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Epstein-Barr virus (EBV) is a ubiquitous viral agent, well known to be associated with lymphoid, epithelial, and smooth-muscle malignancies in immunocompromised individuals. This report describes a 10-year-old patient with an EBV-related liver tumor occurring after kidney transplantation. The neoplasm presented a phenotypic spectrum, ranging from a smooth-muscle tumor to an inflammatory pseudotumor (IPT). The neoplastic cells failed to disclose CD21, CD35, or ALK expression, the latter confirmed by reverse-transcription polymerase chain reaction. Cytogenetic analysis revealed a single clonal cell population showing 46,XY,del (2)(p23),der(3)t (2;3)(p23;q29),der(21) t(Y;21)(q12;p13) karyotype. By metaphase FISH analysis, the neoplastic cells demonstrated the presence of two molecularly different but related aberrant clones, one with the loss of one ALKallele and the second with translocation of the 3′end of ALKkinase domain on the der(3) chromosome. Using FISH with an EBV-specific and 3′end ALKDNA probes, a co-localization of the viral DNA and the ALKsequences was found on the der(3) chromosome. Metaphases with loss of rearranged ALKdid not show integrated virus; instead, viral particles together with an associated 3′end ALKdomain formed an ex-chromosomal, episomal-like type configuration. The interphase study, using dual-color 5′/3′ end ALK FISH assay, revealed 30% of nuclei with only one fused signal, confirming the total loss of one ALKallele in the subset of tumor cells. A combined immunofluorescence and FISH study indicated this separate clonal variant to correspond to desmin-positive smooth-muscle cells. In contrast, desmin-negative myofibroblasts showed the presence of both normal and rearranged ALKalleles. Our results indicate that ALKlocus may be a target of EBV integration, a hitherto unreported finding. Although the sustained clonal expansion in EBV-related smooth-muscle tumors/IPTs may depend on functions provided by the EBV oncogenic proteins, the tumor phenotype may be further modified by the secondary genomic rearrangements imposed by the virus during and/or after the integration event. In this respect, the observed phenotypic heterogeneity most likely reflects divergence during neoplastic progression, with the subsequent expansion of morphologically and molecularly distinct but cytogenetically related clones.