Liver Specialty Evening Conference. Matthew M. Yeh, MD, PhD Professor of Pathology Adjunct Professor of Medicine University of Washington, Seattle

Transcription

1 Liver Specialty Evening Conference Matthew M. Yeh, MD, PhD Professor of Pathology Adjunct Professor of Medicine University of Washington, Seattle

2 Case History A 65 year-old man presents with abdominal pain and abnormal liver tests. Images of the abdomen reveals a liver mass. History of non-invasive low-grade urothelial carcinoma 2 months ago, s/p TURP. No underlying liver diseases or cirrhosis. AFP: Normal.

3 MR Images in Arterial Phase Non-cirrhotic liver with segment 8/4 lesion. Arterial phase hyperenhancment. Courtesy of Dr. Neeraj Lalwani, UWMC, Seattle

4 MR Images in Venous Phase Non-cirrhotic liver with segment 8/4 lesion. Subtle washout on venous phase. Courtesy of Dr. Neeraj Lalwani, UWMC, Seattle

5 MR Images in Delayed Phase Non-cirrhotic liver with segment 8/4 lesion. Delayed phase also shows subtle washout on venous phase. Courtesy of Dr. Neeraj Lalwani, UWMC, Seattle

6 MR Coronal Image in the Delayed Phase Non-cirrhotic liver, lesion within segment 8/4 associated with PV thrombosis. Suspicion of liver primary vs. metastasis Courtesy of Dr. Neeraj Lalwani, UWMC, Seattle

7 Case A CT-guided liver biopsy was performed.

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14 Differential Diagnosis Benign liver lesions Hepatocellular Biliary Miscellaneous Malignant liver lesions Primary Hepatocellular Biliary Other Metastatic

15 Differential Diagnosis Benign liver lesions Hepatocellular Biliary Miscellaneous Malignant liver lesions Primary Hepatocellular Biliary Other Metastatic

16 6 th most common cancer

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18 Hepatocellular Carcinoma Risk Factors Traditional HBV Cirrhosis Alcohol Aflatoxin Recently Recognized HCV Metabolic syndrome and obesity Hemochromatosis Alpha-1-antitrypsin deficiency Hepatocellular adenoma

19 Malignant Liver Neoplasms in Non-Cirrhotic Liver Modified from Dr. Zachary Goodman, with permission

20 Malignant Liver Neoplasms in Cirrhosis Modified from Dr. Zachary Goodman, with permission

21 Differential Diagnosis of HCC in Liver Biopsy in Background of Cirrhosis Cirrhotic nodules Macroregenerative nodules HGDN Cholangiocarcinoma Combined hepatocellular cholangiocarcinoma Metastatic neoplasm

22 Differential Diagnosis of HCC in Liver Biopsy in Background of Non-Cirrhotic Liver Metastatic neoplasm Focal nodular hyperplasia Hepatocellular adenoma Fibrolamellar carcinoma Cholangiocarcinoma Combined hepatocellular cholangiocarcinoma Neuroendocrine neoplasm

23 Histopathology of HCC Evidence of hepatocytic differentiation Neoplastic cells resemble hepatocytes Canaliculi +/- bile Pseudoglandular/pseudoacinar and/or trabecular pattern Evidence of malignancy Lack of normal structures Thickened trabecula or plates Increased unpaired arteries Focal absence of reticulin fibers Increased N/C ratio

24 Pseudoglands in HCC

25 In the Era of Affordable Care Diagnosis of HCC in Liver Biopsy Helpful Features for Hepatocytic Differentiation Bile Mallory-Denk bodies Alpha-1-antitrypsin globules Fat Iron free foci But, they are not always there

26 Diagnostic Feature for Hepatocytic Differentiation: Bile Mallory-Denk bodies

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28 Diagnostic Feature for Hepatocytic Differentiation: A1AT globules

29 Iron Free Foci in HCC Cirrhosis HCC HCC

30 Diagnosis of HCC Immunohistochemistry CK7 (+/-), CK19(+/-) and CK20 (-) Hepatocytic differentiation Alpha fetoprotein (AFP) Hepatocyte specific antigen (Hep Par 1) Glypican-3 Arginase 1 (ARG1) Canalicular staining pattern Polyclonal CEA CD10 Villin Activation of sinusoidal endothelial cells in hepatocytic neoplasm CD34 CD31

31 Polyclonal CEA: Canalicular Staining Pattern

32 CD10 Canalicular Staining Pattern

33 Hep Par 1 Staining Can Be Focal in HCC

34 CD34 cirrhosis FNH HCC CC

35 CD34 Staining in HCC May be Focal

36 CD34 in Cirrhosis Periseptal Staining

37 Hepatocellular Adenoma HCC Reticulin Stain

38 Well-Differentiated HCC Reticulin Stain

39 Reticulin Stain

40 Fatty liver may be misdiagnosed as HCC due to reticulin loss From Singhi et al. Am J Surg Pathol 2012

41 Glypican-3 to Distinguish HCC from Benign Hepatocellular Lesions Glypican-3 (GPC3) A cell surface proteoglycan has been shown to be overexpressed in HCC. To distinguish HCC from benign hepatocellular mass/lesion, and to some extent, from other malignancies

42 Glypican-3 HCC Cirrhosis

43 Glypican-3

44 Diagnostic Pitfalls of GPC3 Focal immunoreactivity can be detected in a small subset of cirrhotic nodules. Also positive in Melanoma SCC of lung non-seminomatous GCT Well Differentiated HCC can be negative. Expression in HCC can be focal. Specificity issue Sensitivity issue GPC-3 expression rate in various types of hepatocellular nodules in the pooled series of 10 studies.

45 Glypican-3 Moderately-Differentiated HCC Well-Differentiated HCC

46 Sensitivities of IHC Markers in HCC, CC, and Metastatic Carcinoma HCC CC Metastatic Adenocarcinoma Hep Par % ~12% ~14% GPC % ~19% ~6% pcea 50-96% NA NA MOC31 ~14% % % CK7 7-20% % ~36% CK8/18 ~70% ~20% NA CK19 10% or more 44-80% ~64% CK20 ~5% ~11% ~74% CD34 ~95% NA NA From Chan E and Yeh MM, Clin Liv Dis 2010

47 Arginase (ARG1): A manganese metalloenzyme active in the urea cycle Diagnosis of HCC Arginase-1 Marker for hepatocytes and hepatocellular neoplasms. Yan et al, Am J Surg Pathol 2010;34:

48 Arginase-1 HCC Liver

49 Arginase-1 in HCC

50 HepPar1 Arg-1 GPC3

51 It s not a Perfect World Hepatoid adenocarcinomas from nonhepatic sites: 4 of 13 (31%) were positive for arginase-1. Reis H et al, Pathology 2015

52 Sensitivity, specificity, positive and negative predictive value of Arginase-1, HepPar-1 for the diagnosis of HCC Sensitivity Specificity PPV NPV Arginase-1 84% 96% 95% 85% HepPar-1 70% 84% 81% 73% Arginase-1 or HepPar-1 84% 80% 88% 83% Arginase-1 and HepPar-1 70% 100% 100% 77% Radwan and Ahmed Diagnostic Pathology 2012

53 Arg1, HepPar-1 and GPC3 in FNA specimen Diagnosis Arg1 (%) HepPar-1 (%) GPC3 (%) HCC (n=29) 23 (79) 24 (83) 24 (83) Metastasis (10.7) (n=28) Benign (n=5) 5 (100) 5 (100) 0 Timek DT et al, AJCP 2012

54 Antibody Arg1, HepPar-1 and GPC3 in FNA specimen Well to moderately differentiated HCC (n=22) Arg-1 20(91) 3(43) HepPar1 20(91) 4(57) GPC3 20 (91) 5 (71) 3 markers positive 17 (77) 2 (29) 2 markers positive 4 (18) 2 (29) 1 marker positive 1(5) 2 (29) Negative for all 3 markers 0 1 (14) Moderately to poorly differentiated HCC (n=7) Timek DT et al, AJCP 2012

55 Use of GPC3 and Arg-1 in Scirrhous Hepatocellular Carcinoma Krings G et al., Modern Pathology 2013

56 Hep Par 1, GPC3, and Arg-1 stainings of scirrhous HCC, classical HCC and ICC Scirrhous HCC (n=20) Classical HCC (n=169) Cholangiocarcinoma (n=16) P-value (scirrhous vs classical HCC) P-value (scirrhous HCC vs CC) HepPar1 (%) GPC3 (%) Arg-1 (%) < <0.001 <0.001 Krings G et al., Modern Pathology 2013

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58 Chromogranin Synaptophysin

59 Hep Par 1 TTF-1 Thyroglobulin

60 In Situ Hybridization for Albumin messenger RNA (Albumin ISH) for Hepatocytic Differentiation Clear cell HCC: 93% (N=30). HCC: 93% (N=42), combined use with Hep Par 1 reaches 100%. Sensitivity for HCC AFP 30-50% GCT Other tumors commonly positive Hep Par 1 >90% Lung, colon, esophageal, gastric CD10 pcea Cytoplasmic 60-90% staining in adenoca GPC % NSGCT, melanoma Arg-1 96% Rare Albumin ISH >95% None Oliveira et al, AJSP 2000 Kakar el al, AJCP 2003 From Shahid et al, AJSP 2015

61 Current Case

62 Hep Par 1

63 Arginase-1

64 Arginase-1

65 Arginase-1

66 CD34

67 CK7

68 CK19

69 CK19

70 Sensitivities of IHC Markers in HCC, CC, and Metastatic Carcinoma HCC CC Metastatic Adenocarcino ma Hep Par % ~12% ~14% GPC % ~19% ~6% pcea 50-96% NA NA MOC31 ~14% % % CK7 7-20% % ~36% CK8/18 ~70% ~20% NA CK19 10% or more 44-80% ~64% CK20 ~5% ~11% ~74% CD34 ~95% NA NA Chan and Yeh, 2010

71 CK7 in Classic HCC

72 CK7 in Fibrolamellar Carcinoma

73 More stains? Mucin stain: Moc-31 stain:

74 More stains? Mucin stain: Negative Moc-31 stain: Negative

75 Additional stains were performed at original institute to exclude other sites Urothelial Lung Adrenal Colonic Prostate Neuroendocrine

76 Additional stains were performed at original institute to exclude other sites Urothelial: Negative Lung: Negative Adrenal: Negative Colonic: Negative Prostate: Negative Neuroendocrine: Negative

77 Melan A

78 Melan A in Melanoma

79 S100

80 Cam 5.2

81 Not a Melanoma Negative S100 Positive CAM5.2 and CK7 Not typical melan-a staining pattern for melanoma

82 Brief Summary IHC Performed by Contributing Pathologists Hep Par 1: Negative Arginase-1: Rare AFP: Negative CD10: Negative Polyclonal CEA: Negative Extensive metastatic markers: Negative

83 More IHC?

84 Glypican-3

85 Albumin ISH Courtesy of Dr. Michael Torbenson

86 Summary Hep Par 1: Negative Arginase-1: Rare AFP: Negative CD10: Negative Polyclonal CEA: Negative GPC3: Positive Albumin ISH: Positive Extensive metastatic markers: Negative

87 Diagnosis Hepatocellular Carcinoma

88 Take Home Points

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90 H&E Take Home Points Diagnosis of HCC History, history, history.. Imaging correlation IHC/special stains Hepatocytic markers (combination of multiple markers may be necessary) Markers to exclude CC and metastasis

91 Acknowledgement Dr. Xianyong (Sean) Gui, Univ of Calgary Dr. Sarag Boukhar, UWMC, Seattle

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