Lin Xiaoqi, Finkelstein Sydney D, Zhu Bing, Silverman Jan F
Department of Pathology, Feinberg School of Medicine, Northwestern Memorial Hospital, Northwestern University, 251 East Huron Street, Feinberg Building 7-209C, Chicago, Illinois 60611, USA.
J Mol Endocrinol. 2008 Oct;41(4):195-203. doi: 10.1677/JME-08-0063. Epub 2008 Jul 15.
Papillary thyroid carcinoma (PTC) frequently presents as a multifocal process. To study the importance of separating independent primary (IP) from intrathyroid metastatic (ITM) PTC, we examined 19 molecular markers on 42 separate tumors from 18 multifocal PTC cases. In 12 of 18 (66.7%) cases, including 6 of 12 (50%) papillary microcarcinoma cases, the same or similar profile of loss of heterozygosities (LOH) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation was demonstrated, indicating that they were from the same primary and represented ITM. Different profiles of LOHs and BRAF mutation were detected in separate tumors of 6 of 18 cases, indicating that they represented IP. Patients with ITM, including papillary microcarcinoma, had significantly increased lymph node metastasis. The frequencies of LOHs of 17q21, 17p13, 10q23, and 22q13 were higher in tumors with lymph node metastasis, suggesting that these LOHs may be important in increased lymph node metastasis. LOH of 9p21 was found at the highest frequency in PTC (53.8%), followed by 1p36 (46.2%), 10q23 (34.6%), and 22q13 (34.6%). Papillary microcarcinoma had acquired similar genomic mutations as conventional PTC, but higher frequencies of mutations of BRAF, 1p36, 18q, and 22q13 were found in the larger PTC, suggesting that they might play a role in the aggressiveness of PTC. Different profiles of mutations were observed in conventional, follicular variants, and diffuse sclerosing variant of PTC, which might influence the different morphological appearances and clinical courses. In conclusion, molecular analysis can separate multifocal IP PTC from ITM PTC, and may be more important than tumor size in predicting lymph node metastasis, aggressiveness, and prognosis of PTC.
甲状腺乳头状癌（PTC）常呈多灶性病变。为研究区分甲状腺内独立原发灶（IP）与甲状腺内转移灶（ITM）性PTC的重要性，我们对18例多灶性PTC病例的42个独立肿瘤进行了19种分子标志物检测。在18例中的12例（66.7%），包括12例中的6例（50%）甲状腺微小癌病例中，检测到相同或相似的杂合性缺失（LOH）和v-raf鼠肉瘤病毒癌基因同源物B1（BRAF）突变谱，表明它们来自同一原发灶，代表ITM。在18例中的6例的不同肿瘤中检测到不同的LOH和BRAF突变谱，表明它们代表IP。包括甲状腺微小癌在内的ITM患者淋巴结转移显著增加。17q21、17p13、10q23和22q13的LOH频率在有淋巴结转移的肿瘤中更高，提示这些LOH可能在淋巴结转移增加中起重要作用。9p21的LOH在PTC中出现频率最高（53.8%），其次是1p36（46.2%）、10q23（34.6%）和22q13（34.6%）。甲状腺微小癌获得了与传统PTC相似的基因组突变，但在较大的PTC中发现BRAF、1p36、18q和22q13的突变频率更高，提示它们可能在PTC的侵袭性中起作用。在PTC的传统型（经典型）、滤泡亚型和弥漫硬化亚型中观察到不同的突变谱，这可能影响不同的形态表现和临床病程。总之，分子分析可区分多灶性IP型PTC与ITM型PTC，且在预测PTC的淋巴结转移、侵袭性和预后方面可能比肿瘤大小更重要。
