In breast cancer, bcl-2 protein is associated with a prognostically favourable phenotype and appears to be related to hormonal regulation, rather than to disabled p53 gene function.

Gastrin-releasing peptide (GRP), the mammalian counterpart of bombesin, was first identified in the nervous system of the gastrointestinal tract. Little is known about its distribution in the human skin or about its function in certain diseases such as malignant melanoma. Recently functional GRP receptors have been found on human melanoma cell lines. We therefore investigated, using immunohistochemistry, whether human melanoma cells express GRP and whether there is a significant change in its distribution among the different clinical types of melanoma and a connection to histopathological features such as growth phase, type of malignant cells, Breslow thickness and Clark level of invasion. We demonstrated the existence of GRP in all clinicopathological types of melanoma; a predilection for quantitatively increased GRP immunostaining was noticed in nodular melanomas (P = 0.007). As well as this, we observed a restriction of GRP expression at a specific level of invasion, i.e. within the reticular dermis (Clark IV) (P = 0.032). GRP immunoreactivity was found to be associated with an increased amount of melanin pigment in malignant cells (P = 0.054). The presence of GRP in malignant melanocytes, along with its association with the various histopathological features, suggests that GRP may play a role in the pathophysiology of this type of cutaneous tumour.

Objective: The pathological distinction between parathyroid neoplasms and hyperplasias remains difficult. Changes in cell cycle control may lead to clonal proliferation and precede tumorigenesis. The parathyroid adenoma 1 oncogene, subsequently identified as the gene encoding cyclin D1, has been shown to be important to parathyroid tumour development. In addition to cell proliferation, the mechanisms of parathyroid cell turnover include apoptosis. The tumour-suppressor activity of the fragile histidine triad gene (FHIT) is linked to its proapoptotic function and cell cycle control. We attempted to evaluate the cellular proliferative kinetics and apoptotic function of the parathyroid glands in patients with non-familial hyperparathyroidism (HPT). Design: Tissue specimens were taken from 40 patients with primary HPT (17 adenomas, two carcinomas and 21 primary hyperplasias) and from 30 patients with secondary HPT. Normal glands served as controls. Methods: In a standard immunohistochemical procedure, monoclonal antibodies to Ki-67 antigen and single-stranded DNA were applied to detect cycling and apoptotic cells respectively; polyclonal antibodies to cyclin D1 and Fhit protein were used. Immunostaining was estimated by image analysis and statistical analysis was subsequently performed. Results: Significantly higher proliferative and apoptotic indexes were detected in the diseased glands in comparison with normal controls. In neoplastic and secondarily hyperplastic glands, apoptotic indexes were higher than in primarily hyperplastic glands; the difference between neoplastic and primarily hyperplastic glands was statistically significant ðP ¼ 0:034Þ: Cyclin D1 was overexpressed in a considerable proportion of tumours (68.4%). A reduction of Fhit protein immunoreactivity was selectively noticed in carcinomas. Conclusions: In primary hyperplasia, the remarkable proliferation of parathyroid glands may be due to the reduction of the apoptotic process. FHIT gene abnormalities are worthy of investigation in parathyroid carcinogenesis.

Estrogen receptors (ERs) have recently been reported to be present in carcinomas of stomach, an organ that has so far been considered as nontarget for sex hormones. Cathepsin D is an estrogen-regulated lysosomal protease that has been overexpressed in breast cancer. ER and cathepsin D immunohistochemical expression were studied in this research in order to estimate their association to known histopathological and clinical parameters and their possible prognostic significance as well. Sixty-two patients with gastric adenocarcinomas were included in this study. The cancers were studied immunohistochemically concerning ER positivity in tumor cell nuclei and cathepsin D cytoplasmic expression. Nuclear ER staining was detected in tumor cells of 25% of male and 27% of female patients. ER positivity was demonstrated mainly in the well and moderately differentiated carcinomas; 87.5% of ER(+) tumors were also characterized as cathepsin D positive and a significant correlation between ER and cathepsin D positive expression was demonstrated (P < 0.05). Cytoplasmic cathepsin D expression was observed in carcinomatous cells of 70.9% of gastric tumors. Early tumor stage and good differentiation were significantly associated with increased cathepsin D expression (P < 0.05, P < 0.001). Histologic type, degree of differentiation and tumor stage were significantly correlated to survival (P < 0.05, P < 0.001 and P < 0.001). The patients who were cathepsin D(+) had a significant prognostic advantage over the cathepsin D(-) patients (P < 0.001). The presence of ER and estrogen-regulated cathepsin D indicates the involvement of sex hormonal factors in these tumors and cathepsin D positive expression in tumor cells seems to be related to better prognosis. Their biological, clinical, and prognostic roles remain to be further elucidated.

Downregulation of nm-23 antimetastasis gene has been associated with disease progression in some human tumors. NPD kinase A is the product of the H1 isotype of the nm23 gene and its value as a marker of metastatic potential is well worth investigating. The expression of the nm23-H1 gene peptide was immunohistochemically evaluated in 191 primary mammary cancer tissues. A three-step immunoperoxidase staining procedure was performed and any association of our results with several classical clinicopathologic indicators, including hormonal status and c-erbB-2 oncoprotein membrane immunoexpression, was examined. NDP kinase A-positive cytoplasmic immunolabeling was noticed in 64% of all specimens (123/191) which frequently demonstrated positive progesterone receptor (PgR) status (p = 0.001) and were furthermore characterized by high PgR immunoreactivity rates. This association was significant by both univariate and multivariate statistical analysis. The double nm23-H1 (+)/PgR(+) phenotype was more frequently detected than any other combined phenotype of these markers. The nm23-H1 gene peptide was generally detected in a remarkable proportion of malignant cells, either in the invasive or the intraductal tumor components. Notably, large-cell ductal carcinomas in situ were characterized by lower nm23-H1 immunoreactivity rates when compared with other in situ cancer types. Quantitatively increased nm23-H1 immunopositive staining was more frequently observed in special histologic types of infiltrating cancers, in high nuclear grade tumors, as well as in carcinomas with high PgR levels (p = 0.05). The nm23-H1 (-)/c-erbB-2(+) phenotype was more often detected in the cancers of this study than the nm23-H1(+)/c-erbB-2(+) one. The former phenotype was correlated to postmenopausal ages as well as to extensive axillary nodal involvement by univariate statistical analysis. It is noteworthy that nm23-H1(-) status, on its own, was not statistically associated either with the presence or with a high number of involved lymph nodes. On the contrary, nm23-H1 immunopositivity was, paradoxically, more frequently observed in tumors of relatively increased TN tumor stage. Tumor progression is thus more likely to depend on the c-erbB-2 gene's overexpression. Possibly, any favorable outcome in nm23-H1(+) cases might be due to the fact that they also express PgR, which is a marker of a more functionally differentiated phenotype.