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BACKGROUND. The differential diagnosis of metastatic clear cell carcinoma is broad. To date, there are no specific immunohistochemical markers for renal cell carcinoma (RCC) in general use. Loss of heterozygosity (LOH) at 3p25.5, the von Hippel-Lindau (VHL) gene locus, is frequent in sporadic clear cell RCC. The authors compared LOH in primary and metastatic RCC through microdissection and the polymerase chain reaction (PCR) to evaluate these techniques as potential diagnostic tools. METHODS. The authors identified 14 patients with known clear cell RCC who underwent fine-needle aspiration (FNA) evaluation of presumed metastatic lesion. Direct-visualization microdissection was performed from archival histologic glass slides of the primary neoplasm and the adjacent normal kidney parenchyma. Malignant cell clusters were microdissected from archival FNA slides of metastatic lesions. The cytology slides were previously stained with either Diff-Quik or Papanicolaou stain. This was followed by a single-step DNA extraction and PCR amplification for evaluation of LOH using polymorphic markers, D3S1038 and D3S1110, flanking the VHL gene. RESULTS. Thirteen of the 14 cases contained DNA suitable for PCR in both the paraffin embedded and the FNA material. Eight of the 13 cases were heterozygous (informative) for the above markers, and 6 of these showed identical allelic loss in the primary and metastatic tumor for either one or both of the markers used. The remaining two cases did not show LOH at the VHL locus with the two polymorphic markers used. CONCLUSIONS. DNA from archival cytologic material stained with Papanicolaou stain or Diff-Quik is reliable for PCR amplification. Visually directed microdissection in combination with PCR has the potential to be a useful technique for confirmatory identification and diagnosis of metastatic clear cell RCC in cytologic material, because a specific genetic abnormality is present in the primary tumor. As characteristic genetic abnormalities are identified in various neoplasms, the use of this technique has the potential for conclusive evaluation of metastatic disease with FNA material, when used in comparison with surgical or cytologic material from the primary tumor. The utility of this combination of techniques has the potential for the molecular diagnosis of morphologically ambiguous cell populations. Cancer (Cancer Cyto pathol) 1997;81:180-6. [C] 1997 American Cancer Society.