В статье представлены современные положения о возможностях скрининга и ранней диагностики гепатоцеллюлярной карциномы с использованием лучевых методов визуализации, неинвазивных серологических и иммуногистохимических маркеров, а также показания и возможности морфологического исследования очаговых образований печени у пациентов из группы риска.
The article presents the current possibilities for screening and early diagnosis of hepatocellular carcinoma with imaging techniques, non-invasive serological and immunohistochemical markers, as well as indications and accuracy for morphological study of focal lesions of the liver in patients of risk group.
1. Amit G. Singal, Pillai A, Tiro A. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLOS One 2014; 11 (4): e1001624.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics 2013. CA Cancer J Clin 2013; 63 (1): 11–30.
3. Ferlay J, Shin HR, Bray F et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127 (12): 2893–971.
4. Centers for Disease Control and Prevention (CDC). Hepatocellular carcinoma – United States, 2001–2006. MMWR Morb Mortal Wkly Rep 2010; 59 (17): 517–20.
5. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127 (5 Suppl. 1): S27–S34.
6. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013; 47 (1): S2–S6.
7. Torres DM, Harrison SA. Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma. Semin Liver Dis 2012; 32 (1): 30–8.
8. Wong R, Corley DA. Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med 2008; 121 (6): 525–31.
9. Simonetti RG, Cammà C, Fiorello F et al. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 1991; 36 (7): 962–72.
10. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981; 2 (8256): 1129–33.
11. Bruix J, Sherman M. AASLD Practice Guideline. Management of hepatocellular carcinoma. Hepatology 2005; 42 (5): 1208–36.
12. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127 (5 Suppl. 1): S35–S50.
13. Davila JA, Morgan RO, Shaib Y et al. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 2004; 127 (5): 1372–80.
14. Yoshida H, Shiratori Y, Moriyama M et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and non-cirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med 1999; 131 (3): 174–81.
15. Wörns MA, Weinmann A, Pfingst K et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol 2009; 43 (5): 489–95.
16. Hassan MM, Hwang LY, Hatten CJ et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002; 36 (5): 1206–13.
17. Shen YC, Hsu C, Cheng CC et al. A critical evaluation of the preventive effect of antiviral therapy on the development of hepatocellular carcinoma in patients with chronic hepatitis C or B: a novel approach by using meta-regression. Oncology 2012; 82 (5): 275–89.
18. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907–17.
19. Чиссов В.И., Старинский В.В., Петрова Г.В. Состояние онкологической помощи населению России в 2013 году. М., 2014.
20. Бисовская Ю.В., Горбунова В.А., Бредер В.В. и др. Сорафениб в лечении распространенного гепатоцеллюлярного рака: анализ российской и австрийской когорт больных. Клин. фармакология и терапия. 2014; 2: 42–7.
21. Morgan RL, Baack B, Smith BD et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013; 158 (5 Pt 1): 329–37.
22. Gurusamy KS, Wilson R, Koretz RL et al. Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention? PLOS One 2013; 8 (12): e83313.
23. Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, 7th ed, Philadelphia, PA: Elsevier Saunders 2003; p. 914–7.
24. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130 (7): 417–22.
25. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 2008; 48: S20–S37.
26. Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–2.
27. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–43.
28. Digumarthy SR, Sahani DV, Saini S. MRI in detection of hepatocellular carcinoma (HCC). Cancer Imaging 2005; 5: 20–4.
29. Sporea I, Badea R, Popescu A et al. Contrast–Enhanced Ultrasound (CEUS) for the evaluation of focal liver lesions – a prospective multicenter study of its usefulness in clinical practice. Ultraschall Med 2014.
30. Sporea I, Martie A, Bota S et al. Characterization of focal liver lesions using contrast enhanced ultrasound as a first line method: a large monocentric experience. J Gastrointestin Liver Dis 2014; 23: 57–63.
31. Kubota K, Ina H, Okada Y, Irie T. Growth rate of primary single hepatocellular carcinoma: determining optimal screening interval with contrast enhanced computed tomography. Dig Dis Sci 2003; 48: 581–6.
32. Sigal A, Volk ML, Waljee A et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009; 30: 37–47.
33. Trinchet JC, Chaffaut C, Bourcier V et al. Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH). Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 2011; 54: 1987–97.
34. Andersson KL, Salomon JA, Goldie SJ, Chung RT. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2008; 6: 1418–24.
35. Singal AG, Conjeevaram HS, Volk ML et al. Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis. Cancer Epidemiol Biomarkers Prev 2012; 21: 793–9.
36. Yu NC, Chaudhari V, Raman SS et al. CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis. Clin Gastroenterol Hepatol 2011; 9: 161–7.
37. Lee KH, O’Malley ME, Haider MA, Hanbidge A. Triple-phase MDCT of hepatocellular carcinoma. AJR Am J Roentgenol 2004; 182: 643–9.
38. Yu MH, Kim JH, Yoon JH et al. Radiology. Small (≤1 cm) Hepatocellular Carcinoma: Diagnostic Performance and Imaging Features at Gadoxetic Acid-enhanced MR Imaging 2014; 271 (3): 748–60.
39. Bolondi L, Gaiani S, Celli N et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 2005; 42 (1): 27–34.
40. Levy I, Greig PD, Gallinger S et al. Resection of hepatocellular carcinoma without preoperative tumor biopsy. Ann Surg 2001; 234 (2): 206–9.
41. Bolondi L, Sofia S, Siringo S et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 2001; 48 (2): 251–9.
42. Solomon R. Contrast-induced acute kidney injury: is there a risk after intravenous contrast? Clin J Am Soc Nephrol 2008; 3: 1242–3.
43. Pitton MB, Kloeckner R, Herber S et al. MRI versus 64-row MDCT for diagnosis of hepatocellular carcinoma. World J Gastroenterol 2009; 15: 6044–51.
44. Purysko AS, Remer EM, Coppa CP et al. LI-RADS: a case-based review of the new categorization of liver findings in patients with end-stage liver disease. Radiographics 2012; 32: 1977–95.
45. Burrel M, Llovet JM, Ayuso C et al. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology 2003; 38: 1034–42.
46. Khalili K, Kim TK, Jang HJ et al. Optimization of imaging diagnosis of 1–2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J Hepatol 2011; 54: 723–8.
47. Ayuso C, Rimola J, Garcia-Criado A. Imaging of HCC. Abdom Imaging 2012; 37: 215–30.
48. Hina Arif-Tiwari, Bobby Kalb, Surya Chundru et al. MRI of hepatocellular carcinoma: an update of current practices Diagn Interv Radiol 2014; 20: 209–21.
49. Becker-Weidman DJ, Kalb B, Sharma P et al. Hepatocellular carcinoma lesion characterization: single-institution clinical performance review of multiphase gadolinium-enhanced MR imaging-comparison to prior same-center results after MR systems improvements. Radiology 2011; 261: 824–33.
50. Catalano OA, Choy G, Zhu A et al. Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging. Radiology 2010; 254: 154–62.
51. Seale MK, Catalano OA, Saini S et al. Hepatobiliary-specific MR contrast agents: role in imaging the liv- er and biliary tree. Radiographics 2009; 29: 1725–48.
52. Nisar P. Malek, Sebastian Schmidt, Petra Huber et al. Clinical practice guidline The Diagnosis and Treatment of Hepatocellular Carcinoma Dtsch Arztebl Int 2014; 111 (7): 101–6.
53. Yan-Jie Zhao, Qiang JU, Guan-Cheng LI. Tumor markers for hepatocellular carcinoma (Review) Molecular and clinical oncology 2013; 1: 593–8.
54. Di Bisceglie AM, Sterling RK, Chung RT et al. HALT-C Trial Group. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial. J Hepatol 2005; 43: 434–41.
55. Yamashita T, Forgues M, Wang W et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68: 1451–61.
56. Villanueva A, Minguez B, Forner A et al. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Annu Rev Med 2010; 61: 317–28.
57. Hoshida Y, Nijman SM, Kobayashi M et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009; 69: 7385–92.
58. Trevisani F, D'Intino PE, Morselli-Labate AM et al. Serum alpha- fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HbsAg and anti-HCV status. J Hepatol 2001; 34: 570–5.
59. Debruyne EN, Delanghe JR. Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications. Clin Chim Acta 2008; 385: 19–26.
60. Singhal A, Jayaraman M, Dhanasekaran DN, Kohli V. Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence. Crit Rev Oncol Hematol 2012; 82: 116–40.
61. Leerapun A, Suravarapu SV, Bida JP et al. The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population. Clin Gastroenterol Hepatol 2007; 5: 394–402.
62. Kobayashi M, Hosaka T, Ikeda K et al. Highly sensitive AFP-L3% assay is useful for predicting recurrence of hepatocellular carcinoma after curative treatment pre- and postoperatively. Hepatology Res 2011; 41: 1036–45.
63. Naraki T, Kohno N, Saito H et al. Gamma-carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin. Biochim Biophys Acta 2002; 1586: 287–98.
64. Nakamura S, Nouso K, Sakaguchi K et al. Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol 2006; 101: 2038–43.
65. Baek YH, Lee JH, Jang JS et al. Diagnostic role and correlation with staging systems of PIVKA-II compared with AFP. Hepatogastroenterology 2009; 56: 763–67.
66. Yamamoto K, Imamura H, Matsuyama Y et al. AFP, AFP-L3, DCP and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC. J Gastroenterol 2010; 45: 1272–82.
67. Zittermann SI, Capurro MI, Shi W, Filmus J. Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res 2005; 65: 6245–54.
68. Shirakawa H, Kumnuma T, Nishimura Y et al. Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. Int J Oncol 2009: 34: 649–56.
69. Кladney RD, Bulla GA, Guo L et al. GP73, a novel Golgi-localized protein upregulated by viral infection. Gene 2000; 249: 53–65.
70. Fritzsche FR, Kristiansen G, Riener MO et al. GOLPH2 expression may serve as diagnostic marker in seminomas. BMC Urol 2010; 10: 4.
71. Kristiansen G, Fritzsche FR, Wassermann K et al. GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue-based diagnostics. Br J Cancer 2008; 99: 939–48.
72. Shi Y, Chen J, Li L et al. A study of diagnostic value of golgi protein GP73 and its genetic assay in primary hepatic carcinoma. Technol Cancer Res Treat 2011; 10: 287–94.
73. Tian L, Wang Y, Xu D et al. Serological AFP/Golgi protein 73 could be a new diagnostic parameter of hepatic diseases. Int J Cancer 2011; 129: 1923–31.
74. Riener MO, Stenner F, Liewen H et al. Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its value as a serum marker in hepatocellular carcinomas. Hepatology 2009; 49: 1602–9.
75. Zhou Y, Yin X, Ying J, Zhang B. Golgi protein 73 versus alpha-fetoprotein as a biomarker for hepatocellular carcinoma: a diagnostic meta-analysis. BMC Cancer 2012; 12: 17.
76. Tangkijvanich P, Tosukhowong P, Bunyongyod P et al. Alpha-L-fucosidase as a serum marker of hepatocellular carcinoma in Thailand. Southeast Asian J Trop Med Public Health 1999; 30: 110–4.
77. Fawzy Montaser M, Amin Sakr M, Omar Khalifa M. Alpha-L-fucosidase as a tumour marker of hepatocellular carcinoma. Arab J Gastroenterol 2012; 13: 9–13.
78. Pillai AA, Fimmel CJ. Emerging serum biomarkers of HCC. Clin Gastroenterol 2012; 27: 247–62.
79. Yao DF, Dong ZZ, Yao M. Specific molecular markers in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2007; 6: 241–7.
80. Wang CS, Lin CL, Lee HC et al. Usefulness of serum des- gamma-carboxy prothrombin in detection of hepatocellular carcinoma. World J Gastroenterol 2005; 11: 6115–9.
81. Guido M, Roskams T, Pontisso P et al. Squamous cell carcinoma antigen in human liver carcinogenesis. J Clin Pathol 2008; 61: 445–7.
82. Trerotoli P, Fransvea E, Angelotti U et al. Tissue expression of squamous cellular carcinoma antigen (SCCA) is inversely correlated to tumor size in HCC. Mol Cancer 2009; 8: 29.
83. Giannelli G, Marinosci F, Sgarra C et al. Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma. Int J Cancer 2005; 116: 579–83.
84. Beneduce L, Castaldi F, Marino M et al. Squamous cell carcinoma antigen-immunoglobulin M complexes as novel biomarkers for hepatocellular carcinoma. Cancer 2005; 103: 2558–65.
85. Pontisso P, Quarta S, Caberlotto C et al. Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma. Int J Cancer 2006; 119: 735–40.
86. Shen Q, Fan J, Yang XR et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol 2012; 13 (8): 817–26. Doi: 10.1016/S1470-2045(12)70233-4.
87. Volinia S, Calin GA, Liu CG et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006; 103: 2257–61.
88. Meng F, Henson R, Wehbe-Janek H et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133: 647–58.
89. Tomimaru Y, Eguchi H et al. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol 2012; 56: 167–75.
90. Zhi H, Zhan J, Deng QL et al. Postoperative detection of AFP mRNA in the peripheral blood of hepatic cellular carcinoma patients and its correlation with recurrence. Zhonghua Zhong Liu Za Zhi 2007; 29: 112–5.
91. Torzilli G, Belghiti J, Makuuchi M. Differences and similarities in the approach to hepatocellular carcinoma between Eastern and Western institutions. Liver Transpl 2004; 10 (2 Suppl. 1): S1–2.
92. Sherman M. Screening for hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19 (1): 101–18.
93. Borzio M, Borzio F, Macchi R et al. The evaluation of fine-needle procedures for the diagnosis of focal liver lesions in cirrhosis. J Hepatol 1994; 20 (1): 117–21.
94. Hayashi PH, Trotter JF, Forman L et al. Impact of pretransplant diagnosis of hepatocellular carcinoma on cadveric liver allocation in the era of MELD. Liver Transpl 2004; 10 (1): 42–8.
95. Scoazec JY, Labadie M, Dumortier J, Valette PJ. Synopsis. Diagnosis of liver nodules: techniques, approach and main practical problems. Gastroenterol Clin Biol 2000; 24 (11): 1095–103.
96. Colombat M, Paradis V, Bieche I et al. Quantitative RT-PCR in cirrhotic nodules reveals gene expression changes associated with liver carcinogenesis. J Pathol 2003; 201: 260–7.
97. Llovet JM, Chen Y, Wurmbach E et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 2006; 131: 1758–67.
98. Wurmbach E, Chen YB, Khitrov G et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 2007; 45: 938–47.
99. Di Tommaso L, Franchi G, Park YN et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 2007; 45: 725–34.
100. Di Tommaso L, Destro A, SeokJY et al. The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J Hepatol 2009; 50: 746–54.
101. Tremosini S, Forner A, Boix L et al. Biopsy diagnosis of hepatocellular carcinoma <2 cm: prospective validation of glypican 3, heat-shock protein 70 and glutamine synthetase staining in fine needle biopsy samples. ILCA book of abstracts 2011.
102. Roskams T, Kojiro M. Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis. Semin Liver Dis 2010; 30: 17–25.
103. Kim H, Choi GH, Na DC et al. Human hepatocellular carcinomas with «Stemness»-related marker expression: keratin 19 expression and a poor prognosis. Hepatology 2011; 54: 1707–17.
104. Durnez A, Verslype C, Nevens F et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology 2006; 49: 138–51.
105. Forner A, Vilana R, Ayuso C et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008; 47: 97–104.
106. Sersté T, Barrau V, Ozenne V 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 2012; 55 (3): 800–6. Doi: 10.1002/hep.24746
107. Roskams T. Anatomic pathology impact on prognosis and response to therapy. Clin Liver Dis 2011; 15: 245–59.