Atypical teratoid/rhabdoid tumor of the central nervous system in an 18-year-old patient.

OBJECTIVE: Atypical teratoid/rhabdoid tumors are aggressive neoplasms of the central nervous system occurring mainly in the early childhood and rarely in adults. We described a case of this tumor in an 18-year-old male patient without previous medical history. MATERIAL AND METHODS: The neoplasm was localized in the right frontotemporal area of the brain and was totally excised. The specimen was fixed in formalin and embedded in paraffin. The histological and immunohistochemical features of the neoplasm were assessed, while sequencing analysis as well as interphase fluorescence in situ hybridization (FISH) were performed. RESULTS: Histological and immunohistochemical analysis demonstrated atypical rhabdoid cells strongly and diffusely positive for EMA and Vimentin as well as focally immunoreactive for SMA and GFAP. Additionally, though no abnormalities detected in the coding sequence of the INI1 gene, interphase FISH studies were consistent with a homozygous deletion of the INI1 gene in the majority of examined nuclei. INI1 immunostaining demonstrated diffuse loss of nuclear INI1 expression in tumor cells. Taken together, the results were consistent with a diagnosis of atypical teratoid/rhabdoid tumor (ATRT). CONCLUSIONS: 26 previous cases of ATRT have been reported in adults, thus far. To our knowledge, this is the eighth case of an ATRT reported in an adult patient having genetic confirmation and the first one in which the tumor is, partly, localized in the right temporal area of the brain. This unusual presentation underlines the necessity of considering this devastating neoplasm in the differential diagnosis of malignant brain tumors of young adults.

Serum interleukin-6 is elevated in symptomatic carotid bifurcation disease.

INTRODUCTION: The levels of circulating proinflammatory cytokines may express the extent of the inflammatory response and their participation in plaque progression and rupture needs to be evaluated. We aimed to investigate differences in circulating levels of proinflammatory cytokines and in plaque infiltration by macrophages between patients undergoing carotid endarterectomy for symptomatic and asymptomatic carotid atherosclerotic disease. METHODS: One hundred nineteen patients (91 men and 28 women; mean age 66 +/- 8 years; range 42-83 years) who underwent carotid endarterectomy for significant (>70%) carotid bifurcation stenosis were enrolled in this study. Patients were characterized as symptomatic (n = 62) or asymptomatic (n = 57) after neurological examination. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP) were evaluated. Macrophage infiltration of the plaque was assessed quantitatively from endarterectomy specimens using the monoclonal antibody CD68. RESULTS: Serum IL-6 levels were significantly higher in patients with symptomatic compared with those with asymptomatic carotid disease (3.3 [2.0-6.5] pg/ml vs 2.5 [1.9-4.1] pg/ml, P = 0.02). TNF-alpha, IL-1beta, SAA, and hs-CRP levels did not differ significantly between the two groups. Symptomatic patients had also more intense macrophage accumulation in the carotid plaque compared with asymptomatic patients (0.6 +/- 0.1% vs 0.4 +/- 0.1%, P < 0.001). Although there were correlations between the levels of the different inflammatory markers, there were no correlation between any of them and the extent of plaque macrophage infiltration. CONCLUSION: Patients with symptomatic carotid atherosclerotic disease have elevated serum IL-6 levels compared with asymptomatic patients. Symptomatic patients have also more intense macrophage infiltration of the atherosclerotic plaque suggesting that inflammatory process may contribute to the destabilization of the carotid plaque.

Immunohistochemical detection of E-cadherin in certain types of salivary gland tumours.

OBJECTIVES: To investigate the topography of E-cadherin and its possible correlation with the histological phenotype of salivary gland tumours. MATERIAL AND METHODS: Archival formalin-fixed, paraffin-embedded sections of 54 benign and 56 malignant tumours and 24 samples of normal and inflamed salivary gland tissue were studied immunohistochemically using an Envision/horseraddish peroxidase (HRP) technique. RESULTS: In normal and inflamed salivary gland samples, E-cadherin was expressed at the membrane of acinar, myoepithelial and ductal cells located at cell-cell contact points. Reduction and/or absence of E-cadherin was only observed in pleomorphic adenoma at the peripheral cells of the duct-like or island structures, or in the cells exhibiting plasmacytoid or stromal differentiation. Neoplastic epithelium in Warthin's tumours and in myoepithelial and oncocytic adenomas was strongly positive. Furthermore, a weak to moderate loss of expression which was related to tissue tumour subtype was seen in malignant tumours such as: adenoid cystic carcinomas; polymorphous low-grade adenocarcinomas; acinic cell carcinomas; and mucoepidermoid low-grade, epithelial-myoepithelial, lymphoepithelial and squamous low-grade carcinomas. Moderate to extreme loss or alternative cytoplasmic non-functional expression were observed in cases of salivary ductal carcinoma, carcinosarcoma, myoepithelial carcinoma, oncocytic adenocarcinoma, unspecified adenocarcinoma and squamous high-grade carcinomas. CONCLUSION: This study suggests a direct association of E-cadherin expression with neoplastic histologic phenotype, which is lost in the more undifferentiated and invasive epithelial salivary gland tumours.

Adult beta-thalassemic patients with chronic hepatitis C: long-term efficacy of alpha-IFN treatment.

Background: The purpose of this study was to assess the effectiveness of alpha-IFN in adult beta-thalassemic patients with chronic hepatitis C. After a long-term follow-up, we describe the special pattern of biochemical and virological response of thalassemics. Methods: Thirty-two anti-HCV-positive adult thalassemic patients (19 female and 13 male, mean age 23.4+/-5.5 years) with biopsy-proven chronic hepatitis were treated with IFN alpha2beta at a dose of 3 MU thrice weekly for 6-12 months. The patients were followed up until 45-62 months after the end of treatment. Results: A sustained response was obtained in eight patients (25%). Only two of the sustained responders (25%) normalized ALT during the first 3 months of treatment. Both early and late biochemical responders cleared HCV-RNA after 6 months of treatment. Eight patients (25%) responded with ALT normalization within 2 months of treatment but relapsed soon after stopping IFN. Sixteen patients (50%) did not respond to IFN. Conclusion: The response rate in multitransfused thalassemic patients with chronic hepatitis C treated with IFN is similar to that in non-thalassemics. The special feature of thalassemics is that early biochemical response does not predict a sustained response; on the contrary, patients who normalize ALT after 6 months of IFN treatment usually do not relapse.

Incidence and histological findings of unsuspected prostatic adenocarcinoma in radical cystoprostatectomy for transitional cell carcinoma of the bladder.

OBJECTIVE: The present study is designed to evaluate the incidence, histological features and significance of prostatic adenocarcinoma in patients undergoing cystoprostatectomy for Transitional Cell Carcinoma (TCC) of the bladder. PATIENTS, MATERIAL AND METHODS: From January 1990 to December 1996, 59 male patients (mean age 66.5 years), with no evidence of prostatic malignancy on preoperative clinical and biochemical assessment, underwent cystoprostatectomy for TCC of the bladder. The bladder was adequately sampled and the entire prostate sectioned at 5-mm intervals and examined histologically, in order to identify unsuspected prostatic cancer (PCa). RESULTS: Sixteen out of 59 patients (27%) were found to have PCa, which was multifocal in 5 cases (31.25%). The mean tumor size was 0.24 cm. The tumors were equally distributed in the anterior and posterior parts of the prostate and in the peripheral and transition zones, with uniform distribution in both prostatic lobes. In 5 patients (31.25%), the single focus of the tumor was in the apex. All were grade I tumors except one, and all were organ-confined with no capsular penetration. The follow-up ranged from 12-74 months (mean 39 months). Within this period, 7 patients died from metastatic bladder cancer. One patient with PCa localized in the prostatic apex had recurrent prostatic disease in the urethro-ileal anastomosis of an orthotopic bladder substitute; he is alive and on androgen deprivation. The remaining patients are relapse-free. CONCLUSIONS: Incidental PCa is quite a common finding in cystoprostatectomy specimens of bladder cancer patients. Its tendency to appear in the apex of the prostate demands careful and complete excision of the organ.

Can p53 nuclear over-expression, Bcl-2 accumulation and PCNA status be of prognostic significance in high-risk superficial and invasive bladder tumours?

AIMS: To evaluate p53 and Bcl-2 expression and proliferating status (PCNA) in subgroups of patients with high-risk superficial and invasive bladder cancer, with relation to cancer progression and death, and to correlate the results with established clinical prognostic factors. METHODS: Paraffin-embedded sections from 42 high-risk superficial (T1G2,T1G3) and 33 invasive (T2-T4aG3 N0M0) tumours were investigated immunohistochemically for p53, Bcl-2 and PCNA. The median follow-up was 52 months. RESULTS: In the cohort of superficial tumours, statistical analysis showed that p53 and PCNA positivity were significant prognostic factors (P-values: 0.008 and 0.006, respectively) for disease-specific death (DSD). When life expectancy was evaluated (log-rank test), p53(+) (P = 0.015) and PCNA(+) (P = 0.017) offered the most accurate prognosis compared to grade, tumour size and multiplicity. Bcl-2 status had no significant effect on patient survival. In the subset of muscle-invasive tumours we failed to demonstrate any important role of p53, Bcl-2 or PCNA positivity. CONCLUSIONS: p53 and PCNA over-expression may offer valuable additional prognostic information in high-risk subgroups of superficial bladder tumours. From our results, Bcl-2 does not appear to contribute significantly to the prognosis of these patients. None of the studied markers offered prognostic information in muscle-invading disease.

Human papilloma virus (HPV) is possibly involved in laryngeal but not in lung carcinogenesis.

Data on human papilloma virus (HPV) involvement in preneoplastic and neoplastic lesions of the larynx and lung are limited and conflicting. The presence of HPV was investigated in a series of laryngeal specimens and non-small cell lung carcinomas (NSCLCs). The laryngeal samples (154) comprised 14 cases with hyperplasia without dysplasia, 49 with dysplasia, and 91 squamous cell carcinomas (SqCCs). The NSCLCs included 31 SqCCs, 32 adenocarcinomas, and 5 undifferentiated large cell carcinomas. Furthermore, we examined, for HPV DNA sequences, 14 bronchial metaplastic squamous lesions located next to cancerous areas. We used a sensitive nested polymerase chain reaction assay (NPCR), dot blotting, and in situ hybridization. The findings were correlated with clinicopathologic features of the patients. In the laryngeal specimens, NPCR analysis showed HPV DNA in 20 (13%) of the 154 specimens. Notably, 19 of 20 HPV-positive cases were carcinomas and only one was a mild dysplastic lesion. Typing of the carcinomas showed single HPV 6, 16, 18, and 33 infection in 1 (1.1%), 12 (13.2%), 2 (2.2%), and 1 (1.1%) samples, respectively, and HPV 6/33, 16/33, and 6/18 coinfection in three carcinomas. In situ hybridization findings were in agreement with PCR results, with the exception of two cases in which HPV 18 DNA was detected only by PCR. HPV was more frequently observed in heavy smokers than in patients with low daily cigarette consumption and nonsmokers (P = .03). There was no correlation between virus infection and gender, grade, and lymph node status of the carcinomas. None of the NSCLCs or adjacent metaplastic squamous epithelium contained HPV DNA sequences. The presented data suggest a contributory role of HPV in late stages of laryngeal carcinogenesis, because all premalignant lesions were negative but one. This study does not support a potential role of HPV in the development of NSCLCs.

Molecular and immunohistochemical evaluation of epidermal growth factor receptor and c-erb-B-2 gene product in transitional cell carcinomas of the urinary bladder: a study in Greek patients.

In this study, the expression of epidermal growth factor receptor (EGFr) and c-erb-B-2 was evaluated in 35 formalin-fixed, paraffin-embedded cases of transitional cell carcinomas of the urinary bladder (TCCs). EGFr and c-erb-B-2 expression was assessed with immunohistochemistry, and molecular analysis of the respective genes was performed with the differential polymerase chain reaction. The results were statistically analyzed in relationship to histologic grade, stage, and clinical outcome. Strong cytoplasmic expression of the EGFr using the polyclonal antibody Ab-4 was found in three (25%) Grade 2 and eight (67%) Grade 3 TCCs (P < 0.01). Two Grade 2 (17%) and 11 (92%) Grade 3 TCCs strongly expressed the anti-c-erb-B-2 Ab-3 antibody. None of Ta/T1 TCCs cases showed strong expression against EGFr, in contrast to c-erb-B-2 where two cases (18%) were found to express an intense immunosignal. Eleven (85%) T2/T3 cases showed strong positivity either against EGFr or c-erb-B-2 (P < 0.001). Eleven patients died within 12 months after the diagnosis, and all of them showed strong expression of EGFr and c-erb-B-2. Amplification of EGFr and c-erb-B-2 genes was identified in one (3%) and four (11%) TCCs cases, respectively. All patients with amplified genes died within 12 months from the date of diagnosis. Our results indicate that simultaneous expression of EGFr and c-erb-B-2 occurs in TCCs, is related to the histologic grade and the stage of the disease, and denotes aggressive biologic behavior.

p53 Overexpression in laryngeal squamous cell carcinoma and dysplasia.

Aim-To investigate the expression of p53 protein in invasive squamous cell carcinoma (SCC) of the larynx and dysplasia in relation to histological grade and tobacco smoking.Method-Paraffin wax embedded tissue sections from 41 cases of invasive SCC of the larynx, 28 cases of dysplasia and 14 control laryngeal biopsy specimens were studied immunohistochemically using two anti-p53 monoclonal antibodies (DO7 and 1801). The Streptavidin/horseradish peroxidase method was used after microwave antigen retrieval and a semiquantitative method was applied to assess the extent of p53 expression.Results-Of the cases of invasive SCC of the larynx, 78% (32/41), regardless of histological grade, overexpressed p53 compared with only 30% (eight of 28) of cases of mild dysplasia. A gradual increase in p53 expression from mild to severe dysplasia (60%) was observed, and only three of 14 control biopsy specimens of laryngeal nodules showed occasional weakly positive basal cells.Conclusion-The gradual increase in p53 expression from mild to severe dysplasia to invasive SCC indicates that p53 overexpression is an early event in laryngeal carcinogenesis which may lead to invasive malignancy. p53 overexpression may be related to environmental factors as most of the patients smoked tobacco. Microwave postfixation may be essential for the reliable detection of p53.

Molecular analysis of p53 gene in laryngeal premalignant and malignant lesions. p53 protein immunohistochemical expression is positively related to proliferating cell nuclear antigen labelling index.

This study was undertaken in order to investigate the molecular nature of the p53 gene in 19 laryngeal squamous cell carcinomas and dysplasias. Moreover, we have examined the possible relationship between proliferating cell nuclear antigen (PCNA) expression and p53 protein detection status in 42 laryngeal premalignant and malignant lesions in which 14 of the 19 samples used in the molecular study were included. p53 gene analysis was performed with the single-strand conformation polymorphism technique. PCNA was stained with the peroxidase/antiperoxidase immunohistochemical method using the monoclonal antibody PC-10. Data from previous work concerning p53 expression was used. We found that 9 of 12 of the immunohistochemically p53 positive (+) cases had mutations in exons 5 or 6. In the remaining immunohistochemically p53(+) and p53 negative (-) specimens there was no indication of sequence alterations. Furthermore, we did not observe any deletions in the chromosomal region 17p31.1 which encodes exons 4-8 of the p53 gene. The PCNA labelling index (LI) increased progressively with p53 protein detection status (percentage of cells immunohistochemically positive for p53). The difference between the group with the higher percentage of p53(+) cells and the others was statistically significant. These data show that although there is a discrepancy between immunohistochemical demonstration of p53 and molecular analysis, a large proportion of the former harbours the mutant form of the protein. In addition, p53 overexpression is positively correlated with PCNA LI, a finding which accompanies tumour progression.

Liver involvement in primary Sjögren's syndrome.

Three hundred patients with primary Sjögren's syndrome (pSS) were investigated for liver involvement using clinical, biochemical, immunological and histological data. Seven per cent of patients showed evidence of liver disease either subclinical (2%) or asymptomatic (5%) with elevated liver enzymes. In 6.6% of patients antimitochondrial antibodies (AMA) were detected by immunofluorescence and 27% of pSS patients showed antibodies to pyruvate dehydrogenase (a-PDH) using ELISA. AMA-positive patients were further investigated with transcutaneous liver biopsy. Ninety-two per cent of patients with AMA showed liver involvement with features of chronic cholangitis similar to stage I primary biliary cirrhosis. It is concluded that liver involvement in pSS patients is rare and subclinical with histological features predominantly of stage I primary biliary cirrhosis. AMA is the most sensitive indicator of underlying liver pathology in pSS patients.

Expression of p53 protein in laryngeal squamous cell carcinoma and dysplasia: possible correlation with human papillomavirus infection and clinicopathological findings.

In order to evaluate the expression of p53 protein in 28 premalignant and 40 malignant squamous cell proliferations of the larynx and its relationship to tobacco consumption, human papillomavirus infection and differentiation grade of the lesions, p53 expression was examined by means of a microwave post-fixation immunohistochemical method using the PAb 240 and PAb 1801 monoclonal antibodies. HPV infection was assessed by non-isotopic in situ hybridization (NISH) and polymerase chain reaction (PCR). A large proportion of carcinomas (77.5%) and dysplasias (61%) expressed p53. No difference was found between differentiation grades of the lesions regarding p53 detection (P > 0.1), but moderate or intense p53 expression was more frequent in the carcinomas (P < 0.05). A statistical correlation was found between cigarette consumption and both p53 detection and p53 staining intensity (P < 0.05 in each case). HPV study revealed HPV 16 and 18 infection only in carcinomas. The frequency was 28% and the physical state of the virus as demonstrated by NISH was integration into the genome. We observed an inverse relationship between HPV infection and p53 expression (P = 0.006). Our findings suggest that p53 overexpression is a common and early event which increases in frequency with progression of laryngeal squamous cell carcinoma. The expression of p53 is influenced by tobacco and high-risk types of HPV.

Is beta-human chorionic gonadotrophin production by transitional cell carcinoma of the bladder a marker of aggressive disease and resistance to radiotherapy?

The biopsies from 75 patients with transitional cell carcinoma of the bladder (25 Ta-T1; 45 T2-T4, 5M) were studied immunohistochemically for the expression of beta-human chorionic gonadotrophin (beta-HCG). Only 5 Ta-T1 tumours contained a small number of beta-HCG positive cells but 24 invasive tumours and all patients with metastases showed increased numbers of positive cells. A significant correlation was found between beta-HCG immunoreactivity and tumour category. In 30 patients with muscle-invasive disease (T2-T4,N0,M0) who were treated with radical radiotherapy a significant correlation was observed between response to treatment and beta-HCG expression; beta-HCG positive tumours did not respond to treatment. A difference in survival was found between patients with tumours negative for beta-HCG compared with patients with positive tumours, all treated with radical radiotherapy. The results indicate that beta-HCG expression increases with tumour invasiveness and the use of immunohistochemistry may prove a useful means of identifying radioresistant and aggressive forms of bladder cancer.

Serial soluble interleukin 2 receptor levels in rheumatoid arthritis: differences in response to glucocorticoid treatment and chrysotherapy.

OBJECTIVE: To analyze the changes in soluble interleukin 2 receptor (sIL-2R) levels following treatment of patients with rheumatoid arthritis (RA). METHODS: Serial measurements of sIL-2R levels were made over 24 weeks in 40 patients with RA, treated with intramuscular (im) gold plus 3 im injections of either 120 mg methylprednisolone acetate or placebo. RESULTS: sIL-2R levels were reduced in the glucocorticoid treated group in contrast to the gold only group, where levels initially increased. At 24 weeks, mean sIL-2R levels did not significantly differ from pretreatment levels in either group, despite improvements in clinical measures. CONCLUSIONS: In our study, sIL-2R levels do not correlate with short term clinical measures of disease activity. Their significance for longer term prognostic use remains to be determined.

Erdheim-Chester disease with epiphyseal and systemic disease.

A case of Erdheim-Chester disease which affected the epiphysis and showed evidence of systemic disease is presented. Clinical and histopathological similarities with other forms of disseminated Langerhans' cell histiocytosis are noted, particularly reaction of infiltrating histiocytes for S100 and HLA-DR.

Intra-abdominal desmoplastic small-cell tumours with divergent differentiation. Report of two cases and review of the literature.

Two intraabdominal desmoplastic small cell tumours presenting in young adult males and involving the entire peritoneum, with no evident single primary site, have been studied. The histological pattern was suggestive of a metastatic small cell epithelial neoplasm, but immunohistochemical study revealed strong reactivity for cytokeratins, vimentin and desmin indicating synchronous epithelial and myogenous differentiation. In addition epithelial membrane antigen and neuron specific enolase were also positive. Electron microscopy showed fairly undifferentiated tumour cells with striking desmosome-like junctions, containing prominent paranuclear whorls of intermediate filaments, and a typical myofibroblastic stroma around neoplastic islands. Although the histogenesis of these recently described and rare tumours still remains uncertain, it seems that they constitute a reproducible entity which requires differential diagnosis from other small cell tumours of childhood and young adulthood.

Monoclonal antibody treatment in rheumatoid arthritis: the clinical and immunological effects of a CD7 monoclonal antibody.

Six patients with rheumatoid arthritis were treated with a CD7 mouse monoclonal antibody, RFT2, daily for 15 days. Only two patients had a significant improvement in clinical disease activity which lasted 7-14 days. No serious adverse effects occurred although all patients developed antibodies against mouse immunoglobulin. During treatment T-lymphocyte numbers decreased and T-lymphocyte CD7 expression was absent in all but one patient.

Gold treatment of rheumatoid arthritis decreases synovial expression of the endothelial leukocyte adhesion receptor ELAM-1.

Leukocyte adhesion receptors on endothelial cells play an important role in the evolution of synovitis. We studied sequential synovial biopsies at Weeks 0, 2 and 12 in 11 patients with rheumatoid arthritis beginning parenteral gold therapy either alone or combined with 120 mg intramuscular methylprednisolone acetate at Weeks 0, 4 and 8 of treatment. Expression of endothelial leukocyte adhesion molecule 1 (ELAM-1) decreased on synovial blood vessels after both 2 and 12 weeks treatment (p less than 0.05), while the overall vascularity of the synovium did not change. Neutrophil numbers within the synovial membrane also decreased although this did not reach statistical significance. In contrast, there was no significant change in numbers or subset distribution of T cells or in Class II MHC expression by synovial lining cells, mononuclear cells or endothelial cells. Our results suggest that one of the early effects of intramuscular gold and glucocorticoid therapy may be a downregulation of the acute inflammatory process associated with the endothelial expression of a neutrophil adhesion receptor and the subsequent recruitment of neutrophils into the joint.