Dysplastic nodules are defined as distinctive liver nodules that differ in size, color, texture or protrusion compared to the surrounding liver tissue, and contain portal tracts. Low grade dysplastic nodules show normal or enlarged hepatocytes without architectural abnormalities, while high grade nodules exhibit cytological and architectural atypia such as small cell changes and pseudogland formation. The document discusses models of dysplastic nodule development and differentiation from hepatocellular carcinoma.

1. Dysplastic Nodules & Hepatocarcinogenesis

2. Differential Diagnosis of: “ Distinctive nodules” in cirrhosis Low grade dysplastic nodules High grade dysplastic nodules Hepatocellular carcinoma (Focal nodular hyperplasia) (Adenoma)

3. Dysplastic nodules are defined as: Distinctive nodules which differ from the surrounding parenchyma in terms of

4. Dysplastic nodules are defined as: Distinctive nodules which differ from the surrounding parenchyma in terms of: size,

5. Dysplastic nodules are defined as: Distinctive nodules which differ from the surrounding parenchyma in terms of: size, color,

6. Dysplastic nodules are defined as: Distinctive nodules which differ from the surrounding parenchyma in terms of: size, color, texture,

7. Dysplastic nodules are defined as: Distinctive nodules which differ from the surrounding parenchyma in terms of: size, color, texture, or degree of bulging from the cut surface

13. Dysplastic nodules are defined as: Distinctive nodules which differ from the surrounding parenchyma in terms of: color, size, texture, or degree of bulging from the cut surface AND contain portal tracts (….?)

15. Low Grade Dysplastic Nodules

16. Features of Low Grade DNs: Normal cytology or Large cell change only No architectural atypia

20. High Grade Dysplastic Nodules

21. Features of High Grade DNs: Cytologic atypia, e.g. small cell change Clone-like domains e.g. Mallory body clustering, iron resistance, fatty or clear cell change, etc. Architectural atypia, e.g. pseudogland formation

26. Incidence of DNs in Cirrhotic Livers # Livers with DNs (%) # Cirrhotic Livers Source Location 10 (24%) 41 Explant Bordeaux 32 (22%) 155 Explant New York 45 (21%) 209 Autopsy Kanazawa 17 (15%) 110 Explant San Francisco 11 (25%) 44 Explant New York 46 (14%) 315 Autopsy Tokushima

27. Chronic Hepatitis Hepatitis B and C Autoimmune hepatitis Metabolic Disease Genetic hemochromatosis A-1-AT Deficiency Chronic Biliary Tract Disease PBC, PSC Toxic Injury Chronic alcoholic liver injury

31. Dysplastic Nodule Development: The Old Model

32. Increased proliferation Nodular HCC Low grade dysplastic nodule Dysplastic nodule containing early HCC Genetic alteration High grade dysplastic nodule Old Model

33. Problems for the Old Model

34. Problem 1 DNs nearly always contain portal tracts

35. Problem 2 DNs have been identified in non-cirrhotic livers.

36. Problem 3 DNs are clonal lesions.

37. An Alternate Model

50. DN predictions based on our alternate hypothesis: Diminished proliferation

51. DN predictions based on our alternate hypothesis: Diminished proliferation Terasaki et al, Am J Clinical Path 1991 Le Bail et al, Human Pathology 1995 Theise et al, Liver 1996

52. DN predictions based on our alternate hypothesis: Diminished proliferation Diminished HSC activation

53. Park YN et al, Liver 1997

54. DN predictions based on our alternate hypothesis: Diminished proliferation Diminished HSC activation

55. DN predictions based on our alternate hypothesis: Diminished proliferation Diminished HSC activation Diminished apoptosis

56. DN predictions based on our alternate hypothesis: Diminished proliferation Diminished HSC activation Diminished apoptosis Park YN et al, Cancer 2001

57. SPREADING MONOCLONAL PROLIFERATION CLONAL DYSPLASTIC NODULE DEVELOPING CIRRHOSIS DIMINISHED HSC ACTIVATION

58. SPREADING MONOCLONAL PROLIFERATION NODULE-IN-NODULE LESION CLONAL DYSPLASTIC NODULE DEVELOPING CIRRHOSIS DIMINISHED HSC ACTIVATION

59. SPREADING MONOCLONAL PROLIFERATION MATURE HEPATOCELLULAR CARCINOMA NODULE-IN-NODULE LESION CLONAL DYSPLASTIC NODULE DEVELOPING CIRRHOSIS DIMINISHED HSC ACTIVATION

60. Aihara T, et al. Clonal analysis of regenerative nodules in hepatitis C virus-induced liver cirrhosis. Gastroenterology 1994; 107: 1805-11.

62. X X X X X X X X X X X

63. X X X X I I I I I I X

64. II II II II I I I I I I II

65. II II II II I I I I I I II

67. SPREADING MONOCLONAL PROLIFERATION MATURE HEPATOCELLULAR CARCINOMA NODULE-IN-NODULE LESION CLONAL DYSPLASTIC NODULE ADJACENT CLONAL CIRRHOTIC NODULES DEVELOPING CIRRHOSIS DIMINISHED HSC ACTIVATION NL or INCREASED HSC ACTIVATION

68. SPREADING MONOCLONAL PROLIFERATION MATURE HEPATOCELLULAR CARCINOMA NODULE-IN-NODULE LESION CLONAL DYSPLASTIC NODULE ADJACENT CLONAL CIRRHOTIC NODULES DEVELOPING CIRRHOSIS DIMINISHED HSC ACTIVATION NL or INCREASED HSC ACTIVATION MULTIPLE, ADJACENT Or DNs w/ INDISTINCT BORDERS MICROSCOPIC HCCs

69. SPREADING MONOCLONAL PROLIFERATION MATURE HEPATOCELLULAR CARCINOMA NODULE-IN-NODULE LESIONS CLONAL DYSPLASTIC NODULE ADJACENT CLONAL CIRRHOTIC NODULES MULTIPLE, ADJACENT Or DNs w/ INDISTINCT BORDERS MICROSCOPIC HCCs DEVELOPING CIRRHOSIS DIMINISHED HSC ACTIVATION NL or INCREASED HSC ACTIVATION

70. Two Variants of Early HCC

71. Early Hepatocellular Carcinoma Vaguely nodular type Distinctly nodular type

72. Diagnostic Re-cap & Cases

73. Features found in dysplastic nodules X Large cell change X Scirrhous change X Angiogenesis (“unpaired arteries”) X Diffuse (or zonal) fatty change X Diffuse hemosiderosis eHCC HGDN LGDN

74. Features found in dysplastic nodules X X X Large cell change X X X Scirrhous change XXX XX X Angiogenesis (“unpaired arteries”) X X X Diffuse (or zonal) fatty change rare rare X Diffuse hemosiderosis eHCC HGDN LGDN LN

76. Case 1 43 year old woman with hepatitis C cirrhosis. Well defined, distinctive nodule measuring 1.9 cm in explanted liver.

77. Case 6B, 2x, H&E

78. Case 6B, 10x, Trichrome

79. Case 6B, 10x, H&E

80. Case 6B, 10x, H&E

81. Case 1 Low grade dysplastic nodule

82. Features found in dysplastic nodules X X Nodule-in-nodule expansile growth (with steatosis or other changes above) X X Mallory body clustering (with/without steatosis, PMNs) X X Iron resistence in otherwise siderotic nodule XX X Pseudoacinar growth X X Small cell change X X X Large cell change X X X Scirrhous change XXX XX X Angiogenesis (“unpaired arteries”) X Diffuse (or zonal) fatty change rare rare X Diffuse hemosiderosis eHCC HGDN LGDN

83. Features found in dysplastic nodules X Stromal invasion X X Nodule-in-nodule expansile growth (with steatosis or other changes above) X X Mallory body clustering (with/without steatosis, PMNs) X X Iron resistence in otherwise siderotic nodule XX X Pseudoacinar growth X X Small cell change X X X Large cell change X X X Scirrhous change XXX XX X Angiogenesis (“unpaired arteries”) X Diffuse (or zonal) fatty change rare rare X Diffuse hemosiderosis eHCC HGDN LGDN

84. Falkowski O, et al J Hepatol 2003

86. Case 2 54 year old man with hepatitis C cirrhosis. Ill defined, 1.0 cm, distinctive nodule identified in explanted liver.

87. Case 6A, 2x, H&E

88. Case 6A, 2x, H&E

89. Case 6A, 2x, H&E

90. Case 6A, 2x, H&E

91. Case 6A, 4x, H&E

92. Case 6A, 4x, H&E

94. Case 6A, 10x, H&E

95. Case 6A, 10x, H&E

96. Case 6A, 10x, H&E

98. Biliary cytokeratins (AE1/AE3)

99. Case 2 Hepatocellular carcinoma arising in high grade dysplastic nodule.

100. The Future…

101. Glypican-3? Immuno. distinguishes HCC from non-HCC

102. HCC HCC

103. HCC HCC HGDN w/ HCC focus

104. CK19 in histologically “ pure” HCC? CK19 positive by immuno indicates prognosis Intermediate between HCC and ChC

105. ?