Comparison of long-term outcome of children and adolescents with disseminated non-lymphoblastic non-Hodgkin lymphoma treated with COMP or daunomycin-COMP: A report from the Children's Cancer Group.

BACKGROUND: Early Children's Cancer Group (CCG) trials indicated that the cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) regimen was superior to the LSA2L2 regimen for non-lymphoblastic (NLB) non-Hodgkin lymphoma (NHL). Studies by other groups suggested that addition of anthracyclines to standard therapies could improve outcome. Therefore, in 1983 CCG initiated study CCG-503, a randomized trial of COMP vs. daunomycin-COMP (D-COMP) in children and adolescents with disseminated NLB NHL. PROCEDURES: Between December 1983 and April 1990, 404 eligible patients were entered. Patients without central nervous system (CNS) or marrow involvement were randomized to receive COMP (N = 139) or D-COMP (N = 145). Randomization was stratified by histology and site of disease. Patients with CNS or marrow involvement (stage IV) were non-randomly treated with D-COMP (N = 120). RESULTS: Ten-year event-free survival in COMP and D-COMP patients was similar: 55 +/- 4.3% (Estimate +/- SE) vs. 57 +/- 4.2% (not significant). Stage I-III patients with large-cell (LC) NHL had worse 10-year event-free survival (EFS) (48 +/- 4.9%) than those with small non-cleaved cell (SNCC) NHL disease (61 +/- 3.5%, P < 0.05 in multivariate analysis), but equivalent survival (65 +/- 4.7% vs. 63 +/- 3.5%) due to significantly higher salvage rates in LC patients, especially those failing more than 12 months from diagnosis. Ten-year EFS in stage IV patients was 39 +/- 5.2%. Addition of daunomycin resulted in higher rates of grade 3/4 hematologic toxicity and stomatitis, as well as late cardiac-related deaths. The incidence of second malignant neoplasms was 1.0% at 10 years. CONCLUSIONS: Addition of daunomycin to standard COMP therapy did not improve outcome in pediatric disseminated NLB NHL. Patients with LC disease had a significantly reduced long-term EFS, but were retrieved at a higher rate than patients with SNCC disease, resulting in equivalent long-term survival.

Mediastinal germ cell tumor in a child with precocious puberty and Klinefelter syndrome.

An 8-year-old boy presented with precocious puberty and a mediastinal mass. A computer search showed that this rare presentation is most common with germ cell tumor of the mediastinum in children with Klinefelter syndrome. The tumor was completely resected after preoperative chemotherapy, and the patient is well 2 years after the operation. In patients with Klinefelter syndrome, germ cell tumors are 50 times more common than in patients without Klinefelter syndrome, usually contain nonseminomatous elements, present at an earlier age, and are seldom testicular in location.

Primary lymphoepithelioma-like carcinoma of the lung in a child. Report of an Epstein-Barr virus-related neoplasm.

Lymphoepithelioma-like carcinoma (LEC), an undifferentiated carcinoma with pronounced lymphocytic infiltration, often is seen in the nasopharynx as well as in other areas. But such primary pulmonary lung neoplasms in children are rare, and we present the first reported case of primary pulmonary LEC in a child.

Primary mediastinal large cell lymphoma in children: a report from the Childrens Cancer Group.

Malignant lymphomas arising in the mediastinum account for approximately 60% of all mediastinal tumors in children; two-thirds are non-Hodgkin's lymphomas and one-third represent Hodgkin's disease. In contrast to adults, in children mediastinal non-Hodgkin's lymphomas are usually synonymous with lymphoblastic lymphoma, and nonlymphoblastic lymphomas are rare. We describe nine children with primary mediastinal large cell lymphoma who were treated with the Children's Cancer Group protocol CCG-503, a randomized phase III protocol for disseminated nonlymphoblastic lymphoma. Histologic subclassification revealed three immunoblastic lymphomas, three multilobated large cell lymphomas, one with clear cell features, and two large noncleaved cell lymphomas. Sclerosis, of variable degrees, was seen in all tumors. Immunophenotyping revealed all tumors to be of B cell lineage. Thymic epithelial cells could be demonstrated, utilizing antibody to keratin, in two of nine patients, suggesting that some of the tumors are of thymic origin. None of the patients had central nervous system or bone marrow involvement. It appears that primary mediastinal nonlymphoblastic lymphomas in children, although much less common, are similar to those seen in adults. These tumors must be differentiated from lymphoblastic lymphoma and Hodgkin's disease, as the therapeutic approach may depend on histologic subtype. Primary mediastinal large cell lymphoma in children appears curable with aggressive treatment in the majority of patients.

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-Hodgkin's 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-Hodgkin's 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.

Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin's lymphoma of children: a report from the Childrens Cancer Study Group.

Successful treatment of localized non-Hodgkin's lymphoma (NHL) in childhood with 18 months of cyclophosphamide, vincristine, methotrexate (MTX), and prednisone (COMP) prompted a randomized clinical trial to determine whether a 6-month course of the same therapy was as effective as an 18-month course when combined with local irradiation. Two successive Childrens Cancer Study Group (CCSG) protocols (CCG 551 and CCG 501) entered 232 eligible patients from October 1979 until April 1986. Initially, all children with localized disease were considered eligible, but by a subsequent amendment, those with lymphoblastic (LB) histology were excluded. Hence, the study population consisted of 211 patients with nonlymphoblastic (NLB) and 21 with LB disease. Early relapses (before 6 months) occurred in 13 patients with NLB histology. Late relapses were seen in seven patients, three with LB histology. Among the 104 randomized patients who followed the prescribed therapy, there were four recurrences and no differences between 6-month and 18-month therapy. The overall survival for NLB disease was 91% on CCG 551 and 98% on CCG 501. We conclude that 6 months of COMP is excellent therapy for children with localized NLB NHL.

Homozygous deletion of the alpha- and beta 1-interferon genes in human leukemia and derived cell lines.

The loss of bands p21-22 from one chromosome 9 homologue as a consequence of a deletion of the short arm [del(9p)], unbalanced translocation, or monosomy 9 is frequently observed in the malignant cells of patients with lymphoid neoplasias, including acute lymphoblastic leukemia and non-Hodgkin lymphoma. The alpha- and beta 1-interferon genes have been assigned to this chromosome region (9p21-22). We now present evidence of the homozygous deletion of the interferon genes in neoplastic hematopoietic cell lines and primary leukemia cells in the presence or absence of chromosomal deletions that are detectable at the level of the light microscope. In these cell lines, the deletion of the interferon genes is accompanied by a deficiency of 5'-methylthioadenosine phosphorylase (EC 2.4.2.28), an enzyme of purine metabolism. These homozygous deletions may be associated with the loss of a tumor-suppressor gene that is involved in the development of these neoplasias. The relevant genes may be either the interferon genes themselves or a gene that has a tumor-suppressor function and is closely linked to them.

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 Children's Cancer Study Group conducted prospective clinical trials of 608 children with non-Hodgkin's 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 (Burkitt's, non-Burkitt's, and "histiocytic"). However, diagnostic reproducibility of the pathologist-of-record was 59 per cent in the Burkitt's and non-Burkitt's lymphoma group. Therefore, 159 cases, agreed on by the pathologist-of-record and the "lymphoma panel" as Burkitt's (77 cases) or non-Burkitt's 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 Burkitt's and 54 per cent of non-Burkitt's lymphoma. Using the "reference diagnoses," we found that the relative frequency of Burkitt's and non-Burkitt's 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 Burkitt's lymphoma; their failure rate was four times that for patient's with non-Burkitt's lymphoma. Newer cell biologic techniques hopefully will enhance histopathologic distinctions that remain the basis for diagnosis.

Association of red cell spherocytosis with deletion of the short arm of chromosome 8.

Congenital spherocytic anemia is a common disorder, but in most cases the nature of the underlying membrane lesion is unknown and the genetic defect has not yet been unequivocally mapped to a chromosome. We studied two dysmorphic siblings with neurologic findings and hemolytic anemia. Clinical and laboratory findings in these two siblings were consistent with the diagnosis of congenital spherocytosis whereas both parents and two unaffected siblings were normal. The two affected children had an abnormal chromosomal complement as a result of a deletion of the short arm of chromosome 8 [(46,XX,del(8)(p11.1p21.1)]. These results suggest that a gene whose deletion results in a congenital spherocytic anemia phenotype resides on this region on the short arm of chromosome 8.

Lymphoblastic leukemia with lymphomatous features associated with abnormalities of the short arm of chromosome 9.

Patients with acute lymphoblastic leukemia (ALL) who present with bulky disease of the lymph nodes, spleen, or mediastinum--so-called "lymphomatous ALL"--appear to represent a distinct subgroup among patients with ALL of T-cell lineage who have different clinical findings, but the biologic basis for these differences is not known. While studying 65 patients with lymphoblastic leukemia whose karyotype was determined at diagnosis, we compared the findings in 8 patients with lymphomatous ALL and 57 patients whose presentations were more typical of ALL. Six patients with lymphomatous ALL had karyotypic abnormalities leading to loss of bands p21-p22 on the short arm of chromosome 9. The mechanisms varied and included deletions, unbalanced translocations, or loss of the entire chromosome. Only 1 of the 57 patients without lymphomatous ALL had an abnormality of chromosome 9 at diagnosis (P less than 0.001). These findings indicate that loss of chromosomal material in the region of 9p21-p22 is closely associated with lymphomatous ALL; by analogy with retinoblastoma, in which gene deletions are associated with an enzyme deficiency, this disease may be related to the loss of the enzyme methylthioadenosine phosphorylase, previously reported in some of these patients.

Human triosephosphate isomerase cDNA and protein structure. Studies of triosephosphate isomerase deficiency in man.

Nine cDNA clones of human adult liver triosephosphate (TP) isomerase have been isolated and characterized. All nine appear to be derived from a single mRNA species. DNA sequencing of one clone, designated pHTPI-5a, defined the last two nucleotides of the methionine initiation codon, the entire 744-nucleotide coding region of the mature polypeptide, and the entire 448-nucleotide 3' untranslated region. The frequency of TP isomerase clones in the cDNA library suggests that TP isomerase mRNA is present in adult liver at approximately 25 copies/cell. A single, low abundance TP isomerase mRNA species was detected in RNA isolated from normal human fibroblast cell lines. Analysis of TP isomerase mRNA levels in cultured fibroblasts of individuals that are homozygous for TP isomerase deficiency revealed normal levels in one and approximately 40% of normal levels in another. From this small patient sampling, it can be concluded that the genetic basis for TP isomerase deficiency is heterogeneous.

Metastatic Wilms' tumor causing acute hepatic-vein occlusion (Budd-Chiari syndrome).

We describe a case of Wilms' tumor in a 6-yr-old girl which extended from the right kidney and completely obstructed the inferior vena cava and hepatic veins to the level of the right atrium, producing an acute Budd-Chiari syndrome. After an initial course of chemotherapy, the primary tumor was excised and, using cardiopulmonary bypass, the tumor thrombus was removed from the inferior vena cava and hepatic veins. The Budd-Chiari syndrome resolved and after triple-drug chemotherapy and radiotherapy under the National Wilms' Tumor Study-2 protocol the child has remained disease-free for 5 yr.

Diffuse malignant peritoneal mesothelioma in a 13-year-old girl. Report of a case and review of the literature.

A case of diffuse malignant peritoneal mesothelioma in a 13-year-old girl is described. The patient had a short history of abdominal pain, distention, and tenderness. At laparotomy she was found to have ascites and numerous nodules and plaques affecting the peritoneal cavity and the omentum. A diagnosis of diffuse pseudotumoral deciduosis was made, which on review was revised to malignant peritoneal mesothelioma. The patient's condition gradually deteriorated and she died 8 months after diagnosis in spite of administration of combination chemotherapy.

Chromosome abnormalities in tumor cells from patients with sporadic Wilms' tumor.

The karyotype of nine of 11 Wilms' tumors was successfully analyzed using chromosome banding techniques. Peripheral lymphocytes had a normal karyotype in all six analyzed cases. Cultured cells from one tumor had a normal karyotype; however, they appeared to be fibroblasts. A chromosome 11 deletion, del(11)(p13p14), similar to that seen in patients with sporadic aniridia, was found as the sole abnormality in cells from one tumor. Abnormalities of chromosome 1 resulting in trisomy for the long arm (q21-q31) were found in five cases. Two of them had a translocation involving 1q and 16q, although the breakpoints in each chromosome appeared to differ in the two cases. Two patients had an isochromosome of the long arm, i(1q), and a fifth case had a duplication of the long arm as a result of karyotypic evolution. Chromosome 16 abnormalities were found in three cases, resulting in the partial monosomy of the long arm, sharing q22 as a common deletion. The same three cases also had trisomy 1q due to an unbalanced translocation of 1q or an i(1q). Trisomy for both chromosomes 9 and 12 were present in three cases. Two patients each had whole or partial trisomy of chromosomes 6, 7, 8, 17, and 18. Our data show that although an 11p deletion can occur as a mutation confined to tumor cells, the most common changes are trisomy for 1q, and less often a deletion of 16q.

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 Children's Cancer Study Group.

Between April 1977, and August 1980, the Children's Cancer Study Group (CCSG) conducted a clinical trial of childhood non-Hodgkin's 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-L2). Using the Rappaport classification, the review pathologist diagnosed the 213 evaluable tissue specimens as follows: lymphoblastic (LC), 73; Burkitt's tumor (BT), 40; "undifferentiated" non-Burkitt's 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.

The treatment of localized non-Hodgkin's lymphoma in children: a report from the Children's Cancer Study Group.

Investigators of the Children's Cancer Study Group entered 73 children with previously untreated localized non-Hodgkin's lymphoma on a prospective randomized trial of systemic treatment with either a four-drug program (cyclophosphamide, vincristine, methotrexate, prednisone [COMP]) or a 10-drug (LSA2-L2 modified) program of 18 months duration. All patients received central nervous system prophylaxis with intrathecal methotrexate and most received local or regional radiation treatment. The three-year relapse-free survival rate for all patients (N = 73) was 84%; for COMP (N = 42) was 85%, and for LSA2-L2 (N = 31) was 84%. Of the 12 patients who suffered adverse events eight relapsed and four died of toxicity. Histopathology was reviewed centrally. Of 32 patients with nonlymphoblastic disease treated with COMP only one relapsed. Of 26 patients treated with LSA2-L2, four relapsed. Patients with localized lymphoblastic disease were uncommon. None of three patients treated with LSA2-L2 relapsed compared with three of nine treated with COMP. COMP is an excellent treatment for patients with localized disease of nonlymphoblastic type, but the relative value of the two regimens for patients with localized lymphoblastic disease is uncertain.

Mediastinal mass in acute lymphoblastic leukemia.

Patients with acute lymphoblastic leukemia who have a mediastinal mass at the time of diagnosis are said to have a poor prognosis. However, many factors which may not be independent contribute to the success of treatment. We compared the disease characteristics and results of therapy in children having large mediastinal masses and lymphoblastic leukemia without mediastinal mass. Patients with a mediastinal mass had less evidence of marrow failure but were burdened with considerably more leukemic cells as measured by peripheral blood white count and extent of lymphadenopathy. Since the presence of mediastinal mass was strongly associated with these and other poor prognostic characteristics, we used multivariate techniques to determine which characteristics were independently associated with an increased risk for relapse. White count, extent of lymphadenopathy, age, and sex were significant predictors of early relapse, but when controlled for these variables the presence of a mass did not predict prognosis.

Neutropenia, recurrent bacterial infections, and congenital deafness in patients with monocytopenia. Absence of peripheral blood colony-stimulating activity.

The factors that regulate granulopoiesis in vivo are unclear, but recent evidence suggests a role for monocytes; these cells produce a leukopoietin termed colony-stimulating activity (CSA), which stimulates growth of colonies of myeloid cells in vitro. We describe a family in which three of four siblings had neutropenia with myeloid marrow hypoplasia, deafness, and monocytopenia. Two of the three affected siblings died of bacterial septicemia; the third sibling, who resided in a long-term care facility, remained relatively free of infections. Studies of this patient's peripheral blood disclosed deficient CSA production consistent with the virtual absence of monocytes. These findings support the purported role of monocytes as a source of peripheral blood leukopoietic factors.