In the present report, we describe a case of in-trahepatic cholangiocarcinoma (ICC) with areas of LELC, exhibiting positivity for EBV-encoded RNA (EBER-1), by in-situ hybridization. The major differential diagnoses considered were me-tastatic undifferentiated nasopharyngeal carcinoma, lymphoepithelioma-like hepatocellular carcinoma, and metastatic LELC from other body sites.
In this case, a thorough clinical and radiological patient evaluation showed no extra hepatic primary tumors, supporting the hepatic origin of this tumor. Furthermore, the tumor negativity for HepParl, and the normal serum AFP level, mitigated against the diagnosis of lymphoepithelioma-like hepatocellular carcinoma. To the best of our knowledge, twelve cases of primary mixed ICC with LELC involving the liver have been reported. A summary of the reported cases of hepatobiliary LELCs is listed in [2
]. In the reported cases, the patients presented with a variety of symptoms such as abdominal fullness, presence of an epigastric mass, or vague epigastric pain. Most of the hepatobiliary masses were found incidentally by sonography. The patients included eight women and five men. Their ages ranged from 19 to 71 years (mean 54; median 56). Grossly, the tumors were described as being well-demarcated, gray-white and firm [2
]. Six of the 13 cases reported that the tumors were non-encapsulated [2
]. Tumor size ranged from 2 to 10 cm. In four patients the tumor was metastatic to regional lymph nodes at presentation or became metastatic during follow-up [2
]. Two of the patients with node metastases (50%) experienced recurrent liver disease within two years and both patients died of their disease.
Primary mixed lymphoepithelioma-like carcinoma and intrahepatic cholangiocarcinoma reported in the English literature
As in our study, the reported cases showed his-tologically two architectural patterns: 1) The ill-defined, syncytial pattern infiltrated by small lymphocytes and 2) The ductular pattern. Cy-tologically the tumors revealed features similar to those described in our case, such as irregular vesicular nuclei with prominent nucleoli and indistinct cellular borders. The feature common to all of the reported cases was a background of dense lymphocytic infiltrate. Lymphoid follicles may be present. The desmoplastic stromal response is usually found within the ICC component of the tumor. Occasionally, a granuloma-tous reaction with multinucleated giant cells has also been described [5
Similar to the previously reported tumors [3
], the immunohistochemical study in this case demonstrated strong positivity for CK7 and AE1/AE3 in the tumor cells that were negative for CK20. Focal mCEA positivity was present in our case. The tumor cells in four of the previously reported cases were negative for CEA. One unique case of hepatocellular carcinoma (HCC) with lymphoepithelioma-like features was reported [6
]. The HCC diagnosis was supported by positive immunoreactivity for HePar 1, an immuno-histochemical marker specific for hepatocellular differentiation. Furthermore, that case was negative for EBV.
Nine of the 13 reported tumors (69%), including the present case, were positive for EBV by EBER -1 in situ hybridization. It has been proposed that EBV may play a role in the tumorgenesis of ICC with LELC. EBV infected ductal epithelium may undergo transformation into cholangiocar-cinoma and the viral genome may be sustained in the undifferentiated carcinoma component [1
]. Clonal proliferation has been demonstrated in LELC of the liver [2
], raising the possibility that EBV infection may have occurred before malignant transformation [1
]. Interestingly two of the 3 patients with negative EBV had chronic viral hepatitis C and one had chronic viral hepatitis B. These patients had liver cirrhosis in the background. The development of LELC in these patients was attributed to the hepatitis virus C and/or B. In our patient the hepatitis viral profile was negative.
The mechanism of viral carcinogenesis for biliary epithelial cells and for hepatocytes, and the molecular mechanism associated with the naso-pharyngeal carcinoma-like morphology warrants further study. Detection of EBV may be significant in the diagnosis and prognosis of these tumor types.
The prognosis of ICC with LELC is difficult to assess due to a limited number of cases reported to date and to the short and inconsistent follow-up periods. Seven out of thirteen (54%) patients are alive without disease. Lymph node metastasis and recurrent tumor appeared to be associated with a poor outcome. Careful long-term follow-up of additional cases is warranted to determine the disease course.
There is no consensus on standardized treatment strategy for primary mixed ICC/LELC. Considering the reported cases, the patients underwent surgical resection of their tumors. Postoperative chemotherapy and radiation were given to two of the patients [3
] one of whom was alive with local recurrence and no distant metastases 2 years after treatment, while the other succumbed to her malignancy 21 months after receivingchemoradiation.
In summary, this report describes an unusual and rare case of primary mixed ICC with LELC that revealed the presence of EBV encoded RNA -1 in the tumor cells. When faced with such a difficult diagnostic challenge, thorough clinical and radiologic testing is required to rule out the possibility of a metastatic LELC to a liver harboring a primary intra-hepatic cholangiocarcinoma. A regular post-operative follow-up of such patients will be important for early detection of recurrent/metastatic disease and to evaluate the efficacy of the therapeutic modalities offered. Furthermore, studies are needed to determine the exact role of EBV in the genesis of this morphologically distinctive neoplasm.