tetracycline and Lymphoproliferative-Disorders

Anatomic pathology has produced considerable knowledge about environmental teratogens and carcinogens. A special disease registry established by a pathologist provided details of the association between oral contraceptives and hepatic neoplams. Pathologists were also involved in establishing in the link between diethylstilbestrol use and clear-cell adenocarcinomas of the vagina. An area of particular interest has been gender and ethnic differences in the incidence of certain diseases. Pathologists further make use of animal studies to investigate the pathogenesis of human tumors. Finally, stored serum or tissue is often used by pathologists to help diagnose diseases retrospectively. Human skin fibroblasts grown in culture and stored have been especially valuable for laboratory research. This chapter briefly highlights some of the milestones in the detection of enviromental effects through anatomic pathology.

Topics: Adenocarcinoma; Animals; Ataxia Telangiectasia; Contraceptives, Oral; Diethylstilbestrol; Disease Models, Animal; Environment; Ethnicity; Female; Geography; Herpesvirus 4, Human; Humans; Liver Neoplasms; Lymphoproliferative Disorders; Osteosarcoma; Pathology, Clinical; Radiation, Ionizing; Sex Factors; Tetracycline; Thorium Dioxide; Tooth Discoloration; Vaginal Neoplasms; X Chromosome

Mutations of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a(-/-) mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.

Topics: Adenoma; Adrenal Cortex Neoplasms; Animals; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; DNA, Antisense; Down-Regulation; Exons; Female; Lymphoproliferative Disorders; Mesoderm; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pregnancy; Promoter Regions, Genetic; Proteins; Tetracycline; Thyroid Neoplasms; Trans-Activators

A 44-year-old woman was seen with the clinical and histologic picture of lymphangiomyomatosis syndrome. She also had dermatologic and neurologic stigmata of tuberous sclerosis. After the development of a recurring chylothorax, she had a downhill course unresponsive to dietary, bronchodilator, corticosteroid and progesterone therapy. In an open lung specimen, the search for steroid receptor for estrogen was positive. The discovery in this case of an estrogen receptor represents important evidence for establishing an association between tuberous sclerosis and lymphangiomyomatosis. Tamoxifen therapy and tetracycline pleurodesis were successful in stopping the progressive course and controlling the chylothorax.

Topics: Adhesiveness; Adult; Chylothorax; Female; Humans; Lung Neoplasms; Lymphangiomyoma; Lymphoproliferative Disorders; Neoplasms, Hormone-Dependent; Pleura; Receptors, Estrogen; Tamoxifen; Tetracycline; Tuberous Sclerosis