胆囊结石患者癌前病变的相继出现以及杂合性缺失的积累提示其与胆囊癌存在因果关联。

Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer.

作者信息

Jain Kajal, Mohapatra Trilochan, Das Prasenjit, Misra Mahesh Chandra, Gupta Siddhartha Datta, Ghosh Manju, Kabra Madhulika, Bansal Virinder Kumar, Kumar Subodh, Sreenivas Vishnubhatla, Garg Pramod Kumar

机构信息

*Departments of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India †Indian Agricultural Research Institute, New Delhi, India; Departments of ‡Pathology §Surgery ¶Pediatrics (Genetics unit), and ‖Biostatistics, All India Institute of Medical Sciences, New Delhi, India.

出版信息

Ann Surg. 2014 Dec;260(6):1073-80. doi: 10.1097/SLA.0000000000000495.

DOI:10.1097/SLA.0000000000000495

PMID:24827397

Abstract

BACKGROUND

Causal association of gallbladder stones with gallbladder cancer (GBC) is not yet well established.

OBJECTIVE

To study the frequency of occurrence of preneoplastic histological lesions and loss of heterozygosity (LOH) of tumor suppressor genes in patients with gallstones.

METHODS

All consecutive patients with gallstones undergoing cholecystectomy from 2007-2011 were included prospectively. Histological examination of the gallbladder specimens was done for preneoplastic lesions. LOH at 8 loci, that is 3p12, 3p14.2, 5q21, 9p21, 9q, 13q, 17p13, and 18q for tumor suppressor genes (DUTT1, FHIT, APC, p16, FCMD, RB1, p53, and DCC genes) that are associated with GBC was tested from microdissected preneoplastic lesions using microsatellite markers. These LOH were also tested in 30 GBC specimens.

RESULTS

Of the 350 gallbladder specimens from gallstone patients, hyperplasia was found in 32%, metaplasia in 47.8%, dysplasia in 15.7%, and carcinoma in situ in 0.6%. Hyperplasia, metaplasia, and dysplasia alone were found in 11.7%, 24.6%, and 1.4% of patients, respectively. A combination of hyperplasia and dysplasia, metaplasia and dysplasia, and hyperplasia, metaplasia, and dysplasia was found in 3.4%, 6.3%, and 4.3% of patients, respectively. LOH was present in 2.1% to 47.8% of all the preneoplastic lesions at different loci. Fractional allelic loss was significantly higher in those with dysplasia compared with other preneoplastic lesions (0.31 vs 0.22; P = 0.042). No preneoplastic lesion or LOH was found in normal gallbladders.

CONCLUSIONS

Patients with gallstones had a high frequency of preneoplastic lesions and accumulation of LOH at various tumor suppressor genes, suggesting a possible causal association of gallstones with GBC.

摘要

背景

胆囊结石与胆囊癌（GBC）之间的因果关联尚未完全明确。

目的

研究胆结石患者癌前组织学病变的发生率以及肿瘤抑制基因杂合性缺失（LOH）情况。

方法

前瞻性纳入2007年至2011年间所有连续接受胆囊切除术的胆结石患者。对胆囊标本进行组织学检查以确定癌前病变。使用微卫星标记，从显微切割的癌前病变中检测与GBC相关的8个位点（即3p12、3p14.2、5q21、9p21、9q、13q、17p13和18q）的肿瘤抑制基因（DUTT1、FHIT、APC、p16、FCMD、RB1、p53和DCC基因）的LOH。这些LOH也在30个GBC标本中进行检测。

结果

在350例胆结石患者的胆囊标本中，增生的发生率为32%，化生为47.8%，发育异常为15.7%，原位癌为0.6%。单纯增生、化生和发育异常分别在11.7%、24.6%和1.4%的患者中发现。增生与发育异常、化生与发育异常以及增生、化生和发育异常同时存在的情况分别在3.4%、6.3%和4.3%的患者中发现。不同位点的所有癌前病变中，LOH的发生率在2.1%至47.8%之间。与其他癌前病变相比，发育异常患者的等位基因缺失分数显著更高（0.31对0.22；P = 0.042）。正常胆囊中未发现癌前病变或LOH。