Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations

Peter Chianchiano, Maryam Kherad Pezhouh, Amy Kim, Claudio Luchini, Andrew M Cameron, Matthew J Weiss, Jin He, Lysandra Voltaggio, Kiyoko Oshima, Robert A Anders, Laura Delong Wood

Research output: Contribution to journalArticle

Abstract

Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes—based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in our cohort, present in 71% of tumors analyzed. Mutations in the remaining genes occurred in less than 20% of analyzed tumors. We were able to determine the relatedness in 58% of the patients analyzed: MC occurred in 41% of patients, with 33% with exclusively MC and 8% with both MC and IM. IM occurred exclusively in 17% of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60% of patients with multifocal HCC.

Original languageEnglish (US)
Pages (from-to)127-134
Number of pages8
JournalHuman Pathology
Volume72
DOIs
StatePublished - Feb 1 2018

Fingerprint

Hepatocellular Carcinoma
Carcinogenesis
Neoplasm Metastasis
Mutation
Neoplasms
Genetic Promoter Regions
Genes

Keywords

  • Intrahepatic metastasis
  • Multicentric carcinogenesis
  • Multifocal hepatocellular carcinoma
  • Next-generation sequencing
  • Sanger sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

@article{7274c9dff6c5453ea06bdb6e7a7c2171,
title = "Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations",
abstract = "Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes—based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in our cohort, present in 71{\%} of tumors analyzed. Mutations in the remaining genes occurred in less than 20{\%} of analyzed tumors. We were able to determine the relatedness in 58{\%} of the patients analyzed: MC occurred in 41{\%} of patients, with 33{\%} with exclusively MC and 8{\%} with both MC and IM. IM occurred exclusively in 17{\%} of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60{\%} of patients with multifocal HCC.",
keywords = "Intrahepatic metastasis, Multicentric carcinogenesis, Multifocal hepatocellular carcinoma, Next-generation sequencing, Sanger sequencing",
author = "Peter Chianchiano and Pezhouh, {Maryam Kherad} and Amy Kim and Claudio Luchini and Cameron, {Andrew M} and Weiss, {Matthew J} and Jin He and Lysandra Voltaggio and Kiyoko Oshima and Anders, {Robert A} and Wood, {Laura Delong}",
year = "2018",
month = "2",
day = "1",
doi = "10.1016/j.humpath.2017.11.011",
language = "English (US)",
volume = "72",
pages = "127--134",
journal = "Human Pathology",
issn = "0046-8177",
publisher = "W.B. Saunders Ltd",

}

TY - JOUR

T1 - Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations

AU - Chianchiano, Peter

AU - Pezhouh, Maryam Kherad

AU - Kim, Amy

AU - Luchini, Claudio

AU - Cameron, Andrew M

AU - Weiss, Matthew J

AU - He, Jin

AU - Voltaggio, Lysandra

AU - Oshima, Kiyoko

AU - Anders, Robert A

AU - Wood, Laura Delong

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes—based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in our cohort, present in 71% of tumors analyzed. Mutations in the remaining genes occurred in less than 20% of analyzed tumors. We were able to determine the relatedness in 58% of the patients analyzed: MC occurred in 41% of patients, with 33% with exclusively MC and 8% with both MC and IM. IM occurred exclusively in 17% of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60% of patients with multifocal HCC.

AB - Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes—based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in our cohort, present in 71% of tumors analyzed. Mutations in the remaining genes occurred in less than 20% of analyzed tumors. We were able to determine the relatedness in 58% of the patients analyzed: MC occurred in 41% of patients, with 33% with exclusively MC and 8% with both MC and IM. IM occurred exclusively in 17% of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60% of patients with multifocal HCC.

KW - Intrahepatic metastasis

KW - Multicentric carcinogenesis

KW - Multifocal hepatocellular carcinoma

KW - Next-generation sequencing

KW - Sanger sequencing

UR - http://www.scopus.com/inward/record.url?scp=85040322682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040322682&partnerID=8YFLogxK

U2 - 10.1016/j.humpath.2017.11.011

DO - 10.1016/j.humpath.2017.11.011

M3 - Article

C2 - 29180252

AN - SCOPUS:85040322682

VL - 72

SP - 127

EP - 134

JO - Human Pathology

JF - Human Pathology

SN - 0046-8177

ER -