Surgery for lymph node metastases of medullary thyroid carcinoma: A review

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells that occurs in hereditary and sporadic clinical settings. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation, and therefore surgery is the most effective option for curative therapy, reduction in tumor burden, or effective palliation. In patients undergoing preventative surgery for hereditary MTC, central lymph node dissection should be considered if the calcitonin level is elevated. Preservation of parathyroid function in these young patients is of paramount importance. In patients with established primary tumors, systematic surgical removal of lymph node basins (compartmental dissection) should be guided by ultrasound mapping of lymph node metastases and level of serum calcitonin. A “berry‐picking” approach is discouraged. Newly approved targeted molecular therapies offer wider treatment options for patients with progressive or metastatic disease. Cancer 2016;122:358–366. © 2015 American Cancer Society.     

甲状腺髓样癌的超声成像特征分析及诊断价值评价

目的:分析甲状腺髓样癌（medullary thyroid carcinoma,MTC）的超声特征,研究并探讨超声成像对甲状腺髓样癌的诊断价值。方法:选取来我院就诊的49例甲状腺髓样癌（MTC）患者的68枚结节,与同期随机选取的60例甲状腺乳头状癌（papillary thyroid carcinoma,PTC）的82枚结节做对比,分析两者的二维超声特点、剪切波弹性成像(shear wave elastography,SWE)的各参数及颈部淋巴结转移情况,病灶均有手术及病理评估。结果:MTC声像图表现为低回声（73.5%）,边界清楚（50.0%）,纵横比＜1（89.7%）,结节内伴钙化（60.2%）,结节内存在血流（58.8%）,合并颈部淋巴结转移（55.1%）;与PTC相比,MTC多表现为结节较大,边界清楚,纵横比＜1,结节内存在血流,结节内钙化多为粗大钙化,易发生淋巴结转移（P<0.05）。MTC的SWE各参数为Emax(48.4±19.1)kPa,Emean(32.3±14.5）kPa。淋巴结超声检查,MTC可疑淋巴结22例,诊断准确率为81.5%。结论:MTC既具有恶性结节的一般特点,又有相对特异的超声表现,超声成像对MTC的早期诊断及手术治疗有较大的参考依据。     

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.     

甲状腺髓样癌颈部淋巴结转移的预测模型

目的:构建甲状腺髓样癌(medullary thyroid carcinoma,MTC)颈部淋巴结转移情况的临床预测模型,个体化预测术前淋巴结转移概率.方法:回顾性筛选美国国立癌症研究所"监测、流行病学和结果"数据库(Surveillance,Epidemiology,and End Results,SEER)中的20...     

Lymph node management in clinically node-negative patients with papillary thyroid carcinoma

Aims

Systematic lymph node dissection in patients with papillary thyroid carcinoma (PTC) remains controversial. The objective of this study was to study the pattern of lymph node spread in patients with PTC clinically node-negative and then to propose a lymph node management strategy.

Methods

We retrospectively reviewed the records of patients who had undergone total thyroidectomy and a systematic central neck dissection (CND) and lateral neck dissection. Ninety patients with PTC without lymph nodes metastases (LNM) detected on preoperative palpation and ultrasonographic examination were included.

Results

Forty-one patients (45.5%) had LNM. Twenty-eight patients (31%) had a central and a lateral involvement. Thirteen patients (14.5%) had only a central involvement. All the patients without LNM in the central compartment were also free in the lateral compartment. There was no correlation between LNM status and TNM staging.The largest LNM in the central compartment was smaller than or equal to 5 mm in 66% of the cases, and that could explain the lack of sensitivity of the preoperative ultrasonographic examination.

Conclusion

CND could be considered at preoperative or intraoperative diagnosis of PTC whereas lateral neck dissection should be performed only in patients with preoperative suspected and/or intraoperatively proven LNM. Systematic CND allows an objective evaluation of lymph node status in this central cervical area where the LNM are particularly small and difficult to detect preoperatively.     

Sentinel lymph node biopsy as guidance for central neck dissection in patients with papillary thyroid carcinoma

BACKGROUND.

Occult lymph node metastasis of papillary thyroid carcinoma (PTC) can be detected by sentinel lymph node (SLN) biopsy, but studies in larger patient cohorts undergoing complete central neck dissection may be required to assess the diagnostic accuracy of SLN. Therefore, the authors prospectively assessed the usefulness of SLN biopsy for the detection of central lymph node metastasis in patients with differentiated PTC who had no suspicious cervical lymphadenopathy.

METHODS.

After peritumoral injection of methylene blue, SLN biopsy was performed in 50 patients with newly diagnosed PTC who had no palpable or ultrasound (US)‐detected lymph node involvement. After SLN biopsy, all patients underwent total thyroidectomy and central neck dissection. The diagnostic accuracy of intraoperative SLN sampling was calculated by comparison with the final pathologic diagnosis.

RESULTS.

SLNs were identified in 46 of 50 patients (92%); of these, 14 SLNs were positive and 32 SLNs were negative on intraoperative frozen sections. One patient had a positive SLN in the jugular region and subsequently underwent modified radical neck dissection. Final pathologic examination revealed that 18 patients (36%), including 4 who had negative SLNs, had central lymph node metastasis. Thus, the sensitivity, specificity, accuracy, and positive and negative predictive values of SLN biopsy were 77.8%, 100%, 92%, 100%, and 88.9%, respectively. Temporary and permanent hypocalcemia developed in 19 patients and 1 patient, respectively. There were no direct complications of SLN sampling.

CONCLUSIONS.

SLN biopsy in patients with PTC without gross clinical or US lymph node involvement was able to detect occult metastasis with high accuracy and may have the potential to select patients who require central neck dissection. Cancer 2008. © 2008 American Cancer Society.     

Use of preoperative lymphoscintigraphy and intraoperative gamma-probe detection for identification of the sentinel lymph node in patients with papillary thyroid carcinoma

Aims

Lymph node metastases for papillary thyroid carcinoma are associated with an increased incidence of locoregional recurrence. The use of preoperative lymphoscintigraphy and intraoperative gamma probe detection to localize the sentinel lymph node in papillary thyroid carcinoma was investigated.

Methods

From February 2004 to December 2005 the sentinel lymph node technique was studied in 64 consecutive patients with cytological evidence of papillary thyroid carcinoma. The day before surgery, patients were submitted to US-guided peri-tumoural injection of the radiotracer and a lymphoscintigraphy was performed. In the operating room a total thyroidectomy was done, and thanks to a hand-held gamma probe the sentinel lymph node and all lymph nodes, belonging to the sentinel node compartment, were removed.

Results

The gamma probe identified the sentinel lymph node in 62 patients (96.8%). We found 48 (77.5%) sentinel lymph node without metastases; 12 (19.3%) with metastases and 2 (3.2%) with micrometastases. In 7 cases (11.3%), with a negative sentinel lymph node, metastases in other nodes of the same region were recorded. In 22 cases (34.3%) the ultrasound give an erroneous indication (P = 0.004). Five patients (8.0%), 4 with multifocal cancer, had a positive postoperative lymphoscintigraphy.

Conclusion

This study shows that the sentinel lymph node technique for papillary thyroid carcinoma is feasible, repeatable, and more accurate than preoperative ultrasound. In cases of multifocal thyroid lesions more patients should be enrolled to establish the utility of the radio-guided technique.     

Predictive factors for detecting malignancy in central and lateral cervical lymph nodes in papillary carcinoma of the thyroid

Aim: To determine the factors for predicting malignant diagnosis and limitations in ultrasonography guided fine‐needle aspiration cytology of central and lateral cervical lymph nodes in patients with primary differentiated thyroid papillary carcinoma. Methods: Biopsies of cervical lymph nodes were performed in 120 patients, 31 of whom had subsequent surgical diagnoses. Factors examined were patient's age and gender of the patients, location (central and lateral compartments), hypoechogenicity with loss of hilum, microcalcification, cystic feature, minimum and maximum diameters and index value (minimum/maximum diameter). Results: The mean minimum diameter and index value of the lymph nodes were 9.9 ± 4.9 mm and 0.60 ± 0.19, respectively. Microcalcifications and cystic parts were specific findings with rates of 93.9% and 95.1%, respectively. Microcalcification, cystic feature, minimum diameter and index value were poor predictors of malignancy. The predictors were central location (P = 0.031) and hypoechogenicity with loss of hilum in lateral neck (P = 0.019). Central nodes led to a major problem for biopsy success due to postoperative changes and anatomic position. Nondiagnostic (30%) nodes were therefore mostly central. Conclusion: The involvement of the central neck should be a major indication of lymph node biopsy and pathological diagnosis regardless of the imaging findings. In the lateral compartment, hypoechogenicity with loss of hilum, microcalcifications, cystic parts and an index value ≥ 0.51 are indications of a lymph node biopsy to rule out malignancy.     

甲状腺乳头状癌颈淋巴结转移规律与手术方式的选择

目的:从甲状腺乳头状癌颈部淋巴结转移规律探讨其最佳手术方式.方法:回顾性分析我院近三年367例甲状腺乳头状癌(papillary thyriod carcinoma,PTC)根治术患者的临床及病理资料.结果:颈淋巴结总转移率为77.11%(283/367),中央区(VI区)转移率为 70.30%(258/367),颈侧区(Ⅱ、Ⅲ、Ⅳ、Ⅴ区)转移率为 62.67%(230/367),颈侧区中的Ⅱ区转移率最高60.49%(222/367).发病年龄、原发灶个数、肿瘤是否累及被膜、癌灶直径、肿瘤边界是否清晰、癌灶位置、超声血流信号分级、癌症是否合并桥本氏甲状腺炎或结节性甲状腺肿对颈部淋巴结转移的影响差异均有统计学意义(P<0.05);性别因素及癌灶是否钙化对颈部淋巴结转移的影响差异无统计学意义(P>0.10),经logistic回归分析发现,肿瘤是否累及被膜对颈部淋巴结转移的影响因素最大.结论:VI区是甲状腺乳头状癌最常见的转移部位,术中应常规清除,其次依次为Ⅱ、Ⅲ、Ⅳ、Ⅴ区.对于患者原发肿瘤若累及包膜、或多发病灶、或癌灶直径>1 cm及患者发病年龄<45岁等应同时做颈侧区清扫.     

Study of Calcitonin and Calcitonin Gene-related Peptide in Patients with Medullary Thyroid Carcinoma

Objective To provide a basis for treatment and prognosis for MTC patients by investigating CT and CGRP. Methods Fifty-eight cases of MTC were selected and the relationship between the CT levels and metastasis was investigated. An immunohistochemical method was used to detect the expression of CT and CGRP in the 58 samples of MTC tissues. The CT and CGRP of new MTC inpatients were measured before operation and in the first few days after operation using a radioimmunoassy. Results 1) The metastatic rate of cervical lymph nodes was a significantly different between the normal serum CT group and the elevated group (P<0. 01). 2) The rate of residual tumor was significantly different between the normal serum CT group one month after operation and the elevated group at the same period (P<0.01).3) In the immunohistochemical study we found the positive rate of CT was about 98%, and the CGRP was 87.8%. 4) Part of the patients had an elevated CGRP level while CT levels were normal. 5) The serum CT levels dropped to a stable range one week after operation. Conclusion The CT levels are a useful index to evaluate the probability of cervical lymph node metastasis and the efficacy of surgical treatment. Measurement of the serum CGRP is an aid for the diagnosis of MTC, especially for those patients whose preoperative CT levels are normal. This work was supported by the Natural Science Foundation from the Tianjin Government.     

Predictive value of tumor thickness for cervical lymph‐node involvement in squamous cell carcinoma of the oral cavity

BACKGROUND:

Tumor thickness (TT) appears to be a strong predictor for cervical lymph‐node involvement in squamous cell carcinoma of the oral cavity (OSCC), but a precise clinically optimal TT cutoff point has not been established. To address this question, the authors conducted a meta‐analysis.

METHODS:

All relevant articles were identified from MEDLINE and EMBASE as well as from cross‐referenced publications cited in relevant articles. Lymph‐node involvement was confirmed and identified as positive lymph‐node declaration (P_LND) by either pathologic positivity on immediate neck dissection or by neck recurrence identified after follow‐up ≥2 years. Odds ratios (OR) were calculated to quantify the predictive value of TT. Negative predictive values (and the percentage of patients falsely predicted to not have P_LND [FN‐P_LND]) were compared to determine the optimal TT cutoff point.

RESULTS:

Sixteen studies were selected from 72 potential studies, yielding a pooled total of 1136 patients. Data were examined for the following TT cutoff points: 3 mm (4 studies, 387 patients), 4 mm (9 studies, 778 patients), 5 mm (6 studies, 367 patients), and 6 mm (4 studies, 488 patients). The OR (95% CI) was 7.3 (5.3‐10.1) for the overall group. The proportion of FN‐P_LND was 5.3% (95% CI, 2.0‐11.2), 4.5% (2.6‐7.2), 16.6% (11.5‐22.8), and 13.0% (9.7‐16.9) for TT<3, <4, <5, and <6 mm, respectively. There was a statistically significant difference between the 4‐mm and 5‐mm TT cutoff points (P = .007).

CONCLUSIONS:

TT was a strong predictor for cervical lymph‐node involvement. The optimal TT cutoff point was 4 mm. Cancer 2009. © 2009 American Cancer Society.     

基础水平降钙素与甲状腺髓样癌颈淋巴结转移相关临床研究(附48例临床分析)

目的　研究基础水平降钙素与甲状腺髓样癌颈淋巴结转移规律及对治疗的作用。方法　自 1989年 5月至 1997年 10月对我院外科治疗的 48例甲状腺髓样癌进行基础水平降钙素检测 ,并分析其和手术范围的关系。结果　48例甲状腺髓样癌中 3 6例行甲状腺癌颈淋巴结清除术 ;8例行甲状腺癌局部广泛切除术 ;4例行患侧甲状腺叶加峡叶切除术。 48例甲状腺髓样癌中 ,基础水平降钙素正常者 2 0例 ,术后病理检查发现淋巴结阳性者 4例 ,淋巴结转移率为2 0 %。基础水平降钙素升高者 2 8例 ,术后病理检查淋巴结阳性者 2 7例 ,淋巴结转移率 96.4%。结论　基础水平降钙素与甲状腺髓样癌颈淋巴结转移呈正相关。升高时 ,应行颈淋巴结清除术。基础水平降钙素正常时临床上无颈淋巴结转移的病人 ,可暂行患侧甲状腺叶加峡叶切除 ,术后紧密随访 ,并予以基础水平降钙素监测。     

Detection of metastatic thyroid carcinoma by 99mTc-pertechnetate in the presence of hyperfunctioning thyroid tissue

Neck metastases secondary to thyroid cancer are rarely visualized scintigraphically in the presence of a functioning thyroid gland. We present a patient with cervical lymph node metastases that take up 99mTc pertechnetate in the presence of hyperfunctioning thyroid tissue and discuss the pathophysiology of this phenomenon.     

Genetic analysis of single disseminated tumor cells in the lymph nodes and bone marrow of patients with head and neck squamous cell carcinoma

Considering the limited information on the biology and molecular characteristics of disseminated tumor cells (DTCs) in head and neck squamous cell carcinoma (HNSCC), we examined the genomic alterations in DTCs from HNSCCs and their potential clinical relevance. To analyze both the lymphatic and hematogenous routes of tumor cell dissemination, we investigated samples from lymph nodes (LNs) and bone marrow (BM) of 49 patients using immunofluorescence double staining for epithelial cells expressing cytokeratin 18 (KRT18) and/or epithelial cell adhesion molecules (EpCAM, CD326). The identified marker‐positive cells were isolated by micromanipulation followed by single‐cell whole‐genome amplification and metaphase‐based comparative genomic hybridization (mCGH) to determine genome‐wide copy number alterations. The findings were correlated with clinical parameters and follow‐up data. We detected chromosomal aberrations in KRT18‐ and EpCAM‐positive cells from both compartments; BM‐derived cells showed a significantly higher percentage of aberrant genome (PAG) per cell than cells detected in LNs. No significant association was found between DTC data and clinical follow‐up. Genomic profiling of BM‐DTCs revealed genomic alterations typical for HNSCC, suggesting hematogenous dissemination of subclones around the time of surgery. In contrast, DTC data in LNs revealed that several marker‐positive cells were not of malignant origin, indicating the presence of epithelial glandular inclusions in parts of the processed neck LN samples. Therefore, DTC detection of LNs in the neck based only on epithelial markers is not advisable and requires detection of chromosomal instability (CIN), gene mutations, or additional markers, which have yet to be identified. Nevertheless, our investigation paves the way for larger studies to focus on HNSCC BM‐DTCs with high‐resolution methods to gain deeper insights into the biology of hematogenous metastasis in this cancer.     

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。     

Delphian 淋巴结与甲状腺乳头状癌临床关系的研究进展

Delphian淋巴结作为Ⅵ区淋巴结的一部分,依据最新国外研究数据显示,其在甲状腺乳头状癌（ PTC）中转移发生率可高达20％左右,而Ⅵ区淋巴结通常被认为是PTC转移的前哨淋巴结,多数学者认为,呈高表达率的Delphian淋巴结在PTC疾病发展过程中可能具有某些特定的临床意义。本文旨在对Delphian淋巴结与甲状腺乳头状癌临床关系的研究进展进行综述。     

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.     

甲状腺癌纵隔淋巴结转移的外科处理

目的评价甲状腺癌上纵隔淋巴清扫的意义。方法回顾性分析1984年至1998年期间,我科收治的79例甲状腺癌上纵隔淋巴清扫患者的临床资料。58例（73．4％）为乳头状甲状腺癌,14例（17．7％）为甲状腺髓样癌,7例（8．9％）为滤泡状甲状腺癌。随诊终止日期为2003年12月。结果经颈上纵隔淋巴清扫62例,胸骨部分劈开上纵隔淋巴清扫10例,全胸骨劈开上纵隔淋巴清扫7例。79例中,3例患者仅行上纵隔清扫,未做颈清扫;76例患者中完成93个颈清扫,47例发生气管旁淋巴结转移。总的5年和10年累积生存率分别为64．6％和63．1％。10例发生上纵隔淋巴结复发,9例死于上纵隔病变,11例发生术后并发症。结论在甲状腺癌上纵隔淋巴结转移的患者中,乳头状甲状腺癌最常见。上纵隔淋巴清扫安全有效,可以改善患者的生活质量,延长患者的生存时间。