Pleomorphic carcinoma of the lung (PCL) is a rare tumor, which constitutes approximately 0.1-0.4% of all lung cancers, and has a poor clinical outcome (1-3). Histologically PCLs exhibit characteristic tumor components, i.e., malignant epithelial and homologous sarcomatoid spindle/giant cells. The recently updated WHO classification defined pleomorphic carcinoma as "a poorly differentiated non-small cell carcinoma, namely, as a squamous cell carcinoma, adenocarcinoma or large cell carcinoma, containing spindle cells and/or giant cells, or as a carcinoma consisting only of spindle cells and giant cells and added that the pleomorphic component should comprise at least 10% of the neoplasm" (4). The co-expression of cytokeratin and vimentin is helpful in the diagnosis of PCL (5-9). The immunoreactivity of epithelial and mesenchymal markers in PCL suggests that PCL is a malignant neoplasm of epithelial origin (10-13). However, a variety of morphologic features in PCL suggest the possibility that PCL might be a heterogeneous group of tumors rather than an epithelial cell-derived malignant tumor.

CD99 is a transmembrane protein encoded by the MIC-2 gene and is characteristically expressed in the Ewing family of tumors/PNETs, a group of small cell tumors of childhood and adolescence with a specific EWS/ETS gene rearrangement (14-16). In addition, its expression also has been reported in lymphoblastic lymphoma/leukemia and some epithelial tumors (17-19). Recently CD99 was found to be a critical molecule that contributes to the regulation of apoptosis and the cell cycle in malignant cells (20). Nevertheless, to the best of our knowledge no study of the expression pattern and biological role of CD99 has been undertaken in PCL. Thus, the aim of this study was to evaluate the expression of CD99/MIC-2 protein in a series of PCLs and to investigate whether this expression is related to morphological differentiation or prognostic implications.

The CD99 protein is ubiquitously expressed in a variety of human normal tissues and malignant cells (21-24). In normal tissue CD99 is highly expressed in cortical thymocytes, pancreatic islet cells, granulosa cells of the ovary, Sertoli's cells and ependymal cells. It is also expressed on fibroblasts, endothelial cells, smooth muscle cells and respiratory epithelial cells in which the level of expression is relatively low (24, 25). Even though CD99 is known to be a specific marker for Ewing/PNET, it is expressed in a variety of tumors (20-22, 24-26). With respect to neoplasms of the lung, CD99 is expressed in 25% of pulmonary neuroendocrine tumors and is preferentially confined to typical carcinoids (19). It is generally accepted that CD99 is not a specific marker for a particular subset of neoplasms. The present study demonstrates that CD99 expression is not only shown by spindle cells and giant cells in PCL, rather all cases containing a carcinomatous component showed various degrees of CD 99 positivity. In terms of sarcomatous component, the percentage of CD99-positive cells was higher in spindle cells than in giant cells. Our results support the concept that CD99/MIC-2 is not a specific marker for distinguishing a particular subset of human tumors. Moreover, it has been reported that CD99 plays critical role in the invasion, motility, and proliferation of malignant cells (27-33). Pelosi et al. reported a statistically significant relationship between the number of CD99 positive cells and the presence of local invasion and/or distant metastasis, and the Ki-67 index in gastrointestinal and pulmonary neuroendocrine tumors (19). These findings suggest that CD99 may be involved in cell-to-cell adhesion of neuroendocrine tumor cells and in downregulation of their proliferative activity. Thus, to explore the biological implication of CD99 in PCL we analyzed patient clinico-pathologic data. However, CD99 expression in PCL was not found to be correlated with patient prognostic parameters. These findings suggest that the expression of CD99 in PCL does not contribute to the anti-proliferation PCL tumor cells.

Although the histogenesis of PCL has not been clearly explored, several groups have suggested the possibility that PCL is a carcinoma with divergent sarcomatous differentiation, rather than being a collision neoplasm. Recently Rossi et al. studied 58 cases of PCL that showed immunoreactivity for CK7 and TTF-1 in the epithelial and sarcomatous elements (34). In addition, three groups have demonstrated that the epithelial and sarcomatous components of PCL show the same genetic abnormalities by microdissection analysis (35-37). These findings support the concept that the sarcomatous components of PCL might be derived from epithelial components. Like CK7, CD99 was also expressed on spindle and/or giant cells as well as PCL carcinomas in the present study. However, these findings inadequately support the concept that spindle and giant cells are derived from carcinoma because CD99 is more widely expressed on human mesenchymal components and sarcomas than carcinomas. Thus, it is more likely that the expression of CD99 on sarcomatous component of PLC reflects tumor cell mesenchymal differentiation status.

In summary, CD 99 was found to be widely expressed in both sarcomatoid and epithelial components in PCL, like other epithelial markers. Although the biological implications of its expression in PCL remain unclear, the clinicopathological analysis demonstrated no direct correlation between the expressions of CD99 in PCL and the clinical indices of PCL patients.