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Fifty-seven cases of T-cell lymphomas (TCL) including 5 lymphoblastic (T-LBL) and 52 peripheral TCL (PTCL) were analyzed by immunohistochemistry for the expression of p53, mdm2, p21, Rb, cyclin D1, cyclin A, cyclin B1, and Ki67/MIB1 proteins and 39/52 PTCL were also analyzed for the expression of p16 protein and for the presence of apoptotic cells by the TUNEL method. The aim was to search for abnormal immunoprofiles of p53 and Rb growth control pathways and to determine the proliferative activity and the apoptotic index of TCL. Abnormal overexpression of p53, p21 and mdm2, in comparison to normal lymph nodes, was found in 12/57, 10/57 and 2/57 cases of TCL, respectively. Abnormal loss of Rb and p16 expression was found in 1/57 and 2/39 cases, respectively, whereas abnormal overexpression of cyclin D1 was not detected in any of the 57 cases. Our data revealed entity-related p53/p21/mdm2 phenotypes. Indeed, most nodal and cutaneous CD30+ anaplastic large cell lymphomas (ALCL) showed concomitant overexpression of p53 and p21 proteins (7/8 cases), and mdm2 was overexpressed in 2 p53-positive nodal ALCL. In contrast, overexpression of p53 was found in 3/17 cases of nodal peripheral TCL unspecified (PTCL-UC) and 2/7 non-ALCL cutaneous pleomorphic TCL. Overexpression of p21 protein was detected in 2/3 p53-positive PTCL-UC and in 1/2 p53-positive non-ALCL cutaneous pleomorphic TCL. Finally, all the remaining 25 cases of TCL did not show p53 and p21 overexpression. Overall, the p53+/p21+ phenotype in 10/57 TCL suggests wild-type p53 capable of inducing p21 expression. The highest apoptotic index (AI) was found in ALCL and a positive correlation between apoptotic index and Ki67 index (p

The immunohistochemical expression of p53, p21, Rb, p16, cyclin D1, Ki67, cyclin A, cyclin B1, p27, bc12, bax, and bak proteins and the apoptotic index (AI) were investigated in 20 normal thymuses (8 adults, 3 adolescents, 5 infants and 4 newborns). The expressions of Rb, Ki67, cyclin A and cyclin B1 were overlapping, being high in the cortex with a tendency for decreased expression toward the medulla. Apoptotic cells were mainly detected in the cortex and the corticomedullary junction, rarely being present in Hassall's corpuscles. The mean values of Ki67, cyclin A, and cyclin B1 expression in thymuses were 77.2%, 32.2% and 21.4% (newborns), 62.4%, 33.7% and 18.5% (infants), 56.9%, 23.4% and 18.9% (adolescents) and 38.7%, 21.7% and 14.6% (adults), respectively. The mean values of AI in thymuses from newborns, infants, adolescents and adults were 1.4%, 2.9%, 2.7% and 3.8%, respectively. This decrease in proliferation and increase in apoptosis may account for the process of thymic involution. P16 expression was widespread with most of Hassall's corpuscles being pl6-positive. P16- positive cells and Hassall's corpuscles increased with the increase in age, in keeping with the suggested role of p16 in cellular senescence. P27 expression was undetectable in subcapsular thymocytes with a tendency for increased expression toward the medulla. The expressions of Ki67, cyclin A and cyclin R1 were inversly related with that of p27, consistent with previous evidence that p27 concentration is reduced when the cell-cycle progresses. P21 and much less frequently p53 proteins were mainly detected in a part of the subcapsular cortical epithelial cells. These findings suggest that a) in thymocytes, the apoptotic pathway is mostly p53-independent and the function of p21 as a negative regulator of the cell cycle must be redundant to other negative regulators, such as p16 and p27 which were abundantly detected in thymocytes and b) in some thymic epithelial cells, the p21 expression may be induced by p53, but in most of them seems to be p53- independent. Most of Hassall's corpuscles were p21- positive, consistent with previous evidence that these structures represent end stages of maturation of thymic medullary epithelium and that p21 protein is involved in the process of terminal differentiation. Cyclin D1 positivity was found in some macrophages. Rc12 expression was mainly seen in medullary thymocytes, reflecting the surviving thymocytes in this region. The expressions of Bax and bak were more widespread in both the medulla and cortex, suggesting that these proteins play a broader role than bc12 in the regulation of thymic apoptosis.

The aim was to investigate the combined immunoexpression of p53, p21, bcl-2, bax, Rb and Ki67 proteins in Hodgkin's lymphomas (HL) and correlate expression patterns with the histotype and the Epstein- Barr Virus (EBV) status. Paraffin-sections from 56 cases of HL (18 nodular sclerosis and 38 mixed cellularity) and from ten "reactive" lymph nodes were investigated. P53, p21, bcl-2, bax, Rb and Ki67 proteins were detected in Hodgkin and Reed-Sternberg (HRS) cells in 35156,56156,24156, 23156,56156 and 56/56 cases of HL, respectively. No correlation was found between the expression of each protein and the EBV status or the histotype of HL. Comparison between p53 and p21 staining revealed two patterns: a) p53+/p21+ (35 cases); and b) p53-/p21+ (21 cases). The pattern p53+/p21+ suggests wild type p53 protein able to induce the expression of p21 while the p53-/p21+ pattern suggests p53-independent p21 expression. These results are consistent with the interpretation that inactivating p53 gene mutations may be rare in HL. Comparison between bcl-2 and bax staining showed a statistically significant relationship (p

Minor labial salivary gland biopsies from 25 patients with secondary Sjogren's syndrome (SS) suffering from rheumatoid arthritis and from 11 patients complaining of ocular dryness associated with rheumatoid arthritis without proven SS, were studied for the immunohistochemical expression of Epidermal Growth Factor (EGF) and its receptor (EGF-r). Minor labial salivary glands from 11 healthy individuals were used as the control. Furthermore, the results were correlated with data retrieved from a previous study on EBV expression by the in situ hybridization method in the same specimens. In 16/25 cases of secondary SS the epithelial duct cells expressed both EGF and EGF-r, particularly in the areas of lymphoepithelial lesion and tissue destruction. Eleven of these cases expressed a positive EBV hybridization signal. In contrast, only 3/11 patients with ocular dryness and 2/11 cases from the group of healthy individuals showed immunoreactivity for EGF/EGF-r. A positive EBV signal was detected in 3/11 and 1/11 of these cases, respectively. These results indicate that EGF and EGF-r may play a crucial role in the evolution of the disease under the constant influence of EBV, which seems to up-regulate the expression of the EGF/EGF-r system. Clin Exp Rheumatol

Immunohistochemical study of epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and transforming growth factor-alpha (TGF-alpha) expression was performed on paraffin-embedded tissue specimens of 70 squamous cell lung carcinomas. The carcinomas were placed to one of the following eight groups, according to the results of EGF, TGF-alpha and EGFR expression: group 1: none, group 2: only EGFR, group 3: EGFR and TGF-alpha, group 4: EGFR and EGF, group 5: TGF-alpha and EGF, group 6: all three, group 7: only TGF-alpha and finally group 8: only EGF. Statistical analysis of the results revealed that the ratio of squamous cell lung carcinomas with lymph node metastasis was significantly higher in groups 4, 5 and 6 (P less than 0.01). We also examined whether EGF receptors were truncated with the use of two monoclonal antibodies directed against different portions of the receptor (EGFR1 and F4). No truncated EGF receptors were detected. These results suggest that lung carcinomas expressing the molecules EGF/EGFR, TFG-alpha/EGFR or TGF/alpha/EGF/EGFR display pathologic features of more aggressive disease. Anticancer Res

In order to understand better the possible role of cell-cycle regulating molecules in the pathogenesis of Hodgkin's disease (HD), the immunohistochemical distribution pattern of p16INK4A was investigated and compared with pRb, p53, and MDM2 protein status in 44 HD cases. Our findings were correlated to the presence of Epstein-Barr virus as detected by RNA in situ hybridization and clinicopathological parameters. p16INK4A protein immunoreactivity was found in all 44 cases with a proportion of Hodgkin-Reed-Sternberg (HRS) cells ranging from 30 to 90%. In 93% of the cases studied, pRb was detected in HRS, whereas all cases showed overexpression of p53. Almost all specimens (98%) were MDM2-positive as evaluated by 1B10 and/or IF2 monoclonal antibodies. EBER 1/2-transcripts were detected in 31.8% (14 of 44) of the examined samples. A significant correlation was observed between immunoreactivity of p16INK4A and MDM2 and the number of HRS cells (P = .0012 and P = .018, respectively). In a subgroup of cases, with p16INK4A expression in more than 50% of HRS cells, the percentage of pRb-positive neoplastic cells was inversely related to that of p16-positive ones (P = .007). No clinicopathological parameters or clinical prognostic indicators, including duration of response to therapy, were statistically related to the expression levels of any of the four proteins investigated or the presence of Epstein-Barr virus. Our findings suggest that p16 and pRb are regularly expressed and that their pathway in cell-cycle machinery seems to be intact in HD. However, further investigation is needed to shed light on the involvement of cell-cycle molecules in Hodgkin's lymphomagenesis and longer patient follow-up is required for conclusive prognostic correlation. Mod Pathol

The aim of this study was to investigate the immunohistochemical expression of the proteins p53, Waf-l/p21, Rb, p16 and Ki67 in 38 cases of multiple myelomas (MM) and 4 cases of solitary extramedullary plasmacytomas in relation to the tumor histological grade and stage. In bone marrow (BM) biopsies from MM, overexpression of p53 and p21 proteins, in comparison to plasma cell infiltrates in non-pathological bone marrow, was defected in 13 out of 38 and 21 out of 38 cases, respectively. The combined immunoexpression of p53 and p21 proteins in the 38 cases of MM showed the following patterns: a) p53+/p21+ (13 cases) b) p53-/p21+ (8 cases) and c) p53-/p21- (17 cases). Rb, p16 and Ki67 proteins were detected in tumor cells in all 38 cases and their expression increased proportionally to tumor grade. The 4 cases of solitary extramedullary plasmacytomas showed the p53+/p21+ pattern in 2 cases and the p53-/p21+ pattern in 2 cases, all of them displaying Rb, p16 and Ki67 expression in tumor cells. The pattern p53+/p21+ might represent cases with wild-type p53 able to induce p21 expression. However; in previous studies p53 mutations were reported in about 3-10% of MM, and they were strongly associated with advanced disease. Thus, in some p53+/p21+ cases associated with high p53 expression and advanced disease, p53 gene cannot be excluded and regulation of p21 expression may be p53- independent. P53 overexpression correlated with increased tumor grade (p < 0.005), advanced histological stage (p

Immunohistochemical study of epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and transforming growth factor-alpha (TGF-alpha) expression was performed on paraffin-embedded tissue specimens of 12 follicular carcinomas, 15 papillary carcinomas and 15 adenomas of the thyroid gland. The tumors were placed in one of the following eight groups, according to the results of EGF, TGF-alpha and EGFR expression: group 1: none, group 2: only EGFR, group 3: EGFR and TGF-alpha, group 4: EGFR and EGF, group 5: TGF-alpha, and EGF, group 6: all three, group 7: only TFG-alpha and, finally, group 8: only EGF. Statistical analysis of the results revealed that the ratio of thyroid carcinomas with lymph node metastasis was significantly higher in groups 3 and 6 for follicular carcinomas (P less than 0.01) and in groups 4, 5 and 6 for papillary carcinomas (P less than 0.01). These results suggest that thyroid carcinomas expressing the systems EGF/EGFR, TGF-alpha/EGFR or TGF-alpha/EGF/EGFR display pathologic features of more aggressive disease. Furthermore, the synchronous expression of EGF, TGF-alpha and EGFR indicates that these carcinomas may regulate their growth by an autocrine and/or paracrine mechanism. In Vivo