We report a case in an elderly adult of a highly malignant liver tumor with blastoid features that resembled hepatoblastoma. A liver tumor with a diameter of 23 cm was removed in a 78-year-old woman. The tumor showed highly differentiated epithelial hepatocellular and poorly differentiated epithelial and mesenchymal components. The blastoid nature and pluripotent differentiation potential were supported by immunohistologic analysis and suggest an origin of a poorly differentiated pluripotent hepatic cell with the potential to mature. We believe that this case of a mixed hepatoblastoma in an adult should be added to the growing number of presumed hepatic precursor cell neoplasms in adults.
(Arch Pathol Lab Med. 2005;129:234-237)
Malignant epithelial liver tumors are among the most frequent carcinomas that occur in adults.1 Far more than 90% represent either hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma. Rare malignancies in adults with epithelial differentiation include combined hepatocellular or cholangiocarcinoma, carcinosarcoma, oval or stem cell neoplasm, and hepatoblastoma.2
In some cases, overlapping features of these entities may complicate the differential diagnosis. Additionally, HCCs may show sarcomatoid (spindle cell) dedifferentiation. Hepatic carcinosarcomas are extremely rare and are composed of a malignant epithelial and mesenchymal component.2 Recently, a few undifferentiated hepatic neoplasms have been reported that show a histomorphologic or immunologie phenotype that resembles liver precursor (oval) cells.3-5 The phenotypes of these so-called oval or stem cell tumors, however, are heterogeneous. Hepatoblastoma accounts for approximately half of the malignant liver tumors in children, with most occurring before the age of 5 years." Adolescents or young adults are rarely affected, and in older individuals comparable tumors are extreme rarities. Fewer than 20 cases have been reported in patients older than 30 years so far.7-10 The existence of hepatoblastoma in elderly patients, however, has been denied by some authors.2 Herein, we present a case of a highly malignant primary liver cell tumor with blastoid features in an elderly woman with morphologic and immunohistologic characteristics that resembled hepatoblastoma.
REPORT OF A Case
A 78-year-old woman was admitted to the hospital with severe weight loss, pain in the right upper abdomen, and heartburn that had lasted for 8 weeks. Mild edemas were present in both legs. Her medical history included hepatitis A 50 years ago and chronic hepatitis B, which was treated successfully with alfa interferon, leading to seroconversion 7 years ago. Computed tomography showed a tumor of approximately 20 cm in diameter located in liver segments V, VI, and VII. The liver function parameters were within the reference range. Serologically, antibodies against hepatitis A virus and hepatitis B virus surface and core antigens were present. The test results for hepatitis B surface antigen and hepatitis C antibodies in the serum were negative. The following tumor markers were determined: α-fetoprotein, more than 121000 ng/mL; CA 19-9, 16 lU/mL; and carcinoembryonic antigen, 0.9 ng/mL. Serum electrophoresis showed a monoclonal gammopathy type IgG λ.
The tumor was removed surgically by a nonanatomical resection of liver segments V, VI, and partially VII. The immediate postoperative course was uneventful, and all liver function parameters remained within the reference range. Twenty-two days after surgery, the patient experienced a prolonged, reversible ischemic neurologic deficit and was admitted to an outside neurologic clinic. She developed cardiovascular failure on day 67 postoperatively. A thrombosis of the intrahepatic veins was diagnosed, and tumor recurrence was suspected. The patient died 2 days later. An autopsy was not performed.
The partial liver resection specimen from the right lobe contained a single, partially necrotic tumor with a maximal diameter of 23 cm. The cut surface was slightly lobular and whitish and showed cystic spaces and areas of hemorrhage. The tumor extended through the liver capsule and infiltrated into the diaphragm.
The tumor was mainly composed of a poorly differentiated, epithelial small cell component (approximately 70%), intermingled with a mesenchymal spindle cell component of approximately 30% (Figure 1, A). The small cell component showed a solid growth pattern and a high tendency for necrosis. The tumor cells revealed a high nuclear-cytoplasmic ratio, poorly defined cytoplasm, and significant hyperchromatic and pleomorphic nuclei. A high frequency of atypical mitoses was seen. Partly, this tumor component resembled intermediate-type small cell carcinoma of the lung. A few foci of ductular differentiation of the epithelial component (
Both main cellular constituents snowed signs of maturation: the small cell component showed multiple foci of changes into a moderately differentiated, medium- to large-sized hepatocytelike cell population with round to ovoid, mildly hyperchromatic nuclei and a broad, well-defined, more eosinophilic cytoplasm. Here, the mitotic activity was reduced. No obvious tendency for necrosis was seen. There were no signs that indicated a replacement of the higher differentiated hepatocyte-like cell population by the small cell population (Figure 1, C). The spindle cell component showed a focal hemangiopericytoma-like pattern with broad arborizing capillary structures. Focal osteoblast-like differentiation and osteoid formation occurred (Figure 1, D).
Although the different histologie pattern could be well identified, tumor cells of intermediate phenotypes were present throughout the tumor, suggesting transitional maturation steps. The nonneoplastic liver showed mild fibrosis without signs of cirrhosis or hepatitis.
The small cell epithelial component showed moderate cytokeratin (CK) 8 and CK19 reactivity and was negative for vimentin and CK7 (Figure 2, D). A partial neuroendocrine phenotype of these tumor cells was suggested by the focal dot-like expression of CK19, CK8, and neuron-specific enolase. The spindle cell component was positive for vimentin and negative for CK7, CK8, and CK19, demonstrating mesenchymal differentiation. In addition, the spindle cells were focally positive for CD34 and strongly for CD56 (neuronal cell adhesion molecule). Both main constituents (small cell and spindle cell components) showed a high proliferative activity of up to 50% Ki-67 positivity, whereas proliferative activity in the more differentiated areas was lower.
Markers of hepatocellular differentiation showed the following reactivity: α-Fetoprotein reacted with hepatocyte-like cells but also cells forming osteoid (Figure 2, B). α^sub 1^-Antitrypsin reactivity was observed in all cell populations with extremely high reactivity in the spindle cell component. HepPar-1 (OCH1E5) was strongly but not uniformly expressed by the hepatocyte-like cells (Figure 2, C). Small cells showed only focal moderate positivity. All cells with mesenchymal phenotype, including osteoid-forming cells, were negative. Albumin showed reactivity with hepatocyte-like small cell and to a lesser extent with the spindle cell component. Ferritin showed a unique reaction pattern with single disseminated but strongly positive cells in the spindle cell and small cell compartment (Figure 2, A). Hepatocyte-like and osteoid-forming cells were strongly positive. CDlO was present with some heterogeneity in all cellular compartments with predominance in the spindle and hepatocyte-like cells. A canalicular pattern, however, was not seen. Thus, immunoreactivity clearly shows the hepatic phenotype of the hepatocyte-like cell population but also partial hepatocellular expression phenomena in all other cellular components of the tumor (Figure 2).
E-cadherin was weakly membranous positive in the highly differentiated hepatic tumor areas and completely negative in all other parts of the tumor. Nuclear β-catenin expression occurred only in the epithelial component of the tumor, whereas p53 showed strong nuclear expression in all tumor cells (Figure 2, E and F). All tumor cells lacked p16 or cyclin Dl expression. The main immunohistologic findings are summarized in the Table.
We describe a case of a highly malignant primary liver tumor in an elderly woman. The tumor was primary to the liver, since no other tumor site was detected by extensive preoperative staging. In addition, the tumor contained areas of definite hepatocellular differentiation as shown by morphologic and immunohistologic analysis. The highly malignant potential of the tumor was confirmed by the predominance of poorly differentiated or undifferentiated morphologic features, a high frequency of atypical mitoses, and a high rate of positivity for the proliferation marker Ki-67.
In the differential diagnosis, the tumor has to be compared with several entities, including HCC with sarcomatoid dedifferentiation, carcinosarcoma, hepatoblastoma, and hepatic precursor cell (oval cell) neoplasms.
In dedifferentiated HCCs, an originally highly or moderately differentiated HCC gives rise to a dedifferentiated sometimes sarcomatoid component that usually marginales or overgrows the better differentiated component during tumor progression due to its more aggressive behavior.2 Usually, a peripheral area of higher differentiation in an otherwise dedifferentiated tumor is detected. In the presented tumor, there was no indication for dedifferentiation. The observed maturation phenomena are generally not observed in dedifferentiated HCC.
One may favor calling this tumor a hepatic carcinosarcoma, but it lacks the typical strict dichotomy of the carcinomatous and sarcomatous elements. Instead, a smooth gradual transition that involves various cells of intermediate phenotype is found throughout the tumor.
Recently, several so-called oval cell or precursor cell tumors have been described. They are characterized by their reactivity with antibodies that typically recognize oval cells or by their histomorphologic features. Robrechts and coworkers3 described a highly malignant, monomorphic, poorly differentiated hepatic neoplasm that strongly reacted with the antibody OV-6. Neoplasms of hepatic differentiation that showed areas that closely resembled the undifferentiated morphologic structure of oval cells have also been reported.5 In both reports, the tumors differed significantly and are also different by morphologic features when compared with the present tumor.
Hepatoblastoma can be subclassified into epithelial (fetal, embryonal and fetal, macrotrabecular, and small cell) and mixed epithelial-mesenchymal (with or without teratoid features) types.11 The present tumor certainly resembles mixed-type hepatoblastoma without teratoid features. Maybe a comparable histogenesis exists. For hepatoblastoma, an origin from a pluripotent precursor cell, the hepatoblast, has been suggested. We do call the presented tumor a hepatoblastoma because of morphologic features and not because of the patient's age. Hepatoblastoma is a tumor of newborn and young children and is extremely rare even in adolescents and young adults. Although a few cases of mixed-type hepatoblastoma have been reported in adults older than 30 years,7-10 existence of hepatoblastoma in older adults has been refused by others.2
In regard to its molecular pathogenesis, the detection of nuclear β-catenin accumulation suggests an oncogene alteration of the wnt/β-catenin pathway. Furthermore, nuclear p53 accumulation indicates that a p53 mutation is also involved in the molecular pathogenesis of this tumor. Frequent alterations of both pathways have been described in HCCs and hepatoblastomas.12
The polymorphic phenotype of the presented tumor may indicate evolution from a pluripotent liver cell with the potential for further maturation. This is supported by the proximity, even intermingling, of all differentiation phenomena. Multiple cell complexes with hepatocyte-like differentiation are embedded into areas of small cell differentiation without any sign of replacement. Cells that represent intermediate differentiation were found in close proximity. Comparable maturation phenomena are frequent findings in childhood tumors. Furthermore, all components, even including spindle and osteoid-forming cells, showed partial hepatocellular differentiation by immunohistologic analysis. Few tumors with comparable morphologic features have been more or less well documented in adults older than 30 years. They have been called mixedtype hepatoblastoma/ hepatic embryonal mixed tumor,13 or malignant mixed tumor of the liver.14 We believe that this case of a mixed hepatoblastoma in an adult should be added to the growing number of presumed hepatic precursor cell neoplasms in adults.
Dr Kasper was supported partly by the Center for Molecular Medicine of the University of Cologne. For all surgical procedures, consent was obtained from the patient. We are very thankful to Ms S. Sattler for her excellent technical assistance and to Mr Y. A. Weidemann for his language review.
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Hans-Udo Kasper, MD; Thomas Longerich, MD; Dirk L. Stippel, MD; Michael A. Kern, MD; Uta Drebber, MD; Peter Schirmacher, MD, PhD
Accepted for publication September 23, 2004.
From the Institute of Pathology (Drs Kasper, Longerich, Kern, Drebber, and Schirmacher), Center for Molecular Medicine (Drs Kasper, Kern, and Schirmacher), and Department of Visceral and Vascular Surgery (Dr Stippel), University of Cologne, Cologne, Germany.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Hans-Udo Kasper, MD, Institute of Pathology, University of Cologne, loseph-Stelzmann-Str 9, D-50931 Koeln, Germany (e-mail: email@example.com).
Copyright College of American Pathologists Feb 2005
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