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-Hodgkin's lymphoma (NHL) treated on previous Children's 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 > or = one-third thoracic diameter at T5 and/or LDH > or =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- vs. high-risk subgroups (100% vs. 61 +/- 11%) (P < 0.003) and (100% vs. 65 +/- 11%) (P < 0.01), respectively. Lactate dehydrogenase (LDH) > or =2 x normal (NL) was associated with significantly poorer outcomes (LDH > or =2 x NL vs. <2 x 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 x NL) and Murphy stage III disease.

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.

The Burkitt-like lymphomas: a Southwest Oncology Group study delineating phenotypic, genotypic, and clinical features.

The Revised European-American Lymphoma classification gives Burkitt-like lymphoma (BLL) provisional status, leaving unresolved the differential diagnosis with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). This study compared the biologic features of adult BLL and DLBCL. The phenotypic distinction between BLL and DLBCL was determined by immunohistochemical staining of frozen tissue from 13 patients with BLL and 55 patients with DLBCL by using an extensive antibody panel including Ki-67, CD10, CD11a/lymphocyte function-associated antigen 1alpha (LFA-1alpha), CD18/LFA-1beta, CD58/LFA-3, and CD54/intercellular adhesion molecule, CD8 for tumor-infiltrating cytotoxic T cells (T-TILs), CD44 homing receptor, and p53 and Bcl-2 oncogenic proteins. Compared with DLBCL, BLL had a higher proliferative rate (mean Ki-67, 88% versus 53%), greater expression of CD10 and p53 antigens, and decreased expression of Bcl-2. BLL cases had a consistent absence of one or more cell adhesion molecules (92% versus 27%), low T-TIL numbers, and absence of CD44 homing receptor (92% versus 14%). The t(8;14) translocation was identified in 80% of BLL cases, but no patients with BLL had the t(14;18) translocation. In a 10-year analysis, median survival of patients with BLL was 1.2 years, and that of patients with DLBCL was 2.5 years. Although the proportion of patients cured was similar in the 2 groups, BLL patients had an increased risk of early death. We conclude that BLL can be recognized by its combined morphologic and phenotypic features and that it represents a high-grade lymphoma much closer to BL than DLBCL. Retention of the BLL category or inclusion of BLL as a variant of BL is biologically and clinically more appropriate than absorbing the category of BLL into DLBCL. (Blood. 2001;97:3713-3720)

Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report.

PURPOSE: Large-cell lymphoma (LCL) arising in the mediastinum (LCL-M) is a heterogeneous group of non-Hodgkin's 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. METHODS: A retrospective review of Children's 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. RESULTS: The 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. CONCLUSION: LCL-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.

Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809.

PURPOSE: S8809 is a randomized phase III trial determining whether intensive cytoreductive treatment, followed by interferon consolidation at the time of minimal residual disease, prolongs the progression-free survival (PFS) or overall survival (OS) of indolent lymphoma patients. PATIENTS AND METHODS: Five hundred seventy-one patients with previously untreated stage III or IV low-grade non-Hodgkin's lymphoma were registered. Patients received six to eight cycles of prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE[day 1]-MOPP[day 8]) chemotherapy or chemotherapy plus radiotherapy. Responding patients were randomized to observation alone or to interferon consolidation. Interferon alpha-2b 2 mU/m(2) was given subcutaneously three times weekly for 2 years. RESULTS: Two hundred sixty-eight eligible patients were randomized to interferon alpha consolidation (n = 144) or observation alone (n = 124). With a median follow-up time from randomization among patients still alive of 6.2 years, the median PFS time was 4.1 years for patients who received interferon consolidation therapy and 3.2 years for patients who were observed after ProMACE-MOPP induction (P =.25). The adjusted hazard ratio for relapse for observation to interferon was 0.83 (95% confidence interval [CI], 0.61 to 1.13). The median OS has not been reached in either group. At 5 years, OS is 78% for the interferon group and 77% for the observation group (P =.65). The adjusted hazard ratio for survival for observation to interferon is 1.11 (95% CI, 0.69 to 1. 79). CONCLUSION: Interferon alpha consolidation therapy after intensive treatment with anthracycline-containing combination chemotherapy and involved-field radiation therapy does not prolong the PFS or OS of patients with low-grade non-Hodgkin's lymphoma.

Primary anaplastic large cell lymphoma of the small intestine.

We describe the clinicopathologic, immunophenotypic, and molecular findings in 4 cases of anaplastic large cell lymphoma (ALCL) arising in the small intestine. All patients were men with acute symptoms of gastrointestinal tract obstruction. The clinical preoperative diagnosis was gastrointestinal carcinoma in 3 cases, and pancreatic carcinoma in 1 case. Histologic examination revealed cohesive aggregates of neoplastic cells, with multiple vesicular nuclei, prominent nucleoli, and abundant amphophilic cytoplasm. There was no clinical or histopathologic evidence of enteropathy. All cases were CD30+, and all showed evidence of T-cell lineage with cytotoxic potential by expression of CD3, CD43, or CD45RO; T-cell intracellular antigen-1; or perforin. One tumor showed p80 and anaplastic lymphoma kinase (ALK) overexpression corroborated by the presence of the t(2:5). One tumor expressed Epstein-Barr virus latent membrane protein. In all cases, the tumor cells were negative for CD20, CD15, CD56, and cytokeratin. Polymerase chain reaction revealed clonal rearrangements of the T-cell receptor gamma-chain gene, without evidence of immunoglobulin heavy-chain gene rearrangement. The diagnosis of primary bowel ALCL is facilitated by immunophenotypic and molecular studies. With 24 months of clinical follow-up, only the patient with the t(2:5)-positive tumor is alive and free of disease, suggesting that p80/ALK overexpression may be a good prognostic indicator.

Relation of cigarette smoking to non-Hodgkin's lymphoma among middle-aged men.

Because of previous inconsistencies in the observed relation of cigarette smoking to non-Hodgkin's lymphoma, this association was investigated in the Selected Cancers Study, a population-based case-control study of 1,193 non-Hodgkin's lymphoma cases and 1,903 controls, conducted between 1984 and 1988. Study subjects were men, and the median age of non-Hodgkin's lymphoma cases was 50 years (range, 32-60 years). As compared with the risk among men who had never smoked cigarettes, the risk among ever smokers was not increased (odds ratio (OR) = 1.05, p approximately 0.50), but the risk was significantly elevated among men who reported smoking > or = 2 1/2 packs per day and among men who had smoked for 30-39 years (OR = 1.45 in each group, p < 0.05). The estimated odds ratio among the 350 heavy smokers (> or = 50 pack-years) was 1.41 (95% confidence interval 1.08-1.85) after controlling for educational achievement, various occupational and medical exposures, and other potential confounders. The observed associations, however, tended to vary by age, with the odds ratio among heavy smokers decreasing from 2.8 among 32- to 44-year-olds to 1.1 among men over 55 years of age. These age-related differences, which may account for some of the inconsistencies seen in previous studies of cigarette smoking and non-Hodgkin's lymphoma, should be considered in future investigations.

Detection of terminal deoxynucleotidyl transferase (TdT) in nonhematopoietic small round cell tumors of children.

In the differential diagnosis of small round cell tumors (SRCTs), terminal deoxynucleotidyl transferase (TdT) is often used as a marker for lymphoblastic lymphomas and leukemias. However, the specificity of TdT using the avidin-biotin-immunoperoxidase (ABC) method is not well documented. To address this issue, we stained paraffin-embedded biopsy specimens of 64 cases of childhood SRCTs using the ABC method with anti-TdT. For any TdT-positive tumors, an additional antibody panel for lymphoid markers was applied. Two patterns of TdT positivity were observed: (1) tumor specific, consisting of strong to moderate nuclear staining, and (2) scattered positive lymphoid cells, usually in a perivascular location and expressing T-cell markers. Analysis showed that 7 of 10 medulloblastomas stained with TdT in a tumor-specific pattern (4 cases moderately to strongly positive in 75-100% of tumor cells, 3 cases weakly to moderately positive in 25-50% of cells). Also, 1 of 19 rhabdomyosarcomas and 1 of 8 Ewing's sarcomas showed moderate to strong tumor-specific TdT staining in 100 and 10% of cells, respectively. Scattered TdT-positive lymphoid cells were observed in 27% of these 64 SRCTs. These findings emphasize that TdT positivity should not be relied upon exclusively for making a diagnosis of lymphoblastic leukemia or lymphoma or ruling out other SRCTs.

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

The non-Hodgkin's 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.

Natural killer-like T-cell lymphoma in the small intestine of a child without evidence of enteropathy.

A previously healthy 6-year-old boy developed symptoms of small intestinal obstruction and was found to have a large intraabdominal mass. At laparotomy the mass involved the jejunum and adjacent mesenteric lymph nodes, requiring resection. Microscopic and immunohistochemical studies demonstrated a T-cell non-Hodgkin's lymphoma, confirmed by finding clonal T-cell receptor-beta and -gamma gene rearrangements by Southern blot analysis. The immunophenotype of this lymphoma-CD3+CD4-CD8-CD56+TIA-1+ beta F1(-)-suggests that the tumor cells are cytotoxic natural killer (NK)-like T cells, probably of CD3+CD4-CD8- intraepithelial cell origin. Examination of the adjacent and distal small intestinal mucosa failed to show any significant pathologic change. This case was unusual because intestinal lymphomas in children are usually of B-cell origin and most commonly have small noncleaved cell morphology. Childhood intestinal T-cell lymphomas have not been the focus of specific study but appear to be rare. In adults, intestinal T-cell lymphomas often arise in the background of gluten-sensitive enteropathy (celiac disease). In contrast, this child had peripheral T-cell lymphoma, with NK-like T-cell features, in the small intestine with no clinical or histologic evidence of enteropathy.

Immunohistochemical reference ranges for B lymphocytes in bone marrow biopsy paraffin sections.

The quantitation of B lymphocytes in paraffin-decalcified bone marrow sections is often used as supportive evidence of primary or residual B-cell lymphoproliferative disorders; however, well-defined normal ranges for B lymphocytes are not available. Thirty-four B5-fixed decalcified bone marrow sections were analyzed from a group of patients having an essentially normal bone marrow morphologic examination and lacking any evidence immunologic or hematopoietic disease. All samples were stained with CD20, CD45RA (4KB5), and DBA.44 for B cells, and CD45RO (UCHL-1) for T cells. Image analysis was performed on all cases. CD20-positive cells ranged from 0% to 5.97%. CD45RA positivity ranged from 0% to 5.48%. DBA.44 was positive in 0% to 2.07% of the cells. CD45RO positivity varied from 0% to 6.7%. These results provide useful immunohistochemical B-lymphocyte reference ranges in B5-fixed paraffin bone marrow sections.

Work-up of lymphadenopathy in children.

Lymphadenopathy occurs frequently in childhood caused by both reactive and neoplastic origins. Correlation of clinical findings, historical information, and patient symptoms may provide important insights into the cause of lymphadenopathy. When malignancy is suspected or if a child does not respond to antibiotic therapy, nodal biopsy or cytological examination may be undertaken to establish a diagnosis. Proper handling of pathologic materials will enhance the pathologist's ability to make an accurate diagnosis and may allow for important ancillary testing to be performed.

Benign lymphadenopathies in children and adolescents.

This article provides and overview of the benign causes of lymphadenopathy (LA) in the pediatric population. Because of the topics' broad nature, this review is a selective one and primarily focuses on benign conditions of lymph nodes that may be confused with malignant disorders or have been described or better defined in recent years. Specifically, these will include infectious LA caused by Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and cat scratch disease (CSD), LA associated with vaccination, drug-associated LA, progressive transformation of germinal centers (PTGC), LA associated with autoimmune disorders, histiocytic proliferations involving lymph nodes, and Kawasaki disease.

Classification of non-Hodgkin's lymphomas in children.

Pediatric non-Hodgkin's lymphomas (NHLs) comprise an important subset of childhood malignancies with characteristic clinical, histologic, cytogenetic, and immunologic findings. Lymphoblastic lymphoma, small noncleaved cell lymphoma, and large cell lymphomas comprise the vast majority of childhood NHLs. Proper distinction of these subsets of NHL has important therapeutic and prognostic implications for the patient.

Immunohistochemical staining for DNA topoisomerase II in non-Hodgkin's lymphomas.

DNA topoisomerase II (topo II) is the target of several clinically useful anticancer drugs. Several of these agents, such as doxorubicin and etoposide (VP-16), are used to treat non-Hodgkin's lymphomas (NHL). To understand the therapeutic selectivity of these drugs, a series of 33 cases of NHL for topo II were analyzed using an immunohistochemical technique that detects the enzyme in formalin-fixed, paraffin-embedded tissue. The average topo II index of high grade (Working Formulation) NHL was 48.6 with a range from 24.4 to 79.7. The average topo II index of low grade (Working Formulation) NHL was 4.4 with a range from 0.9 to 11.2. These two values are statistically different (P < .01). The intermediate grade (Working Formulation) NHL are a heterogeneous group based on topo II staining. The average topo II index value for the intermediate grade neoplasms was 26.7 with a range from 1.4 to 54.9. Because the proliferation marker Ki-67 has been shown to be of prognostic importance when used in the analysis of NHL, 27 cases for also were analyzed for MIB1 (Ki-67). The average MIB1 index of the high grade NHL was 59.8 with a range from 40.7 to 80.3. This average is statistically different (P < .01) than the average MIB1 index of 11.2 (range 1.7-28.3) found in the low grade NHL. Similar to results with topo II, the intermediate grade NHL was a heterogeneous group of tumors with respect to MIBI staining and had an average MIB1 index of 49.1 with a range from 8.9 to 86.7. These results show that high grade NHL have topo II and MIB1 indices that are significantly higher than low grade NHL. Intermediate NHL are more heterogeneous and have topo II and MIB1 indices that range from low to high.

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.

Immunohistochemical staining for DNA topoisomerase II in frozen and formalin-fixed paraffin-embedded human tissues.

DNA topoisomerase II is the molecular target of several clinically useful chemotherapeutic drugs. The sensitivity of cells to drugs that target topoisomerase II is dependent on the cellular content of this enzyme. Drug-sensitive cells have elevated amounts of type II topoisomerase. To determine relative amounts of enzyme in malignant neoplasms, we developed an in situ immunohistochemical stain for topoisomerase II. The stain uses either polyclonal or monoclonal antibodies produced against the alpha isoform of the enzyme. Staining can be done on both frozen and formalin-fixed, paraffin-embedded tissues. By using this immunostain, we found marked differences in enzyme content in several human malignancies.

T-cell lymphocytosis associated with invasive thymomas.

Peripheral T-cell lymphocytosis and bone marrow infiltration is a rarely associated feature of invasive thymomas. Hypotheses for the origin of the circulating lymphocytes include a spillover of tumor lymphocytes into the circulation, a neoplastic lymphoid proliferation, and a reactive proliferation of peripheral lymphocytes resulting from a thymoma-induced immunoregulatory disorder. The authors describe two cases of peripheral T-cell lymphocytosis associated with invasive thymomas with a predominantly lymphocyte-rich, cortical type histologic appearance. In both cases T cells constituted as much as 99% of the circulating lymphoid cell population, according to flow-cytometric analysis before and after treatment, and expressed a mature phenotype consistent with medullary thymic or peripheral T cells (CD2+, CD3+, CD4+ or CD8+, CD5+, CD7+) with predominant expression of the alpha/beta T-cell receptor heterodimer. Bone marrow biopsy specimens showed nodular and interstitial infiltrates of small T cells. No monoclonal rearrangement of the T-cell receptor beta gene was observed. Both cases had a normal female karyotype. Our findings confirm those of previous studies supporting a reactive origin for the peripheral lymphocytosis. Although an immunoregulatory disorder is probably involved in lymphocyte proliferation in situ, we postulate that peripheral lymphocytosis results from augmented release of the more mature thymoma-associated lymphocytes into the circulation through tumor invasiveness. A thymic origin is supported by the presence of a subset of peripheral T cells with low-intensity CD5 expression.