Annulate in four cases of diffuse lymphocytic lymphoma.

Annulate lamellae were observed in 4 cases of diffuse lymphocytic lymphoma. Two lymphomas were well differentiated and 2 were of intermediate differentiation. These lymphomas had additional abnormalities of membranes: specifically, excessive blebbing of nuclear membranes and lattice-like formations of tubular endoplasmic reticulum.

Similarities of surface characteristics of neoplastic well-differentiated lymphocytes from solid tissues and from peripheral blood.

Cells from spleens and lymph nodes infiltrated with neoplastic well-differentiated lymphocytes (WDLT) were investigated for the presence of receptors for unsensitized sheep red blood cells, complement (IgM EAC), and antigen-antibody complexes, as well as for the presence of surface immunoglobulins. In addition, the cells were examined by scanning electron microscopy (SEM). The surface markers and ultrastructure of WDLT cells were compared with those of cells obtained from peripheral blood of patients with chronic lymphocytic leukemia (CLL). Like the CLL populations, most WDLT samples showed a low percentage of unsensitized sheep red blood cell-binding cells and a concomitantly high percentage of IgM EAC-binding cells. Furthermore, a substantial number of WDLT cells in several instances showed a lower binding affinity for IgM EAC than normal lymphocytes, as demonstrated by the poor attachment of the IgM EAC reagent to the WDLT cells in suspension and to frozen tissue sections. Weak IgM EAC binding capacity was demonstrated in the CLL cells as well. WDLT and CLL cells bound the IgG EA complex only when certain sensitive techniques were applied (pelleting). A variable percentage of cells with surface immunoglobulins was found among WDLT and DLL populations. However, accurate counting of surface immunoglobulin-bearing neoplastic cells was very difficult in most cases due to the extremely faint surface fluorescence as compared to normal. SEM did not reveal specific changes in WDLT or CLL cells that would permit their identification as neoplastic lymphocytes. No major differences were found between WDLT and CLL cells and no correlation could be established between SEM appearances and surface markers. As previously observed with other cell populations, the conditions under which the cells were manipulated before fixation (in particular the environmental temperature) seemed to play a major role in the final SEM appearance of both WDLT and CLL cells. The results of our studies indicate that WDLT cells represent a population of B-cells whose surface properties are very similar to those of circulating CLL cells. The poor capacity of WDLT cells and CLL cells to bind IGM EAC or to stain with fluorescein-conjugated antihuman immunoglobulin suggests low density or poor affinity of the surface receptors. In this regard, these neoplastic cells are different from those of follicular lymphomas, also of B-cell origin.

Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations.

Multidrug resistance (MDR), especially that associated with overexpression of MDR1 and its product, P-glycoprotein (Pgp), is thought to play a role in the outcome of therapy for some human tumors; however, a consensus conclusion has been difficult to reach, owing to the variable results published by different laboratories. Many factors appear to influence the detection of Pgp in clinical specimens, including its low and heterogeneous expression; conflicting definitions of detection end points; differences in methods of sample preparation, fixation, and analysis; use of immunological reagents with variable Pgp specificity and avidity and with different recognition epitopes; use of secondary reagents and chromogens; and differences in clinical end points. Also, mechanisms other than Pgp overexpression may contribute to clinical MDR. The combined effect of these factors is clearly important, especially among tumors with low expression of Pgp. Thus, a workshop was organized in Memphis, Tennessee, to promote the standardization of approaches to MDR1 and Pgp detection in clinical specimens. The 15 North American and European institutions that agreed to participate conducted three preworkshop trials with well-characterized MDR myeloma and carcinoma cell lines that expressed increasing amounts of Pgp. The intent was to establish standard materials and methods for a fourth trial, assays of Pgp and MDR1 in clinical specimens. The general conclusions emerging from these efforts led to a number of recommendations for future studies: (a) although detection of Pgp and MDR1 is at present likely to be more reliable in leukemias and lymphomas than in solid tumors, accurate measurement of low levels of Pgp expression under most conditions remains an elusive goal; (b) tissue-specific controls, antibody controls, and standardized MDR cell lines are essential for calibrating any detection method and for subsequent analyses of clinical samples; (c) use of two or more vendor-standardized anti-Pgp antibody reagents that recognize different epitopes improves the reliability of immunological detection of Pgp; (d) sample fixation and antigen preservation must be carefully controlled; (e) multiparameter analysis is useful in clinical assays of MDR1/Pgp expression; (f) immunostaining data are best reported as staining intensity and the percentage of positive cells; and (g) arbitrary minimal cutoff points for analysis compromise the reliability of conclusions. The recommendations made by workshop participants should enhance the quality of research on the role of Pgp in clinical MDR development and provide a paradigm for investigations of other drug resistance-associated proteins.

Effect of the degree of nodularity on the survival of patients with nodular lymphomas.

The survival of patients with favorable lymphoma entered on various Eastern Cooperative Oncology Group (ECOG) studies was analyzed according to the degree of nodularity. A pure nodular pattern (NN), defined as nodularity involving 75% or more of the cross-sectional area, was found to be an important favorable prognostic indicator as compared with a nodular-diffuse pattern (ND). The median survival in 336 patients with NN of 68.2 months was significantly better than the 39.6 months in 87 patients with ND (P less than .003). The median survival in NN-lymphocytic poorly differentiated (LPD) was 77.2 months v 44.3 months for ND-LPD. NN-M median survival of 56.4 months contrasted with only 25.5 months for ND-mixed lymphocytic and histiocytic (M). The degree of nodularity as defined in this study appears to have significant prognostic implication and should be more widely used by pathologists.

End results of treating children with localized non-Hodgkin's lymphomas with a combined modality approach of lessened intensity.

From 1978 to 1982, 28 children with localized non-Hodgkin's lymphomas, stages I and II, were treated with a combined modality protocol, reduced in intensity in comparison to our previous institutional protocol (1975-1978, reported in Cancer 45: 630-637, 1980), and modest by comparison to many current intensive regimens in widespread use. Induction consisted of vincristine (6 weekly doses, 1.5 mg/m2), cyclophosphamide (3 doses, on days 0, 21, and 42, 600 mg/m2 IV), and oral prednisone (40 mg/m2, daily for 1 mo) combined with low-dose, involved-field, supervoltage radiotherapy (2000 rads). Prophylactic treatment of the central nervous system was not given to all children, but only to those with primary tumors in the head and neck region, and consisted of intermittent intrathecal methotrexate only (12 mg/dose, three times in induction, and subsequently every 6 wk). Maintenance therapy, consisting of oral daily 6-mercaptopurine (75 mg/m2) and oral weekly methotrexate (30 mg/m2), was continued for a total duration of 15 mo from diagnosis. Overall, there were 15 children with stage I and 13 with stage II disease, and the majority of the cases (17 of 28) were localized to the head and neck. In addition, 7 children, all stage II, had completely resected gastrointestinal tumors; the other 4 cases presented in inguinal nodes. Histologically, 27 of the 28 tumors were high-grade diffuse (13 undifferentiated, i.e., small noncleaved cell type; 11 histiocytic, i.e., 5 large noncleaved cell type, and 6 immunoblastic type; and 3 lymphoblastic type); 1 case was mixed cell type, nodular and diffuse. All children were judged to be in complete remission at the end of induction, and 24 of 28 (85.7%) remain free of disease 4+ mo to nearly 4 yr from diagnosis (median 24+ mo); 19 have completed all planned therapy and are in unmaintained remission. The 4 cases failing therapy all were characterized by diffuse undifferentiated (small noncleaved cell) histology and exhibited regrowth of local tumor, resulting in a failure rate for this group (4 of 13, 30%) significantly different than for all remaining cases of other histologies (0 of 15), p less than 0.02 by log rank analysis. Patient tolerance to therapy was excellent, with negligible acute toxicity, and ambulatory outpatient management was the norm. Long-term follow-up will be necessary to judge whether adverse late consequences of treatment have been reduced by this approach. We conclude that a reduction in the intensity of therapy for children with stage I and II non-Hodgkin's lymphomas is feasible, apparently without significantly jeopardizing their excellent chance for cure.

Non-Hodgkin's lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution.

Between 1962 and 1986, a total of 338 consecutive newly diagnosed children and adolescents with non-Hodgkin's lymphomas (NHLs) were evaluated and treated at St Jude Children's Research Hospital (SJCRH). Median follow-up is 6.6 years (range, 1.8 to 23 years). The patients ranged in age from 7 months to 21 years (median, 10 years), and 71% were males. All cases were staged (I to IV) by a clinical staging system. Eighteen percent were stage I, 21% stage II, 43% stage III, and 18% stage IV. Cases frankly leukemic at diagnosis (ie, greater than 25% marrow blasts) were excluded from the analysis. Pathologic material from all cases was reviewed and classified according to the Working Formulation. The histologic distribution of cases was as follows: 38.8% diffuse small non-cleaved cell (undifferentiated, Burkitt's and non-Burkitt's); 26.3% diffuse large-cell, mainly immunoblastic; 28.1% lymphoblastic; and 6.8% other. Treatment policy evolved over time to a stage- and histology-specific strategy for treatment assignment, and overall results significantly improved by era from 37% (+/- 5%) 2-year event-free survival (EFS) for patients treated before 1975 to 77% (+/- 4%) since 1978. By univariate and multivariate Cox regression analyses, the era of treatment (hence, the protocol-specific treatment itself), the stage, and the log of the initial serum lactic dehydrogenase (LDH) emerged as the most powerful prognostic indicators, while histology per se was not significantly related to outcome. For the 154 patients treated since 1978, the 2-year EFS by stage was 97% (+/- 3%) for stage I, 86% (+/- 6%) for stage II, 73% (+/- 6%) for stage III, and 47% (+/- 11%) for stage IV (P less than .0001). Compared with our previous experience, we conclude that the cure rate of childhood NHL has doubled in the last decade with modern management.

Results of treatment of advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine.

To address the problem of historically poor results in the treatment of children with advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia (ALL), an intensive chemotherapy regimen was devised using the most effective single agents in high-dose short courses. Treatment commenced with a fractionated schedule of intravenous (IV) cyclophosphamide (300 mg/m2 every 12 hours for six doses) followed immediately by Adriamycin (50 mg/m2) and vincristine (1.5 mg/m2) with combined intrathecal (IT) methotrexate and cytarabine. Predictably, this treatment produced virtually complete disappearance of all tumor and profound myelosuppression. Immediately on hematologic recovery, IV high-dose methotrexate (1,000 mg/m2 over 24 hours) followed by IV cytarabine (400 mg/m2 over the next 48 hours) was administered with leucovorin rescue and repeated IT treatments. The treatment sequence described above is repeated four times, with the dose of cytarabine doubled in succeeding courses, up to 3,200 mg/m2. The entire planned therapy required approximately 24 weeks. Since 1981, we treated a total of 29 children with this approach, 19 of whom had massive unresectable intraabdominal tumor. According to initial extent of disease, 17 were classified as stage III, four as stage IV non-Hodgkin's lymphoma (NHL), and eight as B cell ALL. Eight of the 12 patients with stage IV NHL or B cell ALL had initial involvement of the CNS. Twenty-seven of 29 patients (93%) attained a complete remission. Fourteen of 17 stage III NHL patients remain disease free, for periods ranging from 3+ months to 4 1/2+ years. The actuarial estimate of the proportion of stage III patients remaining disease free at 2 years is 81%. Results in patients with initial involvement of the CNS and/or marrow are much less favorable, with only two of ten patients who attained remission apparently being cured. In addition to stage, the initial serum lactic dehydrogenase (LDH) level emerged as a prognostic indicator, higher levels (over 1,000 IU/L) being associated with the worst prognosis (P less than .05). Major toxicity consisted of severe hematopoietic suppression and febrile episodes associated with neutropenia. We conclude that this treatment is highly effective for advanced-stage Burkitt's tumors in children free of initial CNS involvement.

Mediastinal nonlymphoblastic lymphomas in children: a clinicopathologic study.

The records of 25 pediatric patients with mediastinal nonlymphoblastic lymphoma (NLBL) were reviewed. These patients comprise approximately 5% of all patients with non-Hodgkin's lymphoma (NHL) in the pediatric age group. There were 15 females and ten males. The median age was 13.5 years (range, 2 to 19). Most patients presented with symptoms attributable to a large mediastinal mass, and superior vena cava syndrome was a common feature. Disease was localized to the supradiaphragmatic area in 17 patients (71%) at diagnosis. Pathologic review revealed 22 of these lymphomas to be diffuse histiocytic type in the Rappaport classification, and 20 were large-cell immunoblastic type in the Working Formulation. Treatment regimens were not uniform, but included multiagent chemotherapy in 23 patients and radiation to the mediastinum in 20 patients. Twenty-three patients (92%) attained a complete remission (CR). Of these, 17 (74%) remain disease-free 13 to 65 months from diagnosis (median, 43 months). No CNS relapses have been observed. Mediastinal NLBL in the pediatric age group has distinctive clinicopathologic features that warrant special consideration in the design of treatment protocols.

B-cell lineage confers a favorable outcome among children and adolescents with large-cell lymphoma: a Pediatric Oncology Group study.

PURPOSE: The goal of this study was to assess the immunophenotype of uniformly treated cases of pediatric large-cell non-Hodgkin's lymphoma (NHL) to determine the prognostic importance of B-cell and T-cell lineages and of CD30 positivity. PATIENTS AND METHODS: Sixty-nine patients were analyzed by immunochemistry. All patients were classified histologically, staged in a uniform manner, and treated according to one of two protocols for localized (stage I and II) NHL or advanced (stage III and IV) large-cell NHL. Antibodies included anti-CD45, CD20, CD45Ra, MB-2 (not clustered), CD3, CD45Ro, CD43, CD15, CD30, and CD68. Statistical analysis used the exact conditional chi 2 and Kruskall-Wallace tests for clinical features and the log-rank test to evaluate event-free survival (EFS). RESULTS: Immunophenotypic results demonstrated 25 B-cell, 23 T-cell, and 21 indeterminate lineage. Twenty-seven patients expressed CD30 (17 T-cell and 10 indeterminate lineage), and of these, 22 showed histology of anaplastic large-cell lymphoma (ALCL). B-cell patients were older (P = .018) and showed more favorable survival than patients with T-cell or indeterminate lineage (96% EFS at 3 years, 96% v 67% and 74%, B v T and indeterminate lineage [P = .027]). B-cell lineage was seen more frequently in limited-stage patients, but was also associated with favorable survival when stratified for stage (P = .036). CD30 expression (P = .96) and ALCL histology (P = .90) did not show significant associations with survival. CONCLUSION: We conclude that among pediatric large-cell lymphomas, B-cell lineage is proportionately less frequent than in adults and CD30 antigen-expressing lymphomas are frequent among patients with T-cell and indeterminate lineage. B-cell phenotype tends to occur in older children and is associated with superior survival.

CNS involvement in children with newly diagnosed non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

Pleural effusion is associated with a poor treatment outcome in stage III small non-cleaved cell lymphoma.

The clinical significance of pleural effusion was assessed in 24 children with unresectable abdominal small non-cleaved cell lymphoma (St. Jude Stage III). Patients were consecutively enrolled and treated on a regimen including high dose fractionated cyclophosphamide and co-ordinated high dose methotrexate and cytarabine. The overall results were excellent, with 20 of 24 patients alive and event-free at a median follow-up of 4 years. Only one of the patients who lacked pleural effusion has relapsed (testicular), even though many had massive disease. In contrast, three of seven patients with pleural effusion have failed treatment (p = 0.02) and subsequently died. Two measures of tumor burden, serum lactic dehydrogenase and, in a subset of patients, interleukin-2-receptor levels, were significantly higher in patients with pleural effusion (p = 0.002 and p = 0.05, respectively). These findings suggest that unresectable abdominal small non-cleaved cell lymphoma associated with pleural effusion should be up-staged and that these patients should receive more intensive chemotherapy.

Extranodal primary tumor site indicates poor prognosis in childhood head and neck non-Hodgkin's lymphomas.

As a result of the diversity of lymphoid structures in the head and neck, we analyzed clinical characteristics and outcomes of 87 consecutive children with non-Hodgkin's lymphoma (NHL) arising in this region to determine if the nodal versus extranodal primary site influences prognosis. Thirty-one children had primary nodal NHL whereas 56 had extranodal NHL. The two groups were similar in the distribution of age, gender, race, serum lactic dehydrogenase levels, and disease stage. However, extranodal tumors were slightly more likely to have small non-cleaved cell histology (32/56 versus 11/31, p = 0.07) than nodal tumors. In a multivariate analysis, extranodal involvement (p = 0.017), advanced stage disease (p = 0.054) and treatment era (p = 0.056) were each significantly associated with a shorter time of event-free survival. Children with extranodal and extralymphatic NHL had an even worse treatment outcome than did others (p = 0.006). The poor prognosis of extranodal involvement was also evident among children with stage I or II NHL. We conclude that extranodal involvement has an adverse influence on treatment outcome in children with NHL arising in the head and neck region.

High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkin's disease.

To improve the biologic evaluation of Hodgkin's disease, we determined serum interleukin-2 receptor (IL2R) levels in 88 children with this tumor. In patients with stage III or IV disease, the median receptor level was significantly higher than in patients with lower stages (3195 vs. 1087 U/ml, p = 0.0001). Similarly, the median level for children with stage B disease was 3262 U/ml, compared with 999 U/ml for those lacking constitutional symptoms (p = 0.0001). Patients with very high soluble IL2R levels (greater than or equal to 5000 U/ml) were significantly more likely to fail treatment (p = 0.01), even when the analysis was restricted to groups with advanced disease: stages III and IV (p = 0.0001). When entered in the Cox-proportional hazards model with other potentially useful prognostic factors, soluble IL2R level was found to be an independent predictor of treatment outcome. The relationship of high serum IL2R levels to an adverse clinical outcome in Hodgkin's disease may be explained by a model in which the soluble receptor competes for the ligand with the cellular receptor on normal lymphocytes, thus blocking antitumor immunity dependent on interleukin-2. Alternatively, high serum levels of IL2R may simply reflect increased release of the receptor from activated malignant cells in patients with advanced disease or an otherwise poor prognosis.

Large cell non-Hodgkin lymphoma of childhood: clinical characteristics and outcome.

Less is known about the clinical features and treatment outcome in pediatric large cell non-Hodgkin lymphoma (NHL) than the lymphoblastic and small noncleaved cell subtypes of NHL. To characterize presenting features and assess possible risk factors associated with this diagnosis, we analyzed data for 91 patients treated on a succession of multiagent regimens from 1975 to 1990. Five-year event-free survival (EFS) (+/- SE) was related to disease extent (St Jude system): stage I (n = 24), 95% +/- 5%; stage II (n = 20), 84% +/- 9%; stage III (n = 38), 50% +/- 10%; and stage IV (n = 9), 22% +/- 11%. Advanced stage disease, age < or = 5 years and serum LDH > 500 U/l were associated with poorer EFS in the univariate model (p < 0.001, 0.005, and 0.002, respectively). In the multivariate model, advanced stage and age retained prognostic significance (p = 0.001 and 0.02, respectively), but LDH did not. Among limited stage cases, age < or = 5 years was the only adverse risk feature (p = 0.016); treatment era (pre- vs. post-1979) was the only significant feature in patients with advanced disease (p = 0.004). Intrathoracic primaries were associated with a better outcome than other sites among the 38 stage III patients (p = 0.005). Only one of eight patients with bone marrow disease remains failure-free. The excellent results for limited stage pediatric large cell NHL permit consideration of treatment modifications to decrease toxicity; for cases with advanced disease, especially those with bone marrow involvement, novel therapeutic approaches are clearly needed.

Predominance and characteristics of Burkitt lymphoma among children with non-Hodgkin lymphoma in northeastern Brazil.

The purpose of this paper was to define the histologic distribution, clinical features, and treatment response of childhood non-Hodgkin lymphoma (NHL) in northeastern Brazil. We reviewed medical records and histopathologic studies of 98 children treated for NHL from 1980 to 1987 at a major pediatric cancer center in Recife, Brazil. Treatment outcome was evaluated in relation to tumor burden (stage and serum LDH) and type of therapy (LSA2L2 vs other multiagent chemotherapy). There was a striking predominance of the small noncleaved cell (Burkitt) subtype, which occurred in 92 of the 98 children and adolescents diagnosed with NHL. Subsequent analyses focused on these patients. The majority (n = 84) had advanced (stage III/IV) disease at diagnosis. The abdomen was the most common site of disease (84 cases); jaw involvement was rare (three cases). Five-year event-free survival (excluding treatment refusals) was significantly better for patients with limited vs advanced stage disease (75 +/- 14% vs 42 +/- 6%; P < 0.04). Elevated serum LDH (>500 U/l) was associated with a poorer outcome (P = 0.008). The type of chemotherapy did not affect EFS (P = 0.95). Only 39% of patients are long-term survivors, reflecting the high rate of septic deaths (25% of patients) and parental refusal/abandonment of therapy (10%). Epstein-Barr virus (EBV) was detected in tumor cells from eight of the 11 cases studied. In clinical presentation, these cases resemble sporadic Burkitt lymphoma, yet in their apparent responsiveness to LSA2L2 therapy and association with EBV, they do not. Childhood NHL in northeastern Brazil is predominantly of the Burkitt subtype, and is associated with clinical features that appear to distinguish it from the endemic and sporadic forms of this tumor. These cases may represent a third or intermediate subtype of Burkitt lymphoma.

The Rappaport classification of non-Hodgkin's lymphomas: a closer look using other proposed classifications.

An essential purpose of a pathologic classification of non-Hodgkin's lymphomas is to supply guidance in the clinical management of patients. Ideally, an optimal subclassification should also be scientifically accurate, highly reproducible, and readily teachable. Such a system, when used in conjunction with uniform staging, should enable relatively homogeneous groups of patients to be defined. In the present study, we have evaluated four new systems for possible additions to the traditional Rappaport classifcation. In response to specific questions the following tentative conclusions could be drawn: (1) Within the Rappaport nodular lymphomas, there are no differences in survival between lymphomas that are totally nodular verusus those that are nodular and diffuse. (2) In lymphomas composed of small cleaved follicular center cells of the Lukes-Collins system, survival appears to be independent of pattern (follicular, follicular and diffuse, or diffuse). In contrast, in tumors classified as centroblastic-centrocytic in the Kiel classification or those classified as large cleaved or large noncleaved in the Lukes-Collins system, a totally or partially follicular pattern confers a better prognosis than its diffuse counterpart. (3) The numbers are small but there is no apparent difference in survival between cases of Rappaport's difuse well differentiated lymphocytic lymphomas with or without plasmacytoid differentiation. (4) Within the original Rappaport DPDL there were at least two distinct types of lymphomas: (1) a convoluted lymphoblastic that occurs in younger patients has a high frequency of B symptoms and carries a poor prognosis; and (2) a diffuse lymphoma that is cytologically identical to nodular PDL, occurs in older patients, and has a relatively good prognosis. In August of 1976 Rappaport modified his classification to recognize these lymphoblastic lymphomas as a distinct clinicopathologic entity. (5) In this 22-yr retrospective review, neither the Kiel nor the Lukes-Collins system could identify any relatively favorable subsets within Rappaport's category of diffuse histiocytic lymphoma. Prospective studies applying the same approach to large numbers of patients subjected to modern uniform staging and aggressive combination chemotherapy may provide data upon which to base an optimal subclassification of DHL.

Immunologic and morphologic studies of T cell lymphoma.

Thymic-independent (B) lymphocytes, thymic-independent (T) lymphocytes and histiocytes may be distinguished by the presence of certain surface markers. In addition B and T lymphocytes have been reported to show distinctive surface architecture by scanning electron microscopy. Neoplastic cells from a lymph node and cerebrospinal fluid of a patient with a diffuse malignant lymphoma of the poorly differentiated lymphocytic type were examined in frozen sections and cell suspensions for the presence of surface immunoglobulin and the antigen-antibody-complement (IgMEAC) receptor of B lymphocytes, the presence of the cytophilic antibody (IgGEA) receptor of histiocytes and the ability to form nonimmune rosettes with sheep red blood cells (E) characteristic of T lymphocytes. Cells from the lymph node were also studied by scanning electron microscopy. The majority of neoplastic cells from the lymph node and cerebrospinal fluid formed rosettes with E, but lacked surface immunoglobulin and failed to bind IgMEAC or IgGEA. By scanning electron microscopy the neoplastic cells, although larger in diameter, showed surface architecture similar to normal lymphocytes with a varying number of surface microvilli. These studies suggest that the malignant cells of this lymphoma are of thymic type.

American Burkitt's lymphoma: a clinicopathologic study of 30 cases. II. Pathologic correlations.

Thirty cases of malignant lymphoma, undifferentiated, Burkitt's type are reviewed. An older median age and a predominance of presentation in abdominal and pelvic sites rather than in the jaw distinguishes this series of American patients from those reported from endemic regions in Africa. Bone marrow involvement invariably consisted of massive infiltration recognizable in smear, clot and biopsy preparations. Involvement of the central nervous system or bone marrow was always associated with short survival. In all eight long-term survivors lymphoma was apparently confined to a single site at presentation. At autopsy, the most consistent finding was widespread multiorgan involvement without predilection for lymphoreticular structures. The histologic appearance of the tumor changed after chemotherapy, varying from diffuse necrosis within 48 hours of initial therapy to extreme pleomorphism of tumor cells after 9 months of therapy. In one patient, there was almost complete absence of lymphoma at autopsy in an organ site shown clinically to have been extensively involved by tumor prior to treatment. The diagnostic and therapeutic implications of these findings are discussed.

American Burkitt's lymphoma: a clinicopathologic study of 30 cases. I. Clinical factors relating to prolonged survival.

The presenting clinical characteristics and the results of therapy in 30 cases of American Burkitt's lymphoma are described. Five patients presented with localized disease. The abdomen was the most frequent site of involvement (19 cases). Serum lactic dehydrogenase (LDH) levels closely correlated with extent of tumor mass. Of the 22 patients treated with large doses of parenteral cyclophosphamide, complete remission was achieved in 13 (59 per cent). Of these only four have had a relapse, all within 12 months of treatment. The remainder are alive, free of disease and have not received any treatment for up to 80 months or more. The site and volume of tumor mass predicted for prolonged survival. None of the six patients with bone marrow or central nervous system involvement remained tumor-free. A complete remission was achieved in 8 of 9 patients with presenting LDH levels of less than 700 IU/ml and they have remained free of disease, whereas only 4 of 13 patients with LDH levels greater than 700 IU/ml had a complete response and 3 of these had a relapse within 12 months. In six cases, the massive tumor regression following chemotherapy was associated with serious metabolid consequences including hyperkalemia (six cases), hypocalcemia, hyperphosphatemia (one case) and lactic acidosis (one case). There were four sudden deaths in less than 48 hours after chemotherapy; two of these were attributable to hyperkalemia. In all cases therw were large tumor masses and/or elevated serum LDH levels.

Infectious mononucleosis. The spectrum of morphologic changes simulating lymphoma in lymph nodes and tonsils.

Lymph-node and tonsillar biopsies occasionally are obtained from patients with the infectious mononucleosis syndrome secondary to Epstein-Barr viral infection, particularly if the clinical presentation is atypical and a viral etiology is not suspected. The presence of Reed-Sternberg-like cells in infectious mononucleosis resulting in confusion with Hodgkin's disease is well-known; however, similar difficulty in excluding a non-Hodgkin's lymphoma can be encountered. Eleven cases of reactive lymphoid hyperplasia with the morphologic features of infectious mononucleosis are reported, nine of which had documented Epstein-Barr viral infection. The spectrum of morphologic changes associated with Epstein-Barr viral infection is discussed, with emphasis on the features that permit their distinction from non-Hodgkin's lymphoma. Morphologic features mimicking lymphoma included extensive immunoblastic proliferations in sheets and nodules and marked cytologic atypia. Hodgkin's disease was simulated by the tendency in some cases for the atypical Reed-Sternberg-like cells to cluster about necrotic foci and to show pronounced cytologic atypia. Features permitting the distinction from non-Hodgkin's lymphoma included persistent reactive foci with the classic features of infectious mononucleosis, a polymorphous background of transformed lymphocytes rather than irregular or twisted lymphoid cells as seen in non-Hodgkin's lymphoma, and preservation of underlying reticulin architecture rather than destruction, even in cases with extensive immunoblastic proliferation. Hodgkin's disease was excluded by requiring strict criteria for Reed-Sternberg cells and noting the reactive background as inconsistent with Hodgkin's disease. Immunoperoxidase staining of seven of the cases with anti-Leu-M1 failed to demonstrate immunoreactivity of the Reed-Sternberg-like cells with this monoclonal antibody.