Genetic analysis as an aid in diagnosis for patients with midline carcinomas of uncertain histologies The tumors of nine patients with carcinomas of uncertain histogenesis (eight with poorly differentiated carcinomas involving primarily midline structures and one with a diagnosis of seminoma and atypical clinical features) were studied by cytogenetic and Southern blot analyses. Four of the eight patients with poorly differentiated carcinomas had abnormalities of chromosome 12 consistent with a diagnosis of germ cell tumor. These abnormalities comprised an i(12p) in two patients and a del(12q) in a third patient detected by cytogenetic analysis and multiple copies of 12p detected by Southern blot analysis in a fourth patient. Three of these four patients with a diagnosis of germ cell tumor established by genetic analysis achieved a complete response to cisplatin-based chemotherapy. The tumor biopsy of one patient showed a t(11;22) (q24;q12), and this patient had chemotherapy directed to neuroepithelioma. Cytogenetic analysis was unsuccessful for the tumors of three patients; these tumors did not have multiple copies of 12p detected by Southern blot analysis. These patients did not respond to cisplatin-based chemotherapy. One patient with a diagnosis of extragonadal seminoma failed to respond to cisplatin-based chemotherapy and had a second tumor biopsy performed that demonstrated a t(8;14) (q24;q32). This patient's diagnosis was changed to a non-Hodgkin's lymphoma. Thus, genetic analysis provided a diagnosis in six of nine patients. Cytogenetic and molecular analyses are useful clinical tools for the determination of histogenesis in some patients with poorly differentiated carcinomas of uncertain histology. 