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Initial results (Cancer Res., 48: 1708-1711, 1988) suggest that ovariectomy alters the proliferation of congenital exophytic melanoma in Sinclair swine. In order to provide a phenotypic basis for this effect, histopathological staging of 375 exophytic melanomas from 236 intact male and female Sinclair swine was compared with 114 lesions from 51 gonadectomized (6 weeks of age) and 90 lesions from castrated swine receiving s.c. silastic implants of estradiol during the first year of life. A rapid progression from actively proliferating tumor cells (Stages I-III) to regressive lesions (Stages IV-V) was virtually complete by 16 weeks of age in intact swine of both sexes. Bilateral ovariectomy reduced (P less than 0.02) tumor volume over time compared with intact animals. Replacement of estradiol in gilts increased tumor volume to that in intact animals. In contrast, neither bilateral orchidectomy nor estradiol replacement altered tumor volume in boars. Ovariectomy significantly reduced the tumor macrophage, keratinocyte, and fibroblast invasion that normally replaces tumor cells and expands tumor volume (Stages IV and V) with increasing age. Chronic exposure to estradiol reversed this process. Orchidectomy and estradiol replacement did not significantly affect histopathological stage in boars with increasing age. A significant number (20 of 41; 49%) of Stage III lesions (greater than 75% tumor cells) in swine of both sexes contained low but reproducibly measurable amounts of receptor for estrogen determined radiometrically and by enzyme-linked immunosorbent assay. These results suggest that reproductive steroids influence the natural history of these heritable lesions, and that the effect may be via alteration of host immune status.

We have analyzed the association between host hormonal status and growth rate of congenital exophytic melanomas of Sinclair swine. The growth of multiple exophytic lesions during the first year of life of intact males, orchiectomized males, intact females, and ovariectomized females was quantitated using a proliferative index which assigned a numerical value to fixed increments of gains or losses in tumor volume. The proliferative index from 6 wk (gonadectomy at 6 wk) to 52 wk of age of each treatment group was statistically increased from 0 (P less than 0.01) except that of gonadectomized females. The proliferative indices from lesions in gonadectomized females were significantly lower than those from intact males, intact females, and gonadectomized males. A total of 93 exophytic tumors from 63 swine were biopsied and histopathologically staged according to the degree of progression or regression and analyzed as a function of animal age. There were no Stage I and only two Stage II lesions at the time biopsies were taken. Twenty-six of 32 (81.2%) Stage III tumors were found in swine of both sexes less than 26 wk of age of which 71.8% were found less than 10 wk of age, while 20 of 29 (68.9%) were Stage IV, and only 3 of 32 (9%) were Stage V lesions present in this age group (P less than 0.001, chi 2). Only 20.7% of Stage IV tumors were present prior to 6 wk of age. Preliminary results suggest that castration of either sex also altered tumor histopathology. Our data suggest that a reduction in gonadal steroid secretion was associated with a decrease in exophytic tumor growth rate and regression in animals of both sexes during the first year of life in Sinclair swine. The effect in female swine was due to significant reduction in the proliferative index over the first 6 mo of age.

Genetic studies of familial human cutaneous malignant melanoma have failed to support a single mode of inheritance. To eliminate the complexities of genetic heterogeneity, we have turned to appropriate animal models to gain insights into possible genetic mechanisms that may be applicable to the human. Cutaneous malignant melanoma of Sinclair miniature swine is an inherited malignancy with many of the histopathological characteristics of human melanoma. The actual mode of inheritance of the melanoma has not been determined. Recently, we initiated experiments to characterize the swine major histocompatibility complex in melanoma- and nonmelanoma-bearing animals. These experiments led to the discovery of two loci that are involved in the expression of exophytic melanomas. The first locus lies within the swine major histocompatibility complex where one particular haplotype produces a phenotype in which the effects of a second locus are fully penetrant. The second locus segregates independently of the major histocompatibility complex. The melanoma-producing allele at this second locus is inherited in the heterozygous state and requires a somatic mutation of the normal allele to initiate tumor development.