A LIVER TUMOR WITH AN IDENTITY CRISIS

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1 A LIVER TUMOR WITH AN IDENTITY CRISIS Stephen M. Lagana MD Assistant Professor of Pathology Columbia University Medical Center New York, NY USA Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. I have no relevant financial disclosures Thomas Starzl, MD. Died on March 3, 2017 CASE HISTORY Elderly female ETOH user, but not known to have cirrhosis Abdominal fullness LFT normal 4-5 lesions in the liver with 5.7cm dominant nodule PET CT otherwise normal Biopsy obtained 1

2 Differential Diagnosis, take 1 Histological features of HCC and ChCa (or Met PB Adca) Obviously malignant Obviously carcinoma Not obviously primary or secondary IHC markers of common sites of metastasis negative TTF1 CDX2 PAX8 GATA3 Main considerations: HCC Intrahepatic cholangiocarcinoma (ChCa) Metastatic pancreatobiliary adenocarcinoma Features that favor HCC Cells quite pink Somewhat trabecular No definite gland formation No definite mucin production Features that favor ChCa Extensively fibrotic tumor stroma Wouldn t swear that there are no glands No bile identified 2

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4 Conclusion Preserved portal tract (different case) Scirrhous variant of hepatocellular carcinoma Rare Cords and nests of neoplastic cells in dense fibrous stroma {Matsuura 2005} Cells have hepatoid morphology Must NOT have mucin production Mucin is a feature of adenocarcinoma, not HCC Seems to have similar clinical features and prognosis as traditional HCC Distinction from traditional HCC probably not relevant for clinical care (as of today) Distinction from ChCa and metastatic disease critical Ancillary testing General theme-expresses markers of hepatic and biliary differentiation Need some HCC marker; would not make dx without at least 1 convincing marker Must not produce mucin (should be proven) Newer markers such as albumin ISH and bile salt export pump not yet investigated In my experience, these have both been positive in 2 of 2 cases Immunohistochemistry {Krings 2013} GPC3 and ARG combined for 100% sensitivity {Lagana 2012} Differential Diagnosis, deeper dive Combined HCC-ChCa Should have biphasic morphology Populations should stain distinctively Combined hepatocellular-cholangiocarcinoma with stem cell features, intermediate cell type According to WHO 2010, the cells are small, oval-shaped, with hyperchromatic nuclei and scant cytoplasm Scirrhous HCC cells look like HCC Scirrhous HCC does not express much C-KIT or CD56 {Krings 2013} Fibrolamellar HCC Very different patient population (kids, young adults), no cirrhosis Recent discovery of a chimeric kinase due to a deletion on Ch.19 resulting in DNAJB1-PRKACA transcript {Honeyman 2014} Detectable by PCR, FISH, and mrna ISH {Graham 2015} Newer markers in liver tumors Bile Salt Export Pump Present exclusively in hepatocytes at the bile canaliculus Main driver of bile salt efflux from hepatocyte Genetic lack of BSEP causes PFIC2 4

5 Additional studies on BSEP BSEP was diluted to 1:200 vs. 1:100 and incubation was 15m compared to 32m {Nguyen 2015} Low grade HCC, BSEP High grade HCC High grade HCC, BSEP {Lagana 2015} {Fujikura 2016} Conclusions regarding BSEP Seems to be most specific marker for HCC Due to lack of expression in other cell types/carcinomas, do not need canalicular pattern to consider positive Though usually canalicular Sensitivity is good overall, but drops with worsening differentiation Need to optimize in your lab Useful as part of a panel In-situ hybridization for albumin Targets mrna for albumin Commercially available kit which runs on automated platform Positive HCC, excellent sensitivity (92 of 93 HCC) {Shahid 2015} Intrahepatic cholangiocarcinoma Highly sensitive {Ferrone 2016} Less highly sensitive {Avadhani, USCAP 2017, #1657}, {Lehrke, USCAP 2017, #1680} Bile duct adenomas {Moy 2016} Hepatoblastoma, fibrolamellar HCC {Koehne de Gonzalez USCAP 2016, #1667} Negative Most other cancers (including PDAC, Distal CBD, Klatskin) {Ferrone 2016} Pitfalls Pancreatic acinar carcinoma {Askan 2016} Occasional adca of diverse sites {Lehrke, USCAP 2017, #1680} Albumin ISH in ChCa Conclusions regarding albumin ISH Excellent sensitivity for HCC Probably good sensitivity for intrahepatic ChCa? kit, other factors This multispecificity means cannot help differentiate HCC from ChCa Cannot discriminate BDA vs. ChCa Evolving understanding of pitfalls 5

6 Approach to PD liver tumors Careful H&E assessment, consideration of clinical hx Keep the basics in mind (mucin, bile) Keep the pitfalls in mind Let the amount of tumor determine your work-up No silver bullets Cost of ancillary testing in pathology is a rounding error in cancer care Need to build a base of experience with these tests If limited tumor, get 20 serial blanks with occasional H&E (Bl 10&20) Steve s Preferred Approach (based on literature, experience, and the quirks of our lab). *Combining steps perfectly reasonable HCC stains 1 st line Any Arginase, GPC3, BSEP 2 nd line HepPar, CD10, pcea, AFP Any If all HCC markers, but albumin +, consider IH ChCa. However, if 7/19 and mucin negative, consider undifferentiated carcinoma, favor primary. If albumin and HCC markers negative, consider PD/undiff carcinoma, favor secondary and give ddx based on remainder of markers/histology. PD Tumor Carcinoma Exclude metastasis Albumin ISH Mucin HCC Consider variants. If fibrotic and expresses biliary CK, consider scirrhous HCC. If pediatric, consider FL HCC CK (pan), CK8/18, LMWCK, CK5, CK7, CK19, CK20, S100, HMB45, CD45, CKIT. Let s assume some CK positivity TTF1, GATA3, PAX8, NKX3.1, CDX2. Let s assume not obviously metastatic Positivity favors HCC or IH ChCa. PDAC, Klatskin generally negative IH ChCa R/O combined HCC/Cholangio If lacks classic histo of HCC & ChCa, consider stem cell markers References 1. Askan G, Deshpande V, Klimstra DS, Adsay V, Sigel C, Shia J, et al. Expression of Markers of Hepatocellular Differentiation in Pancreatic Acinar Cell Neoplasms: A Potential Diagnostic Pitfall. Am J Clin Pathol. 2016;146(2): Ferrone CR, Ting DT, Shahid M, Konstantinidis IT, Sabbatino F, Goyal L, et al. The Ability to Diagnose Intrahepatic Cholangiocarcinoma Definitively Using Novel Branched DNA Enhanced Albumin RNA In Situ Hybridization Technology. Ann Surg Oncol. 2016;23(1): Fujikura K, Yamasaki T, Otani K, Kanzawa M, Fukumoto T, Ku Y, et al. BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas. Am J Surg Pathol. 2016;40(5): Graham RP, Jin L, Knutson DL, Kloft Nelson SM, Greipp PT, Waldburger N, et al. DNAJB1 PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015;28(6): Honeyman JN, Simon EP, Robine N, Chiaroni Clarke R, Darcy DG, Lim, II, et al. Detection of a recurrent DNAJB1 PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174): Jensen K, Krusenstjerna Hafstrom R, Lohse J, Petersen KH, Derand H. A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin fixed, paraffin embedded specimens: analytical performance measuring HER2. Mod Pathol. 2017;30(2): Krings G, Ramachandran R, Jain D, Wu TT, Yeh MM, Torbenson M, et al. Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. Mod Pathol. 2013;26(6): Lagana SM, Moreira RK, Remotti HE, Bao F. Glutamine synthetase, heat shock protein 70, and glypican 3 in intrahepatic cholangiocarcinoma and tumors metastatic to liver. Appl Immunohistochem Mol Morphol. 2013;21(3): Lagana SM, Salomao M, Remotti HE, Knisely AS, Moreira RK. Bile salt export pump: a sensitive and specific immunohistochemical marker of hepatocellular carcinoma. Histopathology. 2015;66(4): Matsuura S, Aishima S, Taguchi K, Asayama Y, Terashi T, Honda H, et al. 'Scirrhous' type hepatocellular carcinomas: a special reference to expression of cytokeratin 7 and hepatocyte paraffin 1. Histopathology. 2005;47(4): Moy AP, Arora K, Deshpande V. Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma. Histopathology. 2016;69(3): Nguyen T, Phillips D, Jain D, Torbenson M, Wu TT, Yeh MM, et al. Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma. Arch Pathol Lab Med. 2015;139(8): Shahid M, Mubeen A, Tse J, Kakar S, Bateman AC, Borger D, et al. Branched chain in situ hybridization for albumin as a marker of hepatocellular differentiation: evaluation of manual and automated in situ hybridization platforms. Am J Surg Pathol. 2015;39(1):