CHAPTER I

Introduction NHL accounts for approximately 60% of all lymphomas in children and adolescents. It represents 810% of all malignancies in children between 519 yr of age. Although >70% of patients present with advanced disease at diagnosis, the prognosis has improved dramatically, with survival rates of 9095% for localized disease and 60 90% with advanced disease.

CHAPTER II
2.1 EPIDEMIOLOGY While most children and adolescents with NHL present with de novo disease, a small number of patients develop NHL secondary to specific etiologies, including inherited or acquired immune deficiencies (e.g., severe combined immunodeficiency syndrome, Wiskott-Aldrich syndrome), viral etiologies (e.g., HIV, EBV) or as part of genetic syndromes (e.g., ataxia-telangiectasia, Bloom syndrome). Most children who develop NHL, however, have no obvious genetic or environmental etiology. 2.2 PATHOGENESIS The four major pathological subtypes of childhood and adolescent NHL are Burkitt lymphoma (BL), constituting 40% of NHL; lymphoblastic lymphoma (LL), accounting for 30%; diffuse large B-cell lymphoma (DLBCL), constituting 20%; and anaplastic large cell lymphoma (ALCL), accounting for 10% ( Fig. 496-3 ). Most childhood and adolescent NHLs are high-grade tumors with an aggressive clinical behavior compared to those of adult NHL, which usually are low- to intermediategrade indolent tumors. Almost all childhood and adolescent NHL is derived from germinal center aberrations. Almost all forms of BL and DLBCL are of B cell origin; cases of LL are 80% T cell and 20% B cell; and cases of ALCL are 70% T cell, 20% null cell, and 10% B cell in origin. Some pathological subtypes have specific cytogenetic aberrations. Children with BL commonly have a t(8;14) translocation (90%) or, less commonly, a t(2;8) or t(8;22) translocation (10%). Patients with ALCL commonly have a t(2;5) translocation (5%). Patients with DLBCL and LL have a variety of different cytogenetic abnormalities.

Histopathology of DLCL. Image by KGH.

Malignant B-cell lymphocytes seen in Burkitt's lymphoma image by Louis Staudt, NCI

Follicular lymphoma grade I.

2.3 CLINICAL MANIFESTATIONS The clinical manifestations of childhood and adolescent NHL depend primarily on pathological subtype and primary and secondary sites of involvement. NHLs are rapidly growing tumors and can cause symptoms based on size and location. Approximately 70% present with advanced disease of stages III or IV ( Table 496-4 ), including extranodal disease that manifests as gastrointestinal, bone marrow, and central nervous system (CNS) involvement. BL commonly presents with abdominal (sporadic type) or head and neck (endemic type) disease with involvement of the bone marrow or CNS. LL commonly presents with an intrathoracic or mediastinal supradiaphragmatic mass, and also has a predilection for spreading to the bone marrow and CNS. DLBCL commonly presents with either an abdominal or mediastinal primary and, rarely, dissemination to the bone marrow or CNS. ALCL presents either with a primary cutaneous manifestation (10%) or with systemic disease (fever, weight loss) with dissemination to liver, spleen, lung, mediastinum, or skin; spread to the bone marrow or CNS is rare.

TABLE 1. St. Jude Staging System for Childhood Non-Hodgkin Lymphoma STAGE DESCRIPTION I II A single tumor (extranodal) or single anatomic area (nodal), with the exclusion of mediastinum or abdomen A single tumor (extranodal) with regional node involvement Two or more nodal areas on the same side of the diaphragm Two single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm A primary gastrointestinal tract tumor, usually in the ileocecal area, with or without involvement of associated mesenteric nodes only, which must be grossly (>90%) resected

STAGE DESCRIPTION III Two single tumors (extranodal) on opposite sides of the diaphragm Two or more nodal areas above and below the diaphragm Any primary intrathoracic tumor (mediastinal, pleural, or thymic) Any extensive primary intra-abdominal disease IV Any of the above, with initial involvement of central nervous system or bone marrow at time of diagnosis From Murphy SB: Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: Dissimilarities from lymphomas in adults. Semin Oncol 1980;7:332339. Site-specific manifestations include painless, rapid lymph node enlargement; cough, superior vena cava (SVC) syndrome, dyspnea with thoracic involvement; abdominal (massive and rapidly enlarging) mass, intestinal obstruction, intussusception-like symptoms, ascites with abdominal involvement; nasal stuffiness, earache, hearing loss, tonsil enlargement with Waldeyer ring involvement; and localized bone pain (primary or metastatic). Three clinical manifestations that require special alternative treatment strategies include SVC syndrome secondary to a large mediastinal mass obstructing various blood flow or respiratory airways; acute paraplegias secondary to spinal cord or central nervous system compression from neighboring localized NHL; and tumor lysis syndrome (TLS) secondary to severe metabolic abnormalities, including hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia from massive tumor cell lysis.

2.4 LABORATORY FINDINGS

Recommended laboratory and radiologic testing includes: complete blood count (CBC); electrolytes, uric acid, calcium, phosphorus, bilirubin urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase; bilateral bone marrow aspiration and biopsies; lumbar puncture with CSF cytology, cell count and protein; chest x-ray; and neck, chest, abdominal, and pelvic CT scans, PET scan and bone scan (optional), and head CT scan (optional). The tumor tissue (i.e., biopsy, bone marrow, CSF, or pleural/paracentesis fluid) should be tested by flow cytometry for immunophenotypic origin (T, B, or null) and cytogenetics (karyotype). Additional tests might include fluorescent in situ hybridization (FISH) or quantitative RT-PCR for specific genetic translocations, T and B cell gene rearrangement studies, and molecular profiling by oligonucleotide microarray. Excision biopsy and histopathological examination remain the gold standard for primary diagnosis and classification of non-Hodgkin's lymphoma

TABLE

2-- Pretreatment

Studies

for

Staging

Pediatric

Non-Hodgkin

Lymphoma Complete blood cell count Serum electrolytes, uric acid, lactate dehydrogenase, creatinine, calcium, phosphorus Liver function tests (ALT, AST) Chest radiograph Neck, chest, abdominal, pelvic CT Positive emission tomography scan Bilateral bone marrow aspirate and biopsy Cerebrospinal fluid cytology, cell count, protein

ALT, alanine aminotransferase; AST, aspartate aminotransferase. 2.5 DIFFERENTIAL DIAGNOSIS

Head and neck lymphadenopathy should be differentiated from infectious nodal etiologies; mediastinal masses from HD and germ cell tumors; abdominal involvement from other abdominal malignant masses such as Wilms tumor, neuroblastoma, and rhabdomyosarcoma; and bone marrow involvement from precursor B (Pre-B) acute lymphoblastic leukemia and T-cell acute lymphoblastic leukemia. CT and PET scans, along with flow cytometry, cytogenetic and molecular genetics on biopsy and tumor tissue, usually differentiate NHL from other entities. 2.6 TREATMENT The primary modality of treatment for childhood and adolescent NHL is multiagent systemic chemotherapy and intrathecal chemotherapy. Surgery is used mainly for diagnostic and/or biologic specimens and staging but rarely is used for debulking large masses. Radiation therapy is rarely, if ever, used, except in special circumstances such as CNS involvement in LL or occasionally BL, acute SVC, and acute paraplegias. Patients at diagnosis and at risk of TLS, especially advanced/bulky BL or LL, require vigorous hydration and either a xanthine oxidase inhibitor (allopurinol, 10 mg/kg/day PO divided tid) or, more often, recombinant urate oxidase (rasburicase, 0.2 mg/kg/day PO once daily for 13 days). Specific treatment for localized and advanced disease is similar for BL and DLBCL. Localized BL and DLBCL require 6 wk to 6 mo of multiagent chemotherapy. Common regimens include COPAD (cyclophosphamide, vincristine, prednisone and doxorubicin), as demonstrated by the recent international B-NHL study (FAB/LMB 96 [French-American-British Lymphoma, mature B cell]) or COMP (cyclophosphamide, vincristine, methotrexate, 6-mercaptopurine and prednisone). Advanced disease usually is treated by 46 mo of multiagent chemotherapy such as FAB/LMB 96 protocol therapy or BFM (Berlin Frankfurt Munich) NHL90 protocol therapy.

Localized and advanced LL usually require almost 24 mo of therapy. The best results in advanced LL have been obtained using the BFM NHL 90 protocol, which uses therapeutic approaches similar to those for childhood acute leukemia, which includes an induction cycle of chemotherapy, consolidation phase, interim maintenance phase, reinduction phase (advanced disease only), and a year of maintenance therapy with 6- mercaptopurine and methotrexate. Localized ALCL may require only cutaneous excision or more aggressive therapy similar to that for advanced ALCL. Advanced ALCL commonly is treated with a BFM NHL 90 protocol or with a COG protocol of APO (doxorubicin, prednisone and vincristine) with additional VP-16, Ara-C, or vinblastine. Intrathecal chemotherapy is administered to moderate to advanced disease in all subtypes of childhood and adolescent NHL and may include intrathecal methotrexate, hydrocortisone, or Ara-C. Patients with NHL who develop progressive or relapsed disease require reinduction chemotherapy and either allogeneic or autologous stem cell transplantation. The specific reinduction regimen or transplant depends on the pathologic subtype, previous therapy, site or reoccurrence, and stem cell donor availability. 2.7 SUPPORTIVE CARE Some patients require G-CSF prophylaxis to prevent fever and neutropenia following myelosuppressive chemotherapy and prophylactic antibiotics to prevent infections. Indwelling central venous catheters routinely are placed to facilitate frequent blood draws, chemotherapy and transfusion administration, and parenteral nutrition to prevent weight loss and nutritional debilitation. 2.8 COMPLICATIONS

Patients receiving multiagent chemotherapy for advanced disease are at acute risk for serious mucositis, infections, cytopenias requiring red cell and platelet blood product transfusions, electrolyte imbalance, and poor nutrition. Long-term complications may include growth retardation, cardiac toxicity, gonadal toxicity with infertility, and secondary malignancies. 2.9 PROGNOSIS The prognosis is excellent for most forms of childhood and adolescent NHL. Patients with localized disease have a 90100% chance of survival, and patients with advanced disease have a 6095% chance of survival. The variation in survival depends on pathological subtype, tumor burden at diagnosis as reflected in serum LDH level, presence or absence of CNS disease, and specific sites of metastatic spread. Specific cytogenetic and molecular genetic subtyping also may be important in predicting outcome and influencing specific therapeutic strategies.