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We report a case of hepatic lymphoepithelioma-like carcinoma-hepatocellular carcinoma subtype (LEL-HCC) in a 41-year-old man with chronic hepatitis C virus (HCV) infection. The patient presented with abdominal pain and further assessment revealed a hypoechoic mass on ultrasonography. Serum alpha-fetoprotein (AFP) was 13·6 ng/dl. The patient was diagnosed as hepatocellular carcinoma based on the established triphasic computed tomography (TCT) diagnostic criteria and he underwent a surgical resection of the mass. Microscopic examination showed sheets and cords of malignant epithelial cells intermixed with heavy lymphoid infiltrate, with more than 100 tumor-infiltrating lymphocytes (TILs) per 10 high-power-field (HPF). Based on immunohistochemical studies, the malignant cells were positive for Hep Par 1 and glypican 3, focally positive for cytokeratin 7 (CK7), and negative for cytokeratin 20 (CK20). TILs were diffusely positive for cluster of differentiation 3 CD3 with an approximately equal CD4/CD8 ratio. The patient was recurrence free at 25 months after surgery, as evident by CT and serum alpha-fetoprotein level. LEL-HCC is a rare variant of HCC with a relatively better prognosis. Exploring the potential for immune modulator-based therapy in this subset of tumors is highly recommended.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a distinct variant of HCC that is characterized by dense tumor-infiltrating lymphocytes (TILs). Patients with LEL-HCC also show better clinical outcomes compared to conventional HCC (c-HCC), which is commonly presented with low TIL. Emerging evidence has begun to highlight tumor-intrinsic genetic abnormalities in the tumor-host immune interfaces. However, genome-wide characterization of LEL-HCC remains largely unexplored. Here, we defined the genomic landscape of 12 LEL-HCC using whole-exome sequencing, and further underpinned those genetic alterations related to an immune active microenvironment by comparing findings to 15 c-HCC that were sequenced in parallel. Overall, the mutational load between LEL-HCC and c-HCC was similar. Interestingly, SNV incidences of specific genes (CTNNB1, AXIN1, NOTCH1, and NOTCH2) were significantly higher in c-HCC than LEL-HCC, suggesting a plausible link between activated Wnt/β-catenin and Notch signaling pathways and immune avoidance. Marked focal amplification of chromosome 11q13.3 was prevalent in LEL-HCC. Using The Cancer Genome Atlas dataset, we further established oncogenes expressed from chromosome 11q13.3 (CCND1, FGF19, and FGF4) to be strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Our results have illustrated for the first time the somatic landscape of LEL-HCC, and highlighted molecular alterations that could be exploited in combinatory therapy with checkpoint inhibitors in targeting HCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

Lymphoepithelioma-like carcinoma (LELC) of the liver is extremely rare, and lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant form of HCC, exhibiting relatively good prognosis compared to conventional HCC. LELC is defined as a tumour composed of undifferentiated epithelial cells with densely infiltrating lymphoid stroma. LEL-HCC represents a unique immune response against tumour cells, which may contribute to the superior clinical outcomes. However, the exact aetiology remains unknown. We report a case of a 76-year-old man with a prior hepatitis B virus infection. A 20 mm tumour was detected in the liver. Microscopically, the tumour displayed characteristics of poorly differentiated HCC with a dense lymphocytic and plasma cell infiltration and was diagnosed as LEL-HCC. We describe a unique pathological finding with immunohistochemical data demonstrating T-cell dominant lymphocytic and polyclonal plasma cell infiltration, along with programmed death ligand 1 expression in the tumour cells and lymphocytes.

Rationale: Most cases of primary liver cancer involve hepatocellular carcinoma (HCC). Lymphoepithelioma-like carcinoma (LELC) is defined as a tumor composed of undifferentiated epithelial cells with a prominent lymphoid infiltrate, which is rarely reported. Lymphoepithelioma-like HCC (LEL-HCC) is an uncommon variant of HCC, having an unclear process of development. Here, we report the first case involving simultaneous HCC and LEL-HCC. Patient concerns: A 77-year-old female was accidentally found to have a hypoechoic hepatic nodule via an abdominal ultrasound during a health examination. Abdominal computed tomography scan revealed 2 hepatic nodules with arterial phase enhancement and washout in the late phase. Diagnoses: We diagnosed the case with 2 distinct liver nodules, HCC and LEL-HCC. Interventions: With suspicion of HCC, tumor resection (liver segments 4 and 5) was then performed. Histopathological examination of tumor 1 showed a moderately differentiated HCC and tumor 2 demonstrated a LEL-HCC. Immunohistochemically, the cells of tumor 2 were immunoreactive for cytokeratin (CK), CK7, and CK19. Epstein–Barr virus encoding small RNA (EBER) in situ hybridization results were negative. Outcomes: Six months after resection, intrahepatic tumor recurrence was noted. Radiofrequency ablation was conducted. Lessons: This is an interesting case providing circumstantial evidence of simultaneous development of HCC and LEL-HCC in distinct nodules of the liver with a background of chronic hepatitis B virus infection.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant of HCC with only 22 cases reported in the literature. To better determine the incidence, clinicopathologic features, prognostic significance, and molecular pathogenesis of LEL-HCC, we presented the largest series of LEL-HCC from a 9-year retrospective cohort of patients with HCC undergoing surgical resection. LEL-HCC was identified in 20 patients (4.9%). Compared with patients having HCC without significant tumor-infiltrating lymphocyte (TIL), patients with LEL-HCC had a relatively lower frequency of male sex (P=0.022), tended to present at early-stage disease (80.0% vs. 56.3% as AJCC stage I, P=0.037; 100% vs. 77.3% as BCLC stage 0/A, P=0.010), and all harbored a solitary tumor only (P=0.006). There was no significant difference in the age at presentation, underlying chronic liver disease, cirrhotic background, serum α-fetoprotein level, tumor size, histologic grade, and frequencies of vascular invasion. Most of the TILs in LEL-HCC were cytotoxic T lymphocytes. None of the LEL-HCCs was associated with Epstein-Barr virus. LEL-HCC was associated with better overall (5-y survival: 94.1% vs. 63.9%; P=0.007) and progression-free (5-y survival: 87.8% vs. 46.6%; P=0.002) survivals compared with HCC without significant TIL. The multivariate analysis revealed that LEL-HCC was an independent prognostic factor for overall and progression-free survivals. The adjusted hazard ratio of cancer death and tumor progression for LEL-HCC was 0.12 (P=0.037) and 0.14 (P=0.002), respectively. LEL-HCC did not differ in frequencies of microsatellite instability, BRAF mutation, and DNA hypermethylation. In brief, LEL-HCC is a distinct uncommon variant of HCC characterized by dense cytotoxic T-cell infiltration and favorable prognosis.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a rare form of undifferentiated carcinoma of the liver characterized by the presence of an abundant lymphoid infiltrate. Here, a case of LEL-HCC is described. An 81-year-old woman with a chronic hepatitis C infection was referred to the general surgery department of our hospital in August 2013 with a diagnosis of HCC. A past ultrasound examination had revealed a 60 mm-diameter nodular lesion in the third segment of the liver. After a needle biopsy, the lesion was diagnosed as HCC. The patient underwent surgery with a liver segmentectomy. Two additional nodes on the gastric wall were detected during the surgical operation. The histology of the removed specimen showed a poorly differentiated HCC with significant lymphoid stroma. Immunohistochemical studies revealed that the epithelial component was reactive for CK CAM5.2, CK8, CK18, CEA (polyclonal) and was focally positive for hepar-1 and that the lymphoid infiltrate was positive for CD3, CD4 and CD8. The tumor cells were negative for Epstein-Barr virus. The gastric nodes were ultimately determined to be two small gastrointestinal stromal tumors (GISTs). The synchronous occurrence of HCC and GIST is another very uncommon finding rarely described in the literature. Here, we report the clinicopathological features of our case, along with a review of the few cases present in the literature.

In this review we focus on lymphoepithelioma-like hepatocellular carcinomas (LEL-HCC) and lymphoepithelioma-like cholangiocarcinomas (LEL-ICC). Despite their rarity, these tumors are of general interest because of their epidemiological and clinical features, and because they represent a distinct model of interaction between the immune system and neoplastic cells. Approximately half of LEL-HCC arise in the context of chronic hepatitis C virus (HCV) infection and have been described both in Eastern and Western patients. By contrast, LEL-ICC is associated in almost all cases with Epstein-Barr virus (EBV) infection and exhibits the same epidemiological features of EBV related malignancies. Compared with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma of corresponding stage, both LEL-HCC and LEL-ICC are characterized by lower rates of recurrence after surgery and better overall survival. How this behavior is related to distinct genetic alterations and tumor microenvironment is unclear. The pathophysiological mechanisms of lymphoid infiltrations seem to be different among the two groups of tumors. In fact, LEL-HCC frequently arises in the context of inflammatory changes driven by HCV infection, and has been recognized as a variant of classical hepatocellular carcinoma. At variance, lymphocyte recruitment of LEL-ICC is similar to that described in nasopharyngeal carcinoma and gastric LEL, and possibly depends on the expression pattern of latent EBV infection.

We report a case of hepatic lymphoepithelioma-like carcinoma-hepatocellular carcinoma subtype (LEL-HCC) in a 41-year-old man with chronic hepatitis C virus (HCV) infection. The patient presented with abdominal pain and further assessment revealed a hypoechoic mass on ultrasonography. Serum alpha-fetoprotein (AFP) was 13·6 ng/dl. The patient was diagnosed as hepatocellular carcinoma based on the established triphasic computed tomography (TCT) diagnostic criteria and he underwent a surgical resection of the mass. Microscopic examination showed sheets and cords of malignant epithelial cells intermixed with heavy lymphoid infiltrate, with more than 100 tumor-infiltrating lymphocytes (TILs) per 10 high-power-field (HPF). Based on immunohistochemical studies, the malignant cells were positive for Hep Par 1 and glypican 3, focally positive for cytokeratin 7 (CK7), and negative for cytokeratin 20 (CK20). TILs were diffusely positive for cluster of differentiation 3 CD3 with an approximately equal CD4/CD8 ratio. The patient was recurrence free at 25 months after surgery, as evident by CT and serum alpha-fetoprotein level. LEL-HCC is a rare variant of HCC with a relatively better prognosis. Exploring the potential for immune modulator-based therapy in this subset of tumors is highly recommended.

Aims Carcinomas with lymphoid stroma arising in non-liver-organs have a better prognosis than other carcinomas and may be associated with Epstein-Barr virus. We determined the frequency, characteristics and prognosis of hepatocellular carcinomas with lymphoid stroma. Methods and results Histology of the livers of 162 patients with hepatocellular carcinoma, who underwent an orthotopic liver transplantation, was reviewed independently by three pathologists. Hepatocellular carcinoma with lymphoid stroma was diagnosed when all tumour samples contained more lymphocytes than tumour cells. Epstein-Barr virus was detected by in-situ hybridization and by polymerase chain reaction. Five patients (3.6%) were classified as hepatocellular carcinomas with lymphoid stroma. All patients were males. Cirrhosis was present in four/five patients. Serum alpha-fetoprotein levels were normal. Inter-observer histological reproducibility was good. Tumour cells did not contain Epstein-Barr virus. The five patients were alive without tumour at three years, although two of them had adverse prognostic factors at the time of transplantation (more than one tumour with a diameter > or = 40 mm). Only one patient had tumour recurrence, but he survived 7.6 years post-transplantation. The 5-year survival of patients with hepatocellular carcinoma with lymphoid stroma was better than that of the patients with other types of hepatocellular carcinomas (P = 0.04). Conclusions Hepatocellular carcinoma with lymphoid stroma should be considered as a distinct clinicopathological and prognostic entity.

Lymphoepithelioma-like carcinoma (LELC) of the liver is uncommon, only 20 cases have been reported in the English-language literature so far, and the majority has been identified as cholangiocarcinomas, only four cases were hepatocellular LELC. Here we described a rare case of lymphoepithelioma-like hepatocellular carcinoma (HCC). A 42-year-old Chinese female who was incidentally found to have a liver-occupying lesion during a routine medical examination. Ultrasonography revealed a 47 mm × 33 mm × 36 mm hypoechoic mass in the left lobe. Computed tomography and magnetic resonance imaging displayed a nodular lesions in the left liver lobe. The patient underwent a left-side hepatectomy. Histopathological examination of the resected specimen revealed an undifferentiated carcinoma with a dense lymphocytic infiltrate, predominantly composed of CD3(+) T cells, morphologically similar to nasopharyngeal carcinoma. Immunohistochemically, the tumor cells were positive for CK, EMA, Glypican-3 and hepatocyte, but negative for alpha-fetoprotein, CK19, CK7 and CK20. Epstein–Barr virus (EBV) in situ hybridization was negative. The final histopathological diagnosis was lymphoepithelioma-like HCC without EBV infection.

Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated carcinoma with a dense lymphoid stroma. It has been reported in diverse organs and shows variable association with Epstein-Barr virus (EBV). Only a few EBV positive cases have been observed in the hepatobiliary system, all of which were considered to be cholangiocarcinomas. We report a unique case of hepatocellular LELC arising in a cirrhotic liver with EBV demonstrated in the tumor cells.A 39-year-old Hispanic female underwent an orthotopic liver transplant for end stage liver disease secondary to chronic hepatitis C. A high-grade hepatocellular carcinoma with a dense lymphocytic infiltrate was found in the explant as well as in a portal lymph node. Three months posttransplant, the patient developed numerous hepatic nodules with enlarged periaortic and portacaval lymph nodes. Biopsy of the hepatic nodules showed a recurrent hepatocellular carcinoma devoid of a dense lymphocytic infiltrate. Both the primary and recurrent tumors were positive for EBV by molecular studies. The patient eventually expired from liver failure over a 6-week period.This case represents the first report of EBV-positive hepatocellular LELC. It is particularly interesting given the precipitous clinical outcome, which was possibly related to immunosuppresive therapy.

Lymphoepithelioma is a particular form of undifferentiated carcinoma, characterized by a prominent lymphoid stroma, originally described in the nasopharynx. Lymphoid stroma-rich carcinomas arising in other organs have been termed lymphoepithelioma-like carcinoma (LELC). In the liver, primary LELCs are very rare, and the majority has been identified as cholangiocarcinomas. Here a rare case of lymphoepithelioma-like hepatocellular carcinoma (HCC) is described. A 47-year old woman presented with abdominal pain. Ultrasonography revealed a liver nodule, 2.2 cm in diameter, localized in the right lobe, adjacent to the gallbladder. Viral markers for hepatic B virus (HBV), hepatic C virus (HCV) and Epstein-Barr virus (EBV) were negative. The nodule was hypoechogenic. The patient underwent surgery, with resection of the nodule. Histology showed hepatocellular carcinoma, characterized by a prominent lymphoid infiltrate. At immunocytochemistry, tumor cells were reactive for Hep Par1 and glypican 3. Immunophenotyping of tumor infiltrating lymphocytes evidenced the predominance of CD8+ cytotoxic suppressor T cells. The postoperative clinical outcome was favorable and the patient was recurrence-free 15 mo after resection. This case, to the best of our knowledge, is the first reported non EBV and non cirrhosis-associated lymphoepithelioma-like hepatocellular carcinoma. The association between the lack of EBV infection, the absence of cirrhosis, a “cytotoxic profile” of the inflammatory infiltrate and a good prognosis could identify a variant of lymphoepithelioma-like HCC with a favorable clinical outcome.