John F. Wilson

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 8u2003years (0–21u2003years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH)u2003≥u2003500u2003IU/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 patientsu2003≥u200315‐years‐old compared with <u200a15‐year‐old was 34u2003±u20037 versus 59u2003±u20032% (Pu2003<u20030·05), the 4‐year EFS of M2/M3 compared with M1 BM was 38u2003±u20035 versus 63u2003±u20033% (Pu2003<u20030·001), and the 4‐year EFS with LDHu2003≥u2003500u2003IU/l compared with LDHu2003<u2003500u2003IU/l was 49u2003±u20033 versus 71u2003±u20034% (Pu2003<u20030·001). 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 80u2003±u20036 versus 54u2003±u20032%, Pu2003<u20030·001). 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

PURPOSEnWe 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).nnnPATIENTS AND METHODSnA 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.nnnRESULTSnEvent-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.nnnCONCLUSIONnTreatment 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.

Studies on iron metabolism. V. Further observations on cow's milk-induced gastrointestinal bleeding in infants with iron-deficiency anemia.

By means of a sensitive radioisotopic, technique and alternating periods of controlled diet, 17 of 34 infants with iron-deficiency anemia were shown to have abnormal occult gastrointestinal blood loss which was induced by whole cows milk (WCM), commonly associated with hypoproteinemia, and was ameliorated or, stopped by substitution of soya or proprietary milk formulas for the cows milk feeding. In eight subjects the WCM-induced bleeding did not diminish despite iron therapy so long as WCM was ingested. Limited studies directly implicated bovine serum protein as a probable inciting agent and also demonstrated a correlation between the amount of milk ingested and the degree of bleeding. Follow-up studies on four of the subjects with previous WCM-induced bleeding suggest that the phenomenon may be transient, occurring in infancy, and likely related to development of gastrointestinal immunity. The relative incidence of such WCM-related hemorrhage has not been established, but in our over-all experience it appears to occur in approximately half of young children with iron-deficiency anemia who are ingesting a quart or more of homogenized-pasteurized cows milk daily.

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.

Studies on iron metabolism

Summary A preliminary study of a group of infantswith iron deficiency anemia has revealed evidence of occult gastrointestinal bleeding, precipitins to cows milk, and the passage of serum proteins into gastric juice. These findings are strong evidence of gastrointestinal dysfunction. Guaiac-positive stools were found in 40per cent of the iron-deficient infants tested. Precipitins to cows milk were found in 75 to 80 per cent of the iron-deficient subjects who were taking this food prior to diagnosis. This is regarded as an abnormal finding. Serum proteins in the fasting gastric juice were demonstrated in 12/13 of anemic subjects and in 2/12 of control subjects by means of agar diffusion techniques. Semiquantitative estimates of serum albumin, and gamma globulin in the gastric juice suggest a pathologic loss of these proteins in at least some anemic subjects. These findings suggest the existence of at least 2 forms of iron deficiency anemia in infants; two forms, that is, which are etiologically distinct. The first of these has been termed “primary iron deficiency”; the second is believed to depend on primary sensitization to cows milk. Mechanisms have been proposed to explain the possible interrelationships of the causative factors in each group.

Fatal histiocytic lymphoma of the brain associated with hyperimmunoglobulinemia E and recurrent infections

A 10‐year‐old girl with eczema, asthma, recurrent abscesses, middle ear infections and pneumonias developed a histiocytic lymphoma of the brain. Immunologic evaluation revealed hyperimmunoglobulinemia E, depressed neutrophil chemotaxis, absent delayed hypersensitivity skin tests, low Tlymphocyte numbers and depressed in vitro lymphocyte responses. The occurrence in this patient of a histiocytic lymphoma, which is commonly associated with more classic immunodeficiency syndromes or immunosuppression for transplantation, suggests that individuals with hyperimmunoglobulinemia E and recurrent infections may also be at increased risk for developing unusual malignancies.

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

PURPOSEnNon-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.nnnPATIENTS AND METHODSnWe 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.nnnRESULTSnThe 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).nnnCONCLUSIONnNHL 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.

Large-Cell Lymphoma Arising in the Mediastinum in Children and Adolescents Is Associated With an Excellent Outcome: A Children’s Cancer Group Report

PURPOSEnLarge-cell lymphoma (LCL) arising in the mediastinum (LCL-M) is a heterogeneous group of non-Hodgkins lymphoma (NHL) that includes B-cell lymphomas as well as T-cell lymphomas, including anaplastic LCL. LCL-M is well recognized in young adults but is less well characterized and infrequent in children and adolescents.nnnMETHODSnA retrospective review of Childrens Cancer Group therapeutic studies for nonlymphoblastic lymphomas (CCG-551, CCG-503, CCG-552, and CCG-5911) identified 20 patients with LCL-M, representing 7.2% of all LCLs classified by central pathology review.nnnRESULTSnThe patients ranged in age from 4 to 19 years (median, 12.5 years; mean, 12 years); 55% of the patients were male. Although a variety of chemotherapy regimens were used, response was excellent, with all 20 patients (100%) achieving a complete response. Four patients (20%) experienced relapse locally or in distant sites including brain and kidney. One patient died of sepsis during therapy. For the 20 patients with LCL-M, the product-limit estimated 5-year event-free survival (EFS) and 5-year overall survival (OS) rates are 75% +/- 10% and 85% +/- 8%, respectively. For disseminated LCLs (192 cases), the EFS and OS rates were 50% +/- 4% and 63% +/- 4%, respectively, which differ significantly from the those of the LCL-M cases (EFS, P =.025; OS, P =.034). The 5-year EFS and OS rates for patients with localized LCL (67 cases) were 92 +/- 3% and 97 +/- 2%, respectively.nnnCONCLUSIONnLCL-M is a heterogeneous group of NHLs that makes up approximately 7.2% of LCL in children and adolescents. Response to therapy and OS in this young age group seems excellent and superior to that of disseminated LCLs but inferior to that of other localized LCL. Future studies of LCL-M will evaluate short intense chemotherapy administered without radiation therapy.

The pathology of non-Hodgkin's lymphoma of childhood: II. Reproducibility and relevance of the histologic classification of “undifferentiated” lymphomas (Burkitt's versus non-Burkitt's)*

The Childrens Cancer Study Group conducted prospective clinical trials of 608 children with non-Hodgkins lymphoma from 1977 to 1983. In 1980, significant differences in survival of children with disseminated disease correlated with histologic diagnosis and the randomized treatment employed. A pathology reproducibility review showed the lymphoblastic lymphoma cases to be virtually 100 per cent distinguishable histologically from the nonlymphoblastic lymphomas (Burkitts, non-Burkitts, and histiocytic). However, diagnostic reproducibility of the pathologist-of-record was 59 per cent in the Burkitts and non-Burkitts lymphoma group. Therefore, 159 cases, agreed on by the pathologist-of-record and the lymphoma panel as Burkitts (77 cases) or non-Burkitts lymphoma (82 cases) and designated as the reference diagnosis, were blindly reviewed twice each by two hematopathologists to yield the review diagnoses. Consensus agreement was achieved in 67 per cent of cases overall, 82 per cent of Burkitts and 54 per cent of non-Burkitts lymphoma. Using the reference diagnoses, we found that the relative frequency of Burkitts and non-Burkitts lymphoma was associated with the extent of disease at diagnosis (P = 0.06) but not with other prognostic factors. Despite the difficulties in histologic classification, analyses that used either reference diagnoses or consensus review diagnoses and that were adjusted for extent of disease consistently demonstrated significantly shorter event-free survival for patients having Burkitts lymphoma; their failure rate was four times that for patients with non-Burkitts lymphoma. Newer cell biologic techniques hopefully will enhance histopathologic distinctions that remain the basis for diagnosis.