TRANSFORMING GROWTH-FACTOR-ALPHA (TGF-ALPHA)-PRODUCING GASTRIC-CARCINOMA WITH ACANTHOSIS NIGRICANS - AN ENDOCRINE EFFECT OF TGF-ALPHA IN THE PATHOGENESIS OF CUTANEOUS PARANEOPLASTIC-SYNDROME AND EPITHELIAL HYPERPLASIA OF THE ESOPHAGUS

A case of well-differentiated adenocarcinoma (Borrmann type 3) of the stomach in a 76-year-old man associated with the typical skin manifest ations of acanthosis nigricans and with multiple protruding lesions sh owing epithelial hyperplasia of the esophagus is reported. The advance d tumor was located in the cardiac region of the stomach, and measured approximately 8cm in diameter, with partial invasion to the esophagus . The associated cutaneous lesions were characterized by hyperpigmenta tion and by protruding verrucous papules on the torso, head, face, nec k, upper extremities, perineum, and inguinal region. Histologically, t he protruding skin lesions showed keratinocytes proliferation througho ut the epidermis, resulting in diffuse hyperkeratosis, papillomatosis, and acanthosis of the skin. Immunohistological analysis showed coexpr ession of transforming growth factor alpha (TGF-alpha) and epidermal g rowth factor (EGF) receptors in the tumor from the stomach. It is reas onable to conclude from this evidence that gastric carcinoma cells sec rete TGF alpha in an autocrine for auto-stimulation. EGF receptor expr ession was also noted on the papillomatous hyperplasia of the cutaneou s lesion. Serum level of TGF alpha, determined by an enzyme-linked imm unosorbent assay, was high (144 pg/ml; normal, 22.0 +/- 16 pg/ml (Mean +/- SD)). Serum TGF alpha abruptly decreased to 49pg/ml on day 7 afte r the total gastrectomy, and then gradually increased to 77pg/ml withi n 28 days. Amelioration of the cutaneous lesions and the protruding le sions in the esophagus was observed after surgical resection of the ga stric carcinoma. This suggests that the TGF alpha stimulates the proli feration of keratinocytes involved with EGF receptor. Large amounts of circulating TGF alpha in the blood over a long period released by the primary tumor seem to act as an endocrine-like mechanism causing epid ermal and esophageal epithelial cells to proliferate. There is a possi ble link in the pathogenesis of the acanthosis nigricans as a cutaneou s paraneoplastic syndrome, and epithelial hyperplasia of the esophagus .