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Case Report |
Address correspondence to Jeffrey S-H Tsung, M.D., Department of Pathology and Laboratory Medicine, Koo Foundation Sun Yat-Sen Cancer Center, 125 Lih-Der Road, Taipei 112, Taiwan, ROC; tel 886 2 2897 0011, ext 1408; fax 886 2 2897 2233; e-mail address: tsung{at}mail.kfcc.org.tw.
Abstract
We report an unusual case of intrahepatic cholangiocarcinoma (ICC) with lymphoepithelioma-like carcinoma (LELC) component in a 60-yr-old woman who was found incidentally to have an abdominal mass. Histologically, the tumor showed 2 distinct patterns with dense lymphoplasma cell infiltration. The first pattern, comprising approximately 20% of total tumor volume, showed the features of lymphoepithelioma-like carcinoma, as commonly found in nasopharyngeal carcinoma (NPC). The second pattern was a moderately differentiated cholangiocarcinoma. In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) showed positive nuclear labeling of tumor cells in both patterns, but not in surrounding inflammatory cells. By the polymerase chain reaction, the latent membrane protein gene (LMP-1) in this case was shown to have a 30 bp deletion in the C-terminus, a unique feature in high prevalence areas of undifferentiated nasopharyngeal carcinoma, such as in Taiwan. Presence of the EBV genomes and their expression in the cholangiocarcinoma cells suggested that EBV may play an important role in the pathogenesis of ICC with LELC. In this case, it is unclear why only 20% of the glands were transformed into LELC. The mechanism whereby EBV transforms the malignant glands into the distinct morphology resembling NPC warrants further investigation.
(received 24 May 2004; accepted 30 July 2004)
Keywords: intrahepatic cholangiocarcinoma, lymphoepithelioma-like carcinoma, Epstein-Barr virus, Epstein-Barr virus-encoded RNA, latent membrane protein-1 gene
Introduction
Lymphoepithelioma-like carcinomas (LELCs) are tumors that have been reported in various anatomic sites with morphologic features identical to undifferentiated nasopharyngeal carcinomas [1–9]. Only a few cases of cholangiocarcinomas with an LELC component have been documented [10–16]. In this paper, we describe an additional case of intrahepatic cholangiocarcinoma (ICC) with LELC component. We demonstrated Epstein-Barr virus (EBV)-encoded RNA-1 (EBER-1) in the tumor cells by in situ hybridization. The polymerase chain reaction (PCR) was performed to characterize the latent membrane protein-1 gene (LMP-1).
Case Report
This 60-yr-old Taiwanese woman was a hepatitis B carrier and had been in good health until she developed a sore throat, rhinorrhea, and cough. She sought medical attention at a local hospital where she was incidentally found to have an abdominal mass lesion that was confirmed by ultrasonography. She then came to our hospital for a second opinion and was admitted for evaluation in May 2002. On admission, her physical examination was essentially unremarkable. Laboratory test results, including a clinical chemistry profile and complete blood count, were within normal limits. The serum level of alpha-fetoprotein (AFP) was 3.0 ng/ml (reference range <20 ng/ml). Computed tomography (CT) of the abdomen showed a 3 x 2 x 1.5 cm, lobulated space-occupying lesion in the posterior-medial aspect of the liver, immediately beside the inferior vena cava (Fig. 1
). She promptly underwent resection of the hepatic tumor. At surgery, there was no evidence of metastases. She did not receive chemotherapy or radiation therapy, and was feeling well when she was last seen in May 2004.
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The resected liver specimen measured 9 x 8 x 3 cm and weighed 150 g. There was a well-defined, non-capsulated tumor measuring 3.5 x 3.3 x 2.7 cm. Serial sectioned surfaces were white and firm. Neither necrosis nor hemorrhage was seen (Fig. 2). Microscopically, the tumor was composed of 2 components. The first component, which accounted for approximately 20% of total tumor volume, consisted of an undifferentiated carcinoma in which tumor cells formed ill-defined syncytia infiltrated by small lymphocytes. The tumor cells had irregular large nuclei with vesicular or open chromatin and prominent nucleoli, and were similar to those of nasopharyngeal carcinoma. The second component consisted of a moderately-differentiated adenocarcinoma, forming ductular structures, accompanied by the marked desmoplastic stromal response that is characteristic of cholangiocarcinoma (Fig. 3). The stroma likewise contained lymphoplasma cells. Focal progression from the glandular pattern to the undifferentiated pattern was evident.
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Epstein-Barr virus-encoded RNA-1 (EBER-1) in situ hybridization study.
In-situ hybridization was used to detect EBV-encoded RNA (EBER-1) with a commercially available kit (DAKO), according to the manufacturer’s instructions. A known case of NPC was used as a positive control; a negative control was also included. The tumor cells showed diffuse strong nuclear labeling in syncytial and glandular malignant cells (Fig. 4), in contrast to surrounding negative-labeling reactive lymphocytes.
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Since the first description of ICC with LELC, 11 cases have been reported in the literature [10–16]. Their clinical data are summarized in Table 1. The subjects included 9 orientals, 2 caucasians, and 1 hispanic; there were 5 men and 6 women with ages from 19 to 71 yr. The tumor diameters ranged from 2 to 10 cm. Lymph node metastases developed in 2 patients (cases #1 and #8). Case #1 died of surgical complications. Cases #3 and #11 died of the disease at 48 and 44 mo, respectively, after surgery. Case #8 was still alive at 2 yr follow-up. Follow-up data were unavailable for case #9. The remaining 7 patients were disease-free at follow-up periods ranging from 2 mo to 7 yr. All patients only received surgical resection of the tumor (case #8 refused chemotherapy). Serological studies showed that 3 of the patients were carriers for HBV and 2 were carriers for HCV; none of the patients were carriers for both HBV and HCV.
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All of the reported patients were examined for EBV by EBER-1 in situ hybridization; 3 of these patients were EBV-negative (cases #2, #9, and #10). LMP-1 gene study was performed in 3 of the 9 EBV-positive patients (cases #1, #8, and #12). The result in case #8, reported by Vortmeyer [14], was a wild-type EBV. Case #1 [10] and the present case, which were both from Taiwan, showed a 30-bp deletion that is unique for the EBV in the high prevalence area of undifferentiated nasopharyngeal carcinoma in Taiwan and Southeastern Asia. The LMP-1 gene is considered to be a viral oncogene because of its capacity to transform rodent fibroblasts in vitro and render them tumorigenic in nude mice [22]. The LMP-1 gene also serves as a target for T-cell mediated cytotoxicity. Any mutations in the LMP-1 gene that result in failure of recognition by T cells would allow the LMP-1 variant to escape immunologically-mediated elimination [23]. The deletion strain that is prevalent in Taiwan is observed not only in the cells of NPC, but also in throat washings of healthy individuals [24].
Presence of the EBV genomes and their expression in the cholangiocarcinoma cells suggest that EBV may play an important role in the pathogenesis of ICC with LELC. In the present case, it is unclear why only 20% of the glands were transformed into LELC. Shibata and Weiss [25] found that 16% of gastric adenocarcinomas were EBV-positive. The glands of those gastric adenocarcinomas were not transformed into distinct histological features of LELC. How the EBV infected glandular cells become transformed into a characteristic morphology that resembles NPC is unclear, and warrants further investigation.
In summary, this report demonstrates that EBV genomes were present and expressed within the tumor cells of ICC with LELC. Additional studies are needed to clarify the role of EBV in the oncogenesis of ICC with LELC, and the mechanism whereby EBV transforms neoplastic glands into the distinctive NPC-like morphology.
References
This article has been cited by other articles:
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  P. Xiao, H. Shi, H. Zhang, F. Meng, J. Peng, Z. Ke, K. Wang, Y. Liu, and A. Han Epstein-Barr virus-associated intrahepatic cholangiocarcinoma bearing an intense lymphoplasmacytic infiltration J. Clin. Pathol., January 20, 2012; (2012) jclinpath-2011-200581v1. [Full Text]
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