Lymphoepitelioma-like hepatocellular carcinoma： A case report and a review of the literature

Lymphoepitelioma is a particular form of undifferentiat-ed carcinoma, characterized by a prominent lymphoid stroma, originally described in the nasopharynx. Lym-phoid 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 cholangiocarcino-mas. Here a rare case of lymphoepithelioma-like hepa-tocellular carcinoma （HCC） is described. A 47-year old woman presented with abdominal pain. Ultrasonogra-phy revealed a liver nodule, 2.2 cm in diameter, local-ized 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 nod-ule was hypoechogenic. The patient underwent sur-gery, with resection of the nodule. Histology showed hepatocellular carcinoma, characterized by a promi-nent 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 sup-pressor 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 knowl-edge, is the first reported non EBV and non cirrhosis-associated lymphoepithelioma-like hepatocellular carci-noma. The association between the lack of EBV infec-tion, 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.     

Lymphoepithelioma-like gastric carcinoma: unusual variant in postgastrectomy stump

Gastric lymphoepithelioma--like carcinoma, undifferentiated with lymphoid or medullary stroma, constitutes a 3.8% of gastric carcinomas. Microscopically it is similar to other lymphoepitheliomas, it has an expansive growth and better prognosis than other histologic types. A possible relation to Epstein Barr virus is presumed. A 56 year old female, gastrectomized due to a cancer (Billroth II) 31 years before, showed an ulcer lesion close to the anastomosis at endoscopy. A biopsy was taken with positive result and gastrectomy was performed. The surgical specimen included gastric stump, jejunoanastomosis, omentum and lymph nodes. It had a 4.5 cm, protruded ulcerated lesion, located in anterior wall, 1.5 cm from stomy. It was fixed in buffered formalin, routinely processed and stained with Hematoxilin--Eosin. Immunohistochemistry techniques for CKAE1-AE3, EMA, CEA, CD45, CD20, CD3 and CD45Ro, and PCR for Epstein Barr virus were performed. Microscopically it was constituted by an expansive proliferation of polygonal cells with barely eosinophylic cytoplasm and vesicular nuclei, arranged in small clusters or isolated, positive for CKAE1-AE3, EMA and CEA, with dense mature lymphoid infiltrate, both follicular and diffuse, positive for CD45, CD45Ro, CD3 and CD20. PCR technique for Epstein Barr virus was positive. This has been the first case of this type in our department since 1989. In addition to the peculiar characteristics of this variety, whose differential diagnosis must be made with lymphomas, the origin from gastric stump, where this complication appears with variable rates, the risk being related to the type of surgery and the time elapsed are relevant.     

Lessons from rare tumors: Hepatic lymphoepithelioma-like carcinomas

In this review we focus on lymphoepitheliomalike 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 systemand neoplastic cells. Approximately half of LELHCC 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.     

Coexistence of hepatoma with mantle cell lymphoma in a hepatitis B carrier

The coexistence of hepatocellular carcinoma (HCC) and non-Hodgkin’s lymphoma (NHL) in the liver is rare. Reports show that these patients have cirrhotic livers or hepatitis virus infections before they develop HCC and NHL. We present a patient with hepatitis B virus infection who was transferred to our hospital with a newly detected liver mass; abdominal computed tomography examination showed one hypodense mass of 7 cm in diameter and multiple mesenteric and mediastinal lymph nodes. A liver tumor biopsy showed a hepatoma, and the pathologic findings from an inguinal lymph node excision showed mantle cell lymphoma. An immunohistochemical stain confirmed that the atypical lymphoid cells within the HCC were positive for the CD20, CD5 and cyclin D1 antigens. Taking these findings into account, the hepatic tumor was determined to be a HCC infiltrated by mantle cell lymphoma.     

Combined hepatocellular carcinoma and neuroendocrine carcinoma with sarcomatous change of the liver after transarterial chemoembolization

Primary hepatic neuroendocrine carcinoma is rare and its origin is not clearly understood. An admixture of hepatocellular carcinoma (HCC) and neuroendocrine carcinoma is particularly rare. Here, we report a patient with an extremely rare combination of HCC and neuroendocrine carcinoma of the liver. To our knowledge, this is the first reported case in which the carcinoma showed sarcomatous change. The patient was a 76‐year‐old man who had received outpatient treatment for chronic hepatitis C. On abdominal computed tomography (CT), the hepatic tumor was enhanced in the arterial phase but its density was lower than that of normal liver in the portal phases. His serum α‐fetoprotein (AFP) level was very high. Therefore, transarterial chemoembolization (TACE) was performed based on the diagnosis of HCC. Ten months after TACE, his serum AFP level had increased to the level measured before TACE. Partial hepatectomy was performed because CT revealed poor enhancement of the recurrent tumor. Histopathologically, the tumor consisted of two distinct components: moderately differentiated HCC was intermingled with a neuroendocrine carcinoma, which was accompanied by sarcomatous changes. Immunohistochemically, the neuroendocrine carcinoma cells were positive for CD56, chromogranin A and neuron‐specific enolase, and negative for AFP. The sarcomatous area was positive for AE1/3 and CD56, consistent with sarcomatous change of neuroendocrine carcinoma. The neuroendocrine carcinoma and/or sarcomatous change may have been due to phenotypic changes and/or dedifferentiation of HCC induced by TACE. Six months after surgery, the patient was diagnosed with metastasis of the neuroendocrine carcinoma to sacral bone. He died 7 months after surgery.     

Carcinosarcoma of the liver

Herein we present a 73-year-old man with primary carcinosarcoma of the liver, a rare malignant tumor of the liver. The case was followed up due to HBV-related liver cirrhosis. Regular check-up by ultrasound demonstrated a hyperechoic tumor in the left lobe of the liver, and he was referred and admitted to our hospital. Dynamic CT studies revealed a mostly hypoenhancing hepatic mass with a peripheral ring enhancement. Surgical resection was performed, and the resected tumor was macroscopically a simple nodular type, 3 cm in diameter, with a dense fibrous capsule. Microscopically, undifferentiated cells were dominant in the tumor, while moderately differentiated hepatocellular carcinoma (HCC) were also observed. A transitional zone was noted between the undifferentiated tumor and HCC. Tumor tissue with adenocarcinoma, osteosarcoma and chondrosarcoma were also detected. Immunohistochemical studies demonstrated that tumor cells were HepPar 1 positive in hepatocellular carcinoma, and CK19 and partly CK7 positive in adenocarcinoma. Moreover, CD56, chromogranin A and c-kit were occasionally positive in undifferentiated tumor cells. The diagnosis of carcinosarcoma was made based on the concomitant presence of HCC and sarcomatous components, yet it is noteworthy that various types of tumor cells were observed.     

Reactive lymphoid hyperplasia of the liver： A case report and review of literature

A case of a 53-year-old female patient with reactive lymphoid hyperplasia （RLH）, clinically designated as pseudolymphoma of the liver is described in this article. The patient was admitted to our hospital for further evaluation of hepatic tumors incidentally discovered at another hospital. Various diagnostic methods, including ultrasonography （US）, computerized tomography （CT）, magnetic resonance imaging （MRI） and hepatic angiography displayed three small lesions in the liver with outstanding findings consistent with hepatocellular carcinoma （HCC）. Surgical resection was performed and the three lesions were microscopically diagnosed as RLH of the liver. The lesions comprised a massive infiltration of lymphoid cells with follicles and hyalinized inter- follicular spaces. Immunohistochemical examination revealed that infiltrating lymphocytes had no prominent nuclear atypia and polyclonality. RLH of the liver is a very rare condition and only twelve cases have been reported in the English literature. Majority of the reported cases were middle-aged women and about half of them had some immunologic abnormalities such as autoimmune thyroiditis, Sjogren＇s syndrome, primary immunodeficiency, primary biliary cirrhosis. Since they are olden clinically misdiagnosed as HCC, surgery is the choice of treatment for these patients. Although their pathology resembles malignant lymphoma, the clinical course is completely benign. The authors propose that RLH of the liver can be discriminated from HCC by its clinical features.     

Solitary AFP- and PIVKA-II-producing hepatoid gastric cancer with giant lymph node metastasis

A 61-year-old man was admitted to our hospital because of abdominal pain and an abdominal mass. The patient had anemia and elevated serum alpha-fetoprotein (AFP) (9630ng/mL) and PIVKA-II (91mAU/mL) levels. Roentgenographic examination revealed an extra-gastric tumor in the upper abdomen, and gastroscopy revealed Bormann type 2 gastric cancer in the lower portion of the stomach. The preoperative diagnosis was synchronous gastric cancer and hepatocellular carcinoma (HCC), and surgery was performed. The extra-gastric tumor appeared to be an extra-hepatically growing HCC because the tumor was fed by vessels ramifying from the umbilical portion of the liver. Distal gastrectomy with resection of the extra-gastric tumor was performed, and histological examination of the resected specimen revealed that the gastric cancer was an AFP-producing hepatoid gastric adenocarcinoma and that the extra-gastric tumor was a lymph node metastasis. AFP-producing hepatoid gastric adenocarcinoma tends to metastasize to the regional lymph nodes and form a giant tumor. A giant tumor in the upper abdomen associated with gastric cancer may therefore be a clinical manifestation of AFP-producing hepatoid gastric adenocarcinoma.     

Hepatocellular carcinoma associated with Wilson's disease

A 23-year-old man was admitted to our department due to hemorrhage from gastric varices. He had been diagnosed as having Wilson's disease at the age of 17. Abdominal ultrasonography and computed tomography (CT) showed portal thrombosis and a large mass occupying most of the right lobe in the liver. The tumor was diagnosed as hepatocellular carcinoma (HCC) by image views and tumor markers. He died 3 months after the diagnosis, and an autopsy was performed. Histologic examination of the tumor showed moderately to poorly differentiated HCC. The nontumorous lesion of the liver revealed cirrhosis. HBX-DNA sequence was not detected in the liver. Hepatic cirrhosis is a well-recognized complication of Wilson's disease, but HCC is extremely rare. We describe the clinical findings of this patient and discuss the relationship of the development of HCC with a review of the relevant literature.     

Hepatocellular carcinoma with chondrosarcomatous variation: Case report with immunohistochemical findings, and review of the literature

Hepatocellular carcinoma with chondrosarcomatous variation is very rare. We report a case with the results of pathology examination, and review the literature. The patient, a 72-year-old may had a very large tumor in the liver revealed during follow-up for diabetes mellitus. The liver mass, which was 14 cm in diameter, was diagnosed as hepatocellular carcinoma by abdominal ultrasonography. Anterior segmentectomy and partial liver resection were performed. Histopathology examination revealed that the tumor consisted of two different components: the major one was hepatocellular carcinoma (HCC), which occupied most of the tumor; and a sarcomatous component, which occupied a smaller area, and included spindle-shaped cells with chondroscarcomatous variation. Intrahepatic metastases and tumor thrombi of HCC were also found in portal and hepatic veins. Investigations of the immunohistochemical localization of keratin (KRT), vimentin (VMT), and S-100 protein (S 100) were performed by the avidin-biotin complex method. Some of the spindle cells were immunohistochemically positive for both KRT and VMT, and the chondrosarcomatous cells were positive for S 100. These results strongly suggested that the sarcomatous lesion resulted from a sarcomatous change of HCC.     

Hepatocellular carcinoma occurring in a Crohn's disease patient

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn's disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the nonneoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.     

Primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type: case report and review of the literature

A primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is very rare. We found a solitary mass 27 mm in size in the left lobe of the liver of a 58-year-old Japanese man with a history of hepatitis-C infection. Based on the results of imaging studies, the tumor was diagnosed as a hepatocellular carcinoma (HCC). The left lobe of the liver was lobectomized and microscopic findings showed that the tumor was a hepatic MALT lymphoma, while immunohistochemistry showed it to be positive for CD20 and CD79a. In a fluorodeoxyglucose-positron emission tomography examination integrated with computed tomography scanning (FDG-PET CT) before surgery, the tumor was revealed to have a high standardized uptake value (SUV) for FDG. The patient received chemotherapy after surgery. To the best of our knowledge, 45 cases had been reported with a mean age for all patients of 61.4 years. The pathogenesis remains unclear, although half of the patients had a past history of chronic inflammatory liver disease. Surgical resection was performed in most cases and some patients received postoperative chemotherapy or radiotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.     

Hepatic reactive lymphoid hyperplasia in a patient with primary biliary cirrhosis

Reactive lymphoid hyperplasia (RLH) of the liver is an extremely rare lesion characterized by the proliferation of non-neoplastic lymphocytes forming follicles. Hepatic RLH is known to be associated with gastrointestinal carcinoma and autoimmune diseases including primary biliary cirrhosis (PBC). We report a case of hepatic RLH in a patient with PBC and gastric cancer. A 68 year old Japanese woman with a 10 year history of liver enzyme abnormality was admitted. Laboratory testing revealed that her anti-mitochondrial antibody was markedly elevated. Five mo after the diagnosis of PBC, she was found to have gastric cancer. Abdominal computed tomography disclosed a liver nodule in S8, suggesting metastatic gastric carcinoma. Histopathologically, the resected liver lesion comprised of a nodular proliferation of small lymphocytes with lymphoid follicles. This is the first reported case of hepatic RLH in a patient with both PBC and gastric cancer. Pre-operative diagnosis of hepatic RLH by clinical imaging is extremely difficult. Therefore, a needle biopsy could be useful to make a diagnosis of hepatic RLH, especially to differentiate from metastatic gastrointestinal carcinoma.     

Gallbladder metastases from ductal papillary carcinoma of the breast

Breast cancer occurs primarily in women aged 25 years or older. Breast carcinoma has the potential for widespread dissemination, such as metastasis to axillary lymph nodes, bone, lung, pleura, brain, and soft tissues. Liver, gastrointestinal, and biliary tract involvement are infrequent. We report a patient, a 62-year-old woman, with symptomatic cholelithiasis. The patient proceeded to laparoscopic cholecystectomy. She had a previous history of mastectomy with axillary lymphadenectomy, performed for a breast ductal papillary carcinoma, 10 years prior to the cholecystectomy. The gallbladder was hydropic; the wall was thickened, with a focal broad-based lesion on the mesenteric face of the body. Histopathological evaluation of the focal broad-based lesion of the gallbladder revealed poorly differentiated adenocarcinoma infiltration, without mucosal involvement. Subsequent immunohistochemical examination showed the lesion to be cytokeratin 7(CK7)-positive and cytokeratin 20 (CK20)-negative. Estrogen receptor (ER) and progesterone receptor (PgR) were positive. The final pathological diagnosis was breast ductal papillary carcinoma metastases to the gallbladder. Mammography of the other breast was normal. Computed tomography (CT) scan of the brain, chest, abdomen, and pelvis was performed, without any pathological findings. Bone Tc-99 scintigraphy was normal. Six months after the surgery positron emission tomography (PET) showed no evidence of metastatic disease. Two years after the surgery, the patient died, in the absence of recurrence. A literature review revealed only a few more cases of metastasic breast carcinoma to the gallbladder.     

Neuroendocrine carcinoma of the gastric stump:A case report and literature review

We herein report a case of neuroendocrine carcinoma of the gastric stump found 47 years after Billroth II gastric resection for a benign gastric ulcer. A 74-yearold man was referred to another hospital with melena. Endoscopic examination revealed a localized ulcerative lesion at the gastrojejunal anastomosis. The diagnosis by endoscopic biopsy was neuroendocrine carcinoma. A total gastrectomy of the remnant stomach with D2 lymphadenectomy was performed at our hospital. The lesion invaded the subserosa, and metastasis was found in two of nine the lymph nodes retrieved. The lesion was positive for synaptophysin and chromogranin A, and the Ki-67 labeling index was 60%. The diagnosis of neuroendocrine carcinoma of the gastric stump was confirmed using World Health Organization 2010 criteria. Subsequently, the patient underwent one course of adjuvant chemotherapy with the etoposide plus cisplatin(EP) regimen; however, treatment was discontinued due to grade 3 myelosuppression. The patient showed lymph node metastasis in the region around the gastrojejunal anastomosis in the abdominal cavity 7 mo post-surgery. He then underwent radiotherapy and platinum-based combination chemotherapy; however, the disease progressed and liver recurrence was observed on follow-up computedtomography at 16 mo post-surgery. The patient then received chemotherapy with regimens used for the treatment of small cell lung cancer in first-and secondline settings. The patient died of disease progression 31 months after surgery.     

Primary signet-ring cell carcinoma of the colon at early stage： A case report and a review of the literature

A 67-year-old man, who had undergone surgery to resect multiple gastric cancers 4 years ago, visited our hospital for surveillance colonoscopy. Colonoscopy revealed a discolored, 7-mm in diameter, flat-elevated lesion with central depression in the transverse colon near the splenic flexure. Although the findings of endoscopy and barium enema were suggestive of submucosal invasion, the patient chose to undergo endoscopic mucosal resection. Pathological examination of the resected specimen revealed signet-ring cell carcinoma and a positive surgical margin. A second operation was performed, and no residual tumor or metastasis to lymph nodes was found in the resected specimens. Primary colorectal cancers composed of signet-ring cell carcinoma detected and treated at an early stage are extremely rare. We present a case and review the literature.     

Hepatocellular carcinoma occurring in a Crohn��s disease patient

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn’s disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the non-neoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.     

Spontaneous rupture of metastatic α-fetoprotein-producing gastric cancer of the liver

An 80-year-old man was admitted to our hospital because of the rupture of the liver. Laboratory data showed iron-deficiency anemia, although there was no liver dysfunction. A computed tomography scan showed large liver tumor with intraperitoneal hemorrhage, and since a serum level of α-fetoprotein (AFP) was extremely high, we initially suspected a rupture of hepatocellular carcinoma (HCC). Transarterial embolization was performed to stop bleeding from the tumor, followed by an endoscopic examination that revealed advanced gastric cancer. Histological analysis revealed that both the gastric and the hepatic tumors were moderately to poorly differentiated adenocarcinoma, as well as that both tumors were immunohistochemically positive for AFP. Finally, we diagnosed AFP-producing gastric cancer associated with liver metastasis. Rupture of metastatic liver cancer is rare, and accordingly, distinction from HCC is important, particularly for the cases of AFP-producing gastric cancer.     

Four immunohistochemically different primary liver cancers in one patient

We present a rare case of four immunohistochemically different primary liver cancers developing in a 54-year-old Japanese man with chronic hepatitis C. In 1989, a liver tumor had been detected at another hospital during follow-up of hepatitis C virus (HCV) infection. He was first admitted to our hospital in July 1991, when a well defined hypervascular tumor, measuring 2.5 cm in diameter was found in the S5 subsegment of the liver on computed tomography (CT); S5 subsegmentectomy was therefore performed, in July 1991. Histopathological examination revealed scirrhous hepatocellular carcinoma (SHCC). Immunohistochemical analysis showed that the tumor was negative for mouse monoclonal anti-human hepatocyte antibody (Hep), but was partially positive for a mouse monoclonal antibody specific for cytokeratin 19 (CK19). Six years after the operation, a large tumor, measuring 10 cm in diameter, was found in the S4 subsegment and a 3-cm tumor was found in the caudate lobe on CT scans. Extended left hepatic lobectomy and partial resection of the caudate lobe were performed in August 1997. Histopathological examination revealed a moderately differentiated hepatocellular carcinoma (HCC) with a trabecular pattern, an SHCC with well differentiated HCC at its periphery, and a small incidental cholangiocellular carcinoma (CCC), measuring 1 cm in diameter. The HCC and CCC showed typical immunostaining for Hep and CK19, respectively. The SHCC was positive for both Hep and CK19, showing characteristics different from those of the previously resected SHCC on immunohistochemical analysis. In conclusion, we experienced four immunohistochemically different primary liver cancers in a patient with chronic hepatitis C. Received: January 9, 2001 / Accepted: May 25, 2001 Reprint requests to: S. Ariizumi