Herpes-like DNA sequences in a body-cavity-based lymphoma in an HIV-negative patient.
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Aged↗
Biomedical subjects
J W Said
Publications and source records attributed to J W Said.
Alterations of the p27KIP1 gene in non-Hodgkin's lymphomas and adult T-cell leukemia/lymphoma.
The protein p27KIP1 belongs to a recently identified family of proteins termed cyclin-dependent kinase inhibitors (CDKIs). These proteins play an important role in regulating cell-cycle progression and loss of their function has been implicated in tumorigenesis. Transforming growth factor beta (TGF-beta) may induce cell growth arrest through p27 activation. TGF-beta often loses its ability to arrest growth of transformed cells; this could potentially occur through a defect in p27. To determine the role of p27 in tumorigenesis, we examined its mutational status in 74 non-Hodgkin's lymphomas (NHLs) (52 of B-cell phenotype, 22 of T-cell phenotype), 5 lymphoma cell lines, and 42 adult T-cell leukemias/lymphomas (ATLs) using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and Southern blot analyses. A nonsense mutation (stop codon) that could result in expression of a truncated nonfunctional p27 protein was detected at codon 76 in one case of acute lymphomatous ATL, but not in matched normal tissues. Previously undescribed polymorphisms were also identified at codon 109 in the lymphomas and at codon 55 in the ATLs. Two homozygous deletions of the p27 gene were detected in one case of B-immunoblastic NHL and in one case of acute ATL by Southern blot hybridization. These results indicate that p27 gene alterations are rare events in NHLs and ATLs, but may play an important role in the pathogenesis of some hematologic malignancies.
Base Sequence↗
Deletions of the cyclin-dependent kinase inhibitor genes p16INK4A and p15INK4B in non-Hodgkin's lymphomas.
The tumor suppressor genes p16INK4A and p15INK4B map to the 9p21 chromosomal locus and are either homozygously deleted or mutated in a wide range of human cancer cell lines and tumors. Although chromosome 9 abnormalities have been described in non-Hodgkin's lymphomas (NHLs), to date, the mutational status of these genes has not been determined for these malignancies. A total of five cell lines and 75 NHLs were examined for homozygous deletions or point mutations in the coding regions of both the p15 and p16 genes using Southern blot and/or polymerase chain reaction-single-strand conformation polymorphism analyses. Homozygous deletions of either the p16 gene or both the p15 and p16 genes were observed in one diffuse large B-cell lymphoma cell line and two uncultured lymphomas consisting of one large B-cell and one mixed T-cell lymphoma. In contrast, point mutations were not detected in either the cell lines or lymphomas. These results indicate that the rate of alterations in the p15 and p16 genes is low for lymphomas, but loss of p16 and/or p15 may be involved in the development of some lymphomas.
Base Sequence↗
Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.
BACKGROUND: DNA fragments that appeared to belong to an unidentified human herpesvirus were recently found in more than 90 percent of Kaposi's sarcoma lesions associated with the acquired immunodeficiency syndrome (AIDS). These fragments were also found in 6 of 39 tissue samples without Kaposi's sarcoma, including 3 malignant lymphomas, from patients with AIDS, but not in samples from patients without AIDS. METHODS: We examined the DNA of 193 lymphomas from 42 patients with AIDS and 151 patients who did not have AIDS. We searched the DNA for sequences of Kaposi's sarcoma-associated herpesvirus (KSHV) by Southern blot hybridization, the polymerase chain reaction (PCR), or both. The PCR products in the positive samples were sequences and compared with the KSHV sequences in Kaposi's sarcoma tissues from patients with AIDS. RESULTS: KSHV sequences were identified in eight lymphomas in patients infected with the human immunodeficiency virus. All eight, and only these eight, were body-cavity-based lymphomas--that is, they were characterized by pleural, pericardial, or peritoneal lymphomatous effusions. All eight lymphomas also contained the Epstein-Barr viral genome. KSHV sequences were not found in the other 185 lymphomas. KSHV sequences were 40 to 80 times more abundant in the body-cavity-based lymphomas than in the Kaposi's sarcoma lesions. A high degree of conservation of KSHV sequences in Kaposi's sarcoma and in the eight lymphomas suggests the presence of the same agent in both lesions. CONCLUSIONS: The recently discovered KSHV DNA sequences occur in an unusual subgroup of AIDS-related B-cell lymphomas, but not in any other lymphoid neoplasm studied thus far. Our finding strongly suggests that a novel herpesvirus has a pathogenic role in AIDS-related body-cavity-based lymphomas.
Acquired Immunodeficiency Syndrome↗
Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type IV glycogen storage disease.
Orthotopic liver transplantation has been used to treat glycogen storage disease type IV. Most long-term surviving patients who have undergone liver transplantation have been free of neuromuscular and cardiac morbidity, and regression of cardiac amylopectin infiltration has been reported after liver transplantation. Leukocyte inclusions in glycogen storage disease type IV have also been reported. We present the case of a child who underwent orthotopic liver transplantation for glycogen storage disease type IV. In contrast to previous reports, at autopsy 2 1/2 years after transplantation, there was massive amylopectin deposits in his heart. Further, peripheral leukocytes never showed loss of amylopectin inclusions after transplantation. Orthotopic liver transplantation for type IV glycogen storage disease may not, in all cases, result in improvement in other affected organs. Consideration of multiorgan transplantation appears warranted.
Amylopectin↗
Changes in tonsils and adenoids in children with posttransplant lymphoproliferative disorder: report of three cases with early involvement of Waldeyer's ring.
Posttransplant lymphoproliferative disorder (PTLD) is an infrequent complication of transplantation in children, and this report emphasizes the value of tonsil and adenoid biopsy in the early management of this potentially life threatening condition. In all three cases biopsy specimens of tonsils and adenoids were diagnostic of polymorphic diffuse B-cell hyperplasia (PBCH). Immunophenotyping showed no immunoglobulin (Ig) light chain restriction, although immunoglobulin heavy chain (IgH) gene rearrangement was monoclonal in two cases. Despite an absence of serological evidence for acute Epstein-Barr virus (EBV) infection, EBV was detected in all cases by semiquantitative polymerase chain reaction (PCR) for EBV DNA, by in situ hybridization for EBV mRNA (EBER), and by immunoperoxidase for EBV latent membrane protein (LMP). All three patients were treated with reduced immunosuppression and acyclovir and are well (19, 28, and 28 months' follow-up) with no recurrence. Children without previous EBV exposure may develop PTLD localized to the tonsils/adenoids, and biopsy specimens of these tissues may permit early diagnosis and clinical intervention. Despite monoclonal gene rearrangement in two cases, overall features were not indicative of malignancy. Strong association with EBV is helpful in confirming the diagnosis of PTLD and is consistent with initial presentation in the tonsils/adenoids.
Adenoids↗
Multilocular thymic cyst. A novel thymic lesion associated with human immunodeficiency virus infection.
Thymic involvement is an important feature of human immunodeficiency virus-related disease in the pediatric population. The most common lesions are thymic involution or atrophy, thymitis (thymic lymphoid hyperplasia), and dysinvolution with loss of Hassall's corpuscles. We report a case of an unusual form of thymic enlargement in a human immunodeficiency virus-infected boy. In addition to lymphoid hyperplasia similar to that associated with human immunodeficiency virus infection in lymph nodes and other sites, the thymus was characterized by multilocular cysts with squamous epithelial lining (multilocular cystic lesion of the thymus).
Acquired Immunodeficiency Syndrome↗
The pathology of AIDS.
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AIDS-Related Opportunistic Infections↗
Bcl-2 oncogene protein is preferentially expressed in Reed-Sternberg cells in Hodgkin's disease of the nodular sclerosis subtype.
One hundred three cases of nodular sclerosis (NS) and mixed-cellularity Hodgkin's disease were evaluated for expression of bcl-2 oncogene protein, because previous studies have revealed expression of bcl-2 in these subtypes but only rarely in the nodular lymphocyte-predominance subtype. Reed-Sternberg (RS) cells and lacunar variants were positive for bcl-2 in 51 of 86 NS cases and 4 of 17 mixed-cellularity cases. In individual cases of NS, the percentage of RS cells and lacunar variants positive for bcl-2 ranged from minimal (in 5 cases) to 100% positive (mean, 34%). By univariate analysis, expression of the bcl-2 gene product in RS cells was observed in a significantly greater proportion of NS Hodgkin's disease cases than MC cases (P < .009), a finding that may have implications on the pathogenesis of this disorder.
Adolescent↗
Immunohistochemical detection of Epstein-Barr virus-encoded latent membrane protein in Reed-Sternberg cells and variants of Hodgkin's disease.
A total of 186 specimens of Hodgkin's disease of various histologic types (127 nodular sclerosis, 39 mixed cellularity, 14 lymphocyte predominance, 3 lymphocyte depleted, and 3 unclassified) were evaluated for the presence of latent membrane protein (LMP) and Epstein-Barr virus nuclear antigen-2, two Epstein-Barr virus encoded gene products that appear to play important roles in cell transformation and oncogenesis. Immunoreactivity for LMP was observed in Reed-Sternberg cells and variants of 27/39 (69%) cases of mixed cellularity type, 18/127 (14%) of nodular sclerosis type, 2/3 cases of lymphocyte depleted type, and 1/3 cases of unclassified type. All cases of lymphocyte predominance Hodgkin's disease were nonreactive for LMP. In cases that were reactive for LMP, staining was restricted to Reed-Sternberg cells and variants. Other cells within the proliferation, e.g., lymphocytes, histiocytes, eosinophils, fibroblasts, etc., were nonreactive. The pattern of immunoreactivity for LMP was characterized by strong diffuse cytoplasmic staining, occasionally with membrane accentuation and/or paranuclear staining. Reactivity for LMP was demonstrated in cryostat sections and was also well preserved in paraffin sections of B5- or formalin-fixed tissues. Five of six specimens of Hodgkin's disease (4 mixed cellularity and 2 nodular sclerosis type) that occurred in HIV-positive patients exhibited immunoreactivity for LMP in Reed-Sternberg cells and variants. Cryostat section studies for Epstein-Barr virus nuclear antigen-2 using monoclonal antibody PE-2 failed to reveal staining for 43 cases (26 nodular sclerosis, 12 mixed cellularity, and 5 lymphocyte predominance) after a 2-h incubation with primary antibody.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Monoclonal↗
Is immunoreactivity for p53 useful in distinguishing benign from malignant effusions? Localization of p53 gene product in benign mesothelial and adenocarcinoma cells.
p53 protein is a "natural tumor suppressor" that plays an important role in controlling cell proliferation. Alterations resulting in overexpression of this gene product have been described in a wide variety of human malignancies. We utilize two commercially prepared monoclonal antibodies to assess the potential role of immunoreactivity for p53 protein in distinguishing benign mesothelial from adenocarcinoma cells in effusion smears. p53 protein was detected in adenocarcinoma cells in 78% of the malignant fluids studied. Benign mesothelial cells in 14% of these fluids and in 73% of the benign fluids also stained for p53. Differences in staining were observed with the Bp-53-12-1 and the 1801 antibodies. Intensity, intracellular distribution, and frequency of immunoreactivity within each cell population are described. Observations are discussed in relation to sensitivity and specificity of the monoclonal antibodies for different configurational forms of p53 protein, configurational modifications of p53 protein during the cell cycle, and diagnostic evaluation of effusion smears for the presence of malignant cells. Immunoreactivity for p53 does not correlate with site of primary tumor. Although overexpression of p53 is more frequent in adenocarcinoma cells than in reactive mesothelial cells, p53 protein overexpression is not necessarily indicative of malignancy.
Adenocarcinoma↗
Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines.
Cells with divergent mutant alleles of the p53 gene have different biological and biochemical properties in vitro. Increasing evidence indicates that p53 is a transcriptional activator, and recently, high affinity DNA binding sites for p53 have been identified. The purpose of this study was to determine in vivo, the effect that various mutant p53 proteins have on their ability to mediate transactivation and to bind specifically to DNA. Either a p53 responsive or control reporter gene was transfected into 18 human carcinoma cell lines, having various p53 mutations, either with or without a wild-type p53 expression vector. The CAT activity and DNA gel retardation were studied to measure transactivation and DNA binding by these endogenous p53s. As expected, the endogenously produced wild-type p53 binds to DNA binding sequences and can transactivate a reporter construct containing a p53 high affinity DNA binding site. Four of five cell lines with homozygous p53 mutations at codon 273 (273His), contained p53 which had the ability to bind to p53 DNA binding sequences and transactivate. In contrast, all the homozygous, non-codon 273 mutant p53s (156Pro, 175His, 223Leu, 248Gln, 248Trp, 280Lys) present in the other cell lines had no transactivating ability. These findings suggest that the biology of cancers with mutations at codon 273 may be different than those with p53 mutations at other sites. The p53 from WRO, a thyroid carcinoma cell line with p53 mutation at codon 223 (223Leu), was able to bind p53 DNA recognition sequences, but was unable to transactivate. Interestingly, in a vulvar carcinoma cell line (A431) with a p53 mutation at codon 273 (273His), the p53 was unable to transactivate and gave an aberrant band on gel retardation. Both CEM and SK-UT-1, which have compound heterozygous mutations at codons 175/248 (175His/248His), produced p53 which can complex with DNA, as well as transactivate. In contrast, the p53 in cell lines with either homozygous 175His or 248His p53 mutations, were unable either to transactivate or bind to the p53 response element. A cell line (NPA) heterozygous for 266Glu p53 mutation, was able to efficiently transactivate a reporter containing a p53 DNA binding site, therefore showing no evidence of a dominant negative effect of the endogenous p53 mutant allele. In summary, this in vivo study further supports the idea that different p53 mutant alleles have various properties which may affect their function.
Base Sequence↗
Mutation and protein expression of p53 in acquired immunodeficiency syndrome-related lymphomas.
p53 mutations are found in a variety of neoplasia. B-immunoblastic lymphoma (BIBL) is a rapidly progressive, aggressive lymphoma. As patients with acquired immunodeficiency syndrome (AIDS) live longer, BIBL is becoming an increasing problem. We asked three questions in our study. What is the frequency of p53 mutations in BIBL? Is it more frequent in patients with AIDS? Can immunohistochemical staining of lymph nodes for expression of p53 substitute for mutational analysis of p53 to detect lymphomas with mutated p53? Exons 5, 6, 7, 8 of the p53 gene (hot-spots for mutations) were amplified and examined for mutations by single-strand conformation polymorphism (SSCP) analysis. Altered migration was observed in 7 of 52 BIBL samples. Of these, 4 of 25 were from individuals infected with human immunodeficiency virus (HIV) and 3 of 27 were not infected with HIV. Direct sequencing of amplified material confirmed the presence of mutations in exons 5, 7, 8 of p53. A total of 26 BIBL as well as other lymphoma/leukemia samples, stained strongly by immunohistochemistry with three antibodies directed against human p53. Five of 6 BIBL samples with p53 mutations stained strongly for p53, but 20 lymphoma samples with no detectable p53 mutations also stained strongly for p53. Of note, however, 10 hyperplastic, nonmalignant lymph nodes from individuals either infected or not infected with HIV had negligible staining for p53 protein. In conclusion, p53 mutations occur in about 14% BIBL samples; the frequency of p53 mutations in BIBL in individuals with and without AIDS was similar. Positive p53 immunohistochemistry did not correlate with detectable p53 mutations in the same tissue, but positive immunohistochemical staining for p53 was only found in neoplastic lymph nodes. This latter finding provides a strong warning that p53 immunochemistry with available reagents cannot be used to determine which tumors have mutations of p53.
Base Sequence↗
Localization of p53 protein and human papillomavirus in anogenital squamous lesions: immunohistochemical and in situ hybridization studies in benign, dysplastic, and malignant epithelia.
p53 Protein is a 53-kd nuclear phosphoprotein believed to play an important role in controlling proliferation of neoplastic and normal cells. This "natural tumor suppressor" can be rendered ineffective (or oncogenic) by mutations in the p53 gene or by interactions with proteins synthesized by DNA-transforming viruses, including specific subtypes of human papillomavirus (HPV). We describe the localization of p53 protein in association with HPV in paraffin sections of a spectrum of benign, dysplastic, and malignant anogenital squamous epithelia using immunohistochemical and in situ hybridization techniques. p53 Was detected in 81% of the 48 cases studied. Immunoreactivity for p53 was seen in 83% of the benign and low-grade squamous intraepithelial lesions (SILs), in 73% of the high-grade SILs, and in 86% of the infiltrating squamous carcinomas. In high-grade SILs p53 staining was frequently observed in individual nuclei at various levels of the abnormal epithelium and in the basal layer of the adjacent epithelium, while in squamous metaplasia and low-grade SILs immunostaining for p53 was limited to the basal layer of the epithelium. p53 Was detected in a slightly higher percentage of HPV-positive than HPV-negative epithelia as determined by in situ hybridization. No correlation was observed between p53 immunoreactivity and HPV subtypes. p53 Protein and HPV were detected in anal lesions from a small group of human immunodeficiency virus-positive individuals. Antibodies currently available mainly demonstrate mutant forms of p53 protein that are associated with longer half-lives than the wild-type protein, but demonstration of p53 protein overexpression is not necessarily indicative of malignancy.
Anus Neoplasms↗
A histiocyte-specific marker in the diagnosis of malignant fibrous histiocytoma. Use of monoclonal antibody KP-1 (CD68)
KP-1 (CD68) is a recently described monoclonal antibody to a cytoplasmic epitope present on tissue histiocytes and macrophages. To determine the specificity and sensitivity of this marker in the evaluation of cases of malignant fibrous histiocytoma (MFH), this reagent and a panel of commercially antibodies were used to stain formalin-fixed paraffin sections from 25 cases of MFH and 25 other tumors, including a variety of soft-tissue sarcomas. Eighteen of 25 cases of MFH stained for KP-1 (72%), whereas all other tumors were negative, including 12 cases of pleomorphic soft-tissue sarcoma other than MFH. The percentage of tumor cells staining for KP-1 varied. In 11 cases KP-1 was only focally present, but staining was of a high intensity and associated with minimal nonspecific or background staining. Pleomorphic histiocytic cells and spindle cells from storiform tumors were strongly decorated with antibodies to KP-1 in most cases, and antigen also was present on tumor giant cells. Although alpha-1-antitrypsin and alpha-1-chymotrypsin stained a higher percentage of cases of MFH (92%), immunoreactivity for these markers also was noted in other tumors. Because of its specificity as a histiocyte marker, KP-1 is a useful component in a panel of antibodies for the characterization of soft-tissue sarcomas and the diagnosis of MFH.
Antibodies, Monoclonal↗
The immunohistochemistry of Hodgkin's disease.
Immunohistochemistry is a valuable adjunct to the identification of Hodgkin's disease (HD) Reed-Sternberg (RS) cells, and in the differential diagnosis between HD, non-Hodgkin's lymphomas, and nonlymphoid neoplasms containing RS-like cells. The characteristic phenotype of RS cells in different subtypes of HD is described, with an emphasis on routine immunohistochemical stains. Some of the conflicting literature on this subject is reviewed to highlight pitfalls and controversies in the field.
Antigens, CD↗
Immunohistochemical analysis of p53 expression in malignant lymphomas.
p53 is a tumor suppressor gene that commonly undergoes mutations in human tumors, including lymphomas. Because p53 mutations are not restricted to a single locus, immunohistochemistry is useful to detect p53 expression and correlate this finding with lymphoma phenotype. Cryostat sections from 125 cases of lymphoma were analyzed for p53 expression using three different monoclonal antibodies (pAb 421, 1801, 240) which react with human cellular p53 and a common conformational epitope on mutant p53. A control antibody (pAb 246) reacts only with wild type p53 of murine origin and was negative in all cases. Tissue from 29 cases of lymphoid hyperplasia, including six from human immunodeficiency virus-positive (HIV+) patients, were negative for p53. p53 was predominantly localized in nuclei of high-grade lymphomas, including 14 of 46 cases of B cell immunoblastic lymphomas and two of five T cell immunoblastic lymphomas. p53 expression was relatively common in lymphomas from HIV+ patients, and unusual in intermediate and low-grade lymphomas of follicular center cell type. Low-grade lymphoma of small lymphocytic type disclosed p53+ large cells (paraimmunoblasts) that may play a role in tumor progression in this lymphoma subtype. p53 was also strongly expressed in the nuclei of Reed Sternberg cells from 19 of 37 cases of Hodgkin's disease, including six cases of mixed cellularity, and 13 cases of nodular sclerosing type. Immunohistochemical staining is a rapid method to identify p53 expression in lymphomas.
Animals↗
Undifferentiated (embryonal) sarcoma of the liver. A tumor of uncertain histogenesis showing divergent differentiation.
Pathologic features of eight cases of undifferentiated (embryonal) sarcoma of the liver (USL) in childhood were studied. Light microscopic examination showed a diffuse growth of spindle cells with occasional polygonal cells and multinucleated giant cells and also revealed focal areas of storiform pattern in four tumors, cambium layer formation in one tumor, and alveolar arrangement in one tumor. Immunohistochemical study showed positive staining of proliferating cells for suggestive histiocytic markers (A1AT in 6/6, A1ACT in 5/6, lysozyme in 4/6, and KP1 in 4/6) and for muscle markers (desmin in 4/6 and HHF35 in 3/6). Ultrastructural examination demonstrated that the individual tumors were composed of a mixture of cells having fibroblastic, histiocytoid, fibrohistiocytoid, myofibroblastic, and undifferentiated (primitive mesenchymal) morphologies. Also identified were cells with definite myoblastic morphology in three tumors: leiomyoblastic in one and rhabdomyoblastic in two. In conclusion, the tumor cells in USL show phenotypical diversity comparable to those of malignant fibrous histiocytoma with or without additional rhabdomyosarcomatous or leiomyosarcomatous differentiation.
Actins↗