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Bone marrow involvement is reported in approximately 25% of patients with newly diagnosed acquired immunodeficiency syndrome-related lymphoma (ARL). Studied were 291 patients with ARL, diagnosed and treated at one medical center between 1984 and 1998. Clinical, immunologic, and pathologic characteristics of patients with bone marrow involvement were compared with those of patients without marrow involvement. Bone marrow involvement was present in 55 patients (19%). Small noncleaved lymphoma was diagnosed in 38% of the entire group and was the most common pathologic subtype in patients with bone marrow involvement (55% versus 34%; P =.008). Analysis of complete blood counts revealed a median hemoglobin level of 10.6 g/dL in both marrow-positive and marrow-negative groups. In contrast, a platelet count lower than 100 000/microL was more common in patients with bone marrow involvement (27% versus 11%; P =.02). Patients with marrow involvement were more likely to have leptomeningeal (cerebrospinal fluid [CSF]) lymphoma than patients whose marrows were uninvolved (24% versus 7%; P <.001) and were also more likely to have high lactate dehydrogenase (LDH) (P =.002), bone involvement (P <.001), and/or systemic B symptoms including fever, night sweats, and/or weight loss (P =.05). Median survival did not differ between marrow-positive and marrow-negative groups. On multivariate analysis, factors associated with decreased survival of marrow-positive patients included greater than 50% involvement (P =.002), systemic B symptoms (P =.008), and high-grade histologic type (P =.035). Marrow involvement in ARL correlates with small noncleaved pathology, thrombocytopenia lower than 100 000 mm(3), high LDH, and lymphomatous involvement of the CSF. Survival is statistically shorter in patients with greater than 50% marrow involvement, high-grade pathology, and/or systemic B symptoms.

We describe 35 peripheral lymph nodes classified as mantle cell/marginal zone B-cell hyperplasia with clear cells using morphologic and immunologic findings. For the purpose of this study, we obtained clinical follow-up information and performed immunoglobulin gene rearrangement studies on paraffin sections by polymerase chain reaction. Architecturally, the nodes were suggestive of a benign process: no pericapsular infiltration, sinuses readily identified, scattered reactive follicles present, and paracortical nodular hyperplasia present. No monocytoid B cells were present. Focally, small lymphoid cells with round nuclei and clear cytoplasm (clear cells) formed monomorphic nodular, inverse follicular, and/or marginal zone patterns. Flow cytometry and immunohistochemical analysis revealed neither light chain restriction nor an aberrant B-cell phenotype. Immunoglobulin gene rearrangement studies showed a clonal band in 1 of 26 cases in which DNA was amplified. To ascertain the clinical relevance of this positive case, follow-up information was obtained 30 months after the initial biopsy; the 83-year-old woman was alive without treatment but had splenomegaly and bone marrow involvement by marginal zone B-cell lymphoma. The morphologic and immunologic criteria used for diagnosis of mantle cell/marginal zone B-cell hyperplasia with clear cytoplasm are valid; however, to rule out the possibility of occult lymphoma, immunoglobulin gene rearrangement studies and clinical follow-up are necessary.

Anaplastic large-cell lymphoma (ALCL) is a heterogeneous process that may have a T-cell, B-cell, or indeterminant (null) phenotype and which may or may not express the anaplastic lymphoma kinase (ALK) oncoprotein. Because the clinical significance of these variants of ALCL is unclear, we evaluated the cases of ALCL-T/null and ALCL-B identified in the Non-Hodgkin's Lymphoma Classification Project. We evaluated 1,378 cases of non-Hodgkin's lymphoma (NHL), and a consensus diagnosis of ALCL-T/null was made in 33 patients (2.4%) with a diagnostic accuracy of 85%. Compared to 96 patients with other forms of peripheral T-cell lymphoma (PTCL), those with ALCL-T/null were significantly younger, less likely to have advanced-stage disease or bone marrow involvement, more likely to have a low International Prognostic Index score, and had a significantly better survival. Among those with ALCL-T/null, there were no significant differences in the clinical features or survival on the basis of ALK expression. A consensus diagnosis of ALCL-B was made in 15 patients (1.1%), and the diagnostic accuracy was 67%. However, compared to 366 patients with other forms of diffuse large B-cell lymphoma (DLBCL), those with ALCL-B were no different with regard to clinical features or survival. We conclude that patients with ALCL-T/null have favorable prognostic features and excellent survival and should be separated from those with other forms of PTCL for prognostic and therapeutic purposes. In contrast, patients with ALCL-B appear to be similar to those with other forms of DLBCL., (Copyright 2001 Wiley-Liss, Inc.)

Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P =.25), in Latino/Hispanic individuals (P <.0001), and in those who acquired human immunodeficiency virus (HIV) heterosexually (P =.01). These changes were similar in both countywide, population-based analyses and in those from the single institution. The median CD4(+) lymphocyte count at lymphoma diagnosis has decreased significantly over the years, from 177/dL in the earliest time period (1982-1986), to 53/dL in the last time period from 1995 to 1998 (P =.0006). The pathologic spectrum of disease has also changed, with a decrease in the prevalence of small noncleaved lymphoma (P =.0005) and an increase in diffuse large cell lymphoma (P <.0001). Despite changes in the use of antiretroviral or chemotherapy regimens, the median survival has not significantly changed.

We investigated the clonal relationship between follicular center cell and monocytoid B-cell components of non-Hodgkin lymphoma by isolating the components and comparing the nucleotide sequences of the complementarity-determining region (CDR)3 of the rearranged immunoglobulin heavy chain (IgH) gene. Paraffin blocks from 4 cases with amplifiable DNA using the polymerase chain reaction (PCR) were identified. Multiple representative cell clusters of the 2 components were obtained by microdissection, and the IgH CDR3 was amplified using a seminested PCR. Most of the PCR products obtained from both tumor components in each case had identical lengths when analyzed with polyacrylamide gel electrophoresis (PAGE) and identical migratory patterns on denaturing gradient gel electrophoresis (DGGE). These findings indicate sequence identity of the IgH CDR3 of both tumor components. Sequence analysis showed that point mutations were responsible for bands from the same case that had nonidentical migratory patterns by DGGE. The components in each of the 4 cases studied have the same clonal origin. Intraclonal sequence variations in the IgH gene were observed in 2 cases, consistent with the presence of continued somatic hypermutation after establishment of the clone. The expression of CD10 and bcl-2, as well as the detection of bcl-2 rearrangements in 2 cases, indicate that these lymphomas are of follicular center cell origin.

To ascertain the results of standard ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) in HIV-infected patients with newly diagnosed Hodgkin's disease (HD), a nonrandomized, prospective, multiinstitutional clinical trial was conducted by the AIDS Clinical Trials Group (ACTG), in HIV-infected patients with Hodgkin's disease. All patients received the standard ABVD regimen, with granulocyte-colony-stimulating factor (G-CSF). Antiretroviral therapy was not used. Between May, 1992 and August, 1996, 21 patients were added to the study and treated. The median CD4 count was 113 cells/mm3, and 29% had a history of a clinical AIDS-defining condition before diagnosis of HD. Systemic "B" symptoms were present in 90% at diagnosis. Stage IV HD was present in 67%, with bone marrow involvement in 12 (57%). Nodular sclerosis HD was present in 38%, with mixed cellular disease in 31%. Among all patients entered and treated, complete remission (CR) was attained in 9 (43%; 90% confidence interval [CI], 24%-63%), whereas partial response occurred in 4 (19%), leading to an overall objective response rate of 62% (90% CI, 42%-79%). Despite routine use of G-CSF, 10 patients (47.6%) experienced life-threatening neutropenia, with absolute neutrophil counts <500 cells/mm3. In all, nine opportunistic infections occurred in 6 patients (29%) during the study or shortly thereafter. Median survival was 1.5 years. Results of this study suggest that alternative treatment strategies should be explored, including use of chemotherapy together with antiretroviral therapy.

T-lymphoblastic lymphoma is a high-grade malignant lymphoma. Clinically indolent T-lymphoblastic proliferations have not been described. We present a case report of an indolent T-cell lymphoblastic proliferation studied by histopathology, immunohistochemistry, flow cytometry, antigen receptor gene rearrangement studies, and cytogenetics. The patient had recurrent masses in the upper aerodigestive tract over a 16-year period, was treated by multiple surgical excisions, and never received either chemotherapy or radiotherapy. A proliferation of lymphoblasts was present histologically. The cells were positive for terminal deoxynucleotidyl transferase, CD1, and CD3, and coexpressed CD4 and CD8. No clonal rearrangements of the T-cell receptor beta or gamma chain genes were identified. Cytogenetic studies revealed a questionable inversion of the short arm of chromosome 9, affecting the 9p21-22 region. Although ectopic thymic tissue was considered, the case was considered to be an indolent lymphoblastic proliferation. It should be recognized that rare lymphoblastic proliferations may not behave in a high grade fashion as typically seen in T-lymphoblastic lymphoma.

Purpose: In the International Lymphoma Study Group classification of lymphoma, extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) type is listed as a distinctive entity. However, nodal MZL is listed as a provisional entity because of questions as to whether it is truly a disease or just an advanced stage of MALT-type MZL. To resolve the issue of whether primary nodal MZL without involvement of mucosal sites exists and whether it is clinically different from extranodal MALT-type lymphoma, we compared the clinical features of these two lymphomas., Patients and Methods: Five expert hematopathologists reached a consensus diagnosis of MZL in 93 patients. Seventy-three were classified as having MALT-type MZL because of involvement of a mucosal site at the time of diagnosis, and 20 were classified as having nodal MZL because of involvement of lymph nodes without involvement of a mucosal site., Results: A comparison of the clinical features of nodal MZL and MALT-type MZL showed that more patients with nodal MZL presented with advanced-stage disease (71% v 34%; P =. 02), peripheral lymphadenopathy (100% v 8%; P <.001), and para-aortic lymphadenopathy (56% v 14%; P <.001) than those with MALT-type MZL. However, fewer patients with nodal MZL had a large mass (> or = 5 cm) than those with MALT-type MZL (31% v 68%; P =.03). The 5-year overall survival of patients with nodal MZL was lower than that for patients with MALT-type MZL (56% v 81%; P =.09), with a similar result for failure-free survival (28% v 65%; P =.01). Comparisons of patients with International Prognostic Index scores of 0 to 3 showed that those with nodal MZL had lower 5-year overall survival (52% v 88%; P =.025) and failure-free survival (30% v 75%; P =.007) rates than those with MALT-type MZL., Conclusion: Nodal MZL seems to be a distinctive disease entity rather than an advanced stage of MALT-type MZL because the clinical presentations and survival outcomes are different in these two types of MZL. Clinically, nodal MZL is similar to other low-grade, node-based B-cell lymphomas, such as follicular and small lymphocytic lymphomas.

Benign monocytoid B cells are seen in lymph nodes in different types of lymphadenitis and they occur in the form of clusters within and around sinuses and in the interfollicular areas, but rarely completely surround benign follicles to produce a marginal-zone pattern. The cytologic hallmark of these cells is the presence of abundant pale to clear cytoplasm; these cells usually are of medium size, and they have a rather bland-appearing, irregular nuclei with inconspicuous nucleoli. Malignant monocytoid B-cell proliferations in a lymph node have been classified as monocytoid B-cell lymphomas (MBCL), which are now called nodal marginal-zone B-cell lymphoma (MZL) in the World Health Organization (WHO) classification. In the recently published clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma, 25 of 1,378 cases (1.8%) were classified as primary MZL, whereas four times as many cases (105 or 7.6%) were classified as low-grade mucosa-associated lymphoid tissue (MALT)-type lymphoma. Transformation to large-cell lymphoma at the time of diagnosis was seen in five of 25 (20%) cases of nodal MZL and in 32 of 105 (30%) cases of MALT-type lymphoma. Comparison of the clinical findings at presentation and the survival results indicate that nodal MZL is more aggressive clinically than low-grade MALT-type lymphoma. For example, patients with nodal MZL had a significantly higher incidence of advanced-stage disease, including peripheral and paraaortic lymphadenopathy, than those with MALT-type lymphoma. Moreover, patients with nodal MZL had lower 5-year overall survival and failure-free survival than patients with MALT type lymphoma. When analysis was restricted to those patients with zero to three adverse risk factors in the International Prognostic Index, patients with nodal MZL still had a significantly lower overall and failure-free survival at 5 years than patients with MALT-type lymphoma. We conclude that nodal MZL is a distinctive disease entity and is similar to other low-grade nodal lymphomas, such as the follicular or small lymphocytic lymphomas, but different than MALT-type lymphoma.

Although follicular lymphoma (FL) is very common in the Western world, very little information is available regarding the frequency and significance of monocytoid B cells (MBC) in FL. We recently completed a clinicopathologic study of 1,378 cases of non-Hodgkin's lymphoma. In this study, a research data sheet was designed to conduct research on several types of lymphomas, one part of which was evaluating the presence of intrafollicular clear cells and extrafollicular MBC in 326 cases diagnosed as FL by one of the pathologists (B.N.N.). For each case diagnosed as FL, the presence of intrafollicular clear cells or extrafollicular MBC was scored as pure FL (no intrafollicular clear cells or extrafollicular MBC), FL with intrafollicular clear cells, FL with less than 5% MBC, and FL with greater than 5% MBC. Of 326 cases classified as FL, 252 (77%) had no intrafollicular clear cells or extrafollicular MBC and therefore were called pure FL. In 36 cases (11%), intrafollicular clear cells were seen, but no extrafollicular MBC. There were no clinical differences between such cases and the 252 cases of pure FL. In eight cases of FL (2%), MBC clusters were rare (<5%). In contrast, 30 cases of FL (9%) had a prominent (>5%) proliferation of extrafollicular MBC; these 30 cases had a significantly shorter failure-free survival (P = .001) and overall survival (P = .04) than the 252 cases of pure FL. The shorter survival of these 30 cases appeared to be independent of the international prognostic index (IPI), stage, and treatment. The FFS of this group remained shorter than that of cases with pure FL when the analysis was restricted to patients treated with Adriamycin-containing regimens and either a favorable (0 to 3) IPI score (P = .001) or advanced stage (III/IV) disease (P = .015). In conclusion, FL with a prominent (>5%) MBC component constitutes a substantial proportion (9%) of FL and has distinctive morphology, and these patients have a significantly shorter survival than those with pure FL.

Different histopathologic classifications have been used in the study of malignant lymphomas. The clinical relevance (reproducibility, prognostic value) has not been precisely studied. The "non-Hodgkin's lymphoma classification project" has been organized to study a cohort of 1,403 cases in 9 sites around the world consisting of consecutive patients seen between 1988 and 1990 in order to have a good follow-up. The reproducibility of the up-dated Kiel and the ILSG (REAL) classifications between the 5 visiting expert hematopathologists was pretty good, at least 85% for the majority of the entities. According to survival curves, the lymphomas can be stratified in 4 different groups. Comparison with the international prognostic index demonstrate that for therapeutic strategy both histopathology and index should be used. The results bring a good support to the project of the WHO to propose the first international classification of lymphomas based on both forme classifications.

Background: Several studies from Europe have reported a high prevalence (9% to 32%) of chronic hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin lymphoma. It has been suggested that HCV plays a role in the pathogenesis of B-cell non-Hodgkin lymphoma., Objective: To determine the prevalence of HCV infection in patients with B-cell lymphoma in the United States., Design: Controlled, cross-sectional analysis., Setting: University medical center., Patients: 120 patients with B-cell lymphoma (78% were Hispanic, 9% were black, 7% were Asian, and 6% were white), 154 patients with other malignant hematologic conditions (control group 1), and 114 patients with nonmalignant conditions (control group 2)., Measurements: Samples were tested for antibodies to HCV by enzyme-linked immunosorbent assay. Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. Genotyping for HCV was done with genotype-specific primers from the HCV core region., Results: Infection with HCV was detected in 26 patients (22% [95% CI, 15% to 30%]) with B-cell lymphoma 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). Risk factors for HCV infection were present in 15 patients (60%) with B-cell lymphoma and occurred a median of 15 years before diagnosis of lymphoma. Monocytoid B-cell lymphoma was the most common type of lymphoma found in HCV-positive patients (23% compared with 7% in HCV-negative patients) (P = 0.034)., Conclusions: The prevalence of HCV infection was higher in patients with B-cell non-Hodgkin lymphoma than in controls. The possible role of HCV in the pathogenesis of B-cell lymphoma warrants further investigation.

Background: Pathfinder is an Expert System that assists pathologists in making accurate diagnoses in the domain of lymph-node pathology. Pathfinder provides a differential diagnosis based on the initial histological feature(s) observed by the pathologist, and suggests to the user additional histological features for observation that are likely to narrow the differential diagnosis., Purpose: To evaluate the diagnostic accuracy of pathologists with and without the Pathfinder., Methods: Thirty H&E stained slides from 30 lymph node biopsy specimens on which a Consensus diagnosis was made by two experts were reviewed by 19 pathologists to evaluate Pathfinder. After a period of training, 10 pathologists using Pathfinder (Interactive Computer Method) and 9 pathologists using the Routine Method (diagnosis without computer) determined a differential diagnosis for 15 slides (Test 1). Pathologists were then crossed over, trained, and evaluated the remaining 15 slides (Test 2). For each test, the proportion of "correct" diagnoses was compared between methods. In addition, the information integration attributes (making logical diagnosis given a set of specific histologic features) of Pathfinder and pathologists were compared. Finally, feature identification and quantification skills of pathologists were determined and correlated with the percent correct diagnosis., Results: The diagnostic accuracy using Pathfinder was greater than that using the Routine Method (40% v 32%, P = .02). Diagnostic accuracy for the group of pathologists who made diagnosis using the Routine Method in Test 1 increased when they made diagnosis using Pathfinder in Test 2 (27% to 44%, P < .0001). The proportion of correct diagnosis for the group of pathologists who used Pathfinder in Test 1 remained virtually unchanged when they gave up Pathfinder in Test 2 (35% to 37%). The percentage of incompatible feature identification ("atypical proliferation" diagnosis) was significantly lower after using Pathfinder (P < .0001). In addition, information integration attributes of Pathfinder were significantly superior than that of the pathologists (P < .0001)., Conclusions: Pathfinder is a valuable tool that assists pathologists in making accurate diagnosis because it has superior attributes than pathologists to integrate information and to screen for observations incompatible with any specific disease.

Although the Revised European-American Lymphoma Classification does not utilize the term monocytoid B-cell Lymphoma, there are numerous reasons to support its use in classifying lymphomas of so-called marginal zone B-cell type that contain a distinct population of malignant monocytoid B-cells. In addition, there are other B-cell lymphomas which have very distinctive morphological features, because they show multiple and very well demarcated histologies characterized by presence of cells that appear to be (1) malignant monocytoid B-cells and malignant follicular center cells, or (2) malignant monocytoid B-cells, malignant follicular center cells and malignant plasma cells, or (3) malignant monocytoid B-cells and malignant mantle cells. The neoplastic cells in each of the above three examples show identical light chain restriction and thus they are part of the same neoplastic clone. We believe that there are different types of precursor B-cells (memory or otherwise) for the above cells, and an arrest in differentiation of these precursor B-cells may readily explain the presence of these different morphological combinations. Recognition of these morphological types may lead to further awareness of the possibilities of the existence of multiple, linked pathways of differentiation for lymphoid cells including the possibility of different types of precursor B-cells. Furthermore, an understanding of the uniqueness of monocytoid B-cells would allow pathologists to use terminology that is less redundant and more precise.

Monocytoid B-cell lymphoma, low-grade B-cell lymphoma of mucosa-associated lymphoid tissue, and primary splenic marginal zone cell lymphoma (SMZCL) were originally described as distinct clinicopathologic entities. On the basis of morphologic and immunologic similarities, monocytoid B-cell lymphoma and lymphoma of mucosa-associated lymphoid tissue recently have been grouped together as nodal and extranodal types of marginal zone B-cell lymphomas (MZBCLs) in the Revised European-American Classification of Lymphoid Neoplasms. Primary SMZCL, although related, is considered a separate provisional entity. Trisomies 3, 7, and 12 are common in non-Hodgkin's lymphomas. Several recent studies reported that MZBCLs arising in sites of mucosa-associated lymphoid tissue have a high frequency of trisomy 3. To assess whether similar numerical cytogenetic abnormalities are present in MZBCLs with prominent monocytoid B-cell cytologic features, we performed a retrospective study, using formalin-fixed, paraffin-embedded tissue blocks from 36 cases. By use of fluorescence in situ hybridization to detect chromosome trisomies, we identified trisomy 3 in 11 (85%) of 13 extranodal MZBCLs with monocytoid B cells (MZBCL-Es), in 6 (50%) of 12 nodal MZBCLs of monocytoid B-cell type (MZBCL-Ns), but in only 2 (18%) of 11 SMZCLs. Trisomies 7 and 12 were found at lower frequencies. These data suggest that trisomy 3 is a common numerical chromosomal abnormality of MZBCL-Es and MZBCL-Ns with monocytoid B-cell features. Despite similar morphologic and immunophenotypic characteristics, the low incidence of trisomy 3 in the SMZCL cases implies that this process may be genetically distinct.

As part of an effort to develop a better understanding of the relationship between nodal monocytoid B-cell lymphomas (MBCLs) and follicular lymphomas (FLs) when they coexist (MBCL + FL) and to assess the validity of the morphological criteria for the latter diagnosis, we evaluated follicular colonization, bcl-2 reactivity, light chain restriction, and the presence of t(14;18) in 14 benign lymph node specimens containing benign monoclonal B cells (MBCs), in eight nodal specimens of pure MBCL, and in 17 nodal specimens of MBCL coexisting with FL (MBCL + FL). Follicular colonization by malignant MBCs was observed in six specimens of pure MBCL and in 13 specimens of MBCL + FL. Benign MBCs did not express bcl-2 by immunohistological methods in 11 of 12 benign specimens. In contrast, weak reactivity for bcl-2 was detected in malignant MBCs in four of five specimens of pure MBCL and in the MBCL component in 13 of 15 specimens from the MBCL + FL group. In the FL component of 13 specimens, the bcl-2 was strongly positive. Identical light chain restriction was detected by immunohistological methods in both the FL component and the MBCL component in 15 specimens of MBCL + FL. Polymerase chain reaction analysis did not detect the t(14;18) translocation in any of 10 benign specimens or any of six evaluable pure MBCL specimens. In contrast, the translocation was detected in whole sections from eight of 12 specimens of MBCL + FL. Thus, on the one hand, the high incidences of follicular colonization and the coexistence of MBCL and FL as well as the identical light chain restriction in MBCL and FL components of MBCL + FL cases suggest that possibly these are related closely when they coexist. On the other hand, the bcl-2 and t(14;18) data cannot be used as evidence in support of a close relationship.

Background: Relatives of young adults with Hodgkin's disease are at increased risk of Hodgkin's disease, and lines of evidence implicate both inheritance and environment., Methods: We have identified and followed 432 sets of twins affected by Hodgkin's disease. The number of cases of Hodgkin's disease observed before the age of 50 years in the healthy monozygotic and dizygotic twins of the patients with Hodgkin's 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 Hodgkin's 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 Hodgkin's 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 Hodgkin's was observed., Conclusions: Genetic susceptibility underlies Hodgkin's disease in young adulthood.

Seven cases of large cell lymphoma (LCL) developing simultaneously or secondarily to lymphocyte-predominant Hodgkin's disease (nodular paragranuloma [NP]) were investigated for the presence of Epstein-Barr virus genomic material and the chromosomal translocation t(14;18) involving the major breakpoint region of the bcl-2 gene using the polymerase chain reaction on paraffin-embedded material. The translocation t(14;18) and Epstein-Barr virus could not be demonstrated in any case. The expression of the bcl-2 oncogene product was investigated using immunohistochemistry. Only in one case were the lymphocytic and histiocytic cells positively stained with the bcl-2 antibody, whereas the associated LCL demonstrated a completely negative immunoreaction. In another case the LCL had a positive immunoreaction with this antibody and the corresponding lymphocytic and histiocytic cells were completely negative. We conclude that Epstein-Barr virus infection is rare or absent in NP and in the LCLs associated with NP. The chromosomal translocation t(14;18) does not seem to be a factor in the transformation of NP into LCL.

Monocytoid B-cell lymphoma (MBCL) is a newly recognized, morphologically and immunologically distinct, low-grade B-cell neoplasm that may exist as a pure morphologic entity or as a component of a composite lymphoma. To determine whether cytogenetic abnormalities exist in cases of MBCL, fresh tissue from four lymphoma specimens in which MBCL was a substantial component were analyzed by classic cytogenetics; no pure MBCL cases were available for study. One monoclonal neoplastic population was found in each case by immunophenotyping studies and classic cytogenetics. Clonal cytogenetic abnormalities included -X or +X, t(14;18)(q32;q21), del(6q), t(11;14)(q13;q32), dup(12q), dup(1q), t(2;3)(q13;q29), and der(8)t(8;9)(p11.2;q13). The abnormal clone usually reflected the underlying lymphomatous process, namely, follicular lymphoma [t(14;18)], mantle cell lymphoma [t(11;14)], or small lymphocytic lymphoma (partial trisomy 12). There were no cytogenetic abnormalities common to all neoplasms. Taken together, the cytogenetic and immunologic data suggest that although MBCL may exist as a pure entity, it also may commonly represent a morphologic variant or a component of other primary lymphomatous processes.

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.

To determine which morphologic criteria are most useful in distinguishing reactive from malignant monocytoid B cells (MBCs), we compared 16 monoclonal cases (11 nodal, five extranodal) of monocytoid B-cell lymphoma (MBCL) with 12 cases of various reactive diseases in which MBCs were polyclonal. The results of our study showed that in MBCL the MBC component was the predominant architectural finding and that there was confluence of MBCs in all but one case. In contrast, the MBC component did not predominate in the reactive group (P less than .000001) and focal confluence was seen in only one case. A cytologic comparison showed that in MBCL areas there were more large transformed (prominent nucleolated) MBCs (P = .003), a higher mitotic rate (P = .03), and more nuclear irregularities (P = .007) than were present in the reactive group. In addition, evolution to an aggressive histologic type was found in four cases of MBCL. Our results also revealed concomitant multiple, monoclonal, morphologically distinct populations in other compartments (follicular center cells in seven, mantle cells in five, small lymphocytes in five, and plasma cells in 11). These unique findings can be reconciled by postulating (1) that the simultaneous presence of these diverse cytologic types represents morphologic expressions of a B cell whose population is in different phases of its cell cycle and/or its evolution or (2) that the histogenesis of MBCL is possibly from a nodal pluripotent B-stem cell that can differentiate directly into these various cytologic types.

We address practical issues concerning the construction and use of decision-theoretic or normative expert systems for diagnosis. In particular, we examine Pathfinder, a normative expert system that assists surgical pathologists with the diagnosis of lymph-node diseases, and discuss the representation of dependencies among pieces of evidence within this system. We describe the belief network, a graphical representation of probabilistic dependencies. We see how Pathfinder uses a belief network to construct differential diagnosis efficiently, even when there are dependencies among pieces of evidence. In addition, we introduce an extension of the belief-network representation called a similarity network, a tool for constructing large and complex belief networks. The representation allows a user to construct independent belief networks for subsets of a given domain. A valid belief network for the entire domain can then be constructed from the individual belief networks. We also introduce the partition, a graphical representation that facilitates the assessment of probabilities associated with a belief network. We show that the similarity-network and partition representations made practical the construction of Pathfinder.

The new monoclonal antibody Ki-M1P, which detects a formalin-resistant epitope on conventional paraffin sections, was applied in 20 cases of different stages of Kikuchi-Fujimoto disease. This new pan-macrophage immunoreagent detects plasmacytoid T cells, referred to as plasmacytoid cells, and renders a reliable delineation of these cells against other similar cell types, such as blasts of high-grade B- and T-cell lymphoma. Histiocytes as well as macrophages were strongly positive, and plasmacytoid cells showed a somewhat weaker and primarily granular, intracytoplasmic immunoreactivity. Plasmacytoid cells, being a diagnostic feature of the Kikuchi-Fujimoto disease, facilitate a clear distinction of this disease entity from large cell or high-grade lymphomas. These results may represent an additional argument favoring the histiocytic origin of plasmacytoid cells. Additionally, they may point to an immunohistochemical tool that facilitates the differential diagnosis between Kikuchi-Fujimoto disease, especially in early stages of the disease, and malignant lymphoma.

Pathfinder is an expert system that assists surgical pathologists with the diagnosis of lymph-node diseases. The program is one of a growing number of normative expert systems that use probability and decision theory to acquire, represent, manipulate, and explain uncertain medical knowledge. In this article, we describe Pathfinder and our research in uncertain-reasoning paradigms that was stimulated by the development of the program. We discuss limitations with early decision-theoretic methods for reasoning under uncertainty and our initial attempts to use non-decision-theoretic methods. Then, we describe experimental and theoretical results that directed us to return to reasoning methods based in probability and decision theory.

We present an evaluation of the diagnostic accuracy of Pathfinder, an expert system that assists pathologists with the diagnosis of lymph node diseases. We evaluate two versions of the system using both informal and decision-theoretic metrics of performance. In one version of Pathfinder, we assume incorrectly that all observations are conditionally independent. In the other version, we use a belief network to represent accurately the probabilistic dependencies among the observations. In both versions, we make the assumption--reasonable for this domain--that diseases are mutually exclusive and exhaustive. The results of the study show that (1) it is cost effective to represent probabilistic dependencies among observations in the lymph node domain, and (2) the diagnostic accuracy of the more complex version of Pathfinder is at least as good as that of the Pathfinder expert. In addition, the study illustrates how informal and decision-theoretic metrics for performance complement one another.

Epstein-Barr viral (EBV) infections are associated with Hodgkin's disease (HD). To better characterize this relationship, fixed tissues of infectious mononucleosis, normal and reactive lymph nodes, lymph nodes with progressively transformed germinal centers, and biopsy specimens with the different subtypes of HD were analyzed by polymerase chain reaction (PCR). The presence or absence of EBV, the relative amounts of EBV, and the presence of multiple EBV genotypes as defined by amplification of a polymorphic EBV locus were determined for each specimen. Epstein-Barr virus could be detected from all specimens with infectious mononucleosis (eight of eight cases), generally in relatively large amounts, with multiple EBV genotypes evident in two cases. Epstein-Barr virus could not be detected from normal or reactive lymph nodes (none of 39 cases). Small amounts of EBV could be detected from a minority of cases with progressively transformed germinal centers (two of 16 cases), with multiple EBV genotypes evident in one case. Variable amounts of EBV could be detected from approximately half of the specimens with HD (26 of 50 cases). Epstein-Barr virus was most often detected in the subtypes of mixed cellularity (12 of 15 cases), nodular sclerosis (seven of 14 cases), and lymphocyte depletion (five of seven cases) compared with nodular lymphocyte predominance HD (two of 14 cases). In contrast to specimens with infectious mononucleosis and progressively transformed germinal centers, only one EBV genotype was evident in the specimens with HD. These findings are consistent with the hypothesis that some cases of HD may be directly associated with EBV.

The authors report three cases of Hodgkin's disease (HD) occurring in monocytoid B-cell (MBC) clusters within lymph nodes, a finding heretofore not published. MBC clusters were found mainly in a perisinusoidal and perifollicular distribution in all three cases. Within some of the MBC clusters of each case, small foci of overt necrosis were evident. Sternberg-Reed cells or their variants were found adjacent to all of these foci, as well as within some MBC clusters that were free of necrosis. These findings suggest that the presence of necrosis within MBC clusters has diagnostic utility. In two cases, evidence of HD was detected only within MBC clusters and nowhere else. In the third case, HD was found primarily within MBC clusters. These observations imply that HD arose within MBC clusters. Minimal involvement of lymph node by HD can occur within MBC clusters and should be recognized as such on the basis of morphologic features. The earlier a diagnosis of HD can be made, the better is the patient's outlook for survival.

A newly developed monoclonal antibody, anti-BLA.36, raised against a Hodgkin cell line, was shown to have reactivity with Reed-Sternberg cells and activated B lymphocytes and appears to be distinct from other antibodies which identify antigens of hematopoietic cells. Anti-BLA.36 was evaluated in B5-fixed paraffin-embedded tissue from 16 cases of Hodgkin's disease of various types and 35 cases of non-Hodgkin's lymphomas representative of the different major subtypes. The specificity of anti-BLA.36 was compared with other antibodies that have been used to mark Hodgkin's cells and B lymphocytes: namely, L26, LN-1, Leu-M1 and Ber-H2, as well as UCHL-1, a pan-T lymphocyte marker. In addition, a subset of the cases was evaluated using frozen tissue in order to validate the staining characteristics of anti-BLA.36 as observed in fixed paraffin sections. Anti-BLA.36 was found to react with Hodgkin's cells more consistently than the other antibodies used in this panel. The antibody reacted with an antigen on Reed-Sternberg cells and their variants (Hodgkin's cells) in all four subtypes of Hodgkin's disease, and with a subset of reactive and malignant B lymphocytes, but not with T lymphocytes. It may, therefore, be useful in the evaluation of non-Hodgkin's lymphomas. Finally, this is the first antibody raised to a Hodgkin's cell line which also consistently marks reactive and malignant B cells, but not T cells. The implications of this observation are discussed in relation to the cellular origin of the Reed-Sternberg cell and the overall nature of Hodgkin's disease.

Ongoing research on the differentiation between small-cell and large-cell follicular lymphomas ascertained that image analysis by three-dimensional morphologic transforms permits subtyping of follicular lymphomas with greater accuracy and reproducibility than can be accomplished visually by expert pathologists. The present studies improved the use and interpretation of the minimum tracking algorithm and identical to-filters (binary ranking filters). These filters operate on the voxels that constitute the three-dimensional space encodings of gray-level images and are implemented by the Triakis software system.

Histiocytic necrotizing lymphadenitis is a rare, benign entity described independently both by Kikuchi and Fujimoto et al. This disease, which has a broad morphologic spectrum, can readily be mistaken for malignant lymphoma. Our report on the morphologic features in 10 selected cases of this disease highlights those features that mimicked lymphoma and those that helped us to make an accurate diagnosis. The distinctive features were (a) pathologic areas, which are pale and do not occupy the entire lymph node; (b) preserved sinuses in the uninvolved areas; (c) prominent mottling by histiocytes or transformed lymphoid cells in the nonpathologic areas; (d) frequent absence of overt necrosis; (e) presence of benign histiocytes with moderate to marked nuclear irregularities and scanty to moderate cytoplasm that resembled cleaved cells; (f) variable amounts of nuclear debris, usually extracellular; (g) presence of so-called plasmacytoid T cells at the periphery of or immediately outside the pathologic areas; (h) moderate numbers of mitotic figures and transformed lymphoid cells of medium and large size (immunoblasts); and (i) absence of inflammatory and granulomatous reaction. Because overt necrosis is often absent and histiocytes resemble cleaved cells, we support the suggestion that this entity should be called "Kikuchi-Fujimoto disease" rather than "histiocytic necrotizing lymphadenitis."

The present study was undertaken to establish the incidence of t(14;18) (q32:q21) chromosomal translocations detectable by a polymerase chain reaction (PCR) assay on fixed lymphoma biopsies. DNA samples from 113 formalin-fixed, paraffin-embedded tissue biopsies (non-Hodgkin's lymphomas, 96 cases; Hodgkin's disease, six cases; reactive, 11 cases) were amplified by the PCR. Of the 96 non-Hodgkin's lymphoma cases, 56 had a follicular pattern and 40 had a diffuse pattern. Polymerase chain reaction-amplifiable t(14;18) chromosomal translocations were detected in 23 of 43 follicular low-grade lymphomas, one of eight follicular intermediate grade lymphomas, one of five follicular high-grade lymphomas, and one of 10 diffuse large-cell lymphomas. The remaining 30 diffuse lymphomas represented the spectrum of the Working Formulation classification. There were six biopsy specimens of Hodgkin's disease and 11 biopsy specimens of follicular hyperplasia; all were negative. The translocation was not detected in 16 biopsies (non-Hodgkin's lymphomas, seven cases; follicular hyperplasia, nine cases) from patients infected with the human immunodeficiency virus. Since this procedure uses the widely available fixed paraffin-embedded material, correlative studies between histology and genetic aberrations can be readily undertaken.

We present an overview of our 6-year experience in the design of expert systems for anatomic pathology. Our practical goal is to help practicing pathologists with learning, teaching, and the task of diagnosis by providing them with dynamic expert knowledge by means of a personal computer. This project could only be undertaken by first addressing a scientific goal: to characterize the problem-solving strategies that expert pathologists use in making a diagnosis and to state them in the logical terms of computer science. Our approach has been to build systems first for experimentation and then for use. The result of our work is an integrated computer-based approach that handles expert knowledge as formal relationships and morphologic images and that uses a number of logical strategies to provide multiple perspectives on diagnostic tasks. Configured as a pathologist's workstation, this approach can be expected to enhance the performance of trained general pathologists and pathologists in training. Lymph node pathology has been used as the prototype domain for this research, but care has been taken to seek a generalized authoring and inference structure that can be applied to other areas of pathology by changing the contents but not the structure itself. Excursions into various surgical pathology specialties suggest that the ways the system is constructed and exercised is fundamentally robust. Such computer-based expert systems can be expected to generate a new standard in the practice of pathology--based on the "gold standard" of classical morphology, but including the coordinated use of new methods from immunology and molecular biology in a multidisciplinary approach to diagnosis when these techniques are relevant. The benefits from this technology can be expected to be widespread with the evolution, refinement, and diffusion of these systems.

Non-Hodgkin's lymphomas with a follicular pattern are subdivided on the basis of morphologic criteria into four subtypes. Each subtype has a distinctive natural history, response to therapy and survival, and precise histologic diagnosis is essential for optimal treatment. However, recent studies by a panel of seven expert hematopathologists showed that there was a 20% to 40% likelihood of disagreement in subtyping non-Hodgkin's follicular lymphomas; thus, the likelihood of a patient receiving inappropriate treatment is high. To resolve some of the problems relating to subjective morphologic diagnosis, we have continued to investigate the possibility of using computerized image analysis to perform automated subtyping of follicular lymphomas. In the portion of the study reported herein, a total of 37 cases were selected from the set subtyped by the panel of expert hematopathologists, and digitized images of slides from each case were processed by computer. The computer-generated subtypes were compared with those arrived at by the panel. For the cases analyzed, the computer subtyping was at least as good as, and in some instances superior to, that of most of the expert panelists.

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 (Castleman's disease) and is associated with significant morbidity and mortality.

DNA content and light scatter were measured by flow cytometry (FCM) in 103 patients including 43 patients with non-Hodgkin's lymphoma (NHL), eight patients with Hodgkin's disease (HD), 17 patients with acute lymphoblastic leukemia (ALL), ten patients with acute nonlymphocytic leukemia (ANLL), and 25 patients with chronic lymphoid leukemias. Controls consisted of 42 nonneoplastic specimens obtained from lymph nodes, spleen, bone marrow, and peripheral blood. Each specimen was analyzed after staining with a hypotonic solution of propidium iodide using nuclei isolated from chicken erythrocytes as an internal standard. The DNA content and light scatter of the human populations was expressed as a ratio between the DNA content (or light scatter) of the human G0--G1 cells and that of the chicken erythrocytes nuclei. The mean DNA ratio for the 42 nonneoplastic samples was 2.58 +/- 0.045 (SD). In these samples the DNA coefficient of variation of the human G0--G1 peak ranged from 1.48--3.28% (mean, 2.33 +/- 0.54%). The FCM data in the NHL was compared to morphologic diagnoses made according to the "working formulation of NHL for clinical usage" recently proposed by a panel of international experts. Eight of 17 (47%) low grade NHL, one of two (50%) mycosis fungoides, ten of 14 (71%) intermediate grade NHL, nine of ten (90%) high grade NHL, nine of 17 (53%) ALL, three of ten (30%) ANLL, and seven of 25 (28%) chronic lymphoid leukemias had abnormal DNA ratios indicative of aneuploidy. In addition, several cases had normal DNA ratios but G0--G1 coefficients of variation outside of the normal range. All cases of HD had normal DNA values except one case with a small percentage of near tetraploid cells. The mean percentage of cells with S-phase DNA content for the low grade NHL (2.2 +/- 0.8%) was significantly lower than that of the intermediate grade NHL (12.1 +/- 4.9%; P less than 0.0001). The mean S-phase value for the intermediate grade NHL was significantly lower than that of the high grade NHL (22.6 +/- 11.1%; P less than 0.001). The three prognostic categories of NHL designated by the new formulation were clearly distinguishable by the FCM data. Light scatter was not particularly useful for distinguishing nonneoplastic from neoplastic populations. The mean light scatter coefficient of variation of the ALL (15.2%) was significantly lower than that of ANLL (20.5%), however (P less than 0.04).

A clinicopathologic analysis of 42 cases of non-Hodgkin's 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.

Primary neuroendocrine tumors of the larynx appear to be extremely rare. We report a case of well-differentiated neuroendocrine carcinoma arising in the larynx of a 61-year-old white woman. This case was initially diagnosed as a lymph node metastasis in the neck from an unknown primary carcinoma. Extensive workup subsequently revealed that the larynx was the primary site of the tumor. An electron microscopic study of both the primary and metastatic tumors showed numerous neurosecretory-type granules. Immunohistochemical studies revealed positive immunoreactivity against calcitonin, somatostatin, and ACTH. However, the tumor also displayed focal exocrine differentiation and mucosubstance production. The patient underwent a supraglottic laryngectomy and radical neck dissection and was free of tumor 22 months postoperatively.

Because of the significance attributed by some investigators to the presence of cells with convoluted nuclei in lymphoblastic lymphoma, and the absence of any information on the presence and significance of such cells in acute lymphoblastic leukemia (ALL), we reviewed the blood, bone marrow films, and clinical records of 101 children with ALL. We attempted to determine whether leukemic cells with convoluted nuclei can be recognized in such films, and if so, whether this observation has clinical significance. In fifty-seven of the patients the leukemic cells had convoluted nuclei. For the purposes of this study, our patients were divided into three groups: Group I, 44 patients without cells having convoluted nuclei: Group II, 30 patients with 10% or fewer convoluted nucleus cells (CNC); and Group III, 27 patients with more than 10% CNC. Clinical comparison of the three groups with respect to age and sex distribution, physical and hematologic findings at presentation, response to therapy and survival showed no significant differences. Patients with a mediastinal mass had a significantly shorter survival compared to those without a mediastinal mass, regardless of the presence or absence of CNC (p = 0.0001). Our results indicate that the nuclear convolutions can easily be recognized in blood or bone marrow films of patients with ALL, and that their presence has no provable clinical significance.

A retrospective clinicopathologic study of lymphoblastic lymphoma was based on 95 patients from the files of the Repository Center for Lymphoma Clinical Studies. All patients were treated according to different protocols of Cooperative Oncology groups sponsored by the National Cancer Institute. The patients ranged in age from 4 to 84 years, with a median of 30 years. Sixty-eight patients were male and 27 female, with respective median ages of 27 and 50 years. The male-to-female ratio was 2.5:1. Forty patients had mediastinal masses; 30 (75%) of whom were male. The median survival of all patients was 17 months (range 1-100 months). To ascertain the influence of various clinical and morphologic parameters of survival, univariate and multivariate statistical analyses were performed. Patients older than 30 years of age had significantly lower incidences of mediastinal involvement (P = 0.01), number of mitotic figures (P = 0.04), and development of leukemia (P = 0.02) than patients younger than 30. Whereas lymphoblastic lymphoma is generally considered to be a disease of children and young adults, this study indicates that lymphoblastic lymphoma occurs in all age groups. These findings further suggest that lymphoblastic lymphoma may have a different biologic behavior in older patients.

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.

The Rappaport classification of non-Hodgkin's lymphomas was proposed almost a quarter century ago, before the advent of modern immunology. This classification, which is based entirely on morphologic features, has proved its clinical usefulness. In light of recent scientific advances, however, its terminology is not appropriate. Five new classifications have been proposed recently, each claiming to have more merit than the others. The purpose of this study is to critically analyze and evaluate these newly proposed classifications to determine which classification is conceptually and scientifically acceptable as well as clinically useful. The results of the study show that there are more similarities than differences among the Rappaport. Lukes and Collins, Dorfman, British, and WHO classifications; the Kiel classification, however, is fundamentally different (Tables 8, 9, 11). None of these classifications can be used in its proposed form. Based on the analysis of these classifications, a compromise working classification is proposed which incorporates the relevant concepts and terminology from the Rappaport, Berard, Dorfman, WHO, and Lukes and Collins classifications (Tables 15, 16). The proposed compromise classification is an attempt to reconcile the various classifications, and to stimulate others to offer modifications which may bring about a final solution to the problem of classification of non-Hodgkin's lymphomas.

Three cases of follicular lymphoma in which the follicular center cells exhibited pronounced nuclear irregularities, i.e., convoluted and cerebriform shapes, are described. The cytoplasm in B5-fixed sections was scanty to abundant and showed pale to clear staining, with interlocking cell borders. Although the architectural pattern in these cases suggested B-cell lymphoma, the cytologic features suggested a T-cell phenotype. Immunologic studies of frozen sections by immunohistochemical techniques in all three cases, as well as cell suspension studies in two cases, showed that the follicular center cells, including those with convoluted and cerebriform nuclei, were clearly monoclonal B cells, as evidenced by the presence of only one immunoglobulin light chain on the surfaces. The results of this study suggest that the follicular architectural pattern is a more reliable predictor of the immunologic phenotype than are the cytologic features.

We describe a patient with T-cell prolymphocytic leukemia who developed a large-cell lymphoma of the T-cell type. The neoplastic cells of the large-cell lymphoma demonstrated the same immunologic phenotype (ER+, Leu-3+, Leu-2-, and HLA ABC+) as the cells of the prolymphocytic leukemia, which indicated a clonal evolution of a T-cell prolymphocytic leukemia into a large-cell lymphoma of the T-cell phenotype.

A retrospective analysis of 49 cases of undifferentiated non-Hodgkin's lymphoma, registered through the Pediatric Oncology Group's randomized clinical trials between 1976 and 1982, suggests that the histologic distinction between Burkitt's and non-Burkitt's tumor is clinicopathologically irrelevant in children. Patients with undifferentiated lymphoma were stratified morphologically into three subtypes: Burkitt's (B; 18 patients); non-Burkitt's (NB; 21 patients); and small noncleaved, not-otherwise-specified (NOS; 10 patients). Median age at presentation was 10 years for B; 12 years for NB; 6 years for NOS; and 10 years overall. Univariate analysis of clinical and laboratory data at presentation, yielded no significant differences between B, and NB patients. Complete remissions were obtained in 75% of the patients, and there were no significant differences in complete remission rate among the different morphologic subtypes of undifferentiated lymphoma. There were no significant differences in the estimated disease free survival between B, and NB patients. No morphologic parameters were identified that were predictive of prognosis.