Bharat N. Nathwani

Malignant lymphoma, lymphoblastic.

Among the malignant lymphomas of the diffuse, poorly differentiated lymphocytic type, a cytologically distinctive form can be recognized. It is composed of immature lymphoid cells that are indistinguishable from the cells of acute lymphoblastic leukemia (ALL). Although these neoplasms usually have been classified as malignant lymphoma, lymphoblastic type, they contain, in addition to lymphoblasts, prolymphocytes in varying proportions. On the basis of the nuclear morphology, malignant lymphoma of the lymphoblastic type, (MLLB) can be further divided into those with and those without convoluted nuclei. In our series both groups had the following clinical features in common: 1) frequent occurrence in children and adolescents; 2) clinical presentation with mediastinal masses in 50% of cases; 3) a high incidence of bone marrow and perpheral blood involvement during the course of the disease; and 4) rapid progression of the disease with a median survival of 8 months. Our observations indicate that nuclear convolutions are helpful but not essential for the recognition of a clinicopathologic entity which is histologically and cytologically characterized by 1) the immaturity of the lymphoid cells indistinguishable from the lymphoblasts and prolymphocytes of ALL and 2) a high mitotic index. Because of the frequency with which MLLB progresses into ALL, systemic therapy may be indicated even before this progression is hematologically evident. This indicates the need for morphologic recognition of this malignant lymphoma regardless of the presence of nuclear convolution, age of the patient, and site of presentation.

Hepatitis C Virus Infection in Patients with B-Cell Non-Hodgkin Lymphoma

Hepatitis C virus (HCV) is the major etiologic agent of post-transfusion and sporadic non-A, non-B chronic hepatitis [1, 2]. Although HCV is a hepatotrophic virus, the HCV genome and its replicative intermediate have been detected in peripheral blood mononuclear cells in patients with chronic HCV infection [3]. The association between HCV and type II mixed cryoglobulinemia is unequivocal [4-6]. Antibodies to HCV (anti-HCV) and HCV RNA have been found in up to 98% of patients with mixed cryoglobulinemia [4], and approximately 36% of patients with chronic HCV infection have mixed cryoglobulinemia [7]. Of interest, mixed cryoglobulinemia is considered by some investigators [8, 9] to be a variant of low-grade B-cell non-Hodgkin lymphoma. Because HCV RNA can be detected in the peripheral blood mononuclear cells of patients with chronic hepatitis C [10], the persistence of HCV in these cells may chronically stimulate B-lymphocytes. This may cause clonal expansion of these immunoglobulin-secreting cells and eventually results in malignant B-cell lymphoproliferative diseases. Consistent with this hypothesis, chronic infection of B lymphocytes by a DNA parvovirus was shown to induce polyclonal and, later, monoclonal immunoglobulin production in minks [11]. On the basis of these observations, it has been hypothesized that chronic HCV infection, alone or in combination with other factors, may lead to the development of B-cell lymphoma. Several Italian studies [12-15] have reported a high prevalence (9% to 32%) of chronic HCV infection in patients with B-cell non Hodgkin lymphoma. However, data from the United Kingdom have not confirmed these observations [16, 17]. To determine the prevalence of HCV infection among patients with B-cell non-Hodgkin lymphoma in the United States, we did a controlled study of a large cohort of patients. Methods Patients Between October 1994 and May 1996, 120 consecutive patients with B-cell non-Hodgkin lymphoma were evaluated at the outpatient hematology clinic of the Los Angeles County-University of Southern California (LAC-USC) Medical Center. During the same period, we enrolled 268 additional patients as controls: 154 unselected patients with malignant hematologic conditions other than B-cell non-Hodgkin lymphoma who were seen at the same clinic (control group 1, which comprised 44 patients with acute leukemia, 45 with Hodgkin disease, 11 with T-cell lymphoma, 23 with chronic myelogenous leukemia, 20 with multiple myeloma, 10 with chronic lymphocytic leukemia, and 1 with hairy-cell leukemia) and 114 unselected patients without malignant hematologic conditions who were attending the general medicine clinic at LAC-USC (control group 2, which comprised 69 patients with systemic hypertension or ischemic heart disease, 35 with diabetes mellitus, and 10 with primary hypothyroidism). All potential study participants were tested for antibodies to HIV. Markers for HCV infection (anti-HCV and HCV RNA) and hepatitis B virus infection (hepatitis B surface antigen, antibodies to hepatitis B core antigen, and antibodies to hepatitis B surface antigen) were also determined. Patients who tested positive for antibodies to HIV (2 patients) or hepatitis B surface antigen (6 patients) were excluded. We did not exclude patients with known HCV infection or liver disease. Identical inclusion and exclusion criteria were used to enroll patients and controls. All patients were given a questionnaire that asked about demographic characteristics and potential risk factors for viral hepatitis and chronic liver disease. A patients ethnicity was determined on the basis of self-report. A liver panel, which included prothrombin activity and levels of alkaline phosphatase, albumin, globulin, total and direct bilirubin, lactic dehydrogenase, alanine aminotransferase, and aspartate aminotransferase, was obtained for all patients at the time of evaluation. All patients gave written informed consent, and the study was approved by the institutional review board at LAC-USC Medical Center. Pathologic Evaluation of Lymphoma Lymphoma was diagnosed on the basis of morphologic evaluation of lymph node tissue or extranodal tissues, including bone marrow specimens. Immunophenotypic analysis for surface B- and T-lymphocytic markers was performed by using monoclonal antibodies, as described elsewhere [18, 19]. Non-Hodgkin lymphoma was graded by using the Modified Working Formulation classification [20, 21]. All slides were independently rereviewed by two expert hematopathologists who were not aware of the HCV infection status of the patients. Assessment of Hepatitis C Virus Infection We detected HCV antibodies by using a second-generation enzyme-linked immunosorbent assay (Anti-HCV EIA 2, Ortho Diagnostic Systems, Raritan, New Jersey). Blood samples for HCV RNA determination and HCV genotyping were processed and stored under the optimal conditions described by Davis and colleagues [22]. Serum HCV RNA was measured by a reverse-transcription polymerase chain reaction (RT-PCR) assay (Amplicor HCV test, Roche Molecular Systems, Somerville, New Jersey), as described elsewhere [23]. Briefly, total RNA was extracted from 100 L of serum with guanidinium thiocyanate and precipitated in isopropanol with poly(A) carrier RNA. An equivalent of 5 L of serum was reverse transcribed and amplified in a master mixture containing rTth DNA polymerase, biotinylated primers KY80 and KY78, buffer salts, unguentum, deoxyadenosine triphosphate, deoxycytidine triphosphate, 2-deoxyguanosine-5-triphosphate, and deoxyuridine triphosphate. Deoxyuridine triphosphate was incorporated into each amplification product to serve as a substrate for unguentum (AmpErase, Roche Molecular Systems); this prevented carryover contamination of previously amplified DNA. The reaction was optimized for the use of rTth that, in the presence of manganese, performs both reverse-transcription and DNA-polymerase functions. After RT-PCR was performed, biotin-labeled PCR products were chemically denatured; captured by a solid-phase, HCV-specific probe that was bound to microwell plates; and detected by using an avidin-horseradish peroxidase system with a conventional microtiter plate reader (450 nm). Optical density readings of more than 0.500 were considered positive for HCV, readings of less than 0.300 were considered negative, and readings of 0.300 to 0.500 were considered equivocal. We did HCV genotyping on all HCV RNA-positive specimens by using genotype-specific primers from the HCV core region under conditions described elsewhere [24]. Two rounds of amplification were done: We used genotype-nonspecific primers during the first round and genotype-specific primers during the second round. The amplification products were resolved on 2% agarose gels stained with ethidium bromide. Hepatitis C virus genotype was determined by genotype-specific bands of complementary DNA. Control samples of each detectable genotype (1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a) were evaluated in parallel. Radioimmunoassay (Ausria II, Abbott Laboratories, North Chicago, Illinois) was used to detect hepatitis B surface antigen and antibodies to hepatitis B surface antigen, and enzyme-linked immuno-assay (Corab, Abbott Laboratories) was used to detect antibodies to hepatitis B core antigen. Statistical Analysis The primary comparisons among groups for categorical variables were performed by using the Fisher exact test. We calculated the relative risk and 95% CIs that patients with HCV infection compared with patients without HCV infection would have extranodal lymphoma. We also computed 95% CIs for the prevalence of HCV infection in the B-cell lymphoma group and the two control groups. All CIs were calculated by using StatXact3 for Windows (Cytel Software Corp., Cambridge, Massachusetts). All other analyses were performed by using SAS 6.08 for Windows (SAS Institute, Inc., Cary, North Carolina). Results Patients in the B-cell lymphoma group and the two control groups were similar with respect to age, sex, ethnicity, and risk factors for viral hepatitis (Table 1). The prevalence of anti-HCV and HCV RNA in the three groups are shown in Table 2. Infection with HCV was detected in 26 of 120 patients with B-cell lymphoma (22% [95% CI, 15% to 30%]) compared with 7 of 154 patients (4.5%) in control group 1 and 6 of 114 patients (5%) in control group 2 (P < 0.001). Table 1. Demographic Characteristics of Patients with B-Cell Non-Hodgkin Lymphoma and Controls Table 2. Serologic and Virologic Markers in Hepatitis C Virus-Positive Patients* In the B-cell non-Hodgkin lymphoma group, both HCV RNA and anti-HCV were detected in 21 patients; HCV RNA was the only detectable marker in 4 patients, and HCV RNA was not detected in 1 anti-HCV-reactive patient. All control patients who were considered to be infected with HCV had detectable HCV RNA, although 3 of these patients were anti-HCV negative (Table 2). The most common HCV genotypes in patients with B-cell non-Hodgkin lymphoma were genotype 1a (12 of 26 patients [46%]), genotype 1b (8 of 26 patients [31%]), mixed genotype 1a and 1b (2 of 26 patients [8%]), and genotype 2b (2 of 26 patients [8%]) This incidence is similar to those reported elsewhere [25, 26] for patients with chronic HCV infection in the United States. Chronic liver disease had been diagnosed in 4 HCV-positive patients with B-cell lymphoma (15%) 2 to 6 years before lymphoma was diagnosed. Although 17 of 26 HCV-positive patients with lymphoma had increased aminotransferase activity, only 4 had levels of alanine aminotransferase or aspartate aminotransferase that exceeded 100 U/L. Similarly, most HCV-positive patients in the control groups had only mildly elevated aminotransferase levels. At least one percutaneous risk factor for HCV exposure was identified in 15 of 26 HCV-positive patients (58%) with B-cell non-Hodgkin lymphoma. The period during which patients were at risk for percutaneous exposure to HCV preceded th

Multicentric angiofollicular lymph node hyperplasia: a clinicopathologic study of 16 cases.

A clinicopathologic analysis of 16 cases of multicentric angiofollicular lymph node hyperplasia (MAFH) was performed. Histologically, the disease was characterized by recognizable lymph node architecture that was at least partially intact, by paracortical hyperplasia with prominent vascular proliferation, and by numerous evenly distributed, apparently benign germinal centers of various types, usually including some typical hyaline-vascular centers. At the onset of the disease, 12 patients had the plasma cell (PC) type of MAFH, three patients had the hyaline-vascular (HV) type, and one patient presented with PC and HV types at separate sites. Transitions between the PC and HV types were observed in two cases. Immunologic studies demonstrated polyclonal populations of plasma cells in the lymph nodes of all patients and the absence of suppressor T lymphocytes in the one patient tested. Clinically, the patients had constitutional symptoms, multicentric lymphadenopathy, hepatosplenomegaly in many cases, and abnormal laboratory findings, including anemia, polyclonal hypergammaglobulinemia, and bone marrow plasmacytosis. The 16 patients were placed in four different clinical groups based on presentation and course: stable disease, chronic relapsing disease, aggressive disease, and development of malignant lymphoma. Ten of the 16 patients died (median survival, 26 months; range, eight to 170 months). Multicentric angiofollicular lymph node hyperplasia appears to be a variant of classic angiofollicular lymph node hyperplasia (Castlemans disease) and is associated with significant morbidity and mortality.

Malignant lymphoma arising in angio-immunoblastic lymphadenopathy

This study is based upon 48 patients with angio‐immunoblastic lymphadenopathy and 36 patients whose lymph nodes revealed, in addition to angio‐immunoblastic lymphadenopathy (AILD), histologic features interpreted as malignant lymphoma of the immunoblastic type in the diagnostic biopsy. Progression into immunoblastic lymphoma (IL) was observed in 35%, or eight, of the 23 patients with AILD in whom follow‐up biopsies or autopsy were performed. Multiple clusters or islands of compactly arranged large lymphoid cells constituted the initial histologic evidence of IL. Subsequent tissue examination revealed progression of the disease in the form of diffuse replacement of lymph nodes by the neoplastic cellular proliferation. No significant differences in the past history, clinical or laboratory findings were observed between the patients with AILD and those whose lymph node biopsies were interpreted as AILD + IL. These two groups differed greatly, however, with respect to rate of complete remission following either prednisone or chemotherapy, or both (63% for AILD vs. 26% for AILD + IL; p = 0.01); median survival (35 months for AILD vs. six months for AILD + IL; p = 0.0004); incidence of malignant lymphoma at autopsy (20% for AILD vs. 82% for AILD + IL; p < 0.005); and the finding of extranodal malignant lymphoma at autopsy (10% in AILD vs. 64% in AILD + IL; p < 0.025). In the AILD group, median survival of patients who had complete remission after prednisone was significantly longer than that of patients who had partial or no remissions (p = 0.02) and the same was true for patients who were given chemotherapy (p < 0.003). In the AILD + IL group, a similar difference in the median survival was observed in patients treated with chemotherapy (p < 0.007), but not in those treated with prednisone (p = 0.31).

Concordance for Hodgkin's disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease

BACKGROUND Relatives of young adults with Hodgkins disease are at increased risk of Hodgkins disease, and lines of evidence implicate both inheritance and environment. METHODS We have identified and followed 432 sets of twins affected by Hodgkins disease. The number of cases of Hodgkins disease observed before the age of 50 years in the healthy monozygotic and dizygotic twins of the patients with Hodgkins disease was compared with the number expected from national age-specific incidence rates. RESULTS None of the 187 pairs of dizygotic twins became concordant for Hodgkins disease, whereas 10 of the 179 pairs of monozygotic twins did; in 5 of these pairs, the second case appeared after the original ascertainment. During the observation period, 0.1 (monozygotic) and 0.1 (dizygotic) cases in the unaffected twins were expected. Monozygotic twins of patients with Hodgkins disease thus had a greatly increased risk (standardized incidence ratio, 99; 95 percent confidence interval, 48 to 182), whereas no increase in the risk for dizygotic twins of patients with Hodgkins was observed. CONCLUSIONS Genetic susceptibility underlies Hodgkins disease in young adulthood.

Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.

Malignant lymphoma, intermediate lymphocytic type: A clinicopathologic study of 42 cases

A clinicopathologic analysis of 42 cases of non‐Hodgkins lymphoma of the intermediate lymphocytic type (ILL) having morphologic features between those of well‐differentiated (WDLL) and poorly differentiated lymphocytic lymphoma (PDLL) is presented. In lymph node sections, ILL was characterized by a diffuse proliferation consisting predominantly of small lymphoid cells with slightly irregular or indented nuclei. A mixture of lymphoid cells with entirely round nuclei and lymphoid cells with angulated and cleaved nuclei was also present, but each of these two cell populations did not comprise more than 30% of the total. The median age of the patients was 65 years, and the male‐to‐female ratio was 5:1. Generalized lymphadenopathy was evident in 74% of the patients, and B symptoms were presented in 36%. Peripheral blood involvement was present at the onset of disease in 21% of the patients, and the bone marrow was involved by lymphoma in 76% of those examined. Five percent of the patients had Stage I disease, 24% had Stage III disease, and 71% had Stage IV disease. Ninety‐three percent of the patients received multiagent chemotherapy and 41% achieved a complete remission. The overall median survival was 31 months. Clinical features which appeared to influence survival adversely included the presence of B symptoms (P = 0.007), age greater than 70 years (P = 0.09), an absolute lymphocyte count above 5000/mm3 (P = 0.05), and anemia (P = 0.09). Achievement of a complete remission influenced survival favorably (P = 0.02). Pathologic features which appeared to influence survival included sinus obliteration, which had an adverse effect (P = 0.05), and the presence of residual germinal centers which had a favorable effect (P = 0.06). Patients with 0–5 mitoses/10 high power fields (HPF) had a significantly longer survival than those with more than 20 mitoses/10 HPF (P = 0.02), while those with 6–20 mitoses/10 HPF had an intermediate survival. The clinical and pathological features of patients with ILL suggest that this entity is closely related to PDLL and should be distinguished from WDLL.

Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy.

PURPOSE We reviewed survival data of patients with low-grade lymphoma entered on Southwest Oncology Group (SWOG) lymphoma trials in 1972 to 1983 to determine the utility of doxorubicin-containing therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) in such patients. PATIENTS AND METHODS We identified all patients with low-grade lymphoma, no prior therapy, and stage III or IV disease who were treated with full-dose CHOP induction therapy on any arm of SWOG studies 7204, 7426, or 7713. Survival data for this group of patients were correlated with pretreatment prognostic factors, including histology, patient age, sex, symptom status, performance status, bone marrow or extranodal involvement, and the number of disease sites. The effect of maintenance treatment was also assessed. RESULTS Four hundred fifteen patients met criteria for inclusion in the study group. With median follow-up periods of 12.8 years (maximum, 19.8 years), the median survival duration was 6.9 years. Survival was significantly shorter in patients with follicular mixed or small lymphocytic histology, age greater than 40 years, male sex, B-symptom status, and SWOG performance status greater than 1. Multivariate regression analysis showed histology, age, and sex to be independent predictors of survival. There was no definite survival plateau of cured patients in any subgroup, although the survival curve for follicular mixed histology patients showed long-term survival of approximately 25%. Maintenance therapy did not prolong survival. CONCLUSION Doxorubicin-containing treatment did not prolong the overall median survival of low-grade lymphoma patients compared with results with less-aggressive programs.

AIDS-Related Burkitt's Lymphoma Versus Diffuse Large-Cell Lymphoma in the Pre–Highly Active Antiretroviral Therapy (HAART) and HAART Eras: Significant Differences in Survival With Standard Chemotherapy

PURPOSE To compare outcomes of patients with HIV-Burkitts lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre-highly active antiretroviral therapy (HAART) versus HAART eras. PATIENTS AND METHODS Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART. RESULTS There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm(3) independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era. CONCLUSION Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.

Non‐hodgkin's lymphomas. A clinicopathologic study comparing two classifications

The Lukes and Collins classification is based on the premise that malignant lymphomas (ML) should be classified on the basis of immunologic markers and that the B, T or „undefined”︁ nature of these tumors can be morphologically recognized. The difficulties of achieving this are discussed in this study. The „undefined”︁ type of these investigators posed a particular problem since it appears to be a heterogeneous group which includes ML currently classified as „histiocytic,”︁ lymphoblastic and undifferentiated. The prognosis appeared to be closely related to cytologic types in both the Rappaport and the Lukes and Collins classifications. In the follicular center cell (FCC) lymphomas the overall median survival of patients with follicular lymphomas was longer than that of patients with diffuse lymphoma (p < 0.0001). Extending this comparison to cell types we found longer median survivals of follicular lymphomas in each subgroup but with variable statistical significance. For all cleaved cell lymphoma the p value was 0.02, for the small cleaved cell type 0.16, for the large cleaved cell type 0.09 and for the large noncleaved cell type 0.1. The lymphomas which we identified as being of the diffuse large cleaved FCC type seemed to have a relatively favorable prognosis in comparison to other diffuse large cell lymphomas (p ρ 0.08). However, within this latter group a morphologic separation into large noncleaved FCC, immunoblastic, and true histiocytic seemed difficult. For the purpose of this study, however, we attempted to apply the designation of immunoblastic sarcoma to tumors composed of large lymphoid cells with plasmacytoid features, but found no differences in survival when comparing it with diffuse large noncleaved FCC tumors.