Jayakody S, Reagh J, Bullock M, Aniss A, Clifton-Bligh R, Learoyd D, Robinson B, Delbridge L, Sidhu S, Gill A J, Sywak M
University of Sydney Endocrine Surgical Unit, Suite 202, AMA House, 69 Christie St, St Leonards, Sydney, NSW, 2065, Australia.
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
World J Surg. 2018 May;42(5):1432-1439. doi: 10.1007/s00268-018-4551-8.
Medullary thyroid cancer (MTC) is a rare tumour of neuroendocrine origin with a more aggressive profile than differentiated thyroid cancer. Familial cases of MTC are associated with RET mutations whilst RAS mutations appear to be a frequent finding in RET negative tumours. The aims of this study were to analyse survival outcomes in MTC and to evaluate the role of RAS immunohistochemistry in the identification of sporadic disease.
A retrospective cohort study of consecutive patients with MTC was undertaken. The primary outcome measures were overall survival and disease-free survival. Survival analysis was performed on the basis of sporadic and familial disease. Patients had routine RET testing using the capillary (Sanger) sequencing method. Histopathological MTC slides from 100 patients were tested for HRASQ61R, a common somatic RAS mutation in MTC, with mutation-specific immunohistochemistry (IHC).
A total of 195 patients had surgical treatment of MTC in the period 1980 to 2016. There were 83 males and 112 females with a mean age of 53.0 years. A total of 39 (20%) patients had familial disease. Sporadic cases had a higher median pre-op calcitonin (969.5 vs. 257.5 pg/ml), greater mean primary tumour size (23.5 vs. 12.5 mm) and more distant metastases (12.8 vs. 10.3%). Multivariate analysis showed age (p = 0.005), Multiple Endocrine Neoplasia Type 2 (MEN2) status (p = 0.021) and distant metastasis (p = 0.002) to be significant independent predictors of survival. Significant independent predictors for disease-free survival were age (p = 0.015), MEN2 (p = 0.002), pre-op calcitonin (p = 0.033) and venous invasion (p = 0.001). The overall 5-year survival was 100% for familial MTC and 78% for sporadic MTC. The 10-year disease-free survival was 94% for familial MTC and 61% for sporadic cases. A total of 100 cases of MTC underwent mutation-specific IHC for HRASQ61R. Of these, 18 had confirmed MEN2. IHC had 100% specificity in excluding MEN2. Twelve (12%) of 100 patients stained positive for HRASQ61R mutation.
In the era of genetic testing, RET status significantly influences disease-specific survival in MTC. Mutation-specific IHC for HRASQ61R may have a role in the identification of patients presenting with sporadic disease.
髓样甲状腺癌（MTC）是一种罕见的神经内分泌起源肿瘤，其侵袭性强于分化型甲状腺癌。MTC的家族性病例与RET突变相关，而RAS突变似乎是RET阴性肿瘤中常见的发现。本研究的目的是分析MTC的生存结果，并评估RAS免疫组化在散发性疾病识别中的作用。
对连续的MTC患者进行回顾性队列研究。主要结局指标为总生存期和无病生存期。根据散发性和家族性疾病进行生存分析。患者使用毛细管（桑格）测序法进行常规RET检测。采用突变特异性免疫组化（IHC）对100例患者的MTC组织病理切片进行HRAS Q61R检测，HRAS Q61R是MTC中常见的体细胞RAS突变。
1980年至2016年期间共有195例患者接受了MTC手术治疗。其中男性83例，女性112例，平均年龄53.0岁。共有39例（20%）患者患有家族性疾病。散发性病例术前降钙素中位数较高（969.5 vs. 257.5 pg/ml），原发肿瘤平均大小较大（23.5 vs. 12.5 mm），远处转移更多（12.8% vs. 10.3%）。多因素分析显示年龄（p = 0.005）、2型多发性内分泌腺瘤病（MEN2）状态（p = 0.021）和远处转移（p = 0.002）是生存的重要独立预测因素。无病生存期的重要独立预测因素为年龄（p = 0.015）、MEN2（p = 0.002）、术前降钙素（p = 0.033）和静脉侵犯（p = 0.001）。家族性MTC的总体5年生存率为100%，散发性MTC为78%。家族性MTC的10年无病生存率为94%，散发性病例为61%。共有100例MTC病例接受了HRAS Q61R的突变特异性IHC检测。其中，18例确诊为MEN2。IHC在排除MEN2方面具有100%的特异性。100例患者中有12例（12%）HRAS Q61R突变染色呈阳性。
在基因检测时代，RET状态显著影响MTC的疾病特异性生存。HRAS Q61R的突变特异性IHC可能在散发性疾病患者的识别中发挥作用。
