Dysplastic Nodules. Department of Pathology, Chonbuk National University Medical School. Woo Sung Moon. Introduction

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Dysplastic Nodules Department of Pathology, Chonbuk National University Medical School Woo Sung Moon 만성간질환에발생하는간의결절병변에는재생결절, 형성이상결절및간세포암종이있다.

1 Dysplastic Nodules Department of Pathology, Chonbuk National University Medical School Woo Sung Moon 만성간질환에발생하는간의결절병변에는재생결절, 형성이상결절및간세포암종이있다. 여러인자에의해손상받은간세포는괴사와재생과정을반복하며재생결절, 형성이상결절을형성하는동안유전자의변이와 epigenetic 변화가축적되어조기간세포암종이발생하는것으로알려져있다. 형성이상결절은종양성병변으로구성세포와구조의형태학적이상의정도를기준으로고등급형성이상결절과저등급형성이상결절로나눈다. 이러한이형성결절, 특히고등급의형성이상결절과조기간세포암종의정확한감별진단은환자의치료에필수적이다. 이에고등급의형성이상결절에초점을맞추어형성이상결절과조기간세포암종의형태학적인소견, 형성이상결절의생물학적인경과, 형성이상결절과조기간세포암종의감별진단및분자생물학적특성에대해살펴보고자한다. Introduction Liver nodules, ranging from large regenerative nodules (LRN), dysplastic nodules (DN), and hepatocellular carcinoma (HCC), may develop during chronic liver diseases. 1 Nodular lesions that differ from the surrounding liver parenchyma and that are characterized by cytological or architectural atypia are termed dysplastic nodules (DN), and a DN is a well-known precancerous lesion of HCC. The DNs belong to the borderline malignancy category requiring accurate distinction from early HCC. 1,2 In this issue, we discuss about histological features, natural outcome, differential diagnosis and molecular characteristics of DN. 1. Histological features of dysplastic nodules and early hepatocellular carcinoma DNs are classified as low-grade (LGDN) or high-grade (HGDN) depending on the basis of atypia. 1-3 LGDN shows mild cytological atypia and minimal architectural disturbances compared with that of cirrhotic nodules. HGDN is characterized by both cytological and architectural atypia that approaches but not so overt as to make diagnosis of HCC. Early HCC is a low grade, early-stage tumor that may be difficult to recognize both grossly and microscopically. 23

2 2012 년대한간학회춘계 Single Topic Symposium Table 1. Important Pathologic Features of Hepatocellular Nodules LRN LGDN HGDN WD HCC Cytologic features Small cell change Large cell change ± ± ± - Clonelike foci (clear, fatty) - ± + + Architectural features Plate thickening 3 cells Increased cell density compared with surroundings times >2 times Pseudoglands - - ± + Nodule-in nodule ± Portal tract ± Unpaired arteries and sinusoidal capillarization - ± ± + Stromal invasion Reticulin framework ± Histologically, early HCC is a well-differentiated tumor, commonly composed of small hepatocyte-like cells that merge imperceptibly with the surrounding hepatic parenchyma. Characteristic features, often seen in combination, include 1) increased cell density, more than twice that of surrounding liver, with increase N/C ratio; 2) irregular thin trabecular pattern of growth; 3) pseudo-glandular structures; 4) fatty change; 5) unpaired arteries; and 6) intra-tumoral portal tracts. Because the histological features listed above may be observed in early HCC and HGDN, distinction between the two types of lesion may sometimes be impossible, especially in biopsy specimen. 4 At the other hand of the spectrum, there is currently consensus that distinction between LGDN and LRN of cirrhotic livers cannot be made confidently by morphology alone. 1, 3 Key morphologic features of differential diagnosis are summarized in Table Natural outcome of dysplastic nodules While LRN is thought to carry a malignant potential not greater than that of the adjacent cirrhotic nodules, the natural outcome of DN shows an increased risk of malignant transformation. Among 154 followed cirrhotic patients, cumulative HCC development rates at the first, third, and fifth year were 46.2%, 61.5%, and 80.8% for HGNN; 2.6%, 30.2%, and 36.6% for LGDN; and 3.3%, 9.7%, and 12.4% for regenerating nodule (RN), respectively. 5 The rate of HCC development was significantly higher in the HGDN group than that of LGDN and RN. 5 Borzoi et al. followed 90 cirrhotic patients with 56 LRNs, 16 LGDNs, or 19 HGDNs and demonstrated that the HGDN was associated with a higher risk for HCC development. 6 Takayama et al. reported that histologically proven adenomatous hyperplasia 24

3 문우성 Dysplastic Nodules developed to advanced HCC with a 1-year rate of 22%, 2-year of 50%, and 3-year of 80%. 7 Takayasu et al. studied the natural course of 60 hypoattenuating nodular lesions on CT imaging and found that overall cumulative attenuation conversion rates form hypo- to hyperattenuation were 15.8% at 1 year, 44.3% at 2 years, and 58.7% at 3 years. 8 Taken together, HGDN should be considered a precancerous lesion when it appears during follow-up of chronic liver disease. 3. Diagnosis of dysplastic nodules and early hepatocellular carcinoma before treatment A noninvasive diagnosis of HCC can be obtained when coincidental radiologic findings consisting of arterial hypervascularity and portal or delayed washout. Ultrasound monitoring was recommended and the use of a diagnostic algorithm was suggested, including the detection of arterial hypervascularity and portal or delayed venous washout in only one dynamic radiologic procedure, contrast-enhanced CT, or MRI in updated AASLD guidelines. 9 When these features are not present, either the contrast-enhanced examination or biopsy is recommended. Percutaneous fine needle aspiration performed under CT or US guidance has been adopted worldwide as a safe, efficient and minimally invasive, and low-cost procedure for the diagnosis of hepatic nodular lesions. Unfortunately, HGDN and early HCC may be difficult to distinguish on cytological grounds alone. 10 Liver biopsy still remains as a diagnostic milestone when the imaging profile is not characteristic for HCC. However, diagnosis of a small amount of specimen obtained by needle biopsy is not always easy because of reasons such as sampling error for small lesion around 1 cm with a vague margin and intratumoral heterogeneity. It is generally recommended that biopsy sampling includes both intralesional and extralesional tissue because the architectural and cytological abnormalities are better appreciated by comparing these two regions each other. There are several emerging tumor markers for diagnosis of HCC 11,12 : (a) Glypican-3, a cell surface heparin sulfate proteoglycan has established as a serum and tissue marker for HCC with a sensitivity of 77% and specificity of 96%; (b) Heat shock protein 70 (HSP 70) belongs to a class of genes implicated in the regulation of cell cycle progression, in apoptosis, and in tumorigenesis. Significant up-regulation of HSP 70 was reported in early HCC than in DN among 12,600 genes studied; (c) Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia in the mammalian liver where it has been shown to be restricted to hepatocytes surrounding the terminal hepatic vein. Diffuse and strong staining of GS was observed in 14% of HGDN, 59% of well-differentiated HCC, and 86% of moderately to poorly differentiated HCC. Although needle biopsy is neither perfectly sensitive nor entirely specific, the biopsy of a nodule provides as accurate diagnosis and helps in the therapeutic outcome; morphologic data should always be integrated with clinical, immunohistochemical information with imaging data

4 2012 년대한간학회춘계 Single Topic Symposium 4. Molecular characteristics of dysplastic nodules and early hepatocellular carcinoma It has been shown that DN is monoclonal proliferation of hepatocytes and progressive accumulation of genetic and epigenetic changes in LRN, LGDN, HGDN, and HCC is a feature of the multistep carcinogenesis of HCC HGDN has shortened telomeres with increased telomerase activity and high htert mrna levels similar to that of HCC. 19,20 A few studies attempted to distinguish DN and well differentiated HCC. Nam et al. have demonstrated that 240 of 3084 gene expression profiles can discriminate LGDN, HGDN and early HCC using oligo-nucleotide microarray. 21 More recently, Dong et al. have reported that an analysis of loss of heterozygote patterns of a panel of 22 microsatellite markers is a simple and specific assay for differential diagnosis between HGDN and early minute HCC. 22 Molecular data are still under evaluation as to their diagnostic efficacy. Further genomic and proteomic studies can address gene expression profile in the sequence of cirrhosis-dn-hcc and accurately predict the risk of malignant transformation of non malignant nodules. References 1. Theise ND, Curado MP, Franceschi S, Hytiroglou P, Kudo M, Park YN, Sakamoto M, Torbenson M and Wee A. Hepatocellular carcinoma. In: WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC Press, 2010; Park YN. Update on precursor and early lesions of hepatocellular carcinomas. Arch Pathol Lab Med 2011;135: , 3. Roncalli M, Borzio M, Di Tommaso L. Hepatocellular dysplastic nodules. Hepatol Res 2007;37:S Kondo F. Histological features of early hepatocellular carcinomas and their developmental process: for daily practical clinical application: Hepatocellular carcinoma. Hepatol Int 2009;3: Kobayashi M, Ikeda K, Hosaka T, Sezaki H, Someya T, Akuta N, et al. Dysplastic nodules frequently develop into hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis. Cancer 2006;106: Borzio M, Fargion S, Borzio F, Fracanzani AL, Croce AM, Stroffolini T, et al. Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development. J Hepatol 2003;39: Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Okazaki N, Takayasu K, et al. Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 1990;336: Takayasu K, Muramatsu Y, Mizuguchi Y, Ojima H. CT Imaging of early hepatocellular carcinoma and the natural outcome of hypoattenuating nodular lesions in chronic liver disease. Oncology 2007;72:S Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53: Wee A. Fine needle aspiration biopsy of hepatocellular carcinoma and hepatocellular nodular lesions: role, controversies and approach to diagnosis. Cytopathology 2011;22: Di Tommaso L, Franchi G, Park YN, Fiamengo B, Destro A, Morenghi E, et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 2007;45: Tan CH, Low SC, Thng CH. APASL and AASLD Consensus Guidelines on Imaging Diagnosis of Hepatocellular 26

5 문우성 Dysplastic Nodules Carcinoma: A Review. Int J Hepatol 2011;2011; Sersté T, Barrau V, Ozenne V, Vullierme MP, Bedossa P, Farges O, et al. Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: Role of biopsy. Hepatology 2011 (in press) 14. Paradis V, Laurendeau I, Vidaud M, Bedossa P. Clonal analysis of macronodules in cirrhosis. Hepatology 1998;28: Maggioni M, Coggi G, Cassani B, Bianchi P, Romagnoli S, Mandelli A, et al. Molecular changes in hepatocellular dysplastic nodules on microdissected liver biopsies. Hepatology 2000;32: Sun M, Eshleman JR, Ferrell LD, Jacobs G, Sudilovsky EC, Tuthill R, et al. An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region. Hepatology 2001;33: Um TH, Kim H, Oh BK, Kim MS, Kim KS, Jung G, et al. Aberrant CpG island hypermethylation in dysplastic nodules and early HCC of hepatitis B virus-related human multistep hepatocarcinogenesis. J Hepatol 2011;54: Moinzadeh P, Breuhahn K, Stützer H, Schirmacher P. Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade--results of an explorative CGH meta-analysis. Br J Cancer 2005;92: Oh BK, Kim YJ, Park YN, Choi J, Kim KS, Park C. Quantitative assessment of htert mrna expression in dysplastic nodules of HBV-related hepatocarcinogenesis. Am J Gastroenterol 2006;101: Oh BK, Kim YJ, Park C, Park YN. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am J Pathol 2005;166: Nam SW, Park JY, Ramasamy A, Shevade S, Islam A, Long PM, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology 2005;42: Dong H, Cong WM, Xian ZH, Zhu ZZ. Using loss of heterozygosity of microsatellites to distinguish high-grade dysplastic nodule from early minute hepatocellular carcinoma. Exp Mol Pathol 2011;91:

Alastair Burt Newcastle University

Alastair Burt Newcastle University Benign Hepatocellular adenoma 8170/0 Focal nodular hyperplasia Malignancy-associated and premalignant lesions Large cell change (formerly dysplasia ) Small cell change