Lymphoepithelioma-Like Carcinoma in Liver
2017; Elsevier BV; Volume: 187; Issue: 7 Linguagem: Inglês
10.1016/j.ajpath.2017.02.022
ISSN1525-2191
AutoresIsmaïl Labgaa, Ashley Stueck, Stephen C. Ward,
Tópico(s)Cancer-related molecular mechanisms research
ResumoLiver cancer, primarily encompassing hepatocellular carcinoma and intrahepatic cholangiocarcinoma, has become the second leading cause of worldwide cancer-related death during the past two decades. Lymphoepithelioma-like carcinomas (LELCs) are defined as tumors composed of undifferentiated epithelial cells with a prominent lymphoid infiltrate, and can arise in the liver as hepatocellular or cholangiocarcinoma forms. Patients with liver LELC display distinctive demographics and tumor characteristics. LELCs also appear to be associated with strikingly better outcomes compared to typical liver cancers, with 5-year survival rates of 57% to 100% versus 12% to 68%, respectively. Liver LELCs represent a unique model of immune response in liver cancer. Data on LELCs of the liver remain limited, and future comprehensive studies are needed to further elucidate this disease, which could ultimately offer precious insights for immunotherapeutic strategies in liver cancer. Liver cancer, primarily encompassing hepatocellular carcinoma and intrahepatic cholangiocarcinoma, has become the second leading cause of worldwide cancer-related death during the past two decades. Lymphoepithelioma-like carcinomas (LELCs) are defined as tumors composed of undifferentiated epithelial cells with a prominent lymphoid infiltrate, and can arise in the liver as hepatocellular or cholangiocarcinoma forms. Patients with liver LELC display distinctive demographics and tumor characteristics. LELCs also appear to be associated with strikingly better outcomes compared to typical liver cancers, with 5-year survival rates of 57% to 100% versus 12% to 68%, respectively. Liver LELCs represent a unique model of immune response in liver cancer. Data on LELCs of the liver remain limited, and future comprehensive studies are needed to further elucidate this disease, which could ultimately offer precious insights for immunotherapeutic strategies in liver cancer. Liver cancer is now the fifth leading cause of cancer incidence in males, worldwide.1Torre L.A. Bray F. Siegel R.L. Ferlay J. Lortet-Tieulent J. Jemal A. Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108Crossref PubMed Scopus (23568) Google Scholar Associated with dismal outcomes, its 5-year survival rate is only 16% in the United States, making it the most aggressive malignancy after pancreatic cancer.2DeSantis C.E. Lin C.C. Mariotto A.B. Siegel R.L. Stein K.D. Kramer J.L. Alteri R. Robbins A.S. Jemal A. Cancer treatment and survivorship statistics, 2014.CA Cancer J Clin. 2014; 64: 252-271Crossref PubMed Scopus (2397) Google Scholar During the past 20 years, the number of deaths caused by liver cancer has doubled, and it is now the second leading cause of cancer-related death in the world.3Murray C.J. Vos T. Lozano R. Naghavi M. Flaxman A.D. Michaud C. et al.Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2197-2223Abstract Full Text Full Text PDF PubMed Scopus (6334) Google Scholar As a consequence, liver cancer has dramatically become the leading cause of increasing mortality in the United States during the past two decades.4Llovet J.M. Villanueva A. Lachenmayer A. Finn R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era.Nat Rev Clin Oncol. 2015; 12: 436Crossref PubMed Scopus (101) Google Scholar Most primary liver cancer is composed by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCC). Both tumor types are associated with low survival rates because of their biological aggressiveness, but also because most patients are diagnosed at advanced stages, when therapeutic options remain limited. Substantial efforts have been pursued to better characterize these tumors, on both pathological and genomic levels, allowing the identification of distinctive molecular subclasses. However, these advances have not yet been translated into clinical practice to guide decision making for the management of liver cancer. Originally described in the nasopharynx, lymphoepithelioma-like carcinoma (LELC) is defined as a tumor composed of undifferentiated epithelial cells with a prominent lymphoid infiltrate. Cases were subsequently reported in many other organs, including in liver.5Solinas A. Calvisi D.F. Lessons from rare tumors: hepatic lymphoepithelioma-like carcinomas.World J Gastroenterol. 2015; 21: 3472-3479Crossref PubMed Scopus (22) Google Scholar Hepatic cases of LELC have been observed for both HCC and iCC, and were further designated lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) and lymphoepithelioma-like cholangiocarcinoma (LEL-CC), respectively. LELC of the liver is a relatively rare finding, but the number of reported cases has strikingly increased during the past few years (Figure 1), with data suggesting that this entity may have been underestimated or underrecognized. Not only of great interest for their epidemiological and pathological features, liver LELCs are also associated with markedly better outcomes than typical HCC and iCC. Hepatic LELCs represent a unique model of immune response against liver cancer that may be related to survival benefits, and this deserves further study. This is therefore of particular pertinence, especially when considering the expanding role of immunotherapy in cancer treatment. This review aims to provide a comprehensive overview of the available data on hepatic LELC from epidemiological, clinical, pathological, and research perspectives. To date, 66 cases of LEL-HCC have been reported and are detailed in Table 1. Available demographics of the patients and features of the tumors are displayed in Table 2. Overall, patients were mostly males (64%), with a median age of 58 years (Figure 2A). Sixty-five percent of patients were white, whereas 30% were Asian. The underlying liver was cirrhotic in 46% of the cases, with hepatitis B virus and hepatitis C virus being the underlying cause in 40% and 34%, respectively. Most patients had early-stage HCC, with most single lesions (88%), a median size of 38 mm, and 86% falling within Barcelona Clinic Liver Cancer Group Stage 0-A. Most patients underwent surgical resection [59/65 (91%)], whereas the remaining six LEL-HCC had orthotopic liver transplant.Table 1Reported Cases of LEL-HCCReferenceSexAge, yearsRaceHBV+HCV+EBV+CirrhosisAFP (>20 μg/L)BCLC (0/A)No. of lesionsSize, mmVascular invasionTreatmentFU, monthsOutcomesAn et al6An S.L. Liu L.G. Zheng Y.L. Rong W.Q. Wu F. Wang L.M. Feng L. Liu F.Q. Tian F. Wu J.X. Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature.Int J Clin Exp Pathol. 2015; 8: 3282-3287PubMed Google ScholarM50Asian−+−++−135+LR6AWDChen et al7Chen C.J. Jeng L.B. Huang S.F. Lymphoepithelioma-like hepatocellular carcinoma.Chang Gung Med J. 2007; 30: 172-177PubMed Google ScholarM56Asian−+−+++132−LR21DODCacciato Insilla et al8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google ScholarF81NA−+−−++172NALR15AWODShinoda et al9Shinoda M. Kadota Y. Tsujikawa H. Masugi Y. Itano O. Ueno A. Mihara K. Hibi T. Abe Y. Yagi H. Kitago M. Kawachi S. Tanimoto A. Sakamoto M. Tanabe M. Kitagawa Y. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Surg Oncol. 2013; 11: 97Crossref PubMed Scopus (27) Google ScholarM79Asian−−−−++142−LR20NAWei et al10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google ScholarF42Asian−−−++146NALR8AWODWada et al11Wada Y. Nakashima O. Kutami R. Yamamoto O. Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration.Hepatology. 1998; 27: 407-414Crossref PubMed Scopus (298) Google Scholar10 M/1 F62NA0/1111/11NA6/11NANANA221+/11LR5-y survival: 100%Park et al12Park H.S. Jang K.Y. Kim Y.K. Cho B.H. Moon W.S. Hepatocellular carcinoma with massive lymphoid infiltration: a regressing phenomenon?.Pathol Res Pract. 2009; 205: 648-652Crossref PubMed Scopus (29) Google ScholarM57Asian+−−+−+127NANA60AWODEmile et al13Emile J.F. Adam R. Sebagh M. Marchadier E. Falissard B. Dussaix E. Bismuth H. Reynes M. Hepatocellular carcinoma with lymphoid stroma: a tumour with good prognosis after liver transplantation.Histopathology. 2000; 37: 523-529Crossref PubMed Scopus (46) Google ScholarM50White++−+−+140−OLT120AWODM54White−−−−−+Multifocal20−OLT92DODM59White++−+−−Multifocal50−OLT96AWODM45White−+−+−+120−OLT56AWDM64White−−−+−−Multifocal40+OLT36AWODSi et al14Si M.W. Thorson J.A. Lauwers G.Y. DalCin P. Furman J. Hepatocellular lymphoepithelioma-like carcinoma associated with epstein barr virus: a hitherto unrecognized entity.Diagn Mol Pathol. 2004; 13: 183-189Crossref PubMed Scopus (36) Google ScholarF39Latino−++++110+OLT5PODNemolato et al15Nemolato S. Fanni D. Naccarato A.G. Ravarino A. Bevilacqua G. Faa G. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Gastroenterol. 2008; 14: 4694-4696Crossref PubMed Scopus (36) Google ScholarF47NA−−−−+122NALR15AWODShirabe et al16Shirabe K. Matsumata T. Maeda T. Sadanaga N. Kuwano H. Sugimachi K. A long-term surviving patient with hepatocellular carcinoma including lymphocytes infiltration: a clinicopathological study.Hepatogastroenterology. 1995; 42: 996-1001PubMed Google ScholarF58Asian+−NA+++122NALR78AWODPatel et al17Patel K.R. Liu T.C. Vaccharajani N. Chapman W.C. Brunt E.M. Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases.Arch Pathol Lab Med. 2014; 138: 1193-1202Crossref PubMed Scopus (27) Google ScholarF74White−−−−−−Multifocal65+LR24DODM65White−−−−−+148−LR60UDF65White−−−−++113−LR108AWODF70White−−−−++127−LR72AWODF61White−−−−−−Multifocal95+LR4UDM78White−−−−−+1105+LR48AWDF78White−−−−−+160−LR24AWODF57White−−−−−−1130+LR1UDChan et al18Chan A.W. Tong J.H. Pan Y. Chan S.L. Wong G.L. Wong V.W. Lai P.B. To K.F. Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome.Am J Surg Pathol. 2015; 39: 304-312Crossref PubMed Scopus (42) Google Scholar13 M/7 F58NA17/20008+/2013/2020+/2013815% micro; 10% macroLR5-y survival: 88%Calderaro J et al19Calderaro J. Rousseau B. Amaddeo G. Mercey M. Charpy C. Costentin C. Luciani A. Zafrani E.S. Laurent A. Azoulay D. Lafdil F. Pawlotsky J.M. PD-L1 expression in hepatocellular carcinoma: relationship with clinical and pathological features.Hepatology. 2016; 64: 2038-2046Crossref PubMed Scopus (260) Google Scholar reported 13 cases of LEL-HCC as part of a larger cohort of patients undergoing liver resection for HCC, but no further information regarding this subset of patients was provided.F, female; M, male; +, positive; −, negative; AFP, α-fetoprotein; AWD, alive with disease; AWOD, alive without disease; BCLC, Barcelona Clinic Liver Cancer Group Stage; DOD, died of disease; EBV, Epstein-Barr virus; FU, follow-up; HBV, hepatitis B virus; HCV, hepatitis C virus; LEL-HCC, lymphoepithelioma-like hepatocellular carcinoma; LR, liver resection; NA, not available; OLT, orthotopic liver transplant; POD, postoperative death; UD, unrelated death. Open table in a new tab Table 2Patient Demographics and Tumor CharacteristicsVariableLEL-HCC (n = 66)LEL-CC (n = 27)Sex, male34/53 (64)9/27 (33)Median age, years (range)58 (58–62)57 (46–64)Race White13/20 (65)2/24 (8) Asian6/20 (30)22/24 (92)HBV+21/53 (40)8/27 (30)HCV+18/53 (34)2/27 (7)EBV+1/41 (2)20/27 (74)Cirrhosis24/52 (46)5/27 (19)AFP, >20 ng/L20/40 (50)NABCLC stage, 0/A36/42 (86)NASingle lesion37/42 (88)24/27 (86)Median size, mm (range)38 (22–38)40 (30–60)Treatment Transplant6/65 (9)0/23 (0) Resection59/65 (91)24/24 (100)Data are given as number/total (percentage) unless otherwise indicated.AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer Group Stage; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; LEL-CC, lymphoepithelioma-like cholangiocarcinoma; LEL-HCC, lymphoepithelioma-like hepatocellular carcinoma; NA, not available. Open table in a new tab Calderaro J et al19Calderaro J. Rousseau B. Amaddeo G. Mercey M. Charpy C. Costentin C. Luciani A. Zafrani E.S. Laurent A. Azoulay D. Lafdil F. Pawlotsky J.M. PD-L1 expression in hepatocellular carcinoma: relationship with clinical and pathological features.Hepatology. 2016; 64: 2038-2046Crossref PubMed Scopus (260) Google Scholar reported 13 cases of LEL-HCC as part of a larger cohort of patients undergoing liver resection for HCC, but no further information regarding this subset of patients was provided. F, female; M, male; +, positive; −, negative; AFP, α-fetoprotein; AWD, alive with disease; AWOD, alive without disease; BCLC, Barcelona Clinic Liver Cancer Group Stage; DOD, died of disease; EBV, Epstein-Barr virus; FU, follow-up; HBV, hepatitis B virus; HCV, hepatitis C virus; LEL-HCC, lymphoepithelioma-like hepatocellular carcinoma; LR, liver resection; NA, not available; OLT, orthotopic liver transplant; POD, postoperative death; UD, unrelated death. Data are given as number/total (percentage) unless otherwise indicated. AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer Group Stage; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; LEL-CC, lymphoepithelioma-like cholangiocarcinoma; LEL-HCC, lymphoepithelioma-like hepatocellular carcinoma; NA, not available. From a pathological standpoint, tumors were grossly well circumscribed, gray-yellow-white and soft, with variable encapsulation.6An S.L. Liu L.G. Zheng Y.L. Rong W.Q. Wu F. Wang L.M. Feng L. Liu F.Q. Tian F. Wu J.X. Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature.Int J Clin Exp Pathol. 2015; 8: 3282-3287PubMed Google Scholar, 7Chen C.J. Jeng L.B. Huang S.F. Lymphoepithelioma-like hepatocellular carcinoma.Chang Gung Med J. 2007; 30: 172-177PubMed Google Scholar, 8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google Scholar, 9Shinoda M. Kadota Y. Tsujikawa H. Masugi Y. Itano O. Ueno A. Mihara K. Hibi T. Abe Y. Yagi H. Kitago M. Kawachi S. Tanimoto A. Sakamoto M. Tanabe M. Kitagawa Y. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Surg Oncol. 2013; 11: 97Crossref PubMed Scopus (27) Google Scholar, 10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google Scholar Histologically, the carcinoma was poorly differentiated, composed of atypical cells with syncytial cytoplasm and nuclei with prominent nucleoli, and infiltrated by abundant lymphocytes (Figure 3A). The dense lymphocytic infiltrate distinguishes LEL-HCC from typical poorly differentiated HCC (Figure 3B). In 1998, Wada et al11Wada Y. Nakashima O. Kutami R. Yamamoto O. Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration.Hepatology. 1998; 27: 407-414Crossref PubMed Scopus (298) Google Scholar proposed using a cutoff of >100 tumor-infiltrating lymphocytes in 10 high-power fields to quantitatively define LEL-HCC. Of note, LEL-HCC was subsequently acknowledged by the World Health Organization as a distinctive variant of HCC "with pleomorphic tumor cells intermixed with numerous lymphocytes," but clear cutoffs for number of lymphocytes is not provided.20Bosman F.T. World Health OrganizationInternational Agency for Research on CancerWHO Classification of Tumours of the Digestive System.ed 4. International Agency for Research on Cancer, Lyon2010Google Scholar A few cases of LEL-HCC had well to moderately differentiated components, but the dense lymphocytic infiltrate was constant,11Wada Y. Nakashima O. Kutami R. Yamamoto O. Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration.Hepatology. 1998; 27: 407-414Crossref PubMed Scopus (298) Google Scholar, 12Park H.S. Jang K.Y. Kim Y.K. Cho B.H. Moon W.S. Hepatocellular carcinoma with massive lymphoid infiltration: a regressing phenomenon?.Pathol Res Pract. 2009; 205: 648-652Crossref PubMed Scopus (29) Google Scholar which is in contrast to the LEL-CC, in which non–lymphoepithelioma-like carcinoma has been frequently noted concurrently. A summary of immunohistochemical expression patterns in the carcinomatous component is shown in Table 3. The carcinoma component expresses pankeratin (eg, AE1/AE3),6An S.L. Liu L.G. Zheng Y.L. Rong W.Q. Wu F. Wang L.M. Feng L. Liu F.Q. Tian F. Wu J.X. Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature.Int J Clin Exp Pathol. 2015; 8: 3282-3287PubMed Google Scholar, 8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google Scholar, 10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google Scholar, 13Emile J.F. Adam R. Sebagh M. Marchadier E. Falissard B. Dussaix E. Bismuth H. Reynes M. Hepatocellular carcinoma with lymphoid stroma: a tumour with good prognosis after liver transplantation.Histopathology. 2000; 37: 523-529Crossref PubMed Scopus (46) Google Scholar, 14Si M.W. Thorson J.A. Lauwers G.Y. DalCin P. Furman J. Hepatocellular lymphoepithelioma-like carcinoma associated with epstein barr virus: a hitherto unrecognized entity.Diagn Mol Pathol. 2004; 13: 183-189Crossref PubMed Scopus (36) Google Scholar low-molecular-weight keratin (eg, K8/18),8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google Scholar, 10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google Scholar epithelial membrane antigen,10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google Scholar and HepPar-1.7Chen C.J. Jeng L.B. Huang S.F. Lymphoepithelioma-like hepatocellular carcinoma.Chang Gung Med J. 2007; 30: 172-177PubMed Google Scholar, 8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google Scholar, 9Shinoda M. Kadota Y. Tsujikawa H. Masugi Y. Itano O. Ueno A. Mihara K. Hibi T. Abe Y. Yagi H. Kitago M. Kawachi S. Tanimoto A. Sakamoto M. Tanabe M. Kitagawa Y. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Surg Oncol. 2013; 11: 97Crossref PubMed Scopus (27) Google Scholar, 12Park H.S. Jang K.Y. Kim Y.K. Cho B.H. Moon W.S. Hepatocellular carcinoma with massive lymphoid infiltration: a regressing phenomenon?.Pathol Res Pract. 2009; 205: 648-652Crossref PubMed Scopus (29) Google Scholar, 14Si M.W. Thorson J.A. Lauwers G.Y. DalCin P. Furman J. Hepatocellular lymphoepithelioma-like carcinoma associated with epstein barr virus: a hitherto unrecognized entity.Diagn Mol Pathol. 2004; 13: 183-189Crossref PubMed Scopus (36) Google Scholar, 15Nemolato S. Fanni D. Naccarato A.G. Ravarino A. Bevilacqua G. Faa G. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Gastroenterol. 2008; 14: 4694-4696Crossref PubMed Scopus (36) Google Scholar, 16Shirabe K. Matsumata T. Maeda T. Sadanaga N. Kuwano H. Sugimachi K. A long-term surviving patient with hepatocellular carcinoma including lymphocytes infiltration: a clinicopathological study.Hepatogastroenterology. 1995; 42: 996-1001PubMed Google Scholar Glypican-3 was expressed when tested in two cases.10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google Scholar, 13Emile J.F. Adam R. Sebagh M. Marchadier E. Falissard B. Dussaix E. Bismuth H. Reynes M. Hepatocellular carcinoma with lymphoid stroma: a tumour with good prognosis after liver transplantation.Histopathology. 2000; 37: 523-529Crossref PubMed Scopus (46) Google Scholar There may be focal expression of K19,6An S.L. Liu L.G. Zheng Y.L. Rong W.Q. Wu F. Wang L.M. Feng L. Liu F.Q. Tian F. Wu J.X. Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature.Int J Clin Exp Pathol. 2015; 8: 3282-3287PubMed Google Scholar, 7Chen C.J. Jeng L.B. Huang S.F. Lymphoepithelioma-like hepatocellular carcinoma.Chang Gung Med J. 2007; 30: 172-177PubMed Google Scholar, 17Patel K.R. Liu T.C. Vaccharajani N. Chapman W.C. Brunt E.M. Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases.Arch Pathol Lab Med. 2014; 138: 1193-1202Crossref PubMed Scopus (27) Google Scholar K7,7Chen C.J. Jeng L.B. Huang S.F. Lymphoepithelioma-like hepatocellular carcinoma.Chang Gung Med J. 2007; 30: 172-177PubMed Google Scholar K20,6An S.L. Liu L.G. Zheng Y.L. Rong W.Q. Wu F. Wang L.M. Feng L. Liu F.Q. Tian F. Wu J.X. Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature.Int J Clin Exp Pathol. 2015; 8: 3282-3287PubMed Google Scholar and polyclonal carcinoembryonic antigen (canalicular pattern).8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google Scholar, 17Patel K.R. Liu T.C. Vaccharajani N. Chapman W.C. Brunt E.M. Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases.Arch Pathol Lab Med. 2014; 138: 1193-1202Crossref PubMed Scopus (27) Google Scholar p16 was expressed in three of eight cases tested; human papilloma virus was not identified by in situ hybridization (ISH).17Patel K.R. Liu T.C. Vaccharajani N. Chapman W.C. Brunt E.M. Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases.Arch Pathol Lab Med. 2014; 138: 1193-1202Crossref PubMed Scopus (27) Google Scholar Only one case was assessed for p53, and wild-type expression was found.12Park H.S. Jang K.Y. Kim Y.K. Cho B.H. Moon W.S. Hepatocellular carcinoma with massive lymphoid infiltration: a regressing phenomenon?.Pathol Res Pract. 2009; 205: 648-652Crossref PubMed Scopus (29) Google Scholar In the infiltrating lymphocyte population, most cells were CD3-positive T cells, with focal CD20-positive B cells noted.7Chen C.J. Jeng L.B. Huang S.F. Lymphoepithelioma-like hepatocellular carcinoma.Chang Gung Med J. 2007; 30: 172-177PubMed Google Scholar, 8Cacciato Insilla A. Faviana P. Pollina L.E. De Simone P. Coletti L. Filipponi F. Campani D. Lymphoepithelioma-like hepatocellular carcinoma: case report and review of the literature.World J Gastroenterol. 2015; 21: 10468-10474Crossref PubMed Scopus (17) Google Scholar, 9Shinoda M. Kadota Y. Tsujikawa H. Masugi Y. Itano O. Ueno A. Mihara K. Hibi T. Abe Y. Yagi H. Kitago M. Kawachi S. Tanimoto A. Sakamoto M. Tanabe M. Kitagawa Y. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Surg Oncol. 2013; 11: 97Crossref PubMed Scopus (27) Google Scholar, 10Wei J. Liu Q. Wang C. Yu S. Lymphoepithelioma-like hepatocellular carcinoma without Epstein-Barr virus infection: a case report and a review of the literature.Indian J Pathol Microbiol. 2015; 58: 550-553Crossref PubMed Scopus (12) Google Scholar, 11Wada Y. Nakashima O. Kutami R. Yamamoto O. Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration.Hepatology. 1998; 27: 407-414Crossref PubMed Scopus (298) Google Scholar, 12Park H.S. Jang K.Y. Kim Y.K. Cho B.H. Moon W.S. Hepatocellular carcinoma with massive lymphoid infiltration: a regressing phenomenon?.Pathol Res Pract. 2009; 205: 648-652Crossref PubMed Scopus (29) Google Scholar, 13Emile J.F. Adam R. Sebagh M. Marchadier E. Falissard B. Dussaix E. Bismuth H. Reynes M. Hepatocellular carcinoma with lymphoid stroma: a tumour with good prognosis after liver transplantation.Histopathology. 2000; 37: 523-529Crossref PubMed Scopus (46) Google Scholar, 14Si M.W. Thorson J.A. Lauwers G.Y. DalCin P. Furman J. Hepatocellular lymphoepithelioma-like carcinoma associated with epstein barr virus: a hitherto unrecognized entity.Diagn Mol Pathol. 2004; 13: 183-189Crossref PubMed Scopus (36) Google Scholar, 16Shirabe K. Matsumata T. Maeda T. Sadanaga N. Kuwano H. Sugimachi K. A long-term surviving patient with hepatocellular carcinoma including lymphocytes infiltration: a clinicopathological study.Hepatogastroenterology. 1995; 42: 996-1001PubMed Google Scholar, 17Patel K.R. Liu T.C. Vaccharajani N. Chapman W.C. Brunt E.M. Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases.Arch Pathol Lab Med. 2014; 138: 1193-1202Crossref PubMed Scopus (27) Google Scholar, 18Chan A.W. Tong J.H. Pan Y. Chan S.L. Wong G.L. Wong V.W. Lai P.B. To K.F. Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome.Am J Surg Pathol. 2015; 39: 304-312Crossref PubMed Scopus (42) Google Scholar The T-cell population was predominantly CD8 positive,9Shinoda M. Kadota Y. Tsujikawa H. Masugi Y. Itano O. Ueno A. Mihara K. Hibi T. Abe Y. Yagi H. Kitago M. Kawachi S. Tanimoto A. Sakamoto M. Tanabe M. Kitagawa Y. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature.World J Surg Oncol. 2013; 11: 97Crossref PubMed Scopus (27) Google Scholar, 10Wei J. Liu Q. Wang C. Yu S. 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