Arthur C. Lee

Classification and Behavior of Canine Mammary Epithelial Neoplasms Based on Life-span Observations in Beagles

As part of a study of the effects of low-level radiation, 1,343 Beagles, including 671 males and 672 females, were evaluated over their full lifetime for the occurrence of mammary neoplasia; there were 139 control males and 138 control females and 532 irradiated males and 534 irradiated females. All nodules found in surgical specimens or at necropsy were evaluated histologically. The overall incidence, metastasis and recurrence rates, and contribution to mortality of mammary neoplasms were determined. Based on this unique opportunity to correlate morphologic characteristics with ultimate biological behavior of all mammary tumors in a defined canine population, we propose a histogenetically based reclassification of epithelial mammary tumors. Of the 672 female dogs, 70.8% (476) had at least one mammary neoplasm; 60.7% (408) had more than one. Two male dogs had mammary neoplasms. Of 1,639 mammary carcinomas in the 672 females, 18.7% (307) were classified as ductular carcinomas (arising from the small interlobular or intralobular ductules), whereas 80.7% (1,322) were classified as adenocarcinomas of other histogenetic origin. Of 73 fatal carcinomas, ductular carcinomas accounted for 48 fatalities (65.8%), whereas other adenocarcinomas accounted for only 20 fatalities (27.4%). Radiation had no effect on this ratio. Ductular carcinomas also had a higher rate of metastasis than did adenocarcinomas. Existing classifications of mammary carcinomas do not recognize the characteristic morphologic features, the degree of malignancy, and the prognostic importance of these ductular carcinomas. Metastasis rates did not differ between simple and complex carcinomas or between those lesions and adenocarcinomas in mixed tumors. True carcinosarcomas metastasized more frequently (100%, or 5/5) than did adenocarcinomas in mixed tumors (34.4%, or 22/64), emphasizing the importance of not lumping these tumors under the classification of malignant mixed tumors.

Associations between Lymphocytic Thyroiditis, Hypothyroidism, and Thyroid Neoplasia in Beagles

The thyroids were evaluated in 276 control Beagles that were allowed to live out their full life span (≥ = 12 years) in a closed breeding colony. Lymphocytic thyroiditis was found in 26.3% of the dogs. This lesion was characterized by lymphoplasmacytic inflammation accompanied by follicular destruction. The thyroiditis was progressive, resulting in severe atrophy of follicular tissue, and 44 dogs (15.9%) were diagnosed as hypothyroid at the time of death. In accordance with the experimental protocol, hypothyroid dogs were not given thyroxine replacement therapy. There was a high degree of heritability for the hypothyroidism. Hypothyroid dogs had an increased risk for thyroid follicular epithelial neoplasia and, in particular, for follicular adenocarcinomas. Twenty-four of the 44 hypothyroid dogs (54.5%) had one or more follicular thyroid neoplasms, whereas only 53 of the 232 (22.8%) clinically euthyroid dogs had similar tumors. Multiple thyroid tumors were present in 14 of the 44 (31.8%) hypothyroid dogs but in only 12 of the 232 (5.2%) euthyroid dogs. One or more follicular adenocarcinomas were present in 15 of the 44 (34.1%) hypothyroid dogs but in only 16 of the 232 (6.9%) euthyroid dogs. There was no difference in prevalence of hypothyroidism or tumors between the sexes. The strong association between progressive lymphocytic thyroiditis, hypothyroidism, and thyroid follicular neoplasia in these Beagles probably relates to promotion of residual follicular epithelium by chronic excess thyrotropin stimulation.

Mortality in Beagles Irradiated during Prenatal and Postnatal Development. II. Contribution of Benign and Malignant Neoplasia

To evaluate the lifetime carcinogenic hazards of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days postcoitus or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, neoplasia was a major disease, contributing to mortality in 40% of the dogs. There was a significant increase in benign and malignant neoplasms occurring in young dogs (<4 years old), including fatal malignancies, after irradiation in the perinatal (late fetal and neonatal) periods. The lifetime incidence of fatal neoplasms was also increased in dogs irradiated perinatally. Three malignancies-lymphomas, hemangiosarcomas and mammary carcinomas-accounted for 51% of all fatal tumors. There was an apparent lifetime increase and earlier onset of lymphomas in dogs exposed as fetuses. Fatal hemangiosarcomas were increased in dogs irradiated early and late in gestation. Fatal mammary carcinomas were not increased by irradiation, although non-fatal carcinomas were increased after perinatal exposure. Myeloproliferative disorders and central nervous system astrocytomas appeared to be increased in perinatally irradiated dogs. These data suggest that irradiation in both the fetal and neonatal periods is associated with increased early onset and lifetime cancer risk.

Mortality in beagles irradiated during prenatal and postnatal development. I. Contribution of non-neoplastic diseases.

To evaluate the lifetime health effects of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days after breeding, or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. There was no significant effect of irradiation on mean survival times in any groups. In 1,343 dogs allowed to live out their life span, chronic renal disease was a common cause of mortality, and irradiation in the late fetal or juvenile periods potentiated this disease, resulting in increased mortality due to renal failure. This was consistent with earlier findings of the high radiosensitivity of the kidney in the perinatal period. Hypothyroidism associated with atrophic thyroiditis was decreased by irradiation, a finding contrary to expectation and not easily explained. Diabetes mellitus was increased by irradiation in the mid- and late gestation and juvenile periods, a finding which is intriguing based on early reports of a similar finding in atomic bomb survivors. Though convulsive seizures were a common cause of mortality in the dogs, there was no evidence for increased risk associated with prenatal irradiation as has been reported in humans. Genetic analyses indicated that renal disease, hypothyroidism, diabetes mellitus and convulsive seizures all had a heritable component, but that this did not influence or bias the radiation responses evaluated.

Non-neoplastic and neoplastic thyroid disease in beagles irradiated during prenatal and postnatal development.

To evaluate the lifetime hazards of exposure to ionizing radiation, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures during development. Eight groups of 120 dogs each received mean doses of 16-18 or 81-88 cGy at 8, 28 or 55 days of gestation, or at 2 days after birth. One group of 120 dogs received a mean of 83 cGy at 70 days of age and one group of 240 dogs received a mean of 81 cGy at 365 days of age. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, heritable lymphocytic thyroiditis with hypothyroidism was a major contributor to mortality. Irradiated dogs had a decreased risk for hypothyroidism, a finding that was surprising and not easily explained. Of the 1,343 life-span dogs, those exposed as neonates at 2 days of age or as juveniles at 70 days of age had evidence for an increased risk for thyroid follicular cell neoplasia. Hypothyroid dogs had a significantly increased risk for thyroid neoplasia, including greater risk for carcinomas, but no evidence of a greater sensitivity to radiation-induced tumors. In dogs with normal thyroid function irradiated at 2 or 70 days of age there was increased risk for benign and malignant follicular cell neoplasms, including multiple neoplasms. No difference between sexes was noted. These findings related to age sensitivity in the dog were consistent with the high risk for radiogenic thyroid neoplasia in humans after exposure during early childhood.

Health effects of low-level irradiation during development: experimental design and prenatal and early neonatal mortality in beagles exposed to /sup 60/Co gamma rays

As part of a long-term study of the effects of irradiation during development, prenatal and early neonatal mortality were evaluated for beagles exposed in utero at 8 days postcoitus (dpc), 28 dpc, 55 dpc, or 2 days postpartum. Mean doses used were 0,0.16, or 0.83 Gy. A decrease in whelping rates was observed for female breeders irradiated at 8 dpc. There was a significant decrease in litter sizes from female breeders irradiated at 8 and 28 dpc. Both of these findings are indicative of increased embryonic mortality. There was a significant decrease in the percentage of females born after exposures given at 28 dpc, indicating a differential radiosensitivity by sex. A significant increase in early neonatal mortality up to 14 days of age was observed for beagles exposed 8 or 28 dpc, again with an excess mortality in females.

Transitional Cell Carcinomas of the Urinary Tract in a Colony of Beagle Dogs

Gross and light microscopic features of transitional cell carcinomas (TCC) of the urinary tract were examined in Beagle dogs used for the study of the long-term effects of low-dose, whole-body, 60Co gamma radiation. Thirty-eight cases of TCC occurred among 990 dogs that were from 0 to 14 years of age. There was no conclusive evidence of a radiation effect. The 38 TCC were equally divided between male and female dogs, but there was a significant difference in the sex distribution of urethra-origin TCC. Eleven males had a primary urethral TCC compared to only two females. There was no significant difference between the urethra-origin and bladder-origin TCCs in the number of tumors that caused clinical signs, metastasized, or that contributed to the death of the dog. All cases of urethral TCC in male dogs occurred in the prostatic urethra. The majority of these cases were not recognized to be neoplasms at gross necropsy, but microscopic examination revealed the TCC. Our findings differ from previous reports stating that TCC occurs more frequently in female than male dogs, and they especially differ from reports claiming that urethra-origin TCC is predominately a disease of female dogs.

Retinal Dysplasia and Progressive Atrophy in Dogs Irradiated during Ocular Development

Beagle dogs were given a single, whole-body gamma-radiation exposure at various stages during ocular development and were evaluated for the presence of ocular lesions. Dogs were exposed during middle or late pregnancy at 28 or 55 days postcoitus (dpc) or as neonates at 2 days postpartum (dpp). Mean whole-body and ocular doses ranged from 1.0 to 3.8 Gy. Dogs were sacrificed and ocular lesions were evaluated at 70 days, 2 years, or 4 years of age. Retinal dysplasias and atrophy were the most striking lesions related to radiation exposure. These lesions were bilateral and focal to diffuse in nature, and they increased in severity with increasing radiation dose. The stage of development at irradiation had a marked effect on the distribution of retinal lesions, with the most severe changes being present in that portion of the retina undergoing differentiation at the time of the insult. In dogs sacrificed at 70 days of age the lesions were primarily dysplasias consisting of ectopic nuclear aggregates in the photoreceptor layer, retinal folds, and retinal rosettes. With increasing age (up to 4 years), there appeared to be progression of the extent of the clinically evident lesions, and there was a change in the nature of the lesions from dysplasia to atrophy. This was accompanied by marked attenuation of the retinal vasculature.

Hypodontia in the beagle after perinatal whole-body /sup 60/Co gamma irradiation

As part of a long-term study to evaluate health effects of pre- and postnatal irradiation, dental development was examined. Beagles were irradiated in utero at 8, 28, or 55 days postcoitus or postnatally at 2, 70, or 365 days postpartum. Whole-body 60Co gamma radiation doses ranged from 0 to 3.8 Gy. There was an age-dependent dose-related increase in premolar hypodontia for animals irradiated at 55 days postcoitus or 2 days postpartum with doses of 0.83 Gy or higher and for those irradiated at 28 days postcoitus with 1.2 Gy or higher.