Characterizing the Histologic Morphology of Liver Cancer: Creating a Formalin Fixed Paraffin Embedded Tissue Repository Tamar Taddei, MD

Background Hepatocellular carcinoma is rising in incidence globally, and tripled in the US in over the last three decades It is the 3rd most common cause of cancer-related death worldwide (700,000 deaths/year) HCC is the leading cause of death in cirrhosis WHO – Liver Cancer 2008; El –Serag NEJM 2011, Ryerson et al. Cancer 2016

Incidence/Mortality: HCC vs Others SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute.

HCC Deaths in the “Birth Cohort” Ryerson et al. Cancer 2016

Opportunities and Challenges HCC is the only solid organ tumor that can be diagnosed by radiographic imaging alone Because of this, there is a paucity of tissue for analysis, hampering efforts at developing large repositories Most repositories are representative of early stage cancer and consist entirely of liver resection or explant specimens 85% of HCC in the US is unresectable at diagnosis; 50% present at advanced stages

Opportunities and Challenges Few repositories are morphologically annotated; most clinical annotation cannot match the depth we can offer HCC is a heterogeneous disease and tumor morphology/tumor milieu may give us unique insights into this disease Large genetic studies of HCC have shown no clear, targetable oncogenic addiction loop, so the field is moving to examining the tumor microenvironment

Tumor Heterogeneity Tumor Milieu H HCC F Clear cell HCC Scirrhous HCC Here are three distinct tumor morphologies. In the first slide, the intersection of hepatocytes (H), a band of collagen fibrosis (F), and the tumor (HCC) all intersect. Clear cell HCC Scirrhous HCC Steatotic HCC Mitchell J Clin Gastro 2013

Logistics of Sample Acquisition Identifying tumors and their location (station) Identifying a willing participant (pathologist) Applying for approval (amendment to VACS, IRB protocol, IRB waivers, waiver of non-engagement) Developing a curated list from review of pathology reports Negotiating tissue blocks and/or slides Making shipping as easy as possible

Logistics of Sample Tracking A system to label specimens uniquely Block and slide review for routine and immunohistochemical staining Monitoring the movement of the specimen from pathologist, to research lab for staining, to two pathologists for independent review, then follow-up of additional stains if required Return of block/slides to originating institution, or archive if return is not required Significant station variability!

Logistics of Pathology Review Two pathologists (K. Mitchell-Richards, X. Zhang) Careful histologic and morphologic annotation Several meetings to determine key features to capture in tumor and background, essential stains (e.g. CD4, CD8), and definitions to allow concordant reporting

Pathology Database

Goals and Progress 6 VACS sites participating 10 other stations engaged in discussion, of which 2 have a waiver of non-engagement Tracking and pathology database complete Shipping, receiving, and flow of specimen from arrival to return or archive has been mapped and tested 11 specimens obtained and in the process of review Goal: 250 specimens