Mod Pathol

bcl-6 protein is identified in high-grade but not low-grade mucosa-associated lymphoid tissue lymphomas of the stomach.

Year 1998
Omonishi K. Yoshino T. Sakuma I. Kobayashi K. Moriyama M. Akagi T.
Department of Pathology, Okayama University Medical School, Japan.
The pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is an intriguing issue and is thought to be closely related to Helicobacter pylori infection. Gastric MALT lymphoma is thought to progress from the reactive state to low-grade malignancy and sometimes to high-grade malignancy. In the present study, we examined immunohistochemically the expression of bcl-6 and p53 proteins in gastric MALT and gastric diffuse large lymphoma without low-grade MALT lymphoma component (gastric DLL) to elucidate their role in high-grade transformation of low-grade MALT lymphoma. We detected bcl-6 protein only in the high-grade components in four of eight high-grade MALT lymphoma cases and in four of six gastric DLL cases. In contrast, none of 17 cases of low-grade MALT lymphoma expressed bcl-6 protein (P < .05). p53 protein was detected in the high-grade components in 6 of 8 high-grade MALT lymphoma cases and in 4 of 6 gastric DLL cases, but it was expressed in 2 of 17 cases of low-grade MALT lymphomas. All high-grade gastric MALT lymphomas cases were positive for p53 protein and/or bcl-6 protein. There is a tendency for an inverse relationship between bcl-6 protein and p53 protein. These findings suggest that high-grade transformation of gastric low-grade MALT lymphoma is associated with overexpression of p53 or bcl-6 protein.

Post-transplantation lymphoproliferative disorders in Mexico: an aggressive clonal disease associated with Epstein-Barr virus type A.

Year 1998
Quintanilla-Martinez L. Lome-Maldonado C. Schwarzmann F. Gredler E. Reyes E. Angeles-Angeles A. Fend F.
Department of Pathology, Instituto Nacional de la Nutricion, Mexico City, Mexico. leticiaq@box1.nih.gov
Post-transplantation lymphoproliferative disorders (PT-LPDs) are a complication of immunosuppression with variable clinical behavior and frequent Epstein-Barr virus (EBV) association. There is geographic variation in the association of EBV with certain tumors and a lack of studies of PT-LPDs from developing countries, so we decided to study in detail a series of PT-LPDs from Mexico to identify similarities and differences between populations in Mexico and those in Europe and the United States. We used paraffin-embedded tissue from eight PT-LPDs (six from men, two from women) that arose after renal transplantation. Clinical data, morphologic features, and clonality on the basis of immunoglobulin (Ig) light chain restriction, as well as polymerase chain reaction (PCR) for Ig heavy chain genes, were studied. The presence of EBV was investigated with PCR, immunohistochemical analysis for latent membrane protein (LMP)-1, and in situ hybridization for EBV early RNA transcripts. In addition, the subtype of EBV based on the EBNA 2A and 2B genes and the presence of a 30-bp deletion in the LMP-1 gene were investigated by PCR. Seven (87.5%) of eight cases presented with gastrointestinal involvement; five patients died. Three cases were polymorphic PT-LPDs, four were monomorphic large cell lymphomas (one diffuse large cell, three immunoblastic), and one was unclassifiable. All showed a B-cell phenotype, with a clonal population demonstrated in seven of the eight cases. Tumor cells expressed EBERs in all of the cases and LMP-1 in six of seven evaluable cases. Seven of seven cases showed EBV subtype A. Two (25%) of eight cases had the 30-bp LMP-1 deletion. This study shows that PT-LPDs in Mexico are clonal disorders associated with EBV subtype A. In contrast to series from Europe and the United States, our cases showed a significantly higher incidence of gastrointestinal tract involvement (P < .001), and a lower incidence of the 30-bp LMP-1 deletion, although this was not statistically significant (P < .28).

Expression of the ets-1 proto-oncogene in human pancreatic carcinoma.

Year 1998
Ito T. Nakayama T. Ito M. Naito S. Kanematsu T. Sekine I.
Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Japan.
The proto-oncogene, ets-1, is a transcription factor that controls the expression of a number of genes involved in extracellular matrix remodeling. It might play a role in cell migration and tumor invasion. To elucidate the involvement of Ets-1 in human pancreatic carcinoma, we performed immunohistochemical analysis on tissue from 10 normal pancreases and 103 cases of pancreatic carcinoma. We compared the degree of Ets-1 expression. In addition, among the pancreatic carcinomas, we compared Ets-1 expression in relation to the differentiation, lymph node metastasis and the depth of invasion of the carcinoma. Ets-1 was expressed faintly in normal pancreatic tissue. Among the 103 cases of pancreatic carcinoma, 83 (80.5%) showed positive staining for the Ets-1 protein. Histologically, papillary carcinoma, well-differentiated adenocarcinoma, and moderately differentiated adenocarcinoma expressed high positivity for Ets-1. In contrast, poorly differentiated adenocarcinoma expressed relatively weak positivity for Ets-1. Ets-1 expression had no relation to the presence of lymph node metastasis, tumor size, prognosis, or tumor-node-metastasis stage in pancreatic carcinomas. In situ hybridization also confirmed the presence of ets-1 mRNA in pancreatic carcinomas. We detected expression of ets-1 mRNA in three human pancreatic carcinoma cell lines by the reverse transcription-polymerase chain reaction method. These findings suggest that Ets-1 expression is related to the carcinogenesis of human pancreatic carcinoma, but its relationship to tumor progression is unclear.

Cytomegalovirus infection in the colon of bone marrow transplantation patients.

Year 1998
Kraus MD. Feran-Doza M. Garcia-Moliner ML. Antin J. Odze RD.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
The histologic distinction between cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) in the colon in bone marrow transplantation (BMT) patients relies heavily on the identification of viral inclusions, because the morphologic features of these two diseases are otherwise similar. The aim of this study was to assess (1) the prevalence of colonic CMV infection in BMT patients with the use of DNA in situ hybridization (ISH); and (2) the sensitivity and specificity of light microscopy in establishing a diagnosis of CMV infection in the colon of these patients. Fifty-five colonic mucosal biopsy samples from 50 consecutive allogeneic BMT patients with diarrhea were evaluated histologically for the presence of typical or atypical (suspicious, but not diagnostic) CMV inclusions and, if negative, for the grade of GVHD. CMV DNA ISH analysis was performed on all of the biopsy specimens and was correlated with the histologic and clinical findings. Histologic analysis revealed only one patient with morphologically typical CMV inclusions. Four other cases contained an isolated atypical mesenchymal cell with features considered suspicious, but not diagnostic, for CMV inclusions. All of these five cases exhibited histologic features that were otherwise indistinguishable from GVHD grades 1 to 2. The single case that was histologically positive for CMV was confirmed by DNA ISH. Of the four histologically atypical cases, only one was confirmed to be CMV positive by DNA ISH. Of the remaining 45 patients, 35 had GVHD, 1 had pseudomembranous colitis, 1 had ischemic colitis, and 8 had no abnormalities found. Light microscopic examination is a sensitive method of screening for CMV infection in the colon of BMT patients but is less specific than DNA ISH. CMV infection is an infrequent cause of colitis in our BMT population.

Causes of death in autopsied liver transplantation patients.

Year 1998
Torbenson M. Wang J. Nichols L. Jain A. Fung J. Nalesnik MA.
Department of Pathology, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Liver transplantation is an established treatment for multiple end-stage liver diseases, yet little information is available on the autopsy-determined causes of death in liver transplant recipients. We undertook a retrospective study of the immediate causes of death in all liver transplant recipients who underwent autopsy at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, from January 1982 to January 1997. Infections were the most frequent cause of death, present in 64% of a total of 321 cases. Overall, the infections were bacterial in 48% of the cases, fungal in 22%, and viral in 12%. The ratio of infectious to noninfectious causes of death did not change significantly during the 15-year study period, and the relative percentages of bacterial, fungal, and viral infections showed relatively little variation on a year-to-year basis. Two-thirds of all infections occurred during the first 100 days post transplantation. A precipitous drop in the number of infections (and the number of deaths) occurred by Day 90. Other major causes of death included liver failure (12%), pulmonary failure (10%), multiple organ system (8%), and cardiovascular causes (6%). Infections were the most frequent cause of death in this study population, suggesting that improvement in the prevention and treatment of infections is an important way to improve survival of liver transplant recipients.

Hepatitis C viral genome in a subset of primary hepatic lymphomas.

Year 1998
Ohsawa M. Tomita Y. Hashimoto M. Kanno H. Aozasa K.
Department of Pathology, Osaka University Medical School, Suita, Japan.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are not only hepatotropic but possibly hematotropic. Recent studies showed the presence of HBV in lymphoma cells of extrahepatic origin. In the current study, we examined the presence of HBV DNA and HCV RNA in the tumor tissues of nine patients with primary hepatic lymphoma (PHL). Immunohistochemical study using polyclonal anti-HCV antibody was possible in four cases. The age of the patients ranged from 45 to 78 years (median, 58 yr), with a male-to-female ratio of 2:1. A history of chronic hepatitis was found in three patients and of cirrhosis in one. Histologically, all of the cases were non-Hodgkin's lymphoma of B-cell phenotype, with a diffuse large cell type being the most common. Polymerase chain reaction using both the S and X region primers failed to detect HBV DNA in the lymphoma tissues. The HCV genome was detected by in situ hybridization in the tumor cells but not in the surrounding hepatocytes in the one case of cirrhosis, which probably resulted from a blood transfusion more than 20 years previous; immunohistochemical analysis revealed positive staining for anti-HCV antibody in the cytoplasm of lymphoma cells in this case. In two cases, positive signals were found only in the hepatocytes surrounding the lymphoma. This is the first report showing the presence of the HCV genome in the lymphoma cells of PHL. HCV could be involved in development of PHL directly or via exogenic antigenic stimulus from HCV-infected hepatocytes.

Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin.

Year 1998
Su LD. Atayde-Perez A. Sheldon S. Fletcher JA. Weiss SW.
Department of Pathology, University of Michigan Hospitals, Ann Arbor 48105-0054, USA.
The inflammatory myofibroblastic tumor (IMT) is a distinctive but controversial lesion, usually occurring during childhood, composed of fascicles of bland myofibroblastic cells admixed with a prominent inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils. Often affecting the lung and associated with constitutional symptoms, this lesion has been variously termed plasma cell granuloma, inflammatory pseudotumor, inflammatory myofibrohistiocytic proliferation, and inflammatory fibrosarcoma to reflect divergent views concerning its pathogenesis and level of malignancy. Cytogenetic analysis of an intra-abdominal myxoid hamartoma, a probable variant of this lesion, and a pulmonary IMT demonstrated clonal chromosomal abnormalities, lending support to the view that the IMT might be a neoplasm. There have been few cases studied to date, however, and the extent of cytogenetic anomalies in IMTs is not known. Karyotype analyses were performed on IMTs showing typical histologic features from three children. In addition, one case was studied by fluorescence in situ hybridization. Seventeen of 20 metaphase cells examined from a pulmonary IMT in a 5.5-year-old girl had an abnormal 47,XX+r(ring) karyotype. Fluorescence in situ hybridization studies demonstrated that the ring chromosome contained sequences of chromosome 8. Of 40 metaphase cells studied from a mesenteric IMT in an 8-month-old boy, 12 showed clonal aberrations, characterized as 43,XY,add(1)(p36),add(2)(p24),-6,der(14,22)(q10;q10),-19. Each of 20 metaphase cells examined from a retroperitoneal IMT in a 14-year-old girl contained complex clonal and nonclonal aberrations, characterized as 46-47,X,-X,add(2)(p22),add(2)(q13),+add(2)(q13),+5,-6,+i(7)(p10),add(8)( p11.2),+del(9)(p13),add(11)(p11.2)add(11)(q25),-13,-16,-18,add(19)(q13.1 ),add(19)(q13.1),+20,-21,-22,+mar1,+1-2mars. The presence of clonal chromosomal aberrations in all of the three tumors indicates that the IMT is a neoplastic proliferation.

Primary hepatic low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) associated with primary biliary cirrhosis.

Year 1998
Prabhu RM. Medeiros LJ. Kumar D. Drachenberg CI. Papadimitriou JC. Appelman HD. Johnson LB. Laurin J. Heyman M. Abruzzo LV.
School of Medicine, University of Maryland, Baltimore 21201, USA.
We describe a case of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the liver of a patient with early-stage primary biliary cirrhosis (PBC). The patient, a 62-year old woman, presented with abnormal liver function tests, a positive antimitochondrial antibody titer (1:160), and a liver mass. The resected mass, 6.0 x 5.0 x 4.0 cm, had the features of MALT-type lymphoma. The neoplastic cells were small lymphoid cells of B-cell lineage that surrounded reactive lymphoid follicles and infiltrated bile ductules to form lymphoepithelial lesions. The uninvolved liver had histologic evidence of early stage PBC, characterized by segmental duct destruction with granulomata and an inflammatory infiltrate in the portal triads composed of lymphocytes, plasma cells, and occasional eosinophils. A periportal lymph node showed histologic features of the hyaline-vascular type of Castleman's disease, without evidence of malignant lymphoma. Low-grade B-cell lymphomas of the MALT type rarely arise in the liver and, to our knowledge, have not been reported previously in association with PBC. The association in this case suggests that chronic antigenic stimulation as a result of PBC induced the accumulation of acquired MALT, which subsequently transformed to low-grade B-cell lymphoma.