Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues.

BACKGROUND: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing. PROCEDURE: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55). RESULTS: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL. CONCLUSIONS: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases.

The immunophenotype of T-lymphoblastic lymphoma in children and adolescents: a Children's Oncology Group report.

T-lymphoblastic leukaemia (T-ALL) and T-lymphoblastic lymphoma (T-LBL) are neoplasms derived from immature lymphoid cells of T-cell lineage. These neoplasms are biologically similar, but significant differences may exist between the two given their clinical differences. Although ample data regarding the immunophenotypic characterization T-ALL are available, there is a paucity of such data in children and adolescents with T-LBL. We used flow cytometry and/or immunohistochemistry to characterize the immunophenotypic profile of 180 children and adolescents with newly diagnosed T-LBL enrolled in the Children's Oncology Group 5971 study. Multiple T-cell, B-cell, myeloid, and other markers were evaluated. We identified diagnostically useful immunophenotypic features of T-LBL as well as distinct immunophenotypic subgroups, although none of these was statistically related to event-free or overall survival in this retrospective analysis. Further studies of biologically and immunophenotypically distinct subgroups of T-LBL, such as the early T-cell precursor phenotype, are warranted.

Primary follicular lymphoma of the testis in children and adolescents.

This study reports 6 cases of primary follicular lymphoma of the testis (PFLT) in children and adolescents correlated with clinical presentation, pathologic features, treatment, and outcome. All 6 patients (age, 3 to 16 y; median, 4 y) had PFLT grade 3 with disease limited to the testis, completely resected and treated with 2 courses of chemotherapy (cyclophosphamide, vincristine, prednisone, doxorubicin). Event-free survival was 100% (follow-up: median, 73 mo; mean, 53 mo; range, 6 to 96 mo). In conclusion, clinical outcome in children and adolescents with PFLT is excellent with treatment including complete surgical resection and 2 courses of cyclophosphamide, vincristine, prednisone, doxorubicin.

An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961.

Burkitt lymphoma (BL), an aggressive B-cell malignancy, is often curable with short intensive treatment regiments. Nearly all BLs contain rearrangements of the MYC/8q24 region; however, recent cytogenetic studies suggest that certain secondary chromosomal aberrations in BL correlate with an adverse prognosis. In this multi-centre study, the frequency and impact on clinical outcome of del(13q) and +7 in addition to MYC rearrangements as detected by fluorescence in situ hybridization (FISH) in children and adolescents with intermediate and high-risk BL registered on Children's Cancer Group study CCG-5961 were investigated. Analysis with 13q14.3 and 13q34 loci specific probes demonstrated deletions of 13q in 38/90 (42%) cases. The loss of either 13q14.3 or 13q34 alone occurred in 14% and 8% respectively, while 20% exhibited loss of both regions. Gain of chromosome 7 was observed in 7/68 (10%) cases and MYC rearrangements were detected in 84/90 (93%). Prognostic analysis controlling for known risk factors demonstrated that patients exhibiting loss of 13q, particularly 13q14.3, had a significant decrease in 5-year overall survival (77% vs. 95%, P = 0.012). These observations indicate that del(13q) occurs in childhood BL at frequencies higher than previously detected by classical cytogenetics and underscores the importance of molecular cytogenetics in risk stratification.

Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) makes up 10-20% of pediatric non-Hodgkin lymphoma, and these patients have a significantly better prognosis than adults with DLBCL. The difference in prognosis may be related to clinical, phenotypic, and/or biological differences between adult and pediatric DLBCL. In adult DLBCL, the germinal center (GC) phenotype is associated with a better prognosis than the activated B-cell (ABC) phenotype. However, a high proliferative index and expression of Bcl2 and c-Myc protein have all been associated with worse outcomes. While multiple studies have addressed the phenotype and expression patterns of adult DLBCL, relatively little is known about these biological variables in pediatric DLBCL. The goal of this study was to investigate the proliferative index, the relative frequencies of the GC and non-GC subtypes, and the expression of Bcl2 and c-Myc protein in a cohort of children with DLBCL treated in a uniform manner. PROCEDURE: We performed immunohistochemistry (IHC) for MIB1, CD10, Bcl6, MUM1, Bcl2, and c-Myc on DLBCL tissue from children treated uniformly in the FAB LMB96 trial (SFOP LMB96/CCG5961/UKCCSG/NHL 9600). RESULTS: Compared to published adult DLBCL studies, pediatric DLBCL demonstrated moderate to high proliferation rates (83%), increased c-Myc protein expression (84%), decreased Bcl2 protein expression (28%), and an increased frequency of the GC phenotype (75%). CONCLUSIONS: These findings suggest that there are significant biologic differences between pediatric and adult forms of DLBCL, which may contribute to the superior prognosis seen in the pediatric population relative to adult disease.

Mantle cell lymphoma presenting with unusual morphology in an adolescent female: a case report and review of the literature.

We report the case of an 18-year-old female initially diagnosed with CD5-negative diffuse large B-cell lymphoma in an inguinal lymph node in 1999 who subsequently relapsed with classic-morphology mantle cell lymphoma with involvement of the bone marrow, gastrointestinal tract, and spleen in 2004. Both the 1999 and 2004 lesions were retrospectively positive for Cyclin D1 by immunohistochemistry and positive for t(11:14)(q13;q32) by fluorescence in situ hybridization, and both lesions had identical B-cell receptor gene rearrangements by polymerase chain reaction. This case of a CD5-negative large cell or pleomorphic blastoid variant of mantle cell lymphoma arising in an 18-year-old represents a very early incidence for this type of lymphoma, which is usually not seen in younger patients.

Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report.

Immunophenotypic analysis can identify protein epitopes in non-Hodgkin lymphomas (NHL) that may respond to targeted immunotherapies, such as anti-CD20 and anti-CD52. Recent studies suggest additional targets may provide therapeutic benefits in NHL. This study evaluated protein expression of CD25, CD52, CD74 and CD80 in paediatric NHL to determine possible targets for immune-based therapeutic approaches. Patient samples were derived from paediatric NHL clinical trials sponsored by the Children's Cancer Group (CCG, now the Children's Oncology Group, COG) and included Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), disseminated T- and B-cell lymphoblastic lymphoma (T-LBL and B-LBL) and anaplastic large cell (ALCL). Immunophenotypic studies were performed on formalin-fixed, paraffin-embedded diagnostic tissues. CD25 was expressed in 8% of T-LBL and 75% of ALCL cases, but not in BL, DLBCL, or B-LBL. CD52 was expressed in 99% of cases of paediatric NHL of all subtypes. CD74 was expressed in 100% of B-LBL, BL and DLBCL, but was absent in ALCL and T-LBL. CD80 was expressed in 12% of B-LBL, 6% of BL and 10% of DLBCL cases studied, but was not detected in T-cell NHL. These expression patterns suggest that CD25, CD52 and CD74 may represent potential new therapeutic targets in paediatric NHL.

Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08.

Among pediatric non-Hodgkin lymphomas, one of the most frequent types is lymphoblastic lymphoma (LBL). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but have not been evaluated for prognostic value in pediatric LBL. For the Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 13 patients were enrolled with cytogenetic analysis of LBL and on treatment protocol CCG-502. Pathology material and karyotypes at initial diagnosis were given central review. The patients were aged 6-13 years (median 9 years), with a male-to-female ratio of 12:1. All patients had advanced disease. Disease relapsed in six patients (event-free survival 54% +/- 14%, median 10.8 years). Chromosome abnormalities were identified in 11 (85%), and translocations at 14q11.2 likely involving the T-cell receptor alpha/delta locus (TCR A/D) occurred in 4 (31%). For patients with relapse, four had translocations t(1;14)(p32;q11.2), t(8;14)(q24.1;q11.2), t(11;14)(p13;q11.2), or t(9;17)(q34;q23), involving breakpoints in the regions of TAL1, MYC, LMO2, and NOTCH1, respectively. Pediatric advanced LBLs have a high frequency of chromosome abnormalities; in this limited study, these often involved translocations at 14q11.2, the site of TCR A/D. Translocations possibly involving TAL1, MYC, LMO2, or NOTCH1 may have contributed to poor outcome. Further studies are warranted in larger cohorts of children and adolescents with LBL to evaluate the prognostic significance.

Complex secondary chromosome abnormalities in advanced stage anaplastic large cell lymphoma of children and adolescents: a report from CCG-E08.

Among pediatric non-Hodgkin lymphomas, one of the most distinctive types is anaplastic large cell lymphoma (ALCL). Specific chromosomal abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but chromosome abnormalities have not been evaluated for prognostic value in pediatric ALCL. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, three patients were enrolled with cytogenetic analysis of ALCL and simultaneously enrolled on treatment protocol CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included ages of 9, 12, and 14 years, and a male/female ratio of 1:2. All patients had advanced disease (stage III). Disease progressed or relapsed in two patients, and one died. Chromosomal abnormalities, including t(2;5)(p23;q35), the ALK/NPM fusion gene, and complex karyotypes with multiple additional abnormalities, were identified in all three patients. In two patients with progressive disease or relapse, additional chromosomal abnormalities at 1q21 and 10q24, possibly involving MCL1 and HOX11/TCL3, respectively, may have contributed to worse outcome. Pediatric ALCL cases frequently have complex karyotypes and usually involve ALK/NPM translocations in this limited study. Additional chromosome abnormalities may be involved in the pathogenesis of ALCL. Further studies are warranted in larger cohorts of children and adolescents with ALCL.

Mature B-cell lymphoma in children and adolescents: International group pathologist consensus correlates with histology technical quality.

In pediatric mature B-cell non-Hodgkin lymphoma, international pathologist diagnostic agreement was previously evaluated using the Revised European-American Lymphoma Classification. Surgical biopsy histology technical quality (HTQ) is variable and may affect diagnostic accuracy. This study evaluated diagnostic agreement correlated with HTQ. Surgical biopsies obtained from international protocol FAB LMB96 Treatment of Mature B-Cell Lymphoma/Leukemia for Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and high-grade B-cell lymphoma Burkitt-like (BLL), were independently reviewed by hematopathologists from 3 national groups (Children's Cancer Group, Société Française d'Oncologie Pédiatrique, and United Kingdom Children's Cancer Study Group) to determine each national diagnosis and a final diagnosis. HTQ grades for microscopic tissue sections included: good; medium; low; inconclusive. Final diagnoses in 187 cases included: BL 87 (47%); BLL 20 (11%); DLBCL 64 (34%); other 16 (9%). HTQ grades included: good 10 (5%); medium 100 (54%); low 75 (40%); inconclusive 2 (1%). The rate of uniform agreement between the national diagnoses was significantly higher with good or medium HTQ (62%) than with low HTQ (33%) (P = 0.001). In conclusion, in pediatric mature B-cell non-Hodgkin lymphoma, international pathologist diagnostic agreement is significantly higher in surgical biopsies with better HTQ. Poor HTQ may adversely impact diagnostic ability and affect prognosis and therapeutic management when different treatment regimens are employed for DLBCL versus BL/BLL.

TCL1 expression and Epstein-Barr virus status in pediatric Burkitt lymphoma.

Elevated T-cell leukemia-1 (TCL1) oncoprotein expression might promote human Burkitt lymphoma (BL) because increased TCL1 causes Burkitt-like lymphomas in TCL1 transgenic mice. Epstein-Barr virus (EBV) infection has been implicated as a cause of increased TCL1 expression in multiple BL cell lines, suggesting a critical connection between EBV and TCL1-induced BL. The TCL1 expression and EBV status of 14 sporadic pediatric BL cases was determined by immunohistochemical staining for TCL1 and in situ hybridization for EBV-encoded RNA (EBER). Our results showed TCL1 protein in 11 cases, predominantly in the nucleus with strong-intensity staining. EBER was positive in 4 cases, with 3 of these cases also TCL1+. In the 10 cases that were EBER-, TCL1 was strongly positive in 8. These data indicate that the TCL1 oncoprotein is expressed strongly in most pediatric BL cases. However, persistent EBV is not essential for increased TCL1 expression, although elevated TCL1 and c-MYC coexpression might cooperate in the development of most pediatric and adult BL cases.

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 Children's 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. ;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.

Comparative immunohistochemical analysis of pediatric Burkitt lymphoma and diffuse large B-cell lymphoma.

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) account for nearly all pediatric nonlymphoblastic B-cell lymphomas. Because clinical behavior, prognosis, and response to therapy might differ, diagnostic accuracy is important. Morphologic examination often is sufficient, but occasionally, diagnostic ancillary studies are required. In adults, immunophenotyping is useful; however, pediatric data are limited. We characterized the immunohistochemical expression of 6 proteins (c-myc, CD10, bcl-6, bcl-2, CD138, and MIB-1) in pediatric BL (33 cases) and DLBCL (20 cases) with classic morphologic features. Significant differences in c-myc (BL, 30/33 [91%] vs DLBCL, 5/20 [25%]; P < .0001), bcl-2 (BL, 1/25 [4%] vs DLBCL, 7/19 [37%]; P < .02), and mean MIB-1 (BL, 99% vs DLBCL, 56%; P < .0001) expression were observed. There were no significant differences for CD10 (100% expression in BL and DLBCL), bcl-6 (BL, 23/33 [70%] vs DLBCL, 15/20 [75%]), or CD138 (no expression). Thus, pediatric BL and DLBCL have distinctive immunohistochemical profiles, and staining for c-myc, MIB-1, and bcl-2 might be useful in morphologically difficult cases.

Assessment of minimal residual disease in childhood non-hodgkin lymphoma by polymerase chain reaction using patient-specific primers.

A feasibility study was undertaken to identify patient-specific primers (PSPs) from childhood non-Hodgkin lymphoma (NHL) specimens to detect minimal residual disease (MRD). Eleven tumor specimens were amplified using immunoglobulin heavy chain and T-cell receptor primers to identify PSPs, which were then used to evaluate staging/follow-up specimens. Disease was detected in 19 of 21 staging and 16 of 17 follow-up specimens. Among seven patients in remission by 1 month, PSPs identified MRD in follow-up specimens. This study demonstrated the feasibility of PSPs to identify disease in staging and follow-up specimens, which could be used to develop strategies for MRD analysis in a larger setting.

Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience.

Historically, the survival of children and adolescents with Burkitt's 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 Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's 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) > or = 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 > or = 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 > or = 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 Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.

Childhood and adolescent large-cell lymphoma (LCL): a review of the Children's Cancer Group experience.

We reviewed the clinical characteristics, treatment, and outcome of 67 children with localized and 212 with disseminated large-cell lymphoma (LCL) treated during a 20-year period in 5 consecutive Children's Cancer Group (CCG) non-Hodgkin's lymphoma (NHL) trials. Clinical outcomes for patients treated on the four earlier studies with moderate-dose chemotherapy administered over 12-18 months were compared with patients treated most recently with short, intensive therapy. Median age at diagnosis was 12 years (range: 0-19 years). Male to female ratio was 1.8:1.0. Five-year event-free survival (EFS) was 92% +/- 3.3% and 50 +/- 3.5% for patients with localized LCL and disseminated LCL, respectively. After adjustment for lactate dehydrogenase (LDH), age at diagnosis, and BM involvement, short and intensive therapy as delivered on the most recent study, CCG-5911, was associated with an improved outcome (P< 0.05) compared to the four previous studies. Elevated LDH (> or = 500 IU/L) at diagnosis and young age (<5 years) were both significant independent predictors of poorer long-term EFS (P< 0.05). Long-term survival after relapse or other treatment failure was only 31% +/- 4.7%. In summary, more recent shorter and intense therapy appears to be associated with superior event-free survival for children and adolescents with disseminated LCL. Large numbers of patients treated with shorter and intense therapy are required to confirm these preliminary observations.

B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report.

Paraffin-embedded diagnostic biopsy materials from a large cohort of pediatric and adolescent patients with mature B-cell non-Hodgkin's lymphoma (NHL) treated on the Children's Cancer Group arm of an international cooperative trial were studied to determine their phenotypic features and the feasibility of using targeted bioimmune therapies. There were 345 patients eligible for analysis: 208 with Burkitt's lymphoma (BL), 43 with high-grade B-cell lymphoma, Burkitt-like (HGBL), and 94 with diffuse large B-cell lymphoma (DLBCL). Samples were immunophenotyped centrally using a standard panel that included CD20, CD79a, CD3, and CD45RO. Additional staining with CD22 was performed on a subset of cases. Immunophenotypic studies showed positive staining with CD20 in 100% of cases of BL and HGBL and in 98% of cases with DLBCL. CD22 expression was present in all cases of BL and DLBCL and in 87% of cases HGBL. This study indicates that immune-based therapies such as rituximab and ibritumomab-tiuxetan (anti-CD20) and epratuzumab (anti-CD22) are feasible in pediatric cases of mature B-cell NHLs.

Langerhans cell histiocytosis immunohistochemical expression of fascin, a dendritic cell marker.

Langerhans cell histiocytosis (LCH) is a clonal disorder believed to be derivedfrom cells of the dendritic system. Fascin, a 55-kd actin-bundling protein, represents a highly selective marker for dendritic cells of lymphoid tissues and peripheral blood and is involved in the formation of dendritic processes in maturing epidermal Langerhans cells. Since lesional cells of LCH may represent Langerhans cells arrested at an early stage of activation, immunohistochemical expression offascin in epidermal Langerhans cells and in the lesional cells of 34 cases of LCH was evaluated in paraffin sections using an immunoalkaline phosphatase technique. Though epidermal Langerhans cells were nonreactive for fascin, lesional cells in all LCH cases exhibited immunoreactivityforfascin, CD1a, and S-100 protein. Variation in staining intensity was observed in some cases, possibly reflecting differences in cell maturation or activation. Involved tissues included bone, soft tissue, lymph node, thyroid, orbit, and extradural cranial tissue. Immunoreactivity of lesional cells of LCH for fascin supports their derivation from cells of the dendritic system and represents another alteration in the phenotype of Langerhans cells that is associated with maturation, migration, culture, or clonal expansion.

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-Hodgkin's 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 Children's 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.