O Farrell Legacy UPDATE ON WHO NOMENCLATURE. World Health Organization, 2010 DISCLOSURES WITH EMPHASIS ON PROBLEM HEPATOCELLULAR TUMORS
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1 O Farrell Legacy UPDATE ON WHO NOMENCLATURE WITH EMPHASIS ON PROBLEM HEPATOCELLULAR TUMORS Linda Ferrell, MD University of California San Francisco Vice Chair, Director of Surgical Pathology World Health Organization, 2010 DISCLOSURES I have nothing to disclose. NEIL THEISE, MD 1
2 Key Updates Hepatocellular Adenoma (HCA) Variants Hepatocellular Carcinoma Variants Biliary Intraepithelial Neoplasia (BilIN) Biliary Cystic Neoplasms Hepatocellular Adenomas (HCA) New Classification includes 4 categories WHY DO YOU NEED TO KNOW? HCAs are not rare anymore Each subtype has specific clinical associations and treatment issues Adenoma (HCA): Historical Features Adenoma (HCA): Historical Histologic Features THE OLD VERSION of HCA A RARE lesion of women in child-bearing age with history of OCP Unusual to see 1-2/yr in big centers Rare risk of HCC Common risk of hemorrhagic complications Histology: bland cytology, intact reticulin framework, no mitoses, no ductules Reticulin framework intact, plate architecture and cytology mimics normal patterns 2
3 Adenoma (HCA) Variants of Today Variant 1 HCA: HNF1α-inactivated Variant 1. HNF1α-inactivated HCA Hallmark: Fatty change Variant 2. β-catenin mutated HCA Hallmark: Increased risk for HCC Variant 3. Inflammatory adenoma Hallmark: Obesity/metabolic syndrome association Others (Variant 4 +?) Hallmark: No specific trait Fatty change, large and small droplet Reticulin: small acinar changes Variant 1 HCA: HNF1α-inactivated Variant 1 HCA: HNF1α-inactivated Adenomatosis association: small foci of fatty change ( focal fatty change ) with increased CD34 (not shown) IHC feature: Negative for Liver Fatty Acid Binding Protein (LFABP) 3
4 Variant 1 HCA: HNF1α-inactivated Variant 2 HCA: B-catenin-mutated Summary of clinical features 10% with germline mutations, so can be familial, rarely in men Association with maturity-onset diabetes of the young type 3 (MODY3) Adenomatosis (defined as >10 lesions) No significant risk for HCC Rare, solitary adenomas with HIGH risk of HCC transformation Association with male hormone use Bioulac-Sage et al. HCA subtype classification using molecular markers and IHC: Hepatol 2007;46: Variant 2 HCA: B-catenin-mutated Variant 2 HCA: B-catenin-mutated High risk for HCC B-catenin nuclear staining Glutamine synthetase: Intense, diffuse staining HCC features illustrated here: Loss of reticulin Other features: cytologic atypia, pseudoglandular change 4
5 Variant 2 HCA: B-catenin-mutated High risk for HCC QUESTION: Are these really very well-differentiated, adenoma-like HCCs? Chromosomal studies suggest at least some reported cases are HCC from the outset But we don t know the entire story yet.. S Kakar, J P Grenert, V Paradis, N Pote, S Jakate MD, and L Ferrell. HCCs Arising in Adenomas: Similar Immunohistochemical and Cytogenetic Features in Adenoma and HCC Portions of the Tumor. MODERN PATHOL 2011; 25(Supple 2): 416A. Variant 3 HCA: Inflammatory type Formerly known as Telangiectatic FNH Histologic features include: Ill-defined borders, difficult to identify grossly Dilated sinusoids Focal inflammatory change around arteries Arteries can be in clusters Mild ductular reaction common in periarterial zones Variant 3 HCA: Inflammatory type Variant 3 HCA: Inflammatory type Gross: Slightly redder than background liver Poorly-defined borders, irregular edges Dilated sinusoids, focal inflammation around arteries Artery, inflammation, and ductules Can be difficult to identify radiographically and on gross 5
6 HCA, Inflammatory type: Ductules present with small arteries; hepatocyte cytology usually unremarkable. HCA, Inflammatory type: Ductule present in this zone with arteries Variant 3 HCA: Inflammatory type Variant 3 HCA: Inflammatory type Serum amyloid A (SAA) C-reactive protein (CRP) Clinical features include: Close association with obesity Also seen in males Age of presentation includes yrs Risk for hemorrhage increases with size, with significant diameter at 5 cm Adenomatosis may be common!! 6
7 Variant 3 HCA: Inflammatory type Other histologic features: Background liver with fat and/or SAA+ May also have increase risk for HCC 10% with Beta-catenin mutation Or could there be co-incidental adenoma and HCC occurrence related to metabolic syndrome and background fatty liver? NOTE: There is increased incidence of HCC in patients with fatty liver without cirrhosis! HCA: 4 th Category Remaining adenomas remain unclassified This category is a catch-all for others that don t fit into first 3 variants Account for <10% Other types may still be defined? HCA: Overview of Problems IMPORTANT: We don t know how big the problem is yet, and we don t know exact pathophysiology of these NEW lesions. Big liver centers will see these frequently Other centers may only see these infrequently?? May be difficult to get the experience to: Type variants: can be important (risk of HCC, multifocality, etc) Differentiate from FNH Differentiate from HCC HCAs: What should you do? How to process small biopsy samples: Look for history of obesity, diabetes, mass, fatty liver Don t do standard panel of Tri, iron, PAS, etc. Get unstained X 8-10 at first cut What stains can be done? Common: Reticulin, CD34, SAA, CK7, Beta-catenin Uncommon: Glutamine synthetase, CRP, LFABP Interpretation issues, especially on small biopsies: Many overlapping features with FNH and HCC 7
8 HCAs: What should you do? My Experience: 3 years of FNH and HCA biopsies and resections (>100) stained with full panels to see spectrum of overlapping and diagnostic features Well-differentiated HCC still can be difficult to exclude Diagnosis: Well-differentiated hepatocellular lesion Followup important/resection may be necessary Hepatocellular Carcinoma New recognition of increase risk of HCC associated with fatty liver disease New variants HCC: Special variants HCC: Special variants Lymphoepithelial EBV-associated Pleomorphic and/or small tumor cells with focal syncytial growth Most cases: tumor cells + for EBV Sarcomatoid Most cases contain foci of traditional HCC Complete involvement uncommon More common after therapy Variants not in WHO: Steatohepatitis-like Cirrhosis-like 8
9 HCC: Special variants HCC: Special variants Variants not in WHO: Steatohepatitis-like Cirrhosis-like Variants not in WHO: Steatohepatitis-like Cirrhosis-like Trichrome 9
10 Reticulin Cirrhosis-like HCC (Variant HCC with Multifocality) Cirrhosis-like HCC (in cirrhosis) Diagnostic problem both clinically and microscopically May also have large dominant mass and smaller, cirrhosis like satellite lesions Jakate Ferrell, et al. Diffuse Cirrhosis-like HCC. AJSP 2010; 34: HCC: ISSUES still remaining Variants not strictly defined Scirrhous (fibrosing variants, NOT fibrolamellar) How much fibrosis needed? HCC with K19+: more aggressive clinical course (Combined HCC/CC = Blue mucin and/or glands, K7 and K19+) Do we need to routinely do K19? How much K19+ is significant? Stem-cell-like lesions: small cells positive for stem-cell markers Ckit, CD133, EpCAM, K19 Are these important lesions to distinguish? Biliary Intraepithelial Neoplasia Nomenclature: BilIN 1-3 replacing dysplasia 10
11 BilIN has made it to PRIME TIME! Biliary Intraepithial Neoplasia: BilIN Applicable to all of biliary tree, including gallbladder Zen Y, et al.nakanuma Y. Biliary intraepithelial neoplasia: An international interobserver agreement study and proposal of the revised diagnostic criteria. Modern Pathology 20:701-9, 2007 Excellent images, with consensus from co-authors Consensus for WHO book, minus one person: MacSween book: dysplasia and BilIN both cited Criteria: Similar to PanIN Ex: BilIN3 Intraductal Papillary Neoplasms: IPN Biliary Cystic Neoplasms NEW NOMENCLATURE: Intraductal Papillary Neoplasia Mucinous Cystic Neoplasms Formerly known as intraductal papillomas, papillomatosis, or papillary adenocarcinoma Similar to Intraductal Papillary Mucinous Neoplasms of Pancreas in histologic variants and clinical behavior Classify: low/intermediate, or high grade intraepithelial neoplasia Examine for invasive adenocarcinoma 11
12 Intraductal Papillary Neoplasm: IPN Intraductal Papillary Neoplasm: IPN Gross Intraductal Papillary Neoplasm: IPN Intraductal Papillary Neoplasm: IPN Low/ Intermediate Grade High grade High grade High grade 12
13 Mucinous Cystic Neoplasm (MCN) Mucinous Cystic Neoplasm (MCN) Similar to Pancreas MCN histologically and clinically Women, ovarian-like stroma Classify: low/intermediate, or high grade intraepithelial neoplasia Sample generously to exclude adenocarcinoma, but no definitive amount stated for submission These tumors should be extensively sampled for microscopy, especially in areas of papillary projections and mural nodules. GROSS Mucinous Cystic Neoplasm (MCN) Other changes Infantile hemangioma: nomenclature change from hemangioendothelioma New addition: Calcifying nested epithelial stromal tumor as mixed/uncertain origin Inflammatory Pseudotumor remains in liver as a reactive lesion, both inflammatory and infectious causes 13
14 WHO: Approach to diagnosis Algorithms Solid versus cystic Hepatocytic versus glandular Metastatic tumors and IHC 14
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