CNS involvement in children with newly diagnosed non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

Large proportion of Epstein-Barr virus-associated small noncleaved cell lymphomas among children with non-Hodgkin's lymphoma at a single institution in Moscow, Russia.

To evaluate clinical and biologic features of children with non-Hodgkin's lymphoma (NHL) treated in Moscow, Russia, we studied 53 cases treated in the Republican Children's Hospital from 1990 to 1994. Histologic examination disclosed a predominance of the small noncleaved cell subtype (32 cases, 60%); a smaller percentage of the lymphoblastic and large-cell subtypes (14 cases, 26% and 7 cases, 13%, respectively) were identified. The frequencies of primary sites of involvement in descending order included 60% in abdomen, 19% in mediastinum, 15% in head/neck, and 4% in peripheral nodes. The majority of children presented with advanced stage disease (St. Jude stage III/IV/B-ALL, 92.5%). Of interest, 8 of 15 (53%) small noncleaved cell NHL cases examined contained Epstein-Barr virus (EBV). The high frequency of EBV association in this study suggests that this virus may play a more global role in NHL pathogenesis than previously recognized.

Treatment of children and young adults with early-stage non-Hodgkin's lymphoma.

BACKGROUND: Children and young adults with early-stage non-Hodgkin's lymphoma have an excellent prognosis, but treatment is prolonged and is associated with many side effects. We performed two studies to determine whether therapy could be simplified. METHODS: Between 1983 and 1991, we conducted two consecutive trials in children and young adults (age, <21 years) with early-stage non-Hodgkin's lymphoma. In the first trial, patients were treated for 9 weeks with induction chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, and prednisone, followed by 24 weeks of continuation chemotherapy with mercaptopurine and methotrexate. Half the patients were randomly assigned to receive involved-field irradiation. In the second trial, after the 9 weeks of induction chemotherapy, the patients were randomly assigned to receive 24 weeks of continuation chemotherapy or no further therapy. RESULTS: A total of 340 patients were enrolled in the two trials, 12 of whom did not have complete remissions. One hundred thirteen patients received nine weeks of chemotherapy without radiotherapy, 131 received eight months of chemotherapy without radiotherapy, and 67 received eight months of chemotherapy with radiotherapy. At five years, the projected rates of continuous complete remission were 89, 86, and 88 percent for the three groups, respectively. At five years, event-free survival among the patients with early-stage lymphoblastic lymphoma was inferior to that among the patients with other subtypes of lymphoma (63 percent vs. 88 percent, P<0.001). Continuation therapy was effective only in patients with lymphoblastic lymphoma. CONCLUSIONS: A nine-week chemotherapy regimen without irradiation of the primary sites of involvement is adequate therapy for most children and young adults with early-stage, nonlymphoblastic non-Hodgkin's lymphoma.

Fractionated cylophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (SNCCL): a randomized trial of the Pediatric Oncology Group.

BACKGROUND: The Pediatric Oncology Group (POG) conducted a two-arm, randomized study for the treatment of children and adolescents with stage III small, non-cleaved cell lymphoma (SNCCL). Regimen A, based on the group's previous best treatment for this group of patients, included cyclophosphamide (CTX) and high-dose methotrexate (MTX), as well as vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemoprophylaxis. Regimen B, based on a single institution pilot study (Total B therapy), consisted of two rapidly alternating chemotherapy combinations (CTX, VCR, doxorubicin; MTX, and cytarabine (Ara-C) plus coordinated IT chemotherapy. PROCEDURE: One hundred thirty-four consecutive patients were entered on this study. Seventy patients were randomized to Regimen A, and 64 patients to Regimen B. One hundred and twenty-two patients are eligible for response. RESULTS: Complete remission (CR) was achieved by 81% (52/64) of patients on Regimen A, and 95% (55/58) of patients on Regimen B (p=0.014 one-sided). The two-year event-free survival (EFS) is 64% (SE=6%) on Regimen A, and 79% (SE=6%) on Regimen B (p=0.027 by one-sided logrank test). No patient has relapsed on either regimen after a year from diagnosis, although one patient had a second malignancy at day 371. Severe, but manageable, hematologic toxicity was seen in the majority of patients on both regimens, but was more frequent on Regimen B. CONCLUSIONS: We conclude that the cure rate in stage III SNCCL is significantly improved with the use of a short, six-month chemotherapy regimen of fractionated CTX alternated with coordinated MTX and Ara-C. Results suggest that drug schedule, not simple drug selection, influences outcome.

Predominance and characteristics of Burkitt lymphoma among children with non-Hodgkin lymphoma in northeastern Brazil.

The purpose of this paper was to define the histologic distribution, clinical features, and treatment response of childhood non-Hodgkin lymphoma (NHL) in northeastern Brazil. We reviewed medical records and histopathologic studies of 98 children treated for NHL from 1980 to 1987 at a major pediatric cancer center in Recife, Brazil. Treatment outcome was evaluated in relation to tumor burden (stage and serum LDH) and type of therapy (LSA2L2 vs other multiagent chemotherapy). There was a striking predominance of the small noncleaved cell (Burkitt) subtype, which occurred in 92 of the 98 children and adolescents diagnosed with NHL. Subsequent analyses focused on these patients. The majority (n = 84) had advanced (stage III/IV) disease at diagnosis. The abdomen was the most common site of disease (84 cases); jaw involvement was rare (three cases). Five-year event-free survival (excluding treatment refusals) was significantly better for patients with limited vs advanced stage disease (75 +/- 14% vs 42 +/- 6%; P < 0.04). Elevated serum LDH (>500 U/l) was associated with a poorer outcome (P = 0.008). The type of chemotherapy did not affect EFS (P = 0.95). Only 39% of patients are long-term survivors, reflecting the high rate of septic deaths (25% of patients) and parental refusal/abandonment of therapy (10%). Epstein-Barr virus (EBV) was detected in tumor cells from eight of the 11 cases studied. In clinical presentation, these cases resemble sporadic Burkitt lymphoma, yet in their apparent responsiveness to LSA2L2 therapy and association with EBV, they do not. Childhood NHL in northeastern Brazil is predominantly of the Burkitt subtype, and is associated with clinical features that appear to distinguish it from the endemic and sporadic forms of this tumor. These cases may represent a third or intermediate subtype of Burkitt lymphoma.

The spectrum of mucosa-associated lymphoid tissue lesions in pediatric patients infected with HIV: A clinicopathologic study of six cases.

Mucosa-associated lymphoid tissue (MALT) lesions in nonimmunocompromised individuals include reactive lymphoid proliferations and both low- and high-grade lymphoid neoplasms. These lesions occur at extranodal mucosal sites, such as the gastrointestinal tract, bronchus, salivary gland, and other locations. The spectrum of MALT lesions in children with HIV infection had not been previously described. In this study, six cases that demonstrated the spectrum of MALT lesions in pediatric patients, aged 28 months to 23 years, who had HIV infection were described. Half the patients acquired the infection perinatally, and half acquired it by transfusion. Mucosal sites of involvement included the salivary gland (4 patients), bronchiolar mucosa (2 patients), and oropharyngeal mucosa (1 patient). One patient had lesions in lung and oropharynx sequentially; all others had involvement of solitary sites. The histologic diagnoses included myoepithelial sialadenitis (MESA), MESA with low-grade MALT lymphoma, typical low-grade MALT lymphoma, diffuse large cell lymphoma (DLCL), and atypical pulmonary lymphoid hyperplasia and lymphoid interstitial pneumonitis complex. The two cases of high-grade DLCL were confined to mucosal sites (tonsil and parotid); in one of these patients, a previous biopsy specimen showed a MALT lesion with low-grade features. In two cases, quantitation of the Epstein-Barr virus (EBV) genome by the polymerase chain reaction showed a very high copy number in peripheral blood mononuclear cells but a low copy number in the MALT lesion, which suggested that MALT lesions may not be directly associated with EBV infection. Two patients who had high-grade tumors (DLCL) were successfully treated with chemotherapy and radiation therapy. The remaining patients, all of whom had low-grade MALT lesions, received either corticosteroids or alpha-interferon or no specific therapy; in all patients, the lesions followed an indolent clinical course. Clinicians and pathologists should be alert to the possibility that MALT lesions, including MALT lymphomas, may be present in children who have AIDS.

Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood.

BACKGROUND: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase inappropriately expressed in lymphoid tissue involved by CD30+ anaplastic large-cell lymphoma (ALCL) with the translocation t(2;5)(p23;q35)(, which juxtaposes the nucleophosmin gene (NPM) with that encoding ALK, resulting in a hybrid (NPM-ALK) message. PATIENTS AND METHODS: A polyclonal antibody against residues of the kinase portion of NPM-ALK (designated anti-ALK 11) was tested for clinical utility in paraffin sections of 44 cases of pediatric large-cell lymphoma (LCL) and 17 additional lymphoma cases, by streptavidin-biotin-alkaline phosphatase method. RESULTS: Nineteen of 20 CD30+ cases (the majority exhibiting anaplastic morphology) labeled with anti-ALK 11, and 5/28 CD30- cases were also ALK+ (3 T cells, 1 null cell, and 1 B cell). Sixteen of 17 B-cell pediatric LCLs were negative, as were 6/6 cases of Hodgkin's disease and 7/7 cases of adult B-cell lymphoma. In pediatric LCLs with adequate follow-up (24/44 ALK+), there was no significant association between ALK expression and two-year event-free survival, similar to the finding reported previously for CD30 expression in these cases. CONCLUSION: We conclude that the majority of pediatric CD30+ ALCLs show ALK overexpression, consistent with the presence of the t(2;5)-encoded NPM-ALK fusion, but that the clinical significance of this entity remains unproven.

The problem of classifying lymphomas: an orderly prescription for progress.

In the late 1960s and early 1970s, the most widely recognized 'new' classifications of the non-Hodgkin's lymphomas were those proposed by Rappaport (the 'Rappaport' classification) and by Lennert (the 'Kiel' classification). With the advent of immunologic and histochemical markers in the early 1970s, however, new concepts arose to supplement the traditional purely morphologic approach to diagnosis and classification of these tumors. Lymphomas were increasingly recognized to be neoplasms of the immune system, composed of malignant proliferations which retained many of the morphologic and functional characteristics of their normal counterparts. These advances led to a flurry of new classifications proposed in 1974-1976, leading to confusion for both clinicians and pathologists, perhaps most evident at the International Cancer Congress in Florence in 1974. To address this problem, the National Cancer Institute (USA) sponsored an international workshop of expert pathologists and clinicians on 4-5 September 1975. It became apparent at that meeting that only a well-planned retrospective study would provide data for meaningful progress and resolution of differences. From 1976 to 1980, such a massive collaborative project was accomplished and served as the basis for the Working Formulation for Clinical Usage, proposed as a vehicle for translation among the six tested schema. Since the Working Formulation was published in 1982 there have been momentous strides in scientific and clinical understanding of these cancers, fueled by contributions from immunology, cytogenetics, and molecular biology. To recognize and disseminate understanding of these newer observations, the International Lymphoma Study Group promulgated in 1994 a new proposal entitled 'A Revised European-American Classification of Lymphoid Neoplasms'. As a sequel to another international assembly of pathologists and clinicians, held at the National Cancer Institute (USA) on 21-23 March 1994, a second large-scale retrospective study has been accomplished, the results of which were presented at the Sixth International Conference on Malignant Lymphoma, 5-8 June 1996, along with data from other institutions and cooperative groups. Concurrent with these events, the World Health Organization has enlisted a committee of expert pathologists to prepare a new edition of 'Neoplastic Diseases of Hematopoietic and Lymphoid Tissues'. Composed of 10 pathology subcommittees and a clinical advisory committee, with broad international representation, this body should generate in the near future a consensus proposal with broad scientific and geographic support. These historical and ongoing efforts in lymphoma pathology are a paradigm for progress in clinicopathologic understanding of all cancers.

Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations.

Multidrug resistance (MDR), especially that associated with overexpression of MDR1 and its product, P-glycoprotein (Pgp), is thought to play a role in the outcome of therapy for some human tumors; however, a consensus conclusion has been difficult to reach, owing to the variable results published by different laboratories. Many factors appear to influence the detection of Pgp in clinical specimens, including its low and heterogeneous expression; conflicting definitions of detection end points; differences in methods of sample preparation, fixation, and analysis; use of immunological reagents with variable Pgp specificity and avidity and with different recognition epitopes; use of secondary reagents and chromogens; and differences in clinical end points. Also, mechanisms other than Pgp overexpression may contribute to clinical MDR. The combined effect of these factors is clearly important, especially among tumors with low expression of Pgp. Thus, a workshop was organized in Memphis, Tennessee, to promote the standardization of approaches to MDR1 and Pgp detection in clinical specimens. The 15 North American and European institutions that agreed to participate conducted three preworkshop trials with well-characterized MDR myeloma and carcinoma cell lines that expressed increasing amounts of Pgp. The intent was to establish standard materials and methods for a fourth trial, assays of Pgp and MDR1 in clinical specimens. The general conclusions emerging from these efforts led to a number of recommendations for future studies: (a) although detection of Pgp and MDR1 is at present likely to be more reliable in leukemias and lymphomas than in solid tumors, accurate measurement of low levels of Pgp expression under most conditions remains an elusive goal; (b) tissue-specific controls, antibody controls, and standardized MDR cell lines are essential for calibrating any detection method and for subsequent analyses of clinical samples; (c) use of two or more vendor-standardized anti-Pgp antibody reagents that recognize different epitopes improves the reliability of immunological detection of Pgp; (d) sample fixation and antigen preservation must be carefully controlled; (e) multiparameter analysis is useful in clinical assays of MDR1/Pgp expression; (f) immunostaining data are best reported as staining intensity and the percentage of positive cells; and (g) arbitrary minimal cutoff points for analysis compromise the reliability of conclusions. The recommendations made by workshop participants should enhance the quality of research on the role of Pgp in clinical MDR development and provide a paradigm for investigations of other drug resistance-associated proteins.

B-cell lineage confers a favorable outcome among children and adolescents with large-cell lymphoma: a Pediatric Oncology Group study.

PURPOSE: The goal of this study was to assess the immunophenotype of uniformly treated cases of pediatric large-cell non-Hodgkin's lymphoma (NHL) to determine the prognostic importance of B-cell and T-cell lineages and of CD30 positivity. PATIENTS AND METHODS: Sixty-nine patients were analyzed by immunochemistry. All patients were classified histologically, staged in a uniform manner, and treated according to one of two protocols for localized (stage I and II) NHL or advanced (stage III and IV) large-cell NHL. Antibodies included anti-CD45, CD20, CD45Ra, MB-2 (not clustered), CD3, CD45Ro, CD43, CD15, CD30, and CD68. Statistical analysis used the exact conditional chi 2 and Kruskall-Wallace tests for clinical features and the log-rank test to evaluate event-free survival (EFS). RESULTS: Immunophenotypic results demonstrated 25 B-cell, 23 T-cell, and 21 indeterminate lineage. Twenty-seven patients expressed CD30 (17 T-cell and 10 indeterminate lineage), and of these, 22 showed histology of anaplastic large-cell lymphoma (ALCL). B-cell patients were older (P = .018) and showed more favorable survival than patients with T-cell or indeterminate lineage (96% EFS at 3 years, 96% v 67% and 74%, B v T and indeterminate lineage [P = .027]). B-cell lineage was seen more frequently in limited-stage patients, but was also associated with favorable survival when stratified for stage (P = .036). CD30 expression (P = .96) and ALCL histology (P = .90) did not show significant associations with survival. CONCLUSION: We conclude that among pediatric large-cell lymphomas, B-cell lineage is proportionately less frequent than in adults and CD30 antigen-expressing lymphomas are frequent among patients with T-cell and indeterminate lineage. B-cell phenotype tends to occur in older children and is associated with superior survival.

Clinicopathologic features and treatment outcome of children with large-cell lymphoma and the t(2;5)(p23;q35).

The t(2;5)(p23;q35) was detected in 9 of the 18 cases of large-cell lymphoma with an abnormal karyotype among 115 children with large-cell lymphoma treated at St Jude Children's Research Hospital from 1975 to 1993. When the cases containing the t(2;5) were classified according to the National Cancer Institute Working Formulation, 7 were large-cell, immunoblastic and 2 were diffuse large cell; according to the Kiel classification system, 6 were anaplastic large cell, 2 immunoblastic, and 1 centroblastic. CD30 expression was documented in 6 of 8 cases tested. All patients had nodal disease and 6 had extranodal involvement (bone in 4 cases and skin in 3). Eight of nine had advanced disease at diagnosis (stage Ill in 7 and stage IV in 1). Complete remission (CR) was attained in all patients and 6 remain in first CR for 19+ to 97+ months. Three relapsed, but successfully obtained second remissions; 2 are 58+ and 80+ months after retrieval therapy for local recurrences, and 1 patient died of recurrent disease. The t(2;5)(p23;q35) is associated with, but not limited to, anaplastic histology, a CD30+ T-cell phenotype, advanced stage disease with nodal (+/- extranodal) involvement, and chemosensitivity at diagnosis and relapse.

Factors contributing to the prognostic significance of bone marrow involvement in childhood non-Hodgkin lymphoma.

To evaluate the clinical characteristics and treatment outcome of childhood non-Hodgkin lymphoma (NHL) cases with bone marrow involvement, we studied 13 lymphoblastic, 15 small noncleaved cell, and 8 large cell cases with tumor cells in their marrow. They represented 16%, 11%, and 9% of consecutive NHL cases with these respective histologic subtypes. The treatment outcome differed significantly according to histologic subtype--the 5-year event-free survivals (EFS +/- SE) for large cell NHL, small non-cleaved cell NHL, and lymphoblastic NHL cases were 11 +/- 8%, 40 +/- 20%, and 62 +/- 15%, respectively. Increased serum lactate dehydrogenase (LDH) levels (> 500 U/L) were associated with a poorer EFS (5-year EFS, 0% vs. 50 +/- 10%; P < 0.001). Children < or = 5 years of age had a poorer EFS survival than older children (5-year EFS, 14 +/- 9% vs. 44 +/- 10%; P = 0.03). The degree of bone marrow involvement (< 5% vs. > or = 5%) and race were not significantly associated with treatment outcome. Although intensive chemotherapy has substantially improved survival for patients with advanced stage lymphoblastic or small noncleaved cell lymphoma, patients with large cell NHL and associated marrow involvement continue to have a dismal outcome and require novel or more intensive therapy.

Large cell non-Hodgkin lymphoma of childhood: clinical characteristics and outcome.

Less is known about the clinical features and treatment outcome in pediatric large cell non-Hodgkin lymphoma (NHL) than the lymphoblastic and small noncleaved cell subtypes of NHL. To characterize presenting features and assess possible risk factors associated with this diagnosis, we analyzed data for 91 patients treated on a succession of multiagent regimens from 1975 to 1990. Five-year event-free survival (EFS) (+/- SE) was related to disease extent (St Jude system): stage I (n = 24), 95% +/- 5%; stage II (n = 20), 84% +/- 9%; stage III (n = 38), 50% +/- 10%; and stage IV (n = 9), 22% +/- 11%. Advanced stage disease, age < or = 5 years and serum LDH > 500 U/l were associated with poorer EFS in the univariate model (p < 0.001, 0.005, and 0.002, respectively). In the multivariate model, advanced stage and age retained prognostic significance (p = 0.001 and 0.02, respectively), but LDH did not. Among limited stage cases, age < or = 5 years was the only adverse risk feature (p = 0.016); treatment era (pre- vs. post-1979) was the only significant feature in patients with advanced disease (p = 0.004). Intrathoracic primaries were associated with a better outcome than other sites among the 38 stage III patients (p = 0.005). Only one of eight patients with bone marrow disease remains failure-free. The excellent results for limited stage pediatric large cell NHL permit consideration of treatment modifications to decrease toxicity; for cases with advanced disease, especially those with bone marrow involvement, novel therapeutic approaches are clearly needed.

Extranodal primary tumor site indicates poor prognosis in childhood head and neck non-Hodgkin's lymphomas.

As a result of the diversity of lymphoid structures in the head and neck, we analyzed clinical characteristics and outcomes of 87 consecutive children with non-Hodgkin's lymphoma (NHL) arising in this region to determine if the nodal versus extranodal primary site influences prognosis. Thirty-one children had primary nodal NHL whereas 56 had extranodal NHL. The two groups were similar in the distribution of age, gender, race, serum lactic dehydrogenase levels, and disease stage. However, extranodal tumors were slightly more likely to have small non-cleaved cell histology (32/56 versus 11/31, p = 0.07) than nodal tumors. In a multivariate analysis, extranodal involvement (p = 0.017), advanced stage disease (p = 0.054) and treatment era (p = 0.056) were each significantly associated with a shorter time of event-free survival. Children with extranodal and extralymphatic NHL had an even worse treatment outcome than did others (p = 0.006). The poor prognosis of extranodal involvement was also evident among children with stage I or II NHL. We conclude that extranodal involvement has an adverse influence on treatment outcome in children with NHL arising in the head and neck region.

Clinical significance of histology and immunophenotype in childhood diffuse large cell lymphoma.

To correlate the histologic subtype of diffuse large cell (DLC) lymphoma with immunophenotype, clinical features, and treatment outcome, 88 consecutively diagnosed children with this disease were studied. Of these cases, 42 (48%) were immunoblastic (IB), polymorphous subtype; 17 (19%) IB, plasmacytoid; 8 (9%) IB, clear cell; 6 (7%) IB, not otherwise specified; and 15 (17%) DLC-follicular center cell (DLC-FCC) type. Of 34 cases successfully phenotyped from paraffin sections, 13 were T cell and 9 were B cell; of the remaining cases, 8 were suggestive of T-cell lineage, 3 of B-cell lineage, and 1 of histiocytic differentiation. Although histologic subtype did not correlate with clinical features or outcome, it did correlate with immunophenotype among those cases for which lineage could be unequivocally assigned (5 of 18 IB vs. 4 of 4 DLC cases were B cell; P = 0.02) Immunophenotype was also correlated with stage of disease (11 of 13 T-cell vs. 3 of 9 B-cell cases had stage III-IV disease; P = 0.03). (Stage III includes all primary thoracic tumors; stage IV includes all with central nervous system and/or bone marrow involvement.) Significant prognostic features were clinical stage and era (thus type) of therapy (P less than 0.001). The authors conclude that most cases of large cell non-Hodgkin's lymphoma in children are of IB morphologic type, most frequently of T-cell lineage, and those with T-cell phenotype appeared to have more advanced disease.

Pleural effusion is associated with a poor treatment outcome in stage III small non-cleaved cell lymphoma.

The clinical significance of pleural effusion was assessed in 24 children with unresectable abdominal small non-cleaved cell lymphoma (St. Jude Stage III). Patients were consecutively enrolled and treated on a regimen including high dose fractionated cyclophosphamide and co-ordinated high dose methotrexate and cytarabine. The overall results were excellent, with 20 of 24 patients alive and event-free at a median follow-up of 4 years. Only one of the patients who lacked pleural effusion has relapsed (testicular), even though many had massive disease. In contrast, three of seven patients with pleural effusion have failed treatment (p = 0.02) and subsequently died. Two measures of tumor burden, serum lactic dehydrogenase and, in a subset of patients, interleukin-2-receptor levels, were significantly higher in patients with pleural effusion (p = 0.002 and p = 0.05, respectively). These findings suggest that unresectable abdominal small non-cleaved cell lymphoma associated with pleural effusion should be up-staged and that these patients should receive more intensive chemotherapy.

Follicular lymphomas in pediatric patients.

The clinicopathologic features of twenty cases of follicular lymphoma (FL) in pediatric patients are described. Fifteen boys and five girls were 2 to 20 yr (mean 10 yr) of age at diagnosis. In ten cases (50%) the lymphoma was localized in lymph nodes and in ten cases (50%) in extranodal sites. Fifteen patients had stage I, two stage II and three stage III disease at the time of presentation. The faucial tonsils were the primary site in seven cases, other head and neck sites in five, inguinal lymph nodes in four and possibly another, and the abdomen in two. Six cases (30%) were classified as follicular small cleaved cell type (FSCC), five (25%) as follicular mixed small cleaved and large cell (FMC), and nine (45%) as follicular large cell (FLC). The architectural pattern was purely follicular (F) in five cases (20%), predominantly follicular (F greater than D) in six (30%), follicular and diffuse (F = D) in six (30%) and predominantly diffuse (F less than D) in three (15%). In one case a progression from F greater than D LC to F less than D LC was documented. All patients attained complete remission (CR). One died of acute lymphoblastic leukemia 7 yr after the original diagnosis of FSCC non-Hodgkin's lymphoma (NHL), but the others are all alive and free of disease with a follow-up ranging from 6 mo to 16 yr (median 4 yr). In three patients therapy was initially deferred with no known adverse influence on outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of treatment of childhood localized non-Hodgkin's lymphoma with combination chemotherapy with or without radiotherapy.

Combined radiotherapy and intensive chemotherapy have led to improved prognosis in children with non-Hodgkin's lymphoma, but the toxic effects of these forms of treatment are additive and seriously limit the benefits of their use. In an effort to limit the adverse acute and late effects of treatment, we conducted a randomized, controlled trial to determine whether irradiation of primary sites of involvement could safely be omitted from the treatment of children with localized non-Hodgkin's lymphoma (Stages I and II) who have a favorable prognosis. In addition, the chemotherapy regimen was less intense and shorter (eight months) than usual. A total of 129 patients were randomly assigned to receive either chemotherapy (vincristine, cyclophosphamide, doxorubicin, prednisone, mercaptopurine, and methotrexate) with irradiation (27 Gy) of the involved field (combined chemotherapy and radiotherapy) or chemotherapy alone. Half the patients have been followed for more than 38 months (range, 13 to 68), and the projected disease-free survival (+/- SE) at four years among patients assigned to chemotherapy alone is 87.9 +/- 8.8 percent, as compared with 87.3 +/- 9.4 percent among patients assigned to combined therapy (P = 0.44). The majority of patients tolerated therapy very well, although the toxic effects of treatment (myelosuppression, mucositis, and infection) were significantly worse among patients who received the combination of chemotherapy and radiotherapy. We conclude that most children with localized non-Hodgkin's lymphoma can be cured by a chemotherapy regimen of reduced intensity and duration. Radiotherapy can be safely omitted from the therapy of such children without substantially jeopardizing their excellent chance of cure.

Prognostic factors for patients with diffuse large cell or immunoblastic non-Hodgkin's lymphomas: experience of the non-Hodgkin's Lymphoma Pathologic Classification Project.

Prognostic factors for long-term survival of 312 patients with diffuse large cell or immunoblastic non-Hodgkin's lymphoma are presented based on analysis of the multiinstitution clinicopathologic study sponsored by the National Cancer Institute. At the time of analysis, 75% of the patients had died and the median follow-up for patients still alive was 11 years. The distribution of Ann Arbor stages was 21% stage I, 32% stage II, 17% stage III, and 30% stage IV. Factors of prognostic significance for survival included age, stage, histologic subtype, presence of B symptoms, size of the largest lesion, number of extra-lymphoid organs involved, and extent of lymphatic involvement. Recursive partitioning analysis suggested a prognostic classification system based on stage, age, size of the largest lesion, and presence of mediastinal involvement. Stage I patient less than 50 years of age had a 10 year survival rate of 65% compared to 36% for older stage I patients. Stage II patients less than 65 years old without bulky lesions or mediastinal involvement had a 10 year survival rate of 45% compared to 10% for the poorer risk stage II patients. Although statistically significant prognostic factors were identified for the stage III/IV patients, they were not strong discriminants of 5-10 year survival rate. Because of the correlation among potential prognostic factors, there is no uniquely best classification system. Reasons for discrepancies among reported prognostic factor analyses are discussed, and a prognostic grouping that synthesizes our results with those of others is proposed.

High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkin's disease.

To improve the biologic evaluation of Hodgkin's disease, we determined serum interleukin-2 receptor (IL2R) levels in 88 children with this tumor. In patients with stage III or IV disease, the median receptor level was significantly higher than in patients with lower stages (3195 vs. 1087 U/ml, p = 0.0001). Similarly, the median level for children with stage B disease was 3262 U/ml, compared with 999 U/ml for those lacking constitutional symptoms (p = 0.0001). Patients with very high soluble IL2R levels (greater than or equal to 5000 U/ml) were significantly more likely to fail treatment (p = 0.01), even when the analysis was restricted to groups with advanced disease: stages III and IV (p = 0.0001). When entered in the Cox-proportional hazards model with other potentially useful prognostic factors, soluble IL2R level was found to be an independent predictor of treatment outcome. The relationship of high serum IL2R levels to an adverse clinical outcome in Hodgkin's disease may be explained by a model in which the soluble receptor competes for the ligand with the cellular receptor on normal lymphocytes, thus blocking antitumor immunity dependent on interleukin-2. Alternatively, high serum levels of IL2R may simply reflect increased release of the receptor from activated malignant cells in patients with advanced disease or an otherwise poor prognosis.