Primary combined hepatocellular-cholangiocellular sarcoma: An unusual case

Primary liver carcinosarcoma is rare. Here we report an unusual case of liver carcinosarcoma containing combined hepatocellular cholangiocarcinoma. A mass in the right liver lobe of a 45-year-old man was accidentally discovered by ultrasonic inspection and computed tomography (CT) scan. Surgical resection was performed following a diagnosis of primary liver cancer. Micropathologically, both carcinomatous and sarcomatous elements were present, and diagnosis of liver carcinosarcoma was confirmed. The carcinomatous element consisted of hepatocellular carcinoma and foci of cholangiocellular carcinoma. The sarcomatous element was composed of spindle cells and bizarre cells, as well as foci of osteosarcoma and chondrosarcoma. Hepatocellular carcinoma cells diffusely expressed both hepatocyte specific markers cytokeratin (CK) 8/18 and cholangiocyte specific markers CK19, and sarcoma cells were positive for vimentin. Interestingly, both carcinomatous and sarcomatous cells expressed epithelial membrane antigen. CD117-positive ductular reactions and small undifferentiated cells were observed. A liver progenitor cell origin of the liver carcinosarcoma was proposed.     

Hepatic carcinosarcoma with heterogeneous carcinomatous and sarcomatous elements: report of a case and review of the literature

We report a rare case of hepatic carcinosarcoma consisting of two carcinomatous components and four sarcomatous components. A 54-year-old Japanese man presented with sudden right upper abdominal pain. Computed tomography showed a hepatic tumor measuring 17 cm in the greatest dimension and intractable ascites, suggesting rupture of hepatocellular carcinoma (HCC). Transcatheter arterial embolization was repeated at our hospital, resulting in stabilization of the patient’s general condition. Right anterior and left median sectionectomies were performed. Histologically, the tumor consisted of carcinomatous and sarcomatous elements. The carcinomatous elements consisted of moderately differentiated HCC (positive for hepatocyte antibody, murine monoclonal anti-cytokeratin antibody, and alpha-fetoprotein and negative for S-100 and desmin) and adenocarcinoma (negative for cytokeratin 7 and positive for carcinoembryonic antigen). Sarcomatous elements consisted of undifferentiated spindle cell sarcoma, rhabdomyosarcoma with acidophil striated cells including striped cells (desmin-positive), chondrosarcoma with cartilage matrix (S-100-positive), and osteosarcoma with osteoid. The sarcomatous elements were negative for epithelial markers. The patient is alive at 34 months after the operation with peritoneal dissemination. A total of 23 cases, including the present case, of hepatic carcinosarcoma have been reported in the English language literature. This is the third reported case of hepatic carcinosarcoma with heterogeneous carcinomatous and sarcomatous elements.     

Lymphoepithelioma-like hepatocellular carcinoma: Case report and review of the literature

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.     

Immunohistochemical expression of manganese superoxide dismutase in hepatocellular carcinoma,using a specific monoclonal antibody

The expression of manganese superoxide dismutase (Mn−SOD) was studied immunohistochemically, using a specific monoclonal antibody, in surgically resected hepatocellular carcinoma (HCC) and noncancerous tissues from 47 patients (2 with well-differentiated HCC, 36 with moderately differentiated HCC, 8 with poorly differentiated HCC, and 1 with undifferentiated carcinoma). Cancer cells in 44 patients (93.6%) were positive for Mn−SOD. The staining pattern of cancer cells was mostly homogeneous in well-differentiated HCC, whereas it was heterogeneous in poorly differentiated HCC. Moreover, strongly positive immunoreactivity was observed in noncancerous liver tissues in all patients, especially in normal hepatocytes surrounding HCC, regenerative small hepatocytes in the tumor boundary, and mononuclear inflammatory cells in the necroinflammatory lesions. The positive immunoreactivity for Mn−SOD in patients with HCC appears to reflect increased production of the enzyme protein.     

Primary liver cancer with bidirectional differentiation into hepatocytes and biliary epithelium

A 70-year old Japanese man with hepatitis B infection developed a 4.8-cm liver tumor in the right lobe. Computed tomographic findings suggested hepatocellular carcinoma or combined hepatocellular and cholangiocarcinoma. After right hepatectomy, the cut surface of the resected specimen showed a whitish tumor with indistinct borders. Microscopically, the tumor consisted of pleomorphic, eosinophilic cells forming thickened trabeculae, suggesting hepatocellular carcinoma, and also tumor cells forming glandular structures, suggesting adenocarcinoma. Cells comprising both the trabeculae and the glands were immunoreactive for cytokeratin (CK) 19. In some gland-forming cells, varying immunoreactivity for CK7 and carcinoembryonic antigen (CEA) was observed. In the cytoplasm of cells in the thickened trabeculae, hepatocyte paraffin (HepPar) 1 and alpha-fetoprotein (AFP) were focally reactive. Some of these tumor cells were also reactive for CK19. Accordingly, we concluded that this tumor was a combined hepatocellular and cholangiocarcinoma whose cells had undergone divergent differentiation into hepatocytes and biliary epithelium. Because the tumor expressed markers of both phenotypes, it may have originated from cells intermediate between hepatocytes and biliary epithelium. A few reported cases have shown similar histologic features.     

Alpha-fetoprotein (AFP)- and des-gamma-carboxy prothrombin (DCP)-producing adenocarcinoma of the stomach with liver metastasis in a patient with chronic hepatitis C

A 45-year-old man was admitted to our hospital because of chronic hepatitis C and a large liver tumor accompanied by increased serum levels of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), the tumor markers for hepatocellular carcinoma. Endoscopic examination revealed advanced gastric cancer. Biopsy specimens of the stomach and liver showed gastric adenocarcinoma and its metastasis to the liver. Immunohistochemical studies demonstrated that adenocarcinoma cells both of the stomach and liver, were positive for the antibodies against AFP as well as DCP. Expression of AFP mRNA was shown in the cancer cells of the stomach. Accordingly, we diagnosed this patient with AFP- and DCP-producing adenocarcinoma of the stomach together with liver metastasis.     

Intratumoral sampling variability in hepatocellular carcinoma： A case report

The differential diagnosis between hepatocellular carcinoma （HCC） and regenerative liver nodules and other primary liver tumors may be very difficult, particularly when performed on liver biopsies. Difficulties in histological typing may be often minimized by immunohistochemistry. Among the numerous markers proposed, CK18, Hep Par1 and glypican 3 （GPC3） are considered the most useful in HCC diagnosis. Here we report a case of HCC in a 72-year-old male with HBV- related chronic liver disease, characterized by a marked morphological and immunohistochemical intratumoral variability. In this case, tumor grading ranged from areas extremely well differentiated, similar to regenerative nodule, to undifferentiated regions, with large atypical multinucleated cells. While almost all sub nodules were immunostained by Hep Par 1, immunoreactivity for glypican 3 and for Ckl8 was patchy, with negative tumor region adjacent to the highly immunoreactive areas. Our case stresses the relevance of sampling variability in the diagnosis of HCC, and indicates that caution should be taken in grading an HCC and in the interpretation of immunohistochemical stains when only small core biopsies from liver nodules are available.     

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.     

Laminin induces the expression of cytokeratin 19 in hepatocellular carcinoma cells growing in culture

AIM: To study the abnormal cytokeratin (CK) expression, emergence of CK19 with or without CK7, in liver parenchymal cells and the role of laminin (LN), a basement membrane protein, in this process. METHODS: Six hepatocellular carcinoma (HCC) cell lines were examined for different CKs, LN and its receptor by immunocytochemistry and Western blotting. Double immunofluorescent reaction, laser-scanning confocal microscopy and an in vitro induction procedure were used to demonstrate the role of LN in regulating CK19 expression in these cells. RESULTS: Immunoreactivities for CK8, CK18, CK7 and the receptor for LN were observed in all the six HCC cell lines examined. However, CK19 was merely found in four of the six cell lines, and was in any case associated with LN expression. Laser-scanning confocal microscopy demonstrated the concomitant presence of these two molecules in most of the positive cells. In the two HCC cell lines, originally negative for CK19, addition of LN to the culture medium resulted in an induction of CK19 in a dose-dependent manner. Both the artificially induced and the intrinsic production of CK19 were completely blocked by an antibody to LN. CONCLUSION: LN can induce expression of CK19 in HCC cells in vitro, providing direct evidence for our hypothesis that the abnormal hepatocytic CK19 expression in situ is due to pathologic LN deposition.     

A resected case of metachronous liver metastasis from lung cancer producing alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II)

A resected case of huge liver metastasis of hepatoid adenocarcinoma of the lung is described. A 77-year-old man who presented a solitary huge liver tumor was admitted to our hospital. He had undergone right lower lobectomy of the lung for lung cancer one year before. The view of imaging studies was not a typical one of hepatocellular carcinoma. Serum levels of AFP and PIVKA-II were 334,500ng/mL and 3,890mAU/mL, respectively, and the proportion of AFP L3 was 97.9%. It was thought that they were strongly diagnostic for hepatocellular carcinoma. Extended right lobectomy of the liver was performed. Microscopically, it was poorly differentiated adenocarcinoma and diagnosed as liver metastasis from the formerly resected lung cancer. The tumor was composed of cells with both sheet-like growth and tubule formation. The neoplastic cells, in the sheet-like growth resembled hepatocellular carcinoma cells. By immunohistochemical staining with anti-AFP and anti-PIVKA-II antibodies, cancer cells of both the primary and metastatic lesions were positive. The patient eventually died of multiple liver and bone metastasis 6 months after the operation.     

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     

Preliminary study on the clinical and pathological relevance of gastric hepatoid adenocarcinoma

OBJECTIVE: To appraise the histological characteristics and clinical features of gastric hepatoid adenocarcinoma (GHAC) and their relevance with prognosis. METHODS: From January 2001 to December 2003, six patients were diagnosed and confirmed pathologically in Ruijin Hospital as having a gastric hepatoid carcinoma. All these six patients, together with 30 randomly selected patients with gastric poorly differentiated adenocarcinoma (GPDA) and 30 with a primary hepatocellular carcinoma (HCC) who served as controls, were studied and analyzed clinically, histologically and immunohistologically. RESULTS: The average age of the six patients with GHAC was 66.8 years, and their serum alpha fetoprotein (AFP) level was 84–2230 ng/mL. Of these six patients, two had a recurrence of cancer and two had liver metastasis. Their average survival period was 17 months. Morphologically, the histological appearance was similar to that of HCC, with glycogen granules and hyaline globules arranged in a solid or trabecular pattern and an abundance of blood vessels and sinusoids, while blood vessel or lymphatic invasion were more often seen. Immunohistological staining showed that the tumor cells were positive for AFP and negative for Hepatocyte paraffin 1 (HepPar1), and the tumor cells were separated by CD34‐positive blood vessels into a small trabecular pattern. The GPDA had a solid nest or diffuse distribution pattern and was negative for both AFP and HepPar1. In the HCC, the histological feature was manifested as solid, small and large trabecular patterns with abundance of blood vessels and sinusoids; immunohistochemical staining showed the tumor cells were positive for HepPar1. CONCLUSION: Serum AFP‐positive GHAC occurred more frequently in older patients with higher rates of recurrence and liver metastasis and a poor prognosis. Histologically, GHAC was similar to HCC. The tumor cells that were positive for AFP but negative for HerPar1 could be used to differentiate with GPDA (both AFP and HerPar1 negative) and primary HCC (most AFP and HerPar1 positive).     

A resected case of fibrolamellar hepatocellular carcinoma with chronic hepatitis (type B)]

We report a case of a 34-year-old woman who tested positive for HBs Ag with fibrolamellar hepatocellular carcinoma of the liver. The sister of this patient, who was also positive for HBs Ag, died of hepatocellular carcinoma (HCC). The patient showed elevation of alpha-fetoprotein. Abdominal CT scan showed a tumor in the posterior segment of the liver and hepatic angiography revealed marked neovascularity in the tumor. Partial resection of the liver was performed, and the histological diagnosis was fibrolamellar hepatocellular carcinoma. The patient is now tumor free and doing well 20 months after the operation.     

Establishment and characterization of human hepatocellular carcinoma cell line FHCC-98

AIM: To establish a novel human hepatocellular carcinoma (HCC) cell line FHCC-98 from HCC tissue and to provide a suitable model for studying HCC occurrence, progress and metastasis.METHODS: Serially passaged cells were cultured and their morphologies were observed under light and electron microscope. Cytogenetic study was conducted by using flow cytometry and chromosome analysis. Expressions of tumor markers such as α-fetoprotein (AFP), cytokeratin (CK) and hepatoma metastasis-associated factor HAb18G/CD147 on the FHCC-98 cells were detected by immunocytochemistry or Western blotting. Lactic dehydrogenase (LDH) isoenzymes were detected by polyacrylamide gel electrophoresis (PAGE).Xenograft was performed by inoculating FHCC-98 cells into the flanks of nude mice.RESULTS: Morphology of FHCC-98 cells was the same as that of other malignant cells. The expressions of the cells were positive for HAb18G/CD147 and CK, and negative for AFP. Its population doubling time was 21.4 h. The cell DNA was tetraploid and the major chromosomes were triploid by cytogenetics analysis. The tumorigenicity in nude mice was 100%. PAGE showed four bands representing LDH2, LDH3,LDH4 and LDH5.CONCLUSION: FHCC-98 is a novel HCC cell line and an ideal cell model for further exploring the mechanism of hepatocellular carcinoma invasion and metastasis.     

Hepatocellular carcinoma with sarcomatous change arising in primary biliary cirrhosis

We report an autopsy case of hepatocellular carcinoma (HCC) with sarcomatous change arising in the context of primary biliary cirrhosis (PBC) in a 79-year-old man. Primary biliary cirrhosis was diagnosed (stage I according to Scheuer's classification) by findings on blood biochemical analysis, laparoscopy, and liver biopsy at age 69 years. Five years later, (at age 74 years), a mass lesion was detected in the S₆ region of the liver by abdominal ultrasonography, and target biopsy revealed well differentiated HCC. Blood biochemistry, ultrasonography, and computed tomography findings showed that the PBC had progressed to stage IV (cirrhotic stage). Percutaneous ethanol injection therapy (PEIT) was administered to the HCC several times over a 5-year period; however, the patient died of liver failure in February, 1994 (at age 79 years). Viral markers for hepatitis B and C were negative during the course, and hepatitis C virus RNA was not detected by polymerase chain reaction. Autopsy findings showed liver cirrhosis and diffuse involvement of spindle-shaped sarcomatoid cells in the liver, particularly in the S₆ region, associated with several nodules of trabecular HCC cells. A zone of transition between the sarcomatoid cells and the trabecular hepatocellular carcinoma cells was observed. The sarcomatoid cells were diffusely disseminated in the peritoneal cavity and had metastasized to multiple organs. Immunohistochemically, the cells were positive for fibrinogen, as were the coexisting trabecular hepatocellular carcinoma cells. The HCC had been treated several times with PEIT. Of interest, PEIT may be an important factor in this type of tumor progression.     

肝癌组织中ICAM-1的表达和意义

目的研究细胞间黏附分子-1(1CAM-1)在原发性肝癌中的临床意义.方法以免疫组化方法结合全自动图像分析观察40例肝细胞癌组织及其癌旁组织和28例肝硬化组织中ICAM-1的表达.结果40例肝细胞癌组织ICAM-1表达阳性率为80.0%(32/40)、癌旁组织为57.5%(23/40)、肝硬化为53.6%(15/28),阳性率与组织学分类相关.肝癌组织中ICAM-1含量明显高于癌旁及肝硬化组织(P＜0.05),转移组肝癌中ICAM-1的含量明显高于非转移组(P＜0.05),而癌旁及肝硬化组织中表达差异无显著性(P＞0.05).结论肝癌组织中高度表达ICAM-1,ICAM-1有可能作为判断肝硬化及肝癌发展程度及预后的指标之一.     

肝细胞核因子与肝细胞癌关系的研究进展

肝细胞核因子（HNFs）是一类在肝脏优势表达的转录因子,可调控多种重要肝细胞功能基因表达,在肝脏发育以及肝细胞分化、功能维持中起关键作用。近年来,越来越多的证据显示HNFs家族成员与肝细胞癌（HCC）的发生、发展密切相关。许多研究表明HCC细胞和组织中HNFs表达下调,利用基因工程手段上调HCC细胞中的特定HNF表达,可抑制肿瘤细胞增殖,诱导其向成熟肝细胞分化,为HCC的治疗提供了新的思路。     

原发性肝癌中MDR1基因表达研究

探讨MDR1基因编码的P-糖蛋白（Ppg)在肝癌（HCC）及癌周正常肝组织中的表达及其临床意义。用免疫组化SABC法，检测78例肝癌及60例癌旁组织中Pgp表达，分析肝癌中Pgp表达程度和临床病理特征。（1）Pgp表达主要位于肝癌，胆管上皮细胞膜上，少量位于胞质内；Pgp表达量，在治疗前癌组织中平均为26％，而癌旁组织平均为56％以上，治疗后接近癌旁组织。（2）Pgp表达量与肝癌分化程度有关，分化程度越高，其表达量越高。（3）术后1，3，5年，Pgp高表达组生存率略高于低表达组。     

Cholangiolocellular carcinoma: an innocent-looking malignant liver tumor mimicking ductular reaction

The authors present an interesting case of a 60-year-old man who underwent right hepatectomy for a diagnosis of hepatocellular carcinoma (HCC) on a background of noncirrhotic chronic hepatitis C. Pathologic examination confirmed the presence of HCC near the porta hepatis, which invaded the right portal vein branch. In addition, a well-demarcated 13.5 × 7.8 × 4.0 cm yellow and firm area upstream of the HCC was noted. This yellow area corresponded to a tumoral ductular proliferation, which cytologically was extremely bland, but invaded portal tracts and the adjacent liver parenchyma. This tumoral proliferation mimicked ductular reaction, except that it had more anastomosing structures and was associated with abundant hyalinized fibrotic stroma. Cytologically, the tumor cells had round to oval nuclei with fine chromatin, indistinct nucleoli, and scant cytoplasm. They exhibited immunohistochemical features of hepatic progenitor cells, i.e., expressing CK7, CK19, and N-CAM; and their malignancy was supported by the p53 and Ki67 immunoreactivity. The authors concluded that the patient had cholangiolocellular carcinoma with an aggressive hepatocellular carcinoma component. Cholangiolocellular carcinoma has been reported to be associated with chronic hepatitis C viral infection and to derive from hepatic progenitor cells, which explains why hepatocellular carcinoma and/or cholangiocarcinoma component may be present.     

肝细胞癌组织中PTEN蛋白表达

探讨抑癌基因PTEN在肝细胞癌 (HCC)组织及癌旁组织的表达、临床意义。采用免疫组织化学SP法检测PTEN。 4例正常肝组织均呈PTEN蛋白阳性 ;HCC及其癌旁肝组织中的阳性率分别为 5 8 8%(2 0 / 34)和 10 0 %(34/ 34) ,两者比较差异有显著性 (P <0 0 5 )。中分化癌阳性率为 77 8%(14 / 18) ,低分化阳性率为 2 5 %(3/ 12 ) ,两者比较差异有显著性 (P <0 0 0 1)。PTEN蛋白表达与年龄、性别、肿瘤大小、有无包膜及门脉癌栓均无明显关系 (P >0 0 5 ) ,但与HCC分化程度明显相关 ,HCC分化愈差 ,PTEN蛋白表达愈弱。PTEN蛋白表达与HCC分化程度明显相关。