18-fluorodeoxyglucose positron emission tomography in nonendocrine neoplastic disorders of the gastrointestinal tract
2003; Elsevier BV; Volume: 125; Issue: 4 Linguagem: Inglês
10.1016/s0016-5085(03)01208-3
ISSN1528-0012
AutoresAlessio Annovazzi, Marc Peeters, Annelies Maenhout, Alberto Signore, Rudi Dierckx, Christophe Van de Wiele,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoPositron emission tomography (PET) is a molecular imaging technique based on the use of compounds labeled with positron emitter isotopes that decay, producing a coincident photon pair that can be detected externally by a PET scanner. The most widely used PET tracer for oncologic imaging is 2-18fluoro-2-deoxy-glucose (FDG).1Jones T. The imaging science of positron emission tomography.Eur J Nucl Med. 1996; 23: 807-813Crossref PubMed Scopus (65) Google Scholar The rationale behind its use is the finding of an increased rate of glucose consumption in malignant tissues, caused by an increase in the glycolytic and the number of glucose transporters expressed on malignant cells.2Som P. Atkins H.L. Bandoypadhyay D. Fowler J.J. MacGregor R.R. Matsin K. Oster Z.H. Sacker D.F. Shive C.Y. Turner H. Wan C.N. Wolf A.P. Zabinski S.V. A fluorinated glucose analogue, 2-fluoro-2-deoxy-D-glucose (F-18) non-toxic tracer for rapid tumour detection.J Nucl Med. 1980; 21: 670-675PubMed Google Scholar, 3Warburg O. On the origin of cancer cells.Science. 1956; 123: 309-314Crossref PubMed Scopus (9143) Google Scholar, 4Flier J.S. Mueckler M.M. Usher P. Lodish H.F. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes.Science. 1987; 235: 1492-1495Crossref PubMed Scopus (681) Google Scholar After injection, FDG is transported by facilitated diffusion into neoplastic cells where it is phosphorylated by hexokinase and subsequently trapped because it is not a substrate for the subsequent enzymatic-driven pathways for glucose metabolism. As the neoplastic cells accrue larger amounts of FDG owing to their increased metabolism, increased activity is detected that delineates the hypermetabolic tumor from the surrounding normal tissues. Since its first application in the detection of primary brain tumors, PET has been used increasingly for its ability to detect primary malignant tumors, but also for its ability to detect both regional and distant metastases, distinguish benign from malignant tissue or recurrent cancer from treatment-related scarring, and document response to therapy.5Weber W.A. Avril N. Schwaiger M. Relevance of positron emission tomography (PET) in oncology.Stralenther Onkol. 1999; 175: 356-373Crossref PubMed Scopus (149) Google Scholar When compared with conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), FDG PET has proven to be especially superior in the clinical assessment of the follow-up patient, postsurgery or radiochemotherapy, in whom the normal anatomic planes either are disrupted or modified owing to treatment-induced inflammation and scavenging processes. A limitation of FDG PET is the limited spatial resolution, approximately 5–8 mm for 18F with current PET machines.6Dahlbom M. Hoffman E. Hoh C.K. Schiepers C. Rosenqvist G. Hawkins R.A. Phelps M.E. Whole-body positron emission tomography: part I. Methods and performance characteristics.J Nucl Med. 1992; 33: 1191-1199PubMed Google Scholar Below a threshold of twice this resolution, owing to partial volume effect, tracer activity will be underestimated, which in case of very small lesions or low metabolic activity may lead to false-negative results. On the other hand, because leukocytes and macrophages also accumulate FDG, when selecting for FDG PET, in those patients with inflammatory and infectious conditions, direct comparison with conventional imaging may be advocated to avoid false-positive findings.7Strauss L.G. Fluorine-18 deoxyglucose and false-positive results a major problem in the diagnostics of oncological patients.Eur J Nucl Med. 1996; 23: 1409-1415Crossref PubMed Scopus (484) Google Scholar This report reviews available data on the role of FDG PET in the diagnosis, staging, and treatment monitoring of patients suffering from nonendocrine gastrointestinal tract tumors. A search of the Medline and CancerLit databases covering articles entered between 1989 and February 2003 was performed. In the absence of meta-analyses, all available reports pertaining to a specific topic were included. The incidence of esophageal cancer continues to increase rapidly and its epidemiology is changing; the percentage of cancers of the esophagus, which histologically are adenocarcinomas and therefore located at or near the esophageal-cardial junction, has been increasing substantially compared with squamous cell carcinoma.8Leiper K. Morris A.I. Treatment of oesophago-gastric tumours.Endoscopy. 2002; 34: 139-145Crossref PubMed Scopus (24) Google Scholar Diagnosis is established routinely through endoscopy and biopsy examination. After diagnosis, optimal patient management depends on accurate staging with curative esophagectomy being reserved for those few patients with limited disease and early stage tumors; it offers both a chance for cure and substantial palliation from debilitating symptoms. Current imaging modalities used in the staging of esophageal cancer include CT, endoscopic ultrasonography (EUS), and, occasionally, bronchoscopy and/or ultrasound with puncture of cervical nodes. Although these methods provide a combined accuracy of 70% to 90% in identification of metastatic disease, unfortunately, a substantial number of patients are found to have advanced disease at the time of surgery.9Peters J.H. Hoeft S.F. Heimbucher J. Bremner R.M. DeMeester T.R. Bremner C.G. Clark G.W. Kiyabu M. Parisky Y. Selection of patients for curative or palliative resection of esophageal cancer based on preoperative endoscopic ultrasonography.Arch Surg. 1994; 129: 534-539Crossref PubMed Scopus (59) Google Scholar, 10Chandawarkar R.Y. Kakegawa R. Fujita H. Yamana H. Hayabuthi N. Comparative analysis of imaging modalities in the preoperative assessment of nodal metastasis in esophageal cancer.J Surg Oncol. 1996; 61: 214-217Crossref PubMed Scopus (41) Google Scholar, 11Sugarbaker D.J. Jaklitsch M.T. Liptay M.J. Thoracoscopic staging and surgical therapy for esophageal cancer.Chest. 1995; 107 (218–213)Google Scholar Accordingly, several investigators have assessed the potential of FDG PET to improve the detection of metastatic disease, thereby facilitating selection of candidates for resection. Additionally, a number of investigators have addressed the potential of FDG PET to diagnose esophageal cancer as compared with endoscopy/biopsy examination and CT whereas some investigators addressed the value of FDG PET for monitoring response to neoadjuvant chemotherapy in patients suffering from locoregional disease. The reported sensitivity of FDG PET for diagnosing esophageal cancer as compared with endoscopy and biopsy examination exceeds 90% in most series.12Block M.I. Patterson G.A. Sundaresan R.S. Bailey M.S. Flanagan F.L. Dehdashti F. Siegel B.A. Cooper J.D. Improvement in staging of esophageal cancer with the addition of positron emission tomography.Ann Thorac Surg. 1997; 64: 770-776Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 13Kole A.C. Plukker J.T. Nieweg O.E. Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy.Br J Cancer. 1998; 78: 521-527Crossref PubMed Scopus (183) Google Scholar, 14Kim K. Park S.J. Kim B.T. Lee K.S. Shim Y.M. Evaluation of lymph node metastases in squamous cell carcinoma of the esophagus with positron emission tomography.Ann Thorac Surg. 2001; 71: 290-294Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 15Kato H. Kuwano H. Nakajima M. Miyazaki T. Yoshikawa M. Ojima H. Tsukada K. Oriuchi N. Inoue T. Endo K. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma.Cancer. 2002; 94: 921-928Crossref PubMed Scopus (266) Google Scholar, 16McAteer D. Wallis F. Couper G. Norton M. Welch A. Bruce D. Park K. Nicolson M. Gilbert F.J. Sharp P. Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma.Br J Radiol. 1999; 72: 525-529PubMed Google Scholar This percentage also applies to T1 tumors.16McAteer D. Wallis F. Couper G. Norton M. Welch A. Bruce D. Park K. Nicolson M. Gilbert F.J. Sharp P. Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma.Br J Radiol. 1999; 72: 525-529PubMed Google Scholar In those studies that compared FDG PET with CT, FDG PET either showed a comparable14Kim K. Park S.J. Kim B.T. Lee K.S. Shim Y.M. Evaluation of lymph node metastases in squamous cell carcinoma of the esophagus with positron emission tomography.Ann Thorac Surg. 2001; 71: 290-294Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar or a higher sensitivity12Block M.I. Patterson G.A. Sundaresan R.S. Bailey M.S. Flanagan F.L. Dehdashti F. Siegel B.A. Cooper J.D. Improvement in staging of esophageal cancer with the addition of positron emission tomography.Ann Thorac Surg. 1997; 64: 770-776Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar for the visualization of primary tumors. Because of the absence of anatomic information, FDG-PET examinations are of no added value to CT and EUS for the purpose of assessing the extent of esophageal wall invasion or T status. However, CT shows poor sensitivity for detecting lymph node involvement because small- to normal-sized lymph nodes containing tumor cells are disregarded.17Vilgrain V. Mompoint D. Palazzo L. Menu Y. Gayet B. Ollier P. Nahum H. Fekete F. Staging of esophageal carcinoma comparison of results with endoscopic sonography and CT.AJR Am J Roentgenol. 1990; 155: 277-281Crossref PubMed Scopus (157) Google Scholar, 18Goei R. Lamers R.J. Engelshove H.A. Oei K.T. Computed tomographic staging of esophageal carcinoma a study on interobserver variation and correlation with pathological findings.Eur J Radiol. 1992; 15: 40-44Abstract Full Text PDF PubMed Scopus (17) Google Scholar Additionally, although a higher accuracy of lymph node involvement has been reported for EUS, complete tumor staging is impossible in approximately one third of esophageal cancer patients because of failure of passage through the stenotic lesion.19Tio T.L. Coene P.P. Schouwink M.H. Tytgat G.N. Esophagogastric carcinoma preoperative TNM classification with endosonography.Radiology. 1989; 173: 411-417Crossref PubMed Scopus (142) Google Scholar, 20Massari M. Cioffi U. De Simone M. Lattuada E. Montorsi M. Segalin A. Bonavina L. Endoscopic ultrasonography for preoperative staging of esophageal carcinoma.Surg Laparosc Endosc. 1997; 7: 162-165Crossref PubMed Scopus (39) Google Scholar Therefore, a more accurate diagnostic modality is necessary for preoperative node evaluation of esophageal cancer. This occurs especially because of the number of lymph nodes involved, their location, and related lymph node stage in esophageal cancer and are considered independent prognostic factors.21Korst R.J. Rusch V.W. Venkatraman E. Bains M.S. Burt M.E. Downey R.J. Ginsberg R.J. Proposed revision of the staging classification for esophageal cancer.J Thorac Cardiovasc Surg. 1998; 115: 660-669Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar The role of FDG PET for the purpose of N staging in esophageal cancer has been addressed by several investigators. In 3 series, FDG PET proved more accurate when compared with CT for locoregional lymph node staging.22Flanagan F.L. Dehdashti F. Siegel B.A. Trask D.D. Sundaresan S.R. Patterson G.A. Cooper J.D. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography.AJR Am J Roentgenol. 1997; 168: 417-424Crossref PubMed Scopus (274) Google Scholar, 23Block M.I. Patterson G.A. Sundaresan R.S. Bailey M.S. Flanagan F.L. Dehdashti F. Siegel B.A. Cooper J.D. Improvement in staging of esophageal cancer with the addition of positron emission tomography.Ann Thorac Surg. 1997; 64: 770-776Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 24Choi J.Y. Lee K.H. Shim Y.M. Lee K.S. Kim J.J. Kim S.E. Kim B.T. Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET.J Nucl Med. 2000; 41: 808-815PubMed Google Scholar In one series, Choi et al.24Choi J.Y. Lee K.H. Shim Y.M. Lee K.S. Kim J.J. Kim S.E. Kim B.T. Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET.J Nucl Med. 2000; 41: 808-815PubMed Google Scholar not only compared FDG PET with CT but also with EUS. It was found that FDG PET was able to identify correctly lymph node involvement in 83% of the patients vs. 60% and 58% for CT and EUS, respectively. In addition, FDG PET showed a better accuracy (86%) for the detection of an individual lymph node group metastasis. In 2 other studies, FDG PET either proved inferior to CT scan for locoregional lymph node involvement assessment25Meltzer C.C. Luketich J.D. Friedman D. Charron M. Strollo D. Meehan M. Urso G.K. Dachille M.A. Townsend D.W. Whole-body FDG positron emission tomographic imaging for staging esophageal cancer, comparison with computed tomography.Clin Nucl Med. 2000; 11: 882-887Crossref Scopus (127) Google Scholar or unable to separate and clearly define involved locoregional lymph nodes from primary tumor tissue.16McAteer D. Wallis F. Couper G. Norton M. Welch A. Bruce D. Park K. Nicolson M. Gilbert F.J. Sharp P. Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma.Br J Radiol. 1999; 72: 525-529PubMed Google Scholar With the introduction of PET/CT cameras, which add complementary anatomic detail, the latter problem largely may be circumvented. Regarding M staging, several pilot studies suggested that FDG PET is superior to conventional imaging for the detection of occult distant metastases.13Kole A.C. Plukker J.T. Nieweg O.E. Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy.Br J Cancer. 1998; 78: 521-527Crossref PubMed Scopus (183) Google Scholar, 22Flanagan F.L. Dehdashti F. Siegel B.A. Trask D.D. Sundaresan S.R. Patterson G.A. Cooper J.D. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography.AJR Am J Roentgenol. 1997; 168: 417-424Crossref PubMed Scopus (274) Google Scholar, 23Block M.I. Patterson G.A. Sundaresan R.S. Bailey M.S. Flanagan F.L. Dehdashti F. Siegel B.A. Cooper J.D. Improvement in staging of esophageal cancer with the addition of positron emission tomography.Ann Thorac Surg. 1997; 64: 770-776Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 26Luketich J.D. Friedman D.M. Weigel T.L. Meehan M.A. Keenan R.J. Townsend D.W. Meltzer C.C. Evaluation of distant metastases in esophageal cancer 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68: 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 27Lerut T. Flamen P. Ectors N. Van Cutsem E. Peeters M. Hiele M. De Wever W. Coosemans W. Decker G. Deleyne P. Deneffe G. van Raemdonck D. Mortelmans L. Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction.Ann Surg. 2000; 232: 743-752Crossref PubMed Scopus (248) Google Scholar For instance, in a series of 100 consecutive PET scans analyzed retrospectively, FDG PET was able to detect distant metastases with a sensitivity and specificity of 69% and 93.4% vs. 46.1% and 73.8%, respectively, for CT.26Luketich J.D. Friedman D.M. Weigel T.L. Meehan M.A. Keenan R.J. Townsend D.W. Meltzer C.C. Evaluation of distant metastases in esophageal cancer 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68: 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar Thus, FDG PET might improve the detection rate of stage IV disease as compared with conventional staging modalities. Accordingly, FDG PET has the potential to modify the individual treatment strategy of patients suffering from esophageal cancer, avoiding unnecessary surgery or modifying the surgical approach. Although no study unequivocally proves the benefit, several cancer centers treat patients suffering from locoregional esophageal cancer by neoadjuvant chemoradiation. The usefulness of FDG PET to assess the efficacy of such treatment recently has been evaluated prospectively.28Flamen P. Van Cutsem E. Lerut A. Cambier J.P. Haustermans K. Bormans G. De Leyn P. Van Raemdonck D. De Wever W. Ectors N. Maes A. Mortelmans L. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer.Ann Oncol. 2002; 13: 361-368Crossref PubMed Scopus (317) Google Scholar Results of this study, performed in 36 patients, revealed that patients classified as responders based on FDG PET (expressed as a > 80% reduction of tumor-to-liver uptake ratio) had a better overall survival when compared with nonresponders (16.3 vs. 6.4 months). Additionally, a significant correlation was found between lymph node involvement detected by pretherapy FDG PET and therapy response rate. Analogous findings were reported by Kato et al.29Kato H. Kuwano H. Nakajima M. Miyazaki T. Yoshikawa M. Masuda N. Fukuchi M. Manda R. Tsukada K. Oriuchi N. Endo K. Usefulness of positron emission tomography for assessing the response of neoadjuvant chemoradiotherapy in patients with esophageal cancer.Am J Surg. 2002; 184 (abstr): 279Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar These investigators showed a significant association between the tumor response as assessed by histology with both the reduction in the extent of FDG uptake and the standardized uptake value (a quantitative marker of FDG uptake). To conclude, for the purpose of preoperative staging, FDG PET can be advocated for M staging in patients suffering from esophageal carcinoma in whom conventional staging results are indeterminate or contradictory. T staging in these patients belongs to the morphologic imaging domain whereas N staging by FDG PET proved equally as disappointing as with EUS or CT. Available data on treatment monitoring in esophageal tumors are preliminary and additional studies are mandatory. Cancer of the stomach bears an extremely poor prognosis. Its incidence in the Western World is increasing rapidly. Risk factors in the development of gastric cancer are diets rich in salted, smoked, or poorly preserved foods and Helicobacter pylori infection. Atrophic gastritis, pernicious anemia, gastric polyps, partial gastrectomy, Menetrier’s disease, and hereditary factors are other predisposing factors.30Davis G.R. Neoplasms of the stomach.in: Schleisinger M.H. Fordtran J. Gastrointestinal disease. 5th ed. Saunders, Philadelphia1994: 763-848Google Scholar, 31Elder J.B. Carcinoma of the stomach.in: Haubrich W.S. Schaffnerr F. Bockus gastroenterology. 5th ed. Saunders, Philadelphia1995: 854-874Google Scholar Conventional diagnostic imaging of primary gastric carcinoma is based predominantly on upper gastrointestinal contrast studies. CT and EUS are the most commonly used modalities in the further staging and assessment of resectability. However, the reported accuracy of CT for staging gastric cancer is variable. Although initial reports were extremely optimistic, later reports proved far from promising. The major limitations of CT scan for the purpose of staging gastric cancer appear to be its inability to identify metastases in normal-sized lymph nodes, its inability to differentiate enlarged inflammatory or reactive lymph nodes from metastasized lymph nodes, and its inability to identify peritoneal carcinomatosis and small liver metastases. As for EUS, although it is considered the most sensitive preoperative test for detecting suspicious adenopathies near the gastric wall, reported sensitivities do not exceed 80%. Additionally, the technique is invasive and operator dependent.32Tunaci M. Carcinoma of stomach and duodenum radiologic diagnosis and staging.Eur J Radiol. 2002; 42: 181-192Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar After curative gastrectomy, over 80% of patients develop disease recurrence, some of which develops early (mostly 5 years disease-free interval).33Glimelius N. Ekström K. Hoffman K. Graf W. Sjodon P.O. Haglund U. Svensson C. Enander L.K. Linne T. Sellstrom H. Heuman R. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer.Ann Oncol. 1997; 8: 163-168Crossref PubMed Scopus (720) Google Scholar, 34Akoh J.A. McIntyre I.M.C. Improving survival in gastric cancer review of 5-year survival rates in English language publications from 1970.Br J Surg. 1992; 79: 293-299Crossref PubMed Scopus (211) Google Scholar, 35Shiraishi N. Inomata M. Osawa N. Yasuda K. Adachi Y. Kitano S. Early and late recurrence after gastrectomy for gastric carcinoma.Cancer. 2000; 89: 255-261Crossref PubMed Scopus (163) Google Scholar In the latter group, death from recurrence is rare. Although CT is performed routinely to exclude recurrences of gastric cancer, substantial evidence supporting a role for CT for this purpose is lacking.36Fukuya T. Honda H. Hayashi T. Kaneko K. Tateshi Y. Po T. Maehara Y. Tanaka M. Tsuneyushi M. Masuda K. Lymph node metastases efficacy for detection with helical CT in patients with gastric cancer.Radiology. 1995; 197: 705-711PubMed Google Scholar Despite the shortcomings of currently available imaging modalities in both the staging and detection of recurrence of gastric cancer patients, to date only a limited number of investigators have addressed the potential of FDG PET to visualize primary gastric carcinoma as well as recurrences. McAteer et al.37McAteer D. Wallis F. Couper G. Norton M. Welch A. Bruce D. Park K. Nicolson M. Gilbert F.J. Sharp P. Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma.Br J Radiol. 1999; 72: 525-529PubMed Google Scholar found uptake of FDG in 2 histologically proven primary gastric carcinomas, both T3 tumors. Both patients suffered from N2 disease, which was not identified as separate areas of high activity on PET. Couper et al.38Couper G.W. McAteer D. Wallis F. Norton M. Welch A. Nicholson M. Park K.G. Detection of response to chemotherapy using positron emission tomography in patients with oesophageal and gastric cancer.Br J Surg. 1998; 85: 1403-1406Crossref PubMed Scopus (96) Google Scholar studied a mix of esophageal and gastric cancer patients scheduled to undergo combination chemotherapy. Thirteen of 14 primary lesions were imaged successfully before treatment initiation. The number of gastric carcinomas studied, however, was not mentioned in this report, nor was the potential of FDG PET to detect distant metastases addressed. De Potter et al.39De Potter T. Flamen P. Van Cutsem E. Penninckx F. Filez L. Bormans G. Maes A. Mortelmans L. Whole-body PET with FDG for the diagnosis of recurrent gastric cancer.Eur J Nucl Med. 2002; 29: 525-529Crossref Scopus (146) Google Scholar evaluated 33 patients who had received surgical treatment for gastric cancer with curative intent and who subsequently had undergone FDG PET to exclude recurrence. The overall sensitivity and specificity of FDG PET for diagnosis of recurrence in this series were 70% (14 of 20) and 69% (9 of 13), respectively. The sensitivity for non-signet ring cell carcinomas was slightly higher as compared with tumors with a signet cell differentiation (75% vs. 63%). The lower sensitivity for the detection of signet cell carcinoma hypothetically may result from the high content of metabolically inert mucus leading to reduced FDG uptake, below the detection limits of the PET camera, or from the lack of glucose-1 transporters on the cell membrane on most signet ring cell carcinomas. Interestingly, patients showing FDG uptake had a lower survival time confirming that the FDG avidity, which is correlated with tumor cell metabolism, could represent a prognostic factor, independently from primary tumor staging. In conclusion, available data suggest that FDG PET for the purpose of staging or detection of recurrence in patients suffering from gastric cancer still should be considered experimental. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with an annual incidence ranging from 30 in 100,000 people in Southeast Asia to 2 in 100,000 people in Northern Europe and the United States. Important risk factors for the development of HCC are alcohol abuse and chronic infection with hepatitis B or C virus.40Di Bisceglie A.M. Hepatitis C and hepatocellular carcinoma.Hepatology. 1997; 26: 34-38Crossref PubMed Scopus (427) Google Scholar, 41Haydon G.H. Hayes P.C. 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