A case of well-differentiated adenocarcinoma (Borrmann type 3) of the stomach in a 76-year-old man associated with the typical skin manifestations of acanthosis nigricans and with multiple protruding lesions showing epithelial hyperplasia of the esophagus is reported. The advanced tumor was located in the cardiac region of the stomach, and measured approximately 8 cm in diameter, with partial invasion to the esophagus. The associated cutaneous lesions were characterized by hyperpigmentation and by protruding verrucous papules on the torso, head, face, neck, upper extremities, perineum, and inguinal region. Histologically, the protruding skin lesions showed keratinocytes proliferation throughout the epidermis, resulting in diffuse hyperkeratosis, papillomatosis, and acanthosis of the skin. Immunohistological analysis showed coexpression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) receptors in the tumor from the stomach. It is reasonable to conclude from this evidence that gastric carcinoma cells secrete TGF alpha in an autocrine for auto-stimulation. EGF receptor expression was also noted on the papillomatous hyperplasia of the cutaneous lesion. Serum level of TGF alpha, determined by an enzyme-linked immunosorbent assay, was high (144 pg/ml; normal, 22.0 +/- 16 pg/ml (Mean +/- SD)). Serum TGF alpha abruptly decreased to 49 pg/ml on day 7 after the total gastrectomy, and then gradually increased to 77 pg/ml within 28 days. Amelioration of the cutaneous lesions and the protruding lesions in the esophagus was observed after surgical resection of the gastric carcinoma. This suggests that the TGF alpha stimulates the proliferation 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 epidermal and esophageal epithelial cells to proliferate. There is a possible link in the pathogenesis of the acanthosis nigricans as a cutaneous paraneoplastic syndrome, and epithelial hyperplasia of the esophagus.

BACKGROUND Stepwise progression of peripheral‐type lung adenocarcinoma was characterized morphologically and was related to prognosis. Expression of the tumor suppressor gene p16 in pulmonary adenocarcinoma decreased, mainly as a result of aberrant methylation of the CpG islands of the promoter region. METHODS Aberrant methylation status of the p16 promoter region, the expression of its product, and loss of heterozygosity (LOH) on 9p21 were examined in surgically resected lung specimens from 57 patients (28 males and 29 females) with peripheral‐type lung adenocarcinoma measuring ≤ 2 cm in diameter. RESULTS Aberrant methylation of the p16 promoter region, negative p16 protein expression, and LOH of the 9p21 region were detected in 40.4%, 50.9%, and 40.4% of tumor samples, respectively. The alterations of the p16 gene were associated with poor prognosis, and in particular the prognosis of patients with aberrant p16 methylation was significantly worse than that of patients without aberrant methylation. These alterations also were associated with morphologic classification into bronchioloalveolar carcinoma (BAC) and non‐BAC adenocarcinoma. Both aberrant methylation and LOH of 9p21 were associated with negative protein expression, but the former was correlated more closely with loss of function than was the latter. Cases with both alterations were completely negative for expression of the p16 gene product. CONCLUSIONS Aberrant methylation of the promoter region of the p16 gene and loss of expression of its product were in accord with the multistep progression of peripheral‐type lung adenocarcinoma, and these alterations were associated closely with poor prognosis of the disease. Cancer 2005. © 2004 American Cancer Society.

The GA733 gene family is composed of GA733-1 (TROP2) and GA733-2 (Ep-CAM), whose expression has been examined in various carcinomas and reported to be significantly associated with prognosis. The aim of this study was to investigate the expression of GA733 gene family members and to compare their prognostic significance in pulmonary adenocarcinoma. One hundred thirty paraffin-embedded specimens of small-sized pulmonary adenocarcinoma, less than 2 cm in diameter, were categorized using the classification of small-sized pulmonary adenocarcinoma devised by Noguchi et al. (Cancer 75:2844-2852, 1995) and examined immunohistochemically using a murine monoclonal antibody against Ep-CAM and a goat polyclonal antibody against TROP2. The patient survival rate was calculated using the Kaplan-Meier method. Ep-CAM and TROP2 were similarly expressed in many small-sized pulmonary adenocarcinomas. The expression of Ep-CAM was significantly related to a favorable outcome (p = 0.0185), whereas TROP2 tended to be expressed in cases with an unfavorable outcome (p = 0.0564), and was significantly associated with an unfavorable outcome in nonlepidic-type adenocarcinomas (p = 0.0125). Multivariate analysis showed that TROP2 overexpression and lymph node metastasis were independent prognostic markers. Although the two GA733 proteins share structural similarity, they appear to have opposite biological significances in small-sized adenocarcinomas. As the expression of TROP2 was detected in more poorly differentiated tumors, the protein may have oncogenic activity.

In comparison with other immunohistochemical and histopathologic factors, BAC/LG component is independently and reliably prognostic for small adenocarcinoma of the lung, and, in particular, for the major histologic subtype (adenocarcinoma mixed subtype with BAC/LG), BAC/LG component is more reliably prognostic than lymph node metastasis.

This modality at modest doses was macroscopically and histopathologically effective on tumors particularly in WHO B1 and B2 thymomas than WHO B3 thymoma. The therapeutic benefit of preoperative RT followed by surgery and postoperative RT for stage III thymomas should be defined thoroughly.