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Abnormal sexual differentiation and neoplasia.

The prevalence of neoplasia is increased in individuals with certain disorders of sexual differentiation. Etiology and frequency of neoplasia vary with the particular disorder. In uncomplicated cryptorchidism, the testis is at least 10 times more likely to undergo neoplastic transformation than a normal scrotal testis. Neoplasia probably is a function of both testicular location (intraabdominal) and underlying dysgenetic structure. If cryptorchidism is unilateral, and if orchiopexy has not been performed prior to age 6-10 years, orchiectomy should be encouraged. In those forms of gonadal dysgenesis not associated with a Y chromosome (e.g., 45,X; 45,X/46,XX; 46,XX) there is no definite increase in neoplasia, suggesting that elevated gonadotropin levels per se are not carcinogenic. Gonadal tumors are found in at least 30% of individuals with XY gonadal dysgenesis and are particularly frequent (55%) in H-Y antigen-positive patients. These tumors are almost always gonadoblastomas or dysgerminomas. Similar tumors are found in 15%-20% of 45,X/46,XY individuals. In either situation the neoplastic transformation could be a) secondary to the existence of XY gonadal tissue in an inhospitable environment, or b) integrally related to that process--genetic or cytogenetic--producing the dysgenetic gonads. The risk of neoplasia is sufficiently high that most of these patients should be offered early gonadal extirpation. The prevalence of gonadal tumors is not increased in Klinefelter's syndrome, further indicating that gonadotropins are not carcinogenic per se. However, Klinefelter patients are 20 times more likely to develop a carcinoma of the breast than are 46,XY males. Extragonadal germ cell tumors also are more common. In female pseudohermaphrodites there is probably no increased risk of neoplasia, whereas, in true hermaphrodites neoplasia is unusual but does occur. Neoplasia occurs in patients with complete testicular feminization (complete androgen insensitivity) but rarely in those with incomplete testicular feminization/Reifenstein's syndrome, 5 alpha-reductase deficiency, anorchia, agonadia, or testosterone biosynthetic defects. In complete testicular feminization the risk of malignant tumors is small prior to age 25. After age 25, it is about 2%-5%. Orchiectomy is recommended after pubertal feminization.

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