Fujii H, Zhu X G, Matsumoto T, Inagaki M, Tokusashi Y, Miyokawa N, Fukusato T, Uekusa T, Takagaki T, Kadowaki N, Shirai T
Department of Pathology II, Juntendo University School of Medicine, Tokyo, Japan.
Hum Pathol. 2000 Sep;31(9):1011-7. doi: 10.1053/hupa.2000.9782.
Combined hepatocellular-cholangiocarcinoma (combined HCC/ CC) is a rare form of liver neoplasms showing both hepatocellular (HCC) and bile duct differentiation (CC). In an attempt to clarify the clonality and genetic/phenotypic relationships in the evolution of these neoplasms, we microdissected multiple HCC and CC foci and studied allelic status of chromosome arms 1p, 1q, 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11q, 13q, 16q, 17p, 17q, 18q, and 22q. Overall, the highest frequency of loss of heterozygosity (LOH) was seen on 4q and 17p, followed by 8p and 16q. Of the 11 cases studied, 3 cases did not show any of the identical allelic losses between HCC and CC foci, indicating the biclonal nature. The remaining 8 cases showed multiple allelic losses shared between both components, strongly suggestive of a single clonal derivation. Moreover, 4 of the 8 cases showed additional or divergent allelic losses at more than 1 chromosomal locus only in HCC and/or CC foci. Thus, this heterogeneity was shown to affect the phenotypic diversity of the tumor. Summarizing the genetic patterns, combined HCC/CC could be classified into the following 3 possibilities: (1) collision tumor in which 2 independent neoplastic clones develop at close proximity; (2) single clonal tumor with homogeneous genetic background in both components--histological diversity is thus a manifestation of divergent differentiation potential of a single clone; (3) single clonal process in which genetic heterogeneity in the process of clonal evolution within the tumor parallels histologic diversity; therefore, the tumor in this category is mainly composed of mosaics of closely related subclones.
肝细胞-胆管细胞癌（HCC/CC混合型）是一种罕见的肝脏肿瘤，兼具肝细胞癌（HCC）和胆管分化（CC）特征。为了阐明这些肿瘤在发生发展过程中的克隆性以及基因/表型关系，我们对多个HCC和CC病灶进行了显微切割，并研究了染色体1p、1q、3p、4q、5q、6q、8p、9p、10q、11q、13q、16q、17p、17q、18q和22q臂的等位基因状态。总体而言，杂合性缺失（LOH）频率最高的是4q和17p，其次是8p和16q。在研究的11例病例中，有3例在HCC和CC病灶之间未显示任何相同的等位基因缺失，表明其为双克隆性质。其余8例在两个成分之间均显示出多个共享的等位基因缺失，强烈提示为单克隆起源。此外，8例中的4例仅在HCC和/或CC病灶中显示出在1个以上染色体位点的额外或不同的等位基因缺失。因此，这种异质性被证明会影响肿瘤的表型多样性。总结基因模式，HCC/CC混合型可分为以下三种可能性：（1）碰撞瘤，即两个独立的肿瘤克隆在相邻位置发生；（2）单克隆肿瘤，两个成分具有相同的基因背景，因此组织学多样性是单个克隆分化潜能不同的表现；（3）单克隆过程，肿瘤内克隆进化过程中的基因异质性与组织学多样性平行，因此，这类肿瘤主要由密切相关的亚克隆镶嵌组成。
