Carl R. Kjeldsberg

Burkitt's and Burkitt‐like lymphoma in children and adolescents: a review of the Children's Cancer Group Experience

Summary. Historically, the survival of children and adolescents with Burkitts and Burkitt‐like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Childrens Cancer Group trials conducted on 470 children with disseminated Burkitts and Burkitt‐like lymphoma. Of the patients studied, the median age was 8 years (0–21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) ≥ 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4‐year event‐free survival (EFS) in patients ≥ 15‐years‐old compared with < 15‐year‐old was 34 ± 7 versus 59 ± 2% (P < 0·05), the 4‐year EFS of M2/M3 compared with M1 BM was 38 ± 5 versus 63 ± 3% (P < 0·001), and the 4‐year EFS with LDH ≥ 500 IU/l compared with LDH < 500 IU/l was 49 ± 3 versus 71 ± 4% (P < 0·001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4‐year EFS 80 ± 6 versus 54 ± 2%, P < 0·001). In summary, the outcome for childhood Burkitts and Burkitt‐like lymphoma has recently improved with the use of short and intensive B‐cell non‐Hodgkins lymphoma‐directed therapy.

Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group

PURPOSE We analyzed the long-term results of a Childrens Cancer Group (CCG) randomized study comparing cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) versus LSA2L2 as treatment for childhood non-Hodgkins lymphoma. The initial results were previously reported (N Engl J Med 308:559, 1983). PATIENTS AND METHODS A total of 429 patients are reported here, 68 with localized disease and 361 with disseminated disease. The distribution of disseminated-disease patients by histologic type was 164 lymphoblastic, 60 large-cell, and 137 undifferentiated lymphomas. Median follow-up duration of surviving patients is 8 years. RESULTS Event-free survival (EFS) of patients with localized disease was 84% at 5 years. No differences were seen between the two treatment regimens. Results for patients with disseminated disease was dependent on histologic subtype: patients with lymphoblastic lymphoma did better when treated with LSA2L2 (5-year EFS of 64% v 35% for COMP); COMP produced better results for patients with undifferentiated lymphoma (5-year EFS of 50% v 29% for LSA2L2). Results for large-cell lymphoma patients were similar (5-year EFS of 52% for COMP v 43% for LSA2L2). Five percent of patients died of treatment-related complications while on therapy (primarily infections). Only four deaths without progression have been observed off-therapy (two from restrictive lung disease, one from an acute asthma attack, one from colon cancer). Patient survival rates after recurrence were poor. CONCLUSION Treatment success can be expected in 84% of pediatric patients with localized non-Hodgkins lymphoma. For patients with disseminated disease, treatment success can be expected in 64% of those with lymphoblastic and 50% of those with undifferentiated or large-cell disease. To date, late adverse events are rare.

Morphological subclassification of follicular lymphoma: variability of diagnoses among hematopathologists, a collaborative study between the Repository Center and Pathology Panel for Lymphoma Clinical Studies.

A collaborative study between the Repository Center for Lymphoma Clinical Studies and the members of the lymphoma pathology subcommittee of the major cooperative oncology groups was undertaken in an effort to ascertain the reproducibility and the interobserver agreement for the cytologic diagnosis of follicular lymphomas. A group of 105 patients with follicular lymphomas were subclassified by seven hematopathologists according to two methods. In the first method, cases were subclassified according to the Rappaport, Lukes, and Collins, and Working Formulation systems. In these systems, follicular lymphomas are subclassified by estimation of the different cell populations without the actual counting of cells. With this method, great variability in diagnosis was noted. For example: (1) The consensus diagnosis was that of poorly differentiated lymphocytic lymphoma (PDL) in 39 cases, but among the individual pathologists the number of cases thus diagnosed ranged from 24 to 65; (2) In 40 cases, the consensus diagnosis was follicular lymphoma, mixed-cell type; however, all seven pathologists independently agreed on this subtype in only one case; (3) A major disagreement was noted in 39 cases (37%), in which both diagnostic extremes (small cleaved and large noncleaved) were expressed. In the second method, only precise counts of different cells were made, according to a modification of the method recommended by Berard. With this counting method, diagnoses were independently derived based on the counts provided by the seven pathologists for large cleaved, small noncleaved, and large noncleaved cells. The variability in the results was wide also with this second method. For example, the average number of large cells found by each pathologist was ascertained, and the ranges were determined. The average range was 28 cells, which was considered high. The same determinations were performed only for large noncleaved cells, and the range was found to be 15 cells, which was also considered high. When the diagnoses derived from counts of only large noncleaved cells were compared with the traditional, more subjective diagnoses, fairly close agreement was obtained. In summary, the great variability in diagnoses of follicular lymphomas among pathologists may be attributed to the difficulties inherent in accurate determination of cell size and of the precise percentages of different cells. Until solutions to these problems are developed, one can subclassify follicular lymphomas according to the Berard method or the estimation method.

Prolymphocytic transformation of chronic lymphocytic leukemia

This report describes eight patients with B‐cell chronic lymphocytic leukemia whose disease became more aggressive over a variable period of time. This clinical progression was associated with a change in cell morphology from small lymphocytes to an increasing number of large transformed lymphocytes in the blood, bone marrow, and lymph nodes. In the peripheral blood, the predominant large cell was a prolymphocyte. The small lymphocytes and the prolymphocytes had identical cell surface markers in each patient. However, the prolymphocytes had a greater density of surface immunoglobulin than did the small lymphocytes.

Occupational risk factors for subgroups of non-Hodgkin's lymphoma

The non‐Hodgkins lymphomas (NHL) are a diverse group of neoplasms of the lymphatic system whose incidence has been increasing in recent years. The Centers for Disease Control Selected Cancers Study, a population‐based case‐control study of several cancers, included a large number of cases of NHL and a pathology review, providing a rare opportunity to study risk factors for groups of NHL subtypes. We examined the relation between occupational exposures and three subgroups of NHL: small cell diffuse lymphomas (N = 185), follicular lymphomas (N = 268), and large cell diffuse lymphomas (N = 526). There were 1,659 controls available for comparison. After controlling for demographic variables and previously identified risk factors for NHL, we observed two interesting associations, one between solvent exposure and small cell diffuse lymphomas [odds ratio (OR) = 1.60; 95% confidence interval (CI) = 1.10–2.20], and the other between meat packaging/processing and follicular lymphomas (OR = 1.60; 95% CI = 0.99–2.60). The results of this exploratory analysis are primarily negative. Our lack of positive findings may indicate that the subgroups of NHL used may not be etiologically distinct and that further work needs to be done to develop an NHL classification system that is etiologically informative and useful for epidemiologic studies.

Studies on the pathology of non‐Hodgkin's lymphoma of childhood: I. The role of routine histopathology as a prognostic factor a report from the childrens cancer study group

Between April 1977, and August 1980, the Childrens Cancer Study Group (CCSG) conducted a clinical trial of childhood non‐Hodgkins lymphoma (NHL), randomizing 256 patients to one of two treatment regimens. A 4‐drug regimen (regimen 1, modified cyclophosphamide, Oncorin [vincristine], methotrexate, prednisone [COMP]) was compared with a 10‐drug regimen (regimen 2, modified LSA2‐I2). Using the Rappaport classification, the review pathologist diagnosed the 213 evaluable tissue specimens as follows: lymphoblastic (LC), 73; Burkitts tumor (BT), 40; “undifferentiated” non‐Burkitts type (NB), 67; large cell or “histiocytic” lymphoma (HI), 29; and other types (OT), 4. Concurrence in classification between the review and institutional pathologists was poor when using the above four categories; however, concurrence was 88% between the review pathologist and other hematopathologists, and 99% when classifying the specimens as lymphoblastic or nonlymphoblastic. For patients with nonlocalized disease, this randomized controlled study demonstrated a new important correlation of histopathology with the effectiveness of treatment. When analyzed without stratification into lymphoblastic and nonlymphoblastic types, the two regimens showed identical relapse free survival (RFS) curves for patients with nonlocalized involvement. However, when patients were stratified according to histologic classification, regimen 2 was superior to regimen 1 for patients with lymphoblastic lymphoma, achieving 74% RFS at 30 months compared to 31% for regimen 1 (P = 0.001). Conversely, those with nonlymphoblastic types (BT, NB, HI) treated with regimen 1 had a 58% RFS at 30 months compared to 32% for those treated on regimen 2 (P = 0.01). This study demonstrates that proper, routine histopathologic classification of NHL is the best criterion for choice of therapy in children with nonlocalized involvement. As a result of this study, all patients with nonlocalized disease, diagnosed after August 1980, were no longer randomized but were assigned to the appropriate treatment regimen based on prospective review of histopathology.

Non-Hodgkin's lymphoma in children

Non-Hodgkins lymphomas (NHLS) in children can conveniently be divided into four major types: lymphoblastic lymphoma, Burkitts lymphoma, non-Burkitts lymphoma, and large-cell lymphoma. This article reviews the clinical and histopathologic features of the different types. Recent studies have demonstrated that accurate diagnosis and histopathologic classification of NHL in children provide the optimal basis for selection of therapy.

Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children's Cancer Group Study CCG-E08.

Among pediatric non-Hodgkin lymphomas, the most frequent type is small noncleaved-cell lymphoma (including Burkitt and Burkitt-like). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia (ALL); however, chromosome abnormalities have not been evaluated for prognostic value in pediatric Burkitt and Burkitt-like lymphomas. For Childrens Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 19 patients were enrolled with cytogenetic analysis of Burkitt or Burkitt-like lymphoma and simultaneously enrolled on treatment protocols CCG-503 or CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included an age range of 2 to 14 years (median 8 years) and a male:female ratio of 14:5. All patients had advanced disease (stages III and IV, or ALL). Disease relapsed in five patients (event-free survival 74%, median follow-up 10.4 years). Chromosome abnormalities were identified in 18 patients (95%) including t(8;14)(q24.1;q32) in 12 (63%); t(8;22)(q24.1;q11.2) in 1 (5%); partial duplication of 1q in 7 (37%); and 13q32 abnormalities in 2 (11%). In patients who had relapses, in addition to the t(8;14)(q24.1;q32), two had abnormalities of 13q32 and two had partial duplication of 1q. CMYC translocations were absent in Burkitt-like lymphomas from all three patients. Burkitt and Burkitt-like lymphomas in children have a high frequency of chromosome abnormalities. Burkitt lymphoma abnormalities often involve CMYC translocations, usually a t(8;14)(q24.1;q32). Additional chromosome abnormalities that involved 13q32 and partial duplication of 1q were associated with poor prognosis. Burkitt-like lymphomas were not associated with CMYC translocations. Further studies are warranted in larger cohorts of children and adolescents with Burkitt and Burkitt-like lymphomas.

Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate (‘Orange’) in children with advanced non-lymphoblastic non-Hodgkin's lymphoma: a Children's Cancer Group Report

Despite prolonged therapy (18 months), children with advanced non-lymphoblastic, non-Hodgkins lymphoma (NHL) treated on previous Childrens Cancer Group (CCG) trials achieved less than a 60% 5-year event-free survival (EFS). In this study we piloted a shorter but more intensive protocol (‘Orange’) to determine the feasibility, safety, and efficacy of this alternative treatment approach. Thirty-nine children received a CHOP-based induction, etoposide/ifosfamide consolidation, DECAL (dexamethasone, etoposide, cisplatin, cytosine arabinoside (Ara-C) and L-asparaginase) intensification, and either one or two similar but less intense maintenance courses. Patients were stratified to standard-risk (5 months) vs high-risk (7 months) treatment. High risk was defined as either bone marrow disease, CNS disease, mediastinal mass ⩾ one-third thoracic diameter at T5 and/or LDH ⩾2 times institutional upper limits of normal. All other patients were considered to be standard risk. Results were compared with the previous CCG NHL study (CCG-503). Sixteen and 23 patients were considered standard- vs high-risk, respectively. The 5-year EFS and overall survival (OS) were 77 ± 7% and 80 ± 7%, respectively. The 5-year EFS and OS were significantly better in the standard- vshigh-risk subgroups (100% vs 61 ± 11%) (P < 0.003) and (100% vs 65 ± 11%) (P < 0.01), respectively. Lactate dehydrogenase (LDH) ⩾2 × normal (NL) was associated with significantly poorer outcomes (LDH ⩾2 × NL vs <2 × NL) (5-year EFS: 55 ± 12% vs 100%) (P < 0.0004). This CCG hybrid regimen, ‘Orange’, of short and more intensive therapy resulted in a significant improvement in outcomes compared with the previous CCG trial of more prolonged but less intense therapy. This regimen that deletes high-dose methotrexate, if confirmed in a larger trial, could be considered as an alternative treatment approach in children without high tumor burdens (LDH <2 × NL) and Murphy stage III disease.

Non-Hodgkin’s Lymphoma Arising in Bone in Children and Adolescents Is Associated With an Excellent Outcome: A Children’s Cancer Group Report

PURPOSE Non-Hodgkins lymphoma (NHL) arising in bone is a heterogeneous histologic type of NHL that includes large-cell lymphoma, lymphoblastic lymphoma, and small noncleaved-cell lymphoma. NHL arising in bone is well recognized in adults but is less well characterized and infrequent in children and adolescents. PATIENTS AND METHODS We performed a retrospective review of Childrens Cancer Group (CCG) studies treating children and adolescents with NHL over a 20-year period (CCG-551, CCG-501, CCG-502, CCG-503, CCG-552, CCG-5911, and CCG-5941) and determined the response and event-free survival (EFS) rates in 31 patients with NHL arising in bone. RESULTS The patients ranged in age from 3 to 17 years (median, 11 years; mean, 11 years), and 64.5% were male. All 31 (100%) patients achieved complete response. For 31 patients with NHL arising in bone, the product-limit estimated 5-year EFS was 83.8% +/- 6.7%. EFS in 17 patients with localized disease (Murphy stages I and II) was 94.1% +/- 5.7%, and EFS in 14 patients with disseminated disease (Murphy stage III) was 70.7% +/- 12.4% (log-rank P =.10). EFS in 17 patients treated with chemotherapy and radiation was 70.1% +/- 11.2%, and EFS in 14 patients treated with chemotherapy without radiation was 100% (P =.03). EFS in 26 patients with histology-directed treatment (LSA2-L2 or ADCOMP for lymphoblastic, other therapy for nonlymphoblastic) was 92.2% +/- 5.3%, and in five patients with nonhistology-directed treatment it was 40.0% +/- 21.9% (P <.001). CONCLUSION NHL arising in bone is a heterogeneous type of NHL that makes up approximately 2.0% of NHL in children and adolescents on CCG studies. Response and survival in this young age group seem superb, with histology-directed treatment protocols without radiation in both localized and disseminated disease.