髓样癌全程管理中意义与应用

降钙素（Ctn）是一种参与骨钙代谢的多肽类激素,主要由甲状腺滤泡旁细胞分泌。甲状腺髓样癌（MTC）起源于甲状腺滤泡旁细胞,可大量分泌Ctn。Ctn是MTC最敏感的血清学标记物之一,对于MTC的诊断、术前和术后的评估和管理均有重要意义：（1）对甲状腺结节病人进行Ctn筛查可早期诊断MTC,有助于改善预后。（2）术前Ctn水平与肿瘤恶性程度有关,可辅助决定手术范围。（3）术后随访中监测Ctn可用于预测复发风险,早期发现并处理转移病灶。随着对MTC认识的增加和检测技术的改善,Ctn在各国相关临床指南中的地位也逐渐提升。然而,目前Ctn的检测仍缺乏明确的截断值,Ctn检测的假阳性率较高,并且尚缺乏Ctn筛查的卫生经济学获益证据。对细针穿刺针洗脱液进行Ctn检测可一定程度上提升诊断的准确率,有望成为新的临床切入点。相信通过未来更多研究,Ctn检测在MTC全程管理中的应用框架将日益完善。     

C-cell cancer – prevention and treatment

Introduction: C-cell cancer of the thyroid or medullary thyroid carcinoma (MTC) exists in a sporadic and a hereditary form, the latter of which is part of the multiple endocrine neoplasia type-2 (MEN-2) syndromes. Discussion: MTC metastasises early to local (lymph nodes) and distant sites (liver, lung, bone). Therefore, early detection is mandatory to enable a chance of cure. In sporadic MTC, the sensitive tumour marker calcitonin enables detection of the disease at an early stage. In hereditary MTC, more than 95% of the patients have germline RET mutations. Thus, MEN-2 has become the paradigm for the practice of molecular medicine, and gene carriers can be identified before MTC even occurs. Surgery is the only chance of cure and recently developed surgical techniques provide the therapeutic prerequisite to achieve calcitonin normalisation in both sporadic and hereditary MTC. Received: 19 November 1998 Accepted: 25 November 1998     

Urine calcitonin as a test for medullary thyroid cancer: a new screening procedure.

Although the radioimmunoassay of serum calcitonin (CT) has facilitated the diagnosis of medullary thyroid cancer (MTC) one may encounter patients whose basal serum levels of CT are normal or nearly normal. In such cases clinicians have utilized intravenous stimulation tests such as calcium or pentagastrin to obtain a diagnostic increase in serum CT. We have reported finding immunoreactive CT in the urine of man and have found it to be a useful technique for the diagnosis and study of patients at risk for MTC or other hypercalcitonemic diseases. Using basal urine CT alone we were able to separate 73% of patients at risk for MTC into clearly normal or abnormal groups. For the remaining 27% a stimulation test with subsequent determination of urine CT was required. The radioimmunoassay of urine CT is a simple, reliable, accurate test for the screening diagnosis of MTC. A protocol for the screening workup of a patient at risk for MTC is given.     

Importance of Early Screening and Prophylactic Thyroidectomy in Asymptomatic Nonindex RET Germline Carriers

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and ≥ 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (≥ 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r= 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.     

Useful and limits of the biochemical markers for the diagnosis of thyroid carcinoma

A series of biochemical parameters are useful for the diagnosis and follow-up of differentiated thyroid carcinomas. The measurement of serum thyroglobulin (Tg) is considered for the post-surgical/radioiodine follow-up of papillary/follicular carcinomas. Other than in basal conditions, the importance of Tg levels during TSH stimulation is underlined, either by discontinuation of L-T4 therapy or by recombinant human TSH test. The finding of undetectable Tg levels during TSH stimulation is highly correlated with clinical remission; otherwise, peak Tg levels > 1-2 ng/ml can be suggestive of recurrence/persistence of the disease. The accuracy of Tg measurements for the detection of metastases seems to be higher when compared to 131-1 whole-body scan. The evaluation of basal serum calcitonin levels is recommended for the screening of medullary thyroid carcinoma (MTC). High basal levels suggest the presence of a tumor but a calcitonin increase can be observed also in parafollicular C cell hyperplasia (CCH) and other extra-thyroidal conditions. The pentagastrin test can by pass this obstacle as the calcitonin response seems to be typical of pathological thyroid C cells. The cut-off value of calcitonin response between patients with MTC and CCH remains to be established; the latter condition, however, being considered by some authors as pre-cancerous. After thyroid surgery the measurement of calcitonin constitutes a valid tool for the detection of cure and/or recurrence of the disease. The screening by means of RET oncogene analysis is also described for patients with MTC with Multiple Endocrine Neoplasia (MEN) type 2 syndrome.     

Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma

Lymph node metastases have been proven to be the main prognostic factor in medullary thyroid carcinoma (MTC). This retrospective study was undertaken to evaluate the efficiency of two surgical techniques of regional lymph node dissection with regard to the normalization of pentagastrin-stimulated serum calcitonin level and patient survival: selective lymphadenectomy, i.e., the excision of macroscopically or microscopically involved lymph nodes, versus a systematic lymphadenectomy performed by the new technique of a compartment-oriented microdissection. From 1970 to 1990, 82 patients with sporadic (n=57) and hereditary (n=25) MTC underwent a total of 142 operations including 63 selective lymphadenectomies and, since 1986, 35 systematic lymphadenectomies. The study revealed that in node-positive MTC the rate of interventions with a postoperative normalization of pentagastrin-stimulated serum calcitonin was higher after systematic lymphadenectomy (29.2%) than after selective lymphadenectomy (8.5%) (P<0.01). The rate of patients undergoing repeat surgery due to a recurrence of MTC was 48% after selective lymphadenectomy and 10% after systematic lymphadenectomy. Survival was significantly better for patients after systematic versus selective lymphadenectomy (P<0.005). This study thus emphasizes that systematic lymphadenectomy, using the technique of a compartment-oriented microdissection of cervicomediastinal lymph nodes, represents the preferred surgical treatment as well as the optimum technique in primary as well as secondary node-positive MTC.     

Multiple endocrine neoplasia II A syndrome: relationship between age of the patient, levels of basal calcitonin and size of the thyroid tumor]

This paper presents our experience in four families having the multiple endocrine neoplasia (MEN) II-A syndrome, with a total of 19 affected patients. All had medullary thyroid carcinoma (MTC), 6 also had pheochromocytoma (PH) and 3 had hyperparathyroidism. The screening of the members of the families to measure basal and pentagastrin response calcitonin (CT) serum levels allowed an early diagnosis of medullary thyroid carcinoma, when lesions were only 1 mm in diameter. Measurement of vanillymandelic acid, catecholamines and metanephrines in 24-hour urine collections allowed the diagnosis of pheochromocytoma in patients, some of whom were asymptomatic. A clear relationship was found between the age of the patients, the basal serum calcitonin level and size of the MTC.     

Differential diagnosis of calcitonin-secreting neuroendocrine carcinoma of the foregut by pentagastrin stimulation

BACKGROUND AND AIMS: This study assessed the suitability of pentagastrin stimulation in hypercalcitoninaemia for differential diagnosis of neuroendocrine carcinoma of the foregut. PATIENTS: A prospective institutional study (March 1997-September 1999) was conducted involving all patients admitted to the pneumological and general surgical wards for small cell lung cancer (SCLC) or primary medullary thyroid carcinoma (MTC). Basal and stimulated serum calcitonin levels were measured using an improved immunoradiometrical assay for the monomeric form of calcitonin. RESULTS: Increased basal calcitonin levels were noted in six non-MTC patients (one mediastinal and one laryngeal neuroendocrine carcinoma, and four SCLCs). Because of chronic renal failure, one SCLC patient had to be excluded. The remaining five non-MTC patients with normal renal function were compared to eight primary MTC patients. In terms of pentagastrin stimulation, an increase in serum calcitonin levels of less than twofold the baseline significantly correlated with both non-MTC (r=0.85; P=0.005) and SCLC (r=0.81; P=0.024). Immunostaining of tissue specimens for calcitonin was positive in the patients with mediastinal and laryngeal neuroendocrine carcinoma and in all eight patients with primary MTC, but was negative in the two SCLC patients with adequate tissue samples. CONCLUSIONS: Irrespective of the pathophysiological background, pentagastrin stimulation affords a differential diagnosis in neuroendocrine carcinoma of the foregut when chronic renal failure is excluded.     

甲状腺髓样癌术后的病情监测

目的 研究判断甲状腺髓样癌（ＭＴＣ）患者手术是否成功以及残二定位的方法。方法 对１４例ＭＴＣ术后的患者进行了钙负荷－降钙素激发试验,并检测血癌胚怕（ＣＥＡ）、胃泌素（ＧＳＴ）、肠血管活性肽（ＶＩＰ）,同时对降钙素增高的患者进行生长抑素受体核素显像。结果 １４例２钙负荷－降钙素激发试验后降钙素峰值均升高,其中７例２降钙素基因值异常升高（６９．７－１６６９．１ｎｇ／Ｌ）,峰值更高;对其７例进一步进行Ｓ     

甲状腺髓样癌的超声特征分析

目的:总结甲状腺髓样癌（medullary thyroid cancer, MTC）的超声特征并分析其对MTC诊断的临床价值。方法:回顾性分析2013年4月至2018年11月郑州大学第一附属医院甲状腺外科收治并经手术确诊的91例MTC患者（共103个结节）,其中男36例,女55例,收集其术前超声影像学特征及血清降钙素水...     

Unilateral Surgery Supported by Germline RET Oncogene Mutation Analysis in Patients with Sporadic Medullary Thyroid Carcinoma

Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.     

Familial nonmultiple endocrine neoplasia medullary thyroid carcinoma: an evolving clinical entity.

BACKGROUND. A rare kindred of familial nonmultiple endocrine neoplasia medullary thyroid carcinoma arising from a 73-year-old proband case is reported to further define this distinct entity. METHODS. Twenty-four family members across four generations, four with medullary thyroid carcinoma (MTC) and two with C-cell hyperplasia (CCH), were studied. RESULTS. Basal calcitonin levels were elevated in three patients with MTC and were normal in one patient with microscopic MTC and two patients with CCH who had persistent subtle elevation in calcium and/or pentagastrin-stimulated calcitonin levels. One patient had unilateral MTC without CCH. Associated abnormalities included papillary carcinoma (2), thyroiditis (4), adenoma (2), and colloid nodule (1). Minimum treatment was total thyroidectomy. Two patients with MTC and marked hypercalcitonemia have recurrent disease at 2.5-year and 11-year follow-up. Two patients with MTC and normal or minor elevations in basal calcitonin and two with CCH had normal provocative calcitonin testing at 6 to 18 months follow-up. CONCLUSIONS. Unilateral MTC without CCH and MTC in the elderly do not preclude a familial cause. Microscopic MTC or CCH may be seen with subtle elevations in stimulated calcitonin levels, and recognition allows for curative thyroidectomy. Other apparent dominant thyroid pathologic conditions may occur concomitantly with familial medullary thyroid carcinoma and thus routine calcitonin, and immunohistochemical testing should be performed in patients with an appropriate family history.     

The value of thyroid peroxidase immunohistochemistry for preoperative fine-needle aspiration diagnosis of the follicular variant of papillary thyroid cancer

BACKGROUND: With the use of May-Grunwald-Giemsa staining, cytologic features of the follicular variant of papillary thyroid cancers (FVPTCs) on thyroid fine-needle aspiration (FNA) often resemble those of hyperplastic and adenomatous nodules. Detection of reduced staining after thyroid peroxidase (TPO) immunohistochemistry with monoclonal antibody MoAb47 has been shown to be a helpful diagnostic marker. The purpose of this study was to assess the value of TPO immunohistochemistry for the diagnosis of FVPTC. METHODS: Of 3505 patients with adequate FNA samples, 1576 patients underwent surgical procedures. Histologic examination of the surgical specimen demonstrated papillary thyroid cancer in 227 cases, including 42 FVPTCs (18%). The diagnostic accuracy of standard thyroid FNA and TPO immunohistochemistry, which we use routinely, was compared in these 42 FVPTCs. RESULTS: Standard FNA allowed accurate diagnosis of malignancy in 32 of the 42 FVPTCs and in 170 of the 185 typical papillary thyroid cancers. TPO-immunohistochemistry staining was accurate in all 42 FVPTCs and in 182 of 185 typical PTCs. CONCLUSIONS: FVPTC is a frequent source of false-negative results on standard thyroid FNA. This study shows that TPO immunostaining accurately demonstrates malignancy in these tumors.     

Surgical management of sporadic medullary thyroid cancer

Inherited and sporadic medullary thyroid cancer (MTC) is a rare carcinoma. Sporadic MTCs represent 70% of cases. Diagnosis is currently made with the routine use of serum calcitonin (CT) measurements to screen patients with nodular thyroid disease. Surgery is the only curative treatment of MTC and since cervical lymph nodes metastases are frequent and can occur at an early stage, a standardized lymph node dissection should be associated to total thyroidectomy. However, the extent of lymphadenectomy remains debated. Prognosis of MTC is related to both the stage of the disease and the extent of initial surgery. When tumor remnants persist after surgery, there are very few therapeutic alternatives, and these are generally of limited curative value.     

Hypercalcitoninemia in thyroid conditions other than medullary thyroid carcinoma: a comparative analysis of calcium and pentagastrin stimulation of serum calcitonin

Purpose

Calcitonin screening aims at uncovering occult medullary thyroid cancer (MTC) in patients with nodular thyroid disease. Elevated basal calcitonin serum levels call for calcitonin stimulation, the level of which may direct the extent of surgery. Because pentagastrin has become restricted, calcium has increasingly been used instead for stimulation. This study identified a new spectrum of patients demonstrating a false-positive hypercalcitoninemia in the absence of C-cell disease, carrying multinodular goiter (MNG), thyroiditis, and non-MTC thyroid malignancy, and endeavored to explore the feasibility of extrapolating pentagastrin-stimulated to calcium-stimulated calcitonin thresholds.

Methods

Altogether, 43 (9.5 %) of 455 patients with nodular thyroid disease revealed increased basal calcitonin serum levels between 2005 and 2012, for which they underwent intravenous stimulation with pentagastrin (31 patients) or calcium gluconate (12 patients) before and after primary thyroidectomy.

Results

Stimulation with calcium gluconate resulted in significantly higher and more variable preoperative calcitonin serum levels after 2 (241.2 vs. 104.9 pg/mL; P?=?0.018) and 5 min (240.6 vs. 87.4 pg/mL; P?=?0.007) than stimulation with pentagastrin. Stimulation with calcium gluconate produced 10-fold (nodular goiter), 15-fold (thyroiditis), and 21-fold (thyroid neoplasia other than MTC) calcitonin increases over baseline, as opposed to 5-fold, 10-fold, and 8-fold increases after stimulation with pentagastrin. None of the 43 patients, all of whom reverted to undetectable calcitonin serum levels after thyroidectomy, had immunohistochemical evidence of C-cell disease. Subgroup analyses according to gender and thyroid disease, being limited by the low number of patients in each subgroup, did not yield significant differences.

Conclusions

Calcium stimulation yields significantly greater calcitonin levels than pentagastrin stimulation, precluding generalization of pentagastrin-stimulated to calcium-stimulated calcitonin thresholds. After calcium stimulation, false-positive findings appear to be more common in patients of female gender and patients with thyroiditis and thyroid neoplasia other than MTC, potentially effecting surgical overtreatment.     

Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas.

BACKGROUND: This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). METHODS: Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. RESULTS: Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P = .011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P = .005). CONCLUSIONS: Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC.     

甲状腺髓样癌诊治难点及对策

甲状腺髓样癌预后较差,早期易发生转移。遗传性和散发性髓样癌具有不同临床特征和预后。超声、CT、MRI、骨显像具有特定的诊断价值。降钙素具有诊断特异性,而癌胚抗原有助于评估病情进展。无论遗传性还是散发性髓样癌,均应重视后续的基因检测。遗传性和散发性髓样癌需制定不同的手术策略。颈部局部复发转移的病人应积极手术治疗。晚期进展性髓样癌可进行姑息性手术、外放射治疗或采用酪氨酸激酶抑制剂的全身性治疗。术后监测降钙素和癌胚抗原的倍增时间评估复发和转移。