Angiotropic lymphoma: an immunophenotypically and clinically heterogeneous lymphoma.

Angiotropic lymphoma (AL) is an uncommon lymphoma often presenting with nonspecific clinical features and having a high mortality rate. Although not specifically recognized by the Revised European-American Classification of Lymphoid Neoplasms, it likely will appear as a subtype of diffuse large B-cell lymphoma in the upcoming WHO classification. Some authors may also consider it to be a subtype of cutaneous lymphomas. Recent studies have reported an immunophenotypic heterogeneity of AL, and in rare instances, an association with other NHL. To further characterize AL, we studied the immunophenotype by immunohistochemistry for CD5, CD10, CD20, bcl-2, and bcl-6 in 18 cases of B-cell AL identified at three medical centers in North America. Bcl-2 gene rearrangement status by polymerase chain reaction and Epstein Barr virus status by in situ hybridization also were evaluated. Eight men and 10 women were identified with AL (median age 71 years). Eleven patients were diagnosed in life and seven were diagnosed at autopsy. Neurologic symptoms were the most common presentation, seen in six patients. Skin was the most commonly biopsied site. All showed classic intravascular localization; in two cases, there was also a minor diffuse large cell lymphoma component observed in some organs. Most (89%) of the cases expressed bcl-2 protein; CD10, bcl-6 and CD5 were each expressed in 22% of cases. Based on CD5 and CD10 expression, three major groups were evident: CD5-, CD10- (11 cases); CD5+, CD10- (3 cases), and CD5-, CD10+ (3 cases). Even though a follicle center lymphoma preceded the AL in one patient, we did not detect bcl-2 gene rearrangement in any of these cases. All cases were negative for Epstein Barr virus. Of the five treated with chemotherapy, two achieved a complete remission. Based on these findings, we conclude that ALs are clinically and immunophenotypically heterogeneous and may represent more than one pathogenetic entity. In some instances AL may be preceded by another lymphoproliferative disorder, raising the possibility that some cases of AL may represent a transformation from another type of lymphoma. Cutaneous manifestations of AL are common; however, it appears to be a systemic lymphoma. Although often fatal, patients with AL who are diagnosed early and treated with chemotherapy may achieve remission.

Persistent preswitch clonotypic myeloma cells correlate with decreased survival: evidence for isotype switching within the myeloma clone.

Multiple myeloma (MM) is identified by unique immunoglobulin heavy chain (IgH) variable diversity joining region gene rearrangements, termed clonotypic, and an M protein termed the "clinical" isotype. Transcripts encoding clonotypic pre and postswitch IgH isotypes were identified in MM peripheral blood mononuclear cells (PBMCs), bone marrow (BM), and mobilized blood. For 29 patients, 38 BM, 17 mobilized blood, and 334 sequential PBMC samples were analyzed at diagnosis, before and after transplantation for 2 to 107 months. The clinical clonotypic isotype was readily detectable and persisted throughout treatment. Eighty-two percent of BM and 38% of PBMC samples also expressed nonclinical clonotypic isotypes. Clonotypic immunoglobulin M (IgM) was detectable in 68% of BM and 25% of PBMC samples. Nonclinical clonotypic isotypes were detected in 41% of mobilized blood samples, but clonotypic IgM was detected in only 12%. Patients with persistent clonotypic IgM expression had adverse prognostic features at diagnosis (lower hemoglobin, higher beta(2)-microglobulin) and higher numbers of BM plasma cells compared with patients with infrequent/absent clonotypic IgM. Patients with persistent clonotypic IgM expression had significantly poorer survival than patients with infrequent IgM expression (P <.0001). In a multivariate analysis, persistent clonotypic IgM expression in the blood correlated independently with poor survival (P =.01). In nonobese diabetic severe combined immunodeficiency mice, xenografted MM cells expressed clinical and nonclinical postswitch clonotypic isotypes. MM expressing clonotypic IgM engrafted both primary and secondary mice, indicating their persistence within the murine BM. This study demonstrates that MM clonotypic cells expressing preswitch transcripts are tied to disease burden and outcomes. Because MM pathology involves postswitch plasma cells, this raises the possibility that IgH isotype switching in MM may accompany worsening disease.

Recurrent Epstein-Barr virus associated disease in a cardiac transplant patient: evolution from plasmacytic hyperplasia to diffuse large cell lymphoma.

An Epstein-Barr virus (EBV)-seronegative 31-year-old male underwent cardiac transplantation in 1991 for congenital cardiomyopathy. He presented with a protracted course of waxing and waning lymphadenopathy beginning four years after transplantation with eventual progression to a fulminant EBV-positive large cell lymphoma eight years after transplantation. Risk factors for the development of post-transplant lymphoproliferative disease in this patient, the importance of a standardized approach to pathology in assessing therapeutic options, and the management strategies used are discussed.

Prevalence of gastrointestinal helminths in domestic bison herds in northwestern Alberta.

A fecal survey was conducted to determine the prevalence of gastrointestinal helminth eggs found in 431 domestic bison from 22 herds. Eggs detected (percent of herds affected in parentheses) were: strongyle-type (100%), Capillaria sp. (63.6%), Moniezia sp. (54.6%), Nematodirus sp. (50%), Trichuris sp. (40.9%), and Strongyloides sp. (9.1%).

Effect of radiation on cytokine and cytokine receptor messenger-RNA profiles in p53 wild and mutated human glioblastoma cell lines.

OBJECTIVE: Glioblastoma cells produce cytokines with proinflammatory or immunosuppressive properties, or both, which, in addition to altered p53 gene expression, have been shown to be associated with glioblastoma resistance to radiotherapy. The reported data concerning cytokines have been isolated and sometimes discordant, and a comprehensive profile analysis of cytokines and their corresponding receptors in irradiated glioblastomas has received limited attention. The object of this study was to test the hypothesis that radiation alone in clinically relevant doses would not significantly alter expression of endogenous cytokines and their receptors in human glioblastoma celll ines with wild-type and mutant p53. DESIGN AND METHOD: Culture specimens of 4 glioblastoma cell lines of different p53 gene expression (U87, U118, U251, U373) were irradiated with cobalt 60 at a dose of 10 Gy. After 48 hours, radiosensitivity was defined through a colony formation assay, cell cycle distribution was analyzed by flow cytometry, and cytokine and cytokine receptor messenger-RNA (mRNA) profiles were defined with an RNase protection assay. Different single doses of radiation at varying time intervals after culture were applied also to wild-type p53 cell lines. RESULTS: All cell lines were relatively radioresistant at lower doses of 1 and 2 Gy. Immunosuppressive cytokine and cytokine receptor mRNA of the Th2 (IL-13Ralpha, IL-4) and Th3 family (TGF-beta1, 2 and 3, TGF-betaRI and RII) were expressed. In contrast, only 2 proinflammatory Th1 cytokine receptor genes (IFN-gammaRa and IFN-gammaRbeta), but no significant Th1 cytokine gene expression, were detected. Even though the population examined included a large fraction of reproductively dead cells, cytokine and cytokine receptor mRNA profiles were not altered significantly by irradiation in all cell lines, regardless of the p53 status. CONCLUSION: These results suggest that cobalt irradiation alone at clinically relevant doses does not significantly alter the cytokine and cytokine receptor profiles in human glioblastoma cell lines.

Seroprevalence of Neospora caninum in beef cattle in northern Alberta.

Blood samples were collected from 1806 pregnancy-tested cows from 174 herds at a northern Alberta auction mart in the fall of 1998. One hundred sixty-two (9.0%) of these samples were positive for antibodies to N. caninum. Thirty-five of 260 samples (13.5%) collected from the same region in the 1980s were also serologically positive for N. caninum.

Subglottic stenosis secondary to extramedullary hematopoiesis in a patient with postpolycythemia myeloid metaplasia.

BACKGROUND: Extramedullary hematopoiesis (EMH) is known to occur in myeloproliferative disorders and hemoglobinopathies and is usually seen in the spleen and liver. METHODS: We report the first case of EMH causing subglottic stenosis in a woman with postpolycythemia myeloid metaplasia (PPMM). A tracheotomy was performed to maintain the airway and local radiotherapy was given. RESULTS: Two months after the radiotherapy was completed laryngoscopy showed an unobstructed airway with no evidence of disease, and the patient was successfully decanulated. Magnetic resonance imaging 8 months after radiotherapy confirmed the absence of local disease. CONCLUSION: Consideration should be given to EMH as a possible cause of airway obstruction in the differential diagnosis of a patient with a history of PPMM.

Sinusoidal CD30-positive large B-cell lymphoma: a morphologic mimic of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) has been recognized recently as a distinct clinicopathologic entity, restricted to a subset of CD30-positive diffuse large cell lymphomas of T/null lineage. Some of the characteristic features of ALCL, such as CD30 antigen expression and the presence of large pleomorphic lymphoid cells infiltrating lymph node sinuses, can be found rarely in diffuse large B-cell lymphomas. We collected 11 such cases, and their clinical, morphologic, and immunophenotypic features are reviewed. The age of the patients ranged from 36 to 82 years (mean, 63.2 years) with a male to female ratio of 1:1.2. All neoplasms were nodal with a sinusoidal infiltrative pattern, although four neoplasms also had foci of confluent growth. Eight tumors were composed predominantly of large pleomorphic cells with occasional Reed-Sternberg-like cells. The other three tumors had a higher proportion of large monomorphic lymphoid cells. Necrosis and admixed granulocytes were other common features. Immunophenotypically, all cases were positive for CD30 and CD20 or CD79a. All eight cases examined for anaplastic lymphoma kinase-1 immunoreactivity were negative. In situ hybridization for Epstein-Barr virus RNA was performed in eight cases; two were positive. Excluding one consultation case with no available clinical follow-up data, six patients died of the disease within 3 years and one had disease relapse within 1 year. We conclude that an unusual variant of diffuse large B-cell lymphoma can closely mimic ALCL. However, these neoplasms can be distinguished from ALCL by virtue of their B-lineage and lack of anaplastic lymphoma kinase-1 expression. Evidence of Epstein-Barr virus infection can be found in a small subset of these neoplasms.

Hepatosplenic T-cell lymphoma of alphabeta lineage in a 16-year-old boy presenting with hemolytic anemia and thrombocytopenia.

The authors report an unusual case of peripheral T-cell lymphoma in a 16-year-old boy who presented initially with jaundice, splenomegaly, anemia, and thrombocytopenia. A lymphoma was found subsequently in the spleen, which was infiltrated extensively in the red pulp by medium-sized, blastic-appearing lymphoma cells. Immunologic characterization of these cells revealed positivity for CD3, CD5, CD45RO, CD56, and T-cell intracellular antigen (TIA), and negativity for CD2, CD3, CD4, CD8, CD57, CD34, and terminal deoxynucleotidyl transferase (TdT). Conventional cytogenetic studies revealed the presence of isochromosome 7q. On follow up, this patient deteriorated rapidly, with evidence of liver and bone marrow involvement. Although the overall clinical and pathologic features of this disease were characteristic of hepatosplenic gammadelta T-cell lymphoma, the T-cell receptor of this tumor showed an immunophenotype of alphabeta not gammadelta lineage. Using the Southern blot technique, the authors demonstrated monoclonal gene rearrangement of the T-cell receptor beta-chain. Thus, they confirmed the existence of hepatosplenic alphabeta T-cell lymphoma. In view of its overall similarity to hepatosplenic gammadelta T-cell lymphoma, this unusual entity probably represents a slight biologic variation of the same disease.

Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice.

The myelomagenic capacity of clonotypic myeloma cells in G-CSF mobilized blood was tested by xenotransplant. Intracardiac (IC) injection of NOD SCID mice with peripheral cells from 5 patients who had aggressive myeloma led to lytic bone lesions, human Ig in the serum, human plasma cells, and a high frequency of clonotypic cells in the murine bone marrow (BM). Human B and plasma cells were detected in BM, spleen, and blood. Injection of ex vivo multiple myeloma cells directly into the murine sternal BM (intraosseus injection [IO]) leads to lytic bone lesions, BM plasma cells, and a high frequency of clonotypic cells in the femoral BM. This shows that myeloma has spread from the primary injection site to distant BM locations. By using a cellular limiting dilution PCR assay to quantify clonotypic B lineage cells, we confirmed that peripheral myeloma cells homed to the murine BM after IC and IO injection. The myeloma progenitor undergoes self-renewal in murine BM, as demonstrated by the transfer of human myeloma to a secondary recipient mouse. For 6 of 7 patients, G-CSF mobilized cells from patients who have minimal disease, taken at the time of mobilization or after cryopreservation, included myeloma progenitors as identified by engraftment of clonotypic cells and/or lytic bone disease in mice. This indicates that myeloma progenitors are mobilized into the blood by cyclophosphamide/G-CSF. Their ability to generate myeloma in a xenotransplant model implies that such progenitors are also myelomagenic when reinfused into patients, and suggests the need for an effective strategy to purge them before transplant.

Clinical and legal significance of fragmentation of bullets in relation to size of wounds: retrospective analysis.

OBJECTIVE: To examine the relation between fragmentation of bullets and size of wounds clinically and in the context of the Hague Declaration of 1899. DESIGN: Retrospective analysis of prospectively collected data on hospital admissions. SETTING: Hospitals of the International Committee of the Red Cross. SUBJECTS: 5215 people wounded by bullets in armed conflicts (5933 wounds). MAIN OUTCOME MEASURES: Grade of wound computed from the Red Cross wound classification and presence of bullet fragments on radiography. RESULTS: Of the 347 wounds with fragmentation of bullets, 251 (72%) were large wounds (grade 2 or 3)-that is, those with a clinically detectable cavity. Of the 5586 wounds without fragmentation of bullets, 2915 (52.1%) were large wounds. Only 7.9% (251/3166) of large wounds were associated with fragmentation of bullets. CONCLUSIONS: Fragmentation of bullets is associated with large wounds, but most large wounds do not contain bullet fragments. In addition, bullet fragments may occur in wounds that are not defined as large. Fragmentation of bullets is neither a necessary nor sufficient cause of large wounds, and surgeons should not diagnose extensive tissue damage because of the presence of fragments on radiography. Such findings also do not necessarily represent the use of bullets which contravene the law of war. Future legislation should take into account not only the construction of bullets but also their potential to transfer energy to the human body.

Mortality associated with use of weapons in armed conflicts, wartime atrocities, and civilian mass shootings: literature review.

OBJECTIVE: To determine the implications of variation in mortality associated with use of weapons in different contexts. DESIGN: Literature review. SETTINGS: Armed conflicts and civilian mass shootings, 1929-96. MAIN OUTCOME MEASURE: Mortality from wounds. RESULTS: During the fighting of war the number of people wounded is at least twice the number killed and may be 13 times as high; this ratio of the number wounded to the number killed results from the impact of a weapon system on human beings in the particular context of war. When firearms are used against people who are immobilised, in a confined space, or unable to defend themselves the wounded to killed ratio has been lower than 1 or even 0. CONCLUSIONS: Mortality from firearms depends not only on the technology of the weapon or its ammunition but also on the context in which it is used. The increased mortality resulting from the use of firearms in situations other than war requires a complex interaction of factors explicable in terms of wound ballistics and the psychology of the user. Understanding these factors has implications for recognition of war crimes. In addition, the lethality of conventional weapons may be increased if combatants are disabled by the new non-lethal weapons beforehand; this possibility requires careful legal examination within the framework of the Geneva Conventions.

Effect of type and transfer of conventional weapons on civilian injuries: retrospective analysis of prospective data from Red Cross hospitals.

OBJECTIVE: To examine the link between different weapons used in modern wars and their potential to injury civilians. DESIGN: Retrospective analysis of prospectively collected data about hospital admissions. SETTING: Hospitals of the International Committee of the Red Cross. SUBJECTS: 18 877 people wounded by bullets, fragmentation munitions, or mines. Of these, 2012 had been admitted to the hospital in Kabul within six hours of injury. MAIN OUTCOME MEASURES: Age and sex of wounded people according to cause of injury and whether they were civilians (women and girls, boys under 16 years old, or men of 50 or more). RESULTS: 18.7% of those injured by bullets, 34.1% of those injured by fragments, and 30.8% of those injured by mines were civilians. Of those admitted to the Red Cross hospital in Kabul within six hours of injury, 39.1% of those injured by bullets, 60.6% of those injured by fragments, and 55.0% of those injured by mines were civilians. CONCLUSIONS: The proportion of civilians injured differs between weapon systems. The higher proportion injured by fragments and mines is explicable in terms of the military efficiency of weapons, the distance between user and victim, and the effect that the kind of weapon has on the psychology of the user.

Primary pericardial synovial sarcoma: a case report and literature review.

Primary synovial sarcoma of the heart is a rare tumor, with only six previous cases having been reported in the literature. Treatment has included surgery with or without chemotherapy. We present the first case of a documented synovial sarcoma arising from the pericardium in a 19-year-old man. Molecular analysis for t(X; 18) SYT-SSX gene fusion was positive. Radiation treatment was given postoperatively to the entire heart with a boost to the area where the margins were positive.

Outcome of advanced stage low grade follicular lymphomas in a population-based retrospective cohort.

BACKGROUND: To the authors' knowledge previous reports of patient outcome for advanced stage low grade follicular lymphomas (LGFL) have not been population-based. This is the first report describing the outcome of these patients based on a population-based cohort. METHODS: A retrospective chart review was performed for all patients diagnosed with advanced stage LGFL between 1987-1995 for the adult population of central and northern Alberta, Canada. RESULTS: One hundred and fifty-seven patients were diagnosed with advanced stage LGFL. Approximately 45% of patients had died at last follow-up. Treatment was initiated at the time of diagnosis in 87 patients (55%), with alkylating agents used in 66% of them. Of the 70 patients not treated at the initial diagnosis, 69% had been treated at a median of 16.3 months. The overall median survival was 5.9 years. On univariate analysis, significant variables (P < 0.20) included age, B symptoms, symptomatic lymphadenopathy, symptomatic splenomegaly, splenomegaly, Eastern Cooperative Oncology Group performance status, baseline lactate dehydrogenase (LDH), diffuse component on histology, and treatment at the time of diagnosis. By multivariate analysis, the only factors that influenced survival significantly and independently were baseline LDH and B symptoms. An elevated baseline LDH had a hazard ratio of 2.80 (95% confidence interval [CI], 1.65, 4.74) and a median survival of 8.0 years versus 3.6 years (P < 0.0001). B symptoms had a hazard ratio of 2.30 (95% CI, 1.23, 4.30) and a median survival of 6.5 years versus 3.1 years (P < 0.0067). CONCLUSIONS: Although some patients with advanced stage LGFL enjoy a prolonged survival, 80% of deaths in this cohort were attributable to lymphoma. The median overall survival of 5.9 years offers a less positive perspective on the outcome of these patients than in previous nonpopulation-based reports. This emphasizes the need for further population-based studies as well as new therapeutic approaches, especially those directed toward patients with poor prognostic features such as elevated baseline LDH and B symptoms.

Expression of transmembrane 4 superfamily member, CD9, is related to improved progression-free survival in patients with diffuse non-Hodgkin's lymphoma.

Decreased expression of the transmembrane 4 superfamily member, CD9, is associated with poor prognosis in patients with breast or non-small cell lung cancer. The expression of CD9 in lymphoma was examined in this study. Fifty-one sections with diffuse lymphomas were examined. Thirty-seven had low expression and 14 high expression of CD9. At 5 years the progression-free survival rates were 83.3+/-10.8% and 32.8+/-9.2% (p=0.018), and the actual survival were 83.3+/-10.8% and 56.8+/-8.9% (p=0.256) for those with high and low CD9 expression respectively. Decreased expression of CD9 appears to be a prognostic factor for poor survival in patients with diffuse lymphomas.

Immunohistochemical detection of E2F-1 in non-Hodgkin's lymphomas: a survey of 124 cases.

E2F-1 is a transcription factor that mediates cell cycle progression from the G1 to S phase and is normally regulated by a group of proteins, including cyclin D1. Although deregulation of E2F-1 is implicated in neoplastic transformation, in situ examination of this protein has not been performed to date. Using an immunohistochemical technique applied to routinely fixed, paraffin-embedded tissue sections, we evaluated E2F-1 expression in reactive lymphoid tissues and in 124 cases of non-Hodgkin's lymphoma (NHL) of various types. In reactive lymphoid tissues, E2F-1 was expressed predominantly by large noncleaved cells in germinal centers and by a small subset of cortical thymocytes. Mantle zones and splenic marginal zones were negative. Among the NHLs, four types had a relatively high percentage (> 20%) of E2F-1-positive cells: mantle cell lymphoma (19 of 19), lymphoblastic lymphoma (5 of 5), small noncleaved cell lymphoma (4 of 6), and hepatosplenic gammadelta T-cell lymphoma (3 of 3). The consistent detection of many E2F-1-positive cells in mantle cell lymphoma is in contrast to other small B-cell NHLs (n = 29), which had relatively few (< 10%) E2F-1-positive cells. This finding suggests that immunohistochemical staining for E2F-1 as a supplement to the existing markers, such as cyclin D1, might be useful in the differential diagnosis of NHLs composed of small B cells.