AUTHOR INFORMATION

Section 1 of 12

Authored by J Martin Johnston, MD, Consulting Staff, Department of Pediatrics, Division of Hematology-Oncology, St Luke's Mountain States Tumor Institute

J Martin Johnston, MD, is a member of the following medical societies: American Society of Pediatric Hematology/Oncology

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	J Martin Johnston, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, April 19 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 12

Background: Lymphomas are malignant neoplasms of the lymphoid lineage. Broadly classified as either Hodgkin disease or as non-Hodgkin lymphoma (NHL), these entities are clinically, pathologically, and biologically distinct. Most childhood NHL can be classified according to the National Cancer Institute (NCI) formulation as either lymphoblastic, small noncleaved cell (Burkitt or Burkittlike), or large cell lymphomas (LCLs). In recent years, B-cell LCLs (BLCL) and anaplastic (usually T cell) LCLs (ALCL) have come to be viewed as distinct entities. This article considers these four categories separately. Other less common forms of lymphoma are not discussed.

Since the late 1960s, treatment outcomes for children with NHL have improved steadily. Even patients with advanced disease currently exhibit 65-90% event-free survival (EFS) rates. The backbone of conventional therapy is multiagent chemotherapy tailored to the histologic subtype and clinical stage of disease. In certain individuals with NHL, surgical resection and radiation therapy are also key components of definitive treatment. Newer therapies that target immunologic and biologic aspects of the lymphoma are under development and are just beginning to appear in the clinical arena.

Pathophysiology: Most malignancies arise as localized disease within the organ or tissue of origin, then may secondarily spread via local extension or distant metastases. In contrast, NHL is best regarded as a systemic disease due to the unique anatomy of the lymphoid system and physiology of lymphoid cells, which tend to migrate whether they are normal or malignant.

Childhood NHL generally presents as bulky extramedullary (usually extranodal) disease with or without demonstrable dissemination. The distinction between NHL and acute leukemia is arbitrary; thinking in terms of a spectrum from clinically localized disease to overt leukemia is best. Most treatment protocols now define acute leukemia on the basis of marrow involvement greater than some threshold (typically, a blast count >25%), irrespective of the presence of bulky extramedullary disease. In contrast, a tumor accompanied by marrow involvement less than this threshold constitutes stage 4 lymphoma.

Frequency:

• In the US: Collectively, lymphomas are the third most common childhood malignancy after acute leukemias and brain tumors. Lymphomas constitute 10-12% of childhood cancers. In older adolescents, lymphomas surpass brain tumors in incidence, largely due to the increased frequency of Hodgkin disease in this age group.

  Data from the US Surveillance, Epidemiology, and End Results (SEER) program (1994-98) are exhibited in Table 1. In children, NHL is somewhat less common than Hodgkin disease. However, the incidence of NHL appears to be rising in the US. This trend largely reflects the occurrence of NHL in patients who are immunocompromised (eg, HIV positive) and in patients previously exposed to chemotherapy and radiation as treatment for an unrelated cancer.

  Table 1. Age-Adjusted Incidence of Selected Cancers for Children Aged 0-19 Years

  Location of Cancer	Incidence per 100,000
  All sites	15.9
  Leukemias	3.8
  Brain and other nervous tissues	2.8
  Hodgkin disease	1.3
  Non-Hodgkin lymphoma	1.1
  Bone and joint	1.0
  Soft tissue	1.0
  Kidney and renal pelvis	0.7

• Internationally: As in the US, the incidence of NHL appears to have increased over the last 3 decades in Canada. The cause for this is unclear. Burkitt lymphoma (BL) is significantly more common in sub-Saharan Africa, where it accounts for approximately one half of childhood cancers. Its incidence also appears to be higher in Latin America, North Africa, and the Middle East than in the US, and Europe.

Mortality/Morbidity:

• Rapidly growing or bulky tumors can cause severe metabolic derangement, which may be life threatening. One indicator of the potential for tumor lysis syndrome is an elevated plasma lactate dehydrogenase level or hyperuricemia at diagnosis. The initiation of effective chemotherapy acutely increases the risk of complications including hyperkalemia, hyperphosphatemia, hypocalcemia, oliguria, and renal failure.
  
  
• Other immediate risks depend on the site and extent of involvement. These risks vary according to the histologic subtype of disease.

• Individuals with lymphoblastic lymphoma often present with mediastinal involvement, which may be massive and life threatening. Airway compression is a particular concern and must be considered in any patient with neck or chest disease (see Picture 2). Even in the absence of symptomatic airway compromise, the risk of sudden obstruction may exist if a patient undergoes anesthesia for biopsy or central line placement. In these individuals, possibly consider biopsy under local anesthesia or immediate radiation therapy to the airway, provided that another site of disease is outside the radiation field (to allow subsequent histologic confirmation of the diagnosis).

• Mediastinal tumors also may cause great vessel compression (superior vena cava syndrome) with swelling of the neck, face, and upper extremities. Esophageal compression may cause dysphagia. Pleural effusions sometimes are observed and may be large enough to cause symptoms. In these individuals, thoracentesis may be both therapeutic and diagnostic, thereby obviating biopsies.
  
  
• In the US, most patients with small noncleaved cell lymphomas (SNCCLs) present with abdominal involvement, typically in the ileocecal area and arising from Peyer patches (see Picture 3). A potential complication at diagnosis is bowel obstruction due to direct compression, torsion, or intussusception. Because of bowel perforation, some patients exhibit ascites or the clinical picture of acute appendicitis or peritonitis.
  
  
• In equatorial Africa, SNCCL (ie, endemic BL) classically presents as a mass in the jaw, nasopharynx, or orbit. These masses grow rapidly and can be quite disfiguring.
  
  
• With current treatments, most children with NHL apparently are curable. These results depend upon precise histologic diagnosis, thorough staging of disease, and application of complex multiagent (and sometimes multimodality) treatment. The short-term morbidity of chemotherapy regimens is considerable but usually is manageable. Late effects of treatment are a growing concern as survival rates increase (see Complications).

Race: US incidence is twice as high in Caucasians (9.1 cases per million per y) as in blacks (4.6 cases per million per y).

Sex: US incidence is 2-3 times higher in males than females.

Age: In the US, the age-specific incidence of NHL increases only slightly over the first 2 decades of life. By comparison, the incidence of Hodgkin disease increases more dramatically as children age (see Picture 1). In adulthood, the risk of NHL climbs steadily, whereas the age-specific incidence of Hodgkin disease is biphasic.

CLINICAL

Section 3 of 12

History:

• Presentation is acute or subacute, in contrast to the indolent course that characterizes most adult lymphomas. Duration of symptoms prior to diagnosis is generally 1 month or less.



• Specific complaints vary and depend upon the predominant site(s) of involvement.



• Constitutional symptoms are uncommon, except in patients with anaplastic LCL, many of whom exhibit low-grade fever, malaise, anorexia, or weight loss.



• LCLs are biologically disparate. Accordingly, LCLs have a more varied presentation that may include chest or abdominal complications as described. Rarely, LCL presents as an isolated bone lesion with pain, swelling, and risk of pathologic fracture.



• Bone marrow involvement may cause generalized or migratory bone pain; however, in individuals with NHL, significant cytopenias are uncommon, and their presence suggests a diagnosis of acute leukemia.



• Localized disease can present as lymphadenopathy (usually firm and nontender), tonsillar hypertrophy, or a mass in virtually any location. However, NHL is primarily an extranodal disease in children.



• Patients with supradiaphragmatic disease (eg, lymphoblastic lymphoma) often complain of nonproductive cough, dyspnea, chest pain, and dysphagia.



• Abdominal tumors (usually SNCCL or B-cell LCL) present with abdominal pain, constipation, mass, or ascites. An acute abdomen occasionally is observed and may be mistaken for appendicitis.



• Anaplastic LCL (ie, Ki-1+ lymphoma) sometimes presents with painful skin lesions (which may regress spontaneously), bone lesions, peripheral lymphadenopathy, and hepatosplenomegaly. Less commonly, testicular, lung, or muscle involvement is observed.



• Anaplastic LCL may also exhibit an apparent "cytokine storm," with fevers, vascular leak, and altered blood counts (anemia, thrombocytopenia, leukopenia, leukocytosis).



• Patients occasionally develop symptomatic CNS involvement prior to diagnosis. Headache, meningismus, cranial nerve palsies, and altered sensorium may be observed. Although CNS involvement at diagnosis is uncommon, patients with NHL (particularly SNCCL) occasionally present with symptoms suggestive of meningoencephalitis.

Physical:

• In general, patients often appear mildly to moderately ill and occasionally have a low-grade fever. They may present with pallor, respiratory distress, pain, and discomfort.



• A jaw or orbital mass may be present in as many as 10% of patients in developed countries and is very common in African patients with endemic BL.



• A cervical or supraclavicular mass or adenopathy is firm, fixed, and nontender.



• Dyspnea or stridor may be present with a mediastinal mass. With superior vena cava syndrome, distended neck veins and plethora also may be observed.



• Decreased breath sounds are heard secondary to bronchial obstruction or pleural effusion.



• Thoracic dullness to percussion may be present with pleural effusion.



• Abdominal distension or mass may be present with or without tenderness, rebound tenderness, and/or shifting dullness.



• Painful skin lesions are suggestive of anaplastic LCL.



• Less common physical findings include nasopharyngeal mass, parotid enlargement, nephromegaly, and testicular enlargement. Focal extremity pain or swelling may be present with primary bone lymphoma. Obtundation, agitation, and meningismus may be observed in individuals with CNS involvement.

Causes: In developed countries, most individuals with NHL have no known etiology or association. Epidemiological studies suggest that certain HLA types and even certain blood types may increase or decrease the likelihood of developing NHL. Several epidemiologic studies suggest a role for pesticide exposure in the development of adult NHL; the case for childhood NHL is less compelling but still under investigation. A possible infective etiology for childhood NHL is suggested by the epidemiological association between NHL and certain paternal occupations (ie, that increase contact with other individuals). Conversely, one case-control study suggests that exposure to sunlight may protect against NHL, presumably on the basis of enhanced vitamin D synthesis.

• Immunosuppression and viral infection


• • Immunosuppressed individuals (eg, HIV positive, post–bone marrow transplant) are at higher risk of developing NHL, particularly SNCCL and LCL of B-cell origin.
  
  
  
  • Epstein-Barr virus, which causes B-cell proliferation and in vitro immortalization, has been implicated in most of these lymphomas.
  
  
  
  • Primary CNS lymphoma is more common in these patients.
  
  
  
• Previous Hodgkin disease


• • Patients successfully treated for Hodgkin disease are at increased risk of developing NHL. This appears to reflect the combined effects of chemotherapy, radiotherapy, and the immunosuppressive effects of Hodgkin disease. Adults older than 40 years who have received combined modality therapy are at particular risk, with a 15-year incidence of NHL as high as 39%. Splenectomy, now rarely performed in patients with Hodgkin disease, is another reported risk factor for the development of second malignancies, including NHL.
  
  
  
  • Among pediatric cancer survivors, secondary NHL is less common than in adults. Only 3 individuals with secondary NHL were observed throughout 30,710 person-years of follow-up care in a cohort of 5,484 children treated for various malignancies at Saint Jude Children's Research Hospital. The 15-year actuarial risk of NHL was only 0.16% in this group. However, even among children, patients treated for Hodgkin disease are particularly at risk. In 1991, a literature review revealed 24 incidents of secondary NHL in patients whose primary malignancy had been diagnosed when younger than 20 years, and 18 (75%) of these patients had previous Hodgkin disease.
  
  
  
• Location


• • In sub-Saharan Africa, a strong association exists between the development of endemic BL and prior exposure to both malaria (with resultant T-cell suppression) and Epstein-Barr virus. Recent speculation exists that mosquito-borne arboviruses may also play a role in the development of BL in this part of the world.
  
  
  
  • In addition, exposure to 4-deoxyphorbol ester from the plant Euphorbia tirucalli (via goat's milk) tentatively has been implicated in the pathogenesis of endemic BL.
  
  
  
• Genetic causes


• • The genetic basis of pediatric NHL has been studied extensively. Each subtype of NHL is characterized by 1 or more molecular lesions that contribute to the malignant phenotype. Many of these are chromosomal translocations involving genes for immunoglobulin (Ig) or T-cell receptor molecules. During normal lymphocyte development, these loci undergo recombination that serves to enhance immunologic diversification. Mistargeted recombination leads to translocations with other genes (typically, those that function to regulate cell growth). The resulting dysregulation of these latter genes contributes to the transformed phenotype.
  
  
  
  • For example, the hallmark of BL, observed in approximately 80% of patients, is a t(8;14)(q24;q32) translocation. This juxtaposes c-myc, which encodes a transcription factor important in initiation of the cell cycle, with the Ig heavy chain locus. Less commonly, c-myc is adjoined to the gene encoding the Ig kappa light chain [t(2;8)(p11;q24)] or the lambda light chain [t(8;22)(q24;q11)]. In all 3 instances, the result is aberrant expression of the c-MYC protein under the influence of Ig gene regulatory sequences, which contributes to the pathogenesis of BL.

  • Aside from the t(8;14) translocation, BL frequently exhibits gain(s) of chromosomal material, which can affect any of a number of chromosomes. Abnormalities of chromosome 1q, 7q, or 13q may portend a poor prognosis.
  
  
  
  • A small portion of T-lymphoblastic lymphomas (T-LL) also exhibit translocations involving 1 of the T-cell receptor (TCR) loci: either TCR alpha delta (14q11) or TCR beta (7q34). The most common example (observed in 7% of children with T-LL) is the t(11;14)(p13;q11) translocation, which causes enhanced expression of the LMO2 gene on chromosome 11. This gene encodes a so-called LIM protein, an apparent modulator of gene transcription. A more common abnormality, observed in approximately 25% of T-LL/T-cell acute lymphoblastic lymphoma (ALL), is a deletion within a regulatory region of the gene TAL1. This deletion, which is too small to be detected by conventional cytogenetic techniques, allows aberrant expression of Tal-1, another transcriptional regulator.
  
  
  
  • Inactivation of the multiple tumor suppressor gene 1 (MTS-1/p16INK4 alpha/CDKN2) on chromosome 16 has been identified as a common genetic event in T-cell ALL; its frequency in T-LL also is likely significant. Interestingly, the deletions or disruptions responsible for this inactivation apparently are related to illegitimate activity of the same V(D)J recombinase that mediates TCR gene recombination. Thus, even in the absence of a TCR gene translocation, similar molecular mechanisms may be responsible for the disruption of other genes involved in normal cell cycle control.
  
  
  
  • Some B-lineage LCLs exhibit the same t(8;14)(q24;q32) translocation observed in BL. Conversely, most anaplastic (T-lineage) LCLs in children exhibit a t(2;5)(p23;q35) translocation. This joins the nucleophosmin (NPM) gene on chromosome 5 to a gene designated anaplastic lymphoma kinase (ALK) on chromosome 2 and allows the expression of an NPM/ALK fusion protein, p80. Transcripts of NPM/ALK also are observed in approximately 20% of individuals with NHLs lacking cytogenetic evidence of t(2;5), reflecting an occult or variant translocation. Patients with NHL expressing p80 may have a survival advantage over patients whose lymphomas lack p80.
  
  
  

DIFFERENTIALS

Section 4 of 12

Acute Lymphoblastic Leukemia
Acute Myelocytic Leukemia
Appendicitis
Atypical Mycobacterial Infection
Catscratch Disease
Hodgkin Disease
Intussusception
Lymphadenitis
Lymphoproliferative Disorders
Mononucleosis and Epstein-Barr Virus Infection
Neuroblastoma
Rhabdomyosarcoma
Sarcoidosis
Toxoplasmosis
Tuberculosis
Wilms Tumor

WORKUP

Section 5 of 12

Lab Studies:

• Perform CBC with differential and platelet count to assess possible bone marrow involvement and determine transfusion requirements.



• Perform prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer if patient is febrile or has evidence of sepsis to assess possible disseminated intravascular coagulation, which may require specific therapy.



• Perform blood and urine cultures if patient has a fever, especially with neutropenia. If indicated, also obtain stool and throat cultures.



• Perform serum electrolytes, BUN, creatinine, uric acid, lactate dehydrogenase (LDH), bilirubin, albumin, total protein, aspartate aminotransferase, alanine aminotransferase, calcium, magnesium, and phosphorus to assess renal and hepatic function and monitor for possible tumor lysis syndrome. The level of LDH at diagnosis has prognostic significance in many analyses of treatment outcome.



• Perform HIV serology in patients with risk factors for HIV exposure or with primary CNS lymphoma to exclude a possible predisposing factor.

Imaging Studies:

• Chest radiographs: Obtain posteroanterior and lateral views to assess for possible mediastinal mass, evaluate the airway, and exclude pulmonary parenchymal lesions or associated pneumonia.



• Ultrasound


• • An abdominal ultrasound assesses kidney size and urinary tract patency, particularly as a prelude to chemotherapy (ie, to anticipate prolonged excretion and excess toxicity).
  
  
  
  • When symptoms are present, a testicular ultrasound identifies additional sites of disease.
  
  
  
• Computed tomography scan


• • A CT scan of the chest, abdomen, and pelvis can be used for staging as outlined in Table 2. A chest CT scan is indicated if the patient is stable to assess for degree of tracheal compression.
  
  
  
  • A head CT scan excludes mass lesions and possible meningeal involvement in the individual with CNS disease.
  
  
  
• Bone scan and skeletal survey: When additional symptoms are present, these tests identify additional sites of disease.



• Gallium-67 scan: This is a highly recommended test. Some tumors are gallium avid and their response to treatment can be assessed by this modality. Occult sites of disease also may be identified. More recently, positron emission tomography (PET) scanning has been used similarly.

Other Tests:

• Serology for varicella, measles, herpes simplex virus, Epstein-Barr virus, cytomegalovirus (CMV), hepatitis A, hepatitis B, and hepatitis C


• • Perform to document susceptibility in patients who will be receiving immunosuppressive therapy.
  
  
  
  • These tests possibly can provide evidence of causation (Epstein-Barr virus).
  
  
  
  • Serology can identify patients who may benefit from transfusion with CMV-negative blood products (especially if bone marrow transplantation eventually is offered).
  
  
  
  • Perform to allow confirmation of prior hepatitis virus exposure before blood transfusions are administered.
  
  
  
• Echocardiogram: Perform to obtain a prechemotherapy baseline prior to administering anthracyclines, which can cause cardiomyopathy.

Procedures:

• Bilateral (superior to unilateral) bone marrow aspirates and biopsies


• • Biopsy is necessary to assess for evidence of bone marrow involvement in patients with lymphomas.
  
  
  
  • More than 25% marrow blasts generally is regarded as diagnostic of acute leukemia, whereas lower levels of involvement with lymphoma indicate stage 4 disease.

  • Polymerase chain reaction (PCR) assays are being used experimentally to detect and monitor minimal residual disease (MRD) in the marrow. In the future, postinduction measurement of MRD may allow more precise determination of treatment response and/or treatment assignment.
  
  
  
• Lumbar puncture with cerebrospinal fluid cell count and differential: This test assesses CNS involvement, the presence of which alters therapy.



• Biopsy


• • A histologic diagnosis must be obtained. In patients with an abdominal tumor, tissue is generally available from a resection or intraoperative biopsy.
  
  
  
  • Patients with mediastinal disease frequently have enlarged supraclavicular or cervical nodes, which can provide a diagnosis without thoracotomy.
  
  
  
  • Alternatively, a diagnosis may be made using pleural fluid (see Picture 4), involved bone marrow (especially if CBC results are abnormal and/or imaging studies demonstrate abnormal marrow signal), or, rarely, cerebrospinal fluid.
  
  
  
• Central venous access


• • For most patients, a central venous access device is necessary for management of chemotherapy.
  
  
  
  • If feasible, multiple procedures (ie, line placement, biopsy, lumbar puncture, bone marrow aspiration) can be performed under 1 anesthesia.
  
  
  
  • As noted previously, patients with mediastinal disease must be approached cautiously if general anesthesia is considered. Unrecognized airway compression can lead to obstruction with disastrous consequences.
  
  
  

Lymphoblastic lymphoma (LL) cells are indistinguishable from the lymphoblasts of ALL. The cells are monotonous with a high nuclear-to-cytoplasmic ratio. Nuclei often are convoluted with finely stippled chromatin; nucleoli usually are visible but not prominent. Immunohistochemical analysis usually reveals T-cell markers, including CD5 and CD7. Common ALL antigen (CALLA) occasionally is observed. A minor subset of LLs expresses the precursor B-cell phenotype typical of childhood ALL, including the following surface antigens: CALLA, B4, and the human leukocyte antigen HLA-DR.

SNCCLs can be classified as either BL or non-Burkitt lymphoma (Burkittlike, BLL). The distinction may be subtle, and its clinical significance is unclear. BL cells are notably uniform in size and shape and usually exhibit multiple prominent nucleoli. In contrast, extensive cellular pleomorphism or, on occasion, the presence of a single nucleolus in most cells favors a diagnosis of BLL. Relative to LL cells, SNCCLs exhibit slightly more abundant cytoplasm, which is very basophilic and usually contains lipid-filled vacuoles. Tumors often are infiltrated by macrophages, lending the classic starry-sky appearance, which is not pathognomic of BL, however. The tumor cells are mature B cells, as evidenced by surface expression of Ig (usually IgM), CD19, CD20, and HLA-DR. CALLA usually is present.

Immunophenotypic analyses suggest that BLL cells are more likely than BL cells to express the BCL-6 oncogene and also exhibit lower levels of apoptosis. Thus, BLL appears to be biologically distinct from BL and is perhaps more closely related to the B large cell lymphomas.

LCLs are a heterogeneous group. Most cases can be classified into one of two groups. The B cell–derived LCLs merge histologically with the SNCCLs, and at the level of cell surface protein expression, these tumors are currently indistinguishable. If infiltrating macrophages are present, they can serve as a yardstick by which the tumor cells are measured. In B-LCL, many or most of the tumor nuclei are larger than those of the macrophages. In contrast, the more common anaplastic LCLs are T cell derived, as evidenced by TCR gene rearrangements; however, they may express few T-cell surface markers. Their hallmark is the expression of CD30, or Ki-1+, an antigen first recognized on Hodgkin lymphoma cells. Other cell surface markers that may be observed are HLA-DR and the interleukin-2 receptor. Finally, a small number of LCLs do not exhibit a clear T-cell or B-cell phenotype; at least some of these tumors are of histiocytic origin.

For a particular tumor, agreement among pathologists sometimes may be difficult; however, the synthesis of histologic, immunohistochemical, cytogenetic, and clinical and/or anatomic data almost always results in a clear diagnosis.

Staging: Several systems have been proposed, but the Saint Jude system (ie, Murphy system) has gained the widest acceptance. This system is presented below in Table 2.

Table 2. Staging for Non-Hodgkin Lymphoma According to the Saint Jude System

Stage	Definition
I	Single tumor (extranodal) or single anatomic area (nodal), excluding mediastinum or abdomen
II	Single tumor (extranodal) with regional node involvement, OR
	Primary gastrointestinal tumor ± associated mesenteric node involvement, with gross total resection, OR
	On same side of diaphragm: 2 or more nodal areas, or 2 single (extranodal) tumors ± regional node involvement
III	Any primary intrathoracic tumor (mediastinal, pleural, thymic), OR
	Any extensive abdominal tumor (unresectable), OR
	Any primary paraspinous or epidural tumor, regardless of other sites, OR
	On both sides of the diaphragm: 2 or more nodal areas, or 2 single (extranodal) tumors ± regional node involvement
IV	Any of the above with initial CNS or marrow (<25%) involvement

TREATMENT

Section 6 of 12

Medical Care: Proper care requires referral to a comprehensive tertiary care center. The intensity of current treatment regimens, particularly for advanced stages of disease, dictates inpatient administration of chemotherapy, as well as aggressive support by a team experienced in the care of immunosuppressed children.

Prior to and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome. This term describes metabolic derangements caused by a highly proliferative and/or bulky malignancy. Renal involvement by lymphoma is an additional risk factor.

Hyperuricemia or tubular obstruction may lead to acute renal failure, requiring dialysis. In general, this is not a contraindication to continuing chemotherapy. However, some protocols now include a preliminary phase of gentler cytoreductive chemotherapy, designed to avoid these metabolic complications.

With all patients, administer intravenous fluids at twice maintenance rates, usually without potassium. Add sodium bicarbonate to the intravenous fluid to achieve moderate alkalinization of the urine (pH approximately 7.0). This enhances the excretion of tumor metabolites. For example, the solubility of uric acid is 10-12 times higher than at pH 5.0, whereas the solubility of xanthine is doubled. Avoid a higher urine pH to prevent crystallization of hypoxanthine or calcium phosphate. Administer allopurinol to prevent or correct hyperuricemia.

Follow laboratory examinations necessary to monitor tumor lysis syndrome throughout initial therapy (as often as 2-4 times/d). This is especially important during the first 48-72 hours of therapy in a patient with bulky disease.

If present, fever simply may reflect the underlying malignancy; however, consider empiric broad-spectrum antibiotic coverage until sepsis or focal infection (eg, due to bowel perforation) has been excluded.

Current treatment regimens are based primarily on the immunophenotype (B cell vs T cell) of the particular lymphoma. In broad terms, T-cell therapies are longer and less intensive (particularly with respect to the use of alkylating agents), while B-cell therapies are shorter and employ higher doses of alkylators and antimetabolites. Current survival rates for patients with advanced disease are 65-75% for lymphoblastic lymphoma (T-cell disease) and 80-90% for B-cell lymphomas.

Lymphoblastic lymphoma

Between 1986 and 1989, in a Children's Cancer Group (CCG) trial (see Table 3), 143 subjects with LL (of whom only 10% had localized disease) received treatment with a modified LSA₂L₂ regimen; their 5-year EFS was 74%.

Table 3. Children's Cancer Group Trial Modified LSA₂L₂ Therapy (per Children's Cancer Group Protocol 552)

Phase	Cycle	Drug	Route
Induction		Cyclophosphamide, vincristine, daunorubicin	IV
		Cytarabine (AraC), methotrexate	IT
		Prednisone	PO
Consolidation		Cytarabine (AraC)	IV or SC
		6-thioguanine	PO
		Methotrexate	IT
		L-asparaginase	IM
		Carmustine (BCNU)	IV
Maintenance A minimum of 5 repeated courses (total duration of therapy >18 months) exist. Each course* consists of 4 cycles of rotating drug pairs, administered every 2 weeks (once blood counts have recovered) *(IT methotrexate, day 0 of each course)	1	6-thioguanine	PO
		Cyclophosphamide	IV
	2	Hydroxyurea	PO
		Daunorubicin	IV
	3	Methotrexate	PO
		Carmustine (BCNU)	IV
	4	Cytarabine (AraC)	IV or SC
		Vincristine	IV

German Berlin, Frankfurt, Muenster treatment protocol

The German Berlin, Frankfurt, Muenster (BFM) protocols have demonstrated excellent results for patients with ALL or LL. As reported in 1995, 71 subjects with stage III or IV non-B NHL (see Children's Oncology Group protocols) received treatment as exhibited in Table 4. In comparison to LSA₂L₂, this regimen adds a re-induction phase and features a less complicated and less intense maintenance phase. As originally reported, it also included prophylactic cranial irradiation during re-induction. These patients exhibited a 6-year EFS of 79%.

Table 4. Non-Hodgkin Lymphoma-BFM 86 Therapy for non-B Disease* Stages III and IV

Phases	Drug	Route
Induction	Prednisone, 6-mercaptopurine	PO
	Vincristine, daunorubicin, cyclophosphamide, cytarabine (AraC)	IV
	L-asparaginase	IM
	Methotrexate	IT
Consolidation	6-mercaptopurine	PO
	Methotrexate with leucovorin rescue	IV
	Methotrexate	IT
Re-induction	Dexamethasone, 6-thioguanine	PO
	Vincristine, doxorubicin, cyclophosphamide, cytarabine (AraC)	IV
	L-asparaginase	IM
	Methotrexate	IT
Maintenance (continued until 24 months after diagnosis)	6-mercaptopurine, methotrexate	PO

* Diagnoses included lymphoblastic lymphoma of T-cell or precursor B-cell type, immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients with Ki-1+ anaplastic LCL were not included

Children's Oncology Group protocols

The most recent Children's Oncology Group phase 3 protocol (A5971) for children with advanced-stage T-cell LL featured a 4-way randomization between this "German" BFM therapy, a "CCG" modified version of BFM (which does not include high-dose methotrexate/leucovorin during consolidation), and intensified versions of these two protocols (with earlier introduction of daunomycin and cyclophosphamide). Results from this comparison are still pending.

The COG is developing specific protocols for treatment of T-cell diseases (both T-LL and T-ALL). In particular, studies will examine the role of nelarabine (previously known as compound 506U78), a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G) that has shown efficacy in T-cell malignancies.

Additional treatment details

For advanced-stage LL, as for ALL, relatively long intervals of treatment have been most successful. Typically, the maintenance phase lasts 18-30 months. Some shorter protocols also have been investigated. For example, the CCG-5941 protocol examined an aggressive, 11-month multiagent protocol; final results are pending.

Localized LL is unusual. In the previously described BFM study, only 6 of 77 subjects with non-B NHL had stage I or stage II disease. When results from multiple series are combined, these patients appear to have an excellent prognosis with approximately 80% long-term survival, but a consensus on optimal therapy is lacking. Treatment options include both LSA₂L₂ and NHL-BFM 86 (with the re-induction phase eliminated). Patients with localized LL are included in COG-A5971: they receive a CCG modified version of the BFM protocol (as described above) that includes re-induction but with fewer doses of intrathecal chemotherapy during the maintenance phase.

Alternatively, simpler regimens have demonstrated comparable results. For example, protocol 77-04 from the NCI included alternating cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and high-dose methotrexate (with leucovorin rescue). Aggressive intrathecal prophylaxis with AraC and methotrexate was included, but local radiation therapy was not offered routinely. Total duration of therapy was 15 cycles (approximately 60 wk).

Small noncleaved cell lymphoma

Table 5. Clinical Risk Groups, International Trial for Patients With Small Noncleaved Cell Lymphoma (CCG 5961)

Clinical Group	Subjects, Estimated %	Definition
A	10%	All resected stage I or abdominal stage II tumors
B	65%	Unresected stage I or II; stage III; stage IV with no CNS involvement and fewer than 25% marrow blasts
C	25%	CNS involvement or more than 25% marrow blasts

Table 6. Standard Therapy for Subjects in International Trial for Patients With Small Noncleaved Cell Lymphoma, Group A

	Drug	Route
All subjects receive 2 cycles	Prednisone	PO
	Vincristine, cyclophosphamide, doxorubicin	IV
	Filgrastim (granulocyte colony-stimulating factor [G-CSF]), to enhance neutrophil recovery	SC or IV

For patients with advanced disease (groups B and C), an initial moderately intensive “reduction” phase of chemotherapy was included, intended to reduce tumor burden with minimal risk of inducing or exacerbating tumor lysis syndrome. The experimental treatment arms for these patients (not shown here) involved incremental reductions of chemotherapy intensity and/or duration; In Group C patients, early analysis of results suggested that the less intensive, experimental treatment arms yielded an inferior outcome. Thus, it appears unwise to decrease therapy in this subgroup of patients.

Table 7. Standard Therapy for Subjects in International Trial for Patients With Small Noncleaved Cell Lymphoma, Group B

Phase	Drug	Route
Reduction	Prednisone	PO
	Vincristine, cyclophosphamide	IV
	Methotrexate/hydrocortisone	IT
Induction (2 cycles, starting 7 d after reduction)	Prednisone	PO
	Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin	IV
	Methotrexate/hydrocortisone	IT
	Filgrastim (granulocyte colony-stimulating factor [G-CSF])	SC or IV
Consolidation (2 cycles)	Methotrexate with leucovorin rescue, cytarabine (AraC)	IV
	Methotrexate/hydrocortisone, cytarabine (AraC)/hydrocortisone	IT
	Filgrastim (granulocyte colony-stimulating factor [G-CSF])	SC or IV
Maintenance (1 cycle)	Prednisone	PO
	Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin	IV
	Methotrexate/hydrocortisone	IT

Table 8. Standard Therapy for Subjects in International Trial for Patients With Small Noncleaved Cell Lymphoma, Group C

Phase	Drug	Route
Reduction	Prednisone	PO
	Vincristine, cyclophosphamide	IV
	Methotrexate/cytarabine (AraC)/hydrocortisone	IT
Induction (cycle 1, starting 7 d after reduction)	Prednisone	PO
	Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin	IV
	Methotrexate/cytarabine (AraC)/hydrocortisone	IT
	Filgrastim (granulocyte colony-stimulating factor [G-CSF])	SC or IV
Induction (cycle 2)	Prednisone	PO
	Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin	IV
	Methotrexate/cytarabine (AraC)/hydrocortisone	IT
	Filgrastim (granulocyte colony-stimulating factor [G-CSF])	SC or IV
Consolidation (2 cycles)**	High-dose cytarabine (AraC), etoposide (VP-16)	IV
	Filgrastim (granulocyte colony-stimulating factor [G-CSF]), days 7-21	SC or IV
**For patients with CNS involvement, during consolidation cycle 1 only
	High-dose methotrexate with leucovorin rescue	IV
	Methotrexate/cytarabine (AraC)/hydrocortisone	IT
Maintenance 1	Prednisone	PO
	Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin	IV
	Methotrexate/cytarabine (AraC)/hydrocortisone	IT
Maintenance 2	Cytarabine (AraC), etoposide (VP-16)	IV
Maintenance 3	Prednisone	PO
	Vincristine, cyclophosphamide, doxorubicin	IV
Maintenance 4	Cytarabine (AraC), etoposide (VP-16)	IV

Future protocols for patients with B-NHL will use monoclonal antibodies (eg, anti-CD20 rituximab) for children with high-risk disease (ie, patients with CNS disease at diagnosis or with advanced-stage disease and elevated levels of LDH).

Large cell lymphoma

Patients with B cell-derived LCLs are treated effectively using regimens for SNCCL (see Small noncleaved cell lymphoma). In fact, the recent international protocol allowed enrollment of subjects with LCL as well as those with SNCCL. Outcomes are similar between the 2 groups.

An alternative therapy is the "APO" regimen (Adriamycin, prednisone, vincristine [Oncovin]; with the later addition of methotrexate and 6-mercaptopurine). A randomized study of children with LCLs (including B-LCL) showed no advantage when cyclophosphamide was added to this regimen. Thus, it has the advantage of avoiding exposure to an alkylating agent; however, the cumulative dose of doxorubicin is 450 mg/m².

Anaplastic (T-cell) large cell lymphoma treatment

The therapy for anaplastic (T-cell) LCLs is somewhat controversial. Good results (EFS 65-80%) have been reported with a number of protocols, some based on ALL therapy, others similar or identical to B-cell lymphoma protocols.

Perhaps the best results of treatment for Ki-1+ anaplastic LCL were reported by the BFM group, using a B-cell lymphoma regimen that does not include local radiation therapy. Among 62 patients (none with bone marrow disease and only 1 with CNS involvement), 4 failed to enter remission, 1 died of infection, and 7 experienced a relapse. At the time of the report, 50 patients remained in a continuous first complete remission, and 56 were alive. The calculated EFS at 9 years was 83%.

Table 9. Prephase Therapy for BFM 90 Ki-1+ Anaplastic Large Cell Lymphoma

Phase	Drug	Route
Prephase (all patients)	Prednisone	PO
	Cyclophosphamide	IV
	Methotrexate/cytarabine (AraC)/prednisolone	IT

Subsequent therapy is based on stage (using a modified St Jude system) as follows:

• Patients with stage I or resected stage II disease receive cycles A-B-A.

• Patients with unresected stage II or stage III disease receive cycles A-B-A-B-A-B.

• Patients with stage IV disease (or multifocal bone disease) receive cycles AA-BB-CC-AA-BB-CC.

Table 10. Subsequent Therapy for BFM 90 Ki-1+ Anaplastic Large Cell Lymphoma

Cycle	Drug	Route
A	Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), cytarabine (AraC)	IV
	Methotrexate/cytarabine (AraC)/prednisolone	IT
B	Dexamethasone	PO
	Methotrexate with leucovorin rescue, cytarabine (AraC), doxorubicin	IV
	Methotrexate/cytarabine (AraC)/prednisolone	IT
AA	Dexamethasone	PO
	Vincristine, high-dose methotrexate with leucovorin rescue, ifosfamide, cytarabine (AraC), etoposide (VP-16)	IV
	Methotrexate/cytarabine (AraC)/prednisolone	IT
BB	Dexamethasone	PO
	Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin	IV
	Methotrexate/cytarabine (AraC)/prednisolone	IT
CC	Dexamethasone	PO
	Vindesine, high-dose cytarabine (AraC), etoposide (VP-16)	IV
	Methotrexate/cytarabine (AraC)/prednisolone	IT

A more recent report describes the results of virtually identical therapy (dexamethasone was used in the pre-phase, instead of prednisone) in 89 children. The overall EFS at five years was 76%.

As noted previously, good results have also been seen using the less-complicated APO regimen.

A recent randomized study of children with LCL (including both B-LCL and anaplastic LCL) showed no apparent advantage when intermediate-dose methotrexate and high-dose cytarabine were added to an APO backbone.

A report from the French Society of Pediatric Oncology described surprising efficacy of monotherapy with vinblastine for relapsed anaplastic LCL, even in patients who previously had undergone myeloablative therapy with autologous bone marrow transplantation. The role of vinblastine in front-line therapy for anaplastic LCL is being examined in a COG protocol that compares the standard APO regimen to an experimental arm that includes vinblastine.

Treatment of relapsed disease

As front-line therapies for pediatric NHL continue to evolve and improve, the treatment of relapses becomes increasingly problematic.

Reinduction regimens use novel chemotherapy combinations (eg, ifosfamide, carboplatin, etoposide, or “ICE”). Depending on the presence of certain cell-surface markers, monoclonal antibodies (eg, anti-CD20 rituximab) may be added to the regimen.

In most cases, myeloablative chemotherapy—with either autologous stem-cell rescue or allogeneic bone marrow transplantation—may offer the best chance for curative consolidative therapy.

Surgical Care:

• Even for patients with bulky NHL, debulking surgery is not crucial to effective therapy. For example, chemotherapy is quite effective in relieving partial airway or bowel obstruction (see Picture 3, Picture 4). In rare instances, a resection may be required for this purpose.



• The chief role for surgery is obtaining tissue for diagnosis. Thus, excision of an easily accessible lymph node (when present) is preferable to a thoracotomy or laparotomy, unless symptoms dictate otherwise. Even moderately aggressive surgery generally is not necessary or helpful.



• One exception (and one potential therapeutic dilemma) involves abdominal B-cell NHL. If (1) an intestinal primary lesion can be resected along with all involved adjacent lymph nodes, (2) marginal lymph nodes are free of disease, and (3) no evidence of further dissemination (eg, to CNS or marrow) is present, the patient can be assigned to clinical group A (see Table 5), and the prescribed chemotherapy regimen is far less toxic. Therefore, a surgeon treating a reasonably small abdominal NHL is advised to perform a lymph node dissection and attempt to excise all visible tumor; however, this surgery is performed only if it can be accomplished without significant morbidity. Heroic attempts at resection are best avoided since most patients with unresected disease still can be cured. Furthermore, a prolonged postoperative recovery may delay the start of chemotherapy and potentially compromise its effectiveness.



• Second-look surgery may be helpful in assessing the viability of residual masses. Such cases require highly individualized approaches. Alternatively, uptake of gallium-67 suggests viability of residual masses in patients whose tumors are gallium avid.

Consultations: Patients with childhood NHL frequently present in a tenuous condition because of airway compromise, metabolic derangements, and/or infection. In the initial stages of therapy, patients may be unstable or deteriorating. Thus, the support of a pediatric ICU is highly desirable.

• If available, a pediatric intensivist should be made aware of the patient in the event that respiratory management or pressor support becomes necessary.

• Consider consultation with a radiation oncologist. In general, radiation therapy has a limited role in the treatment of childhood NHL, and it is applied almost exclusively in situations deemed to be real or potential emergencies.


• • Mediastinal irradiation may be helpful in patients with impending airway obstruction, especially if general anesthesia is contemplated for biopsy or central line placement.
  
  
  
  • For patients with LL, low-dose radiation therapy often is used for treatment of neurologic involvement (eg, cranial nerve palsies, intracerebral extension of tumor, paraplegia).
  
  
  
  • Radiation has demonstrated minimal efficacy for patients with SNCCL, presumably because of the rapid growth of these cells. Although a dose of radiation may result in significant "cell kill," the rapid regrowth of surviving cells between doses of radiation largely negates the benefit. Hyperfractionated radiotherapy (ie, > 1 dose daily) offers a theoretic advantage, as does low-dose continuous radiation, although the unfeasibility of the latter all but precludes its use.
  
  
  
  • Finally, consider radiotherapy in any patient with documented residual disease following chemotherapy and in patients with bulky disease at relapse.
  
  
  
• Notify a nephrologist if the patient has substantial tumor lysis syndrome and dialysis is under consideration.

MEDICATION

Section 7 of 12

As discussed in Medical Care, these agents are used in combination schedules, and doses are tailored to the histologic subtype of lymphoma and stage of disease.

Drug Category: Corticosteroids -- Elicit anti-inflammatory properties and cause profound and varied metabolic effects. Modify body's immune response to diverse stimuli.

Drug Name	Methylprednisolone (Medrol) -- Mechanism of cytotoxicity unknown, but apparently mediated through glucocorticoid receptors.
Pediatric Dose	5-25 mg/m2/d PO/IV 4-10 mg IT
Contraindications	Documented hypersensitivity; avascular necrosis of bone; systemic fungal infection (relative CI)
Interactions	Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases risk of hypokalemia; may alter response to Coumadin anticoagulants (usually inhibitory, but also unsubstantiated reports of potentiation)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Immunosuppression; weight gain; hypertension; osteopenia; myositis; striae; cataracts; poor linear growth; gastritis can be reduced by coadministration of antacids or inhibitors of gastric acid secretion

Drug Name	Dexamethasone (Decadron) -- Mechanism of cytotoxicity unknown, but apparently mediated through glucocorticoid receptors; apparently enhanced CNS penetration (relative to prednisone).
Pediatric Dose	8-10 mg/m2/d PO/IV
Contraindications	Avascular necrosis of bone; systemic fungal infection (relative CI)
Interactions	Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases risk of hypokalemia; may alter response to Coumadin anticoagulants (usually inhibitory, but also unsubstantiated reports of potentiation)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Immunosuppression; weight gain; hypertension; osteopenia; myositis; striae; cataracts; avascular necrosis of bone; poor linear growth; gastritis can be reduced by coadministration of antacids or inhibitors of gastric acid secretion

Drug Category: Antineoplastics agents -- Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).
Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy and is the rationale behind current cyclic dosage schedules.
Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Name	Daunorubicin (Cerubidine) -- An anthracycline. Multiple mechanisms of action include DNA intercalation, topoisomerase-mediated DNA strand breaks, and oxidative damage via free radical production.
Pediatric Dose	30-60 mg/m2 IV
Contraindications	Documented hypersensitivity; myocardial damage; cumulative anthracycline dose >450 mg/m2 is relative contraindication
Interactions	Increased risk of cardiotoxicity when combined with heart irradiation
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; diarrhea; alopecia; cardiotoxicity; tissue damage with extravasation

Drug Name	Doxorubicin (Adriamycin) -- An anthracycline. Multiple mechanisms of action include DNA intercalation; topoisomerase-mediated DNA strand breaks; and oxidative damage via free radical production.
Pediatric Dose	25-60 mg/m2 IV
Contraindications	Documented hypersensitivity; myocardial damage; cumulative anthracycline dose >450 mg/m2 is relative contraindication
Interactions	Increased risk of cardiotoxicity when combined with heart irradiation; may potentiate toxicity of other chemotherapeutic agents including cyclophosphamide and mercaptopurine
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; diarrhea; alopecia; cardiotoxicity; tissue damage with extravasation

Drug Name	Cytarabine (Cytosine arabinoside, AraC, Cytosar-U) -- An antimetabolite. Cytotoxic analogue of deoxycytidine, which interferes with DNA replication and repair through incorporation into DNA and inhibition of DNA polymerase.
Pediatric Dose	75-100 mg/m2 IV 16-30 mg IT
Contraindications	Documented hypersensitivity
Interactions	Possible decrease in steady-state digoxin levels if coadministered with beta-acetyldigoxin (not digitoxin)
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; diarrhea; mucositis; alopecia; ocular toxicity; neurotoxicity

Drug Name	6-mercaptopurine (Purinethol) -- Purine analogue, metabolites of which are incorporated into DNA, inhibiting synthesis.
Pediatric Dose	25-60 mg/m2 PO
Contraindications	Documented hypersensitivity; severe liver disease and bone marrow depression; thiopurine methyltransferase deficiency requires dosage adjustment
Interactions	Absorption of PO 6-MP is enhanced significantly by coadministration of allopurinol; following pretreatment with allopurinol, reduce dose by 75%; food decreases bioavailability
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; mucositis; hepatotoxicity

Drug Name	6-thioguanine (Purinethol) -- Purine analogue, metabolites of which are incorporated into DNA, inhibiting synthesis
Pediatric Dose	50-60 mg/m2 PO
Contraindications	Documented hypersensitivity; hepatic venoocclusive disease; thiopurine methyltransferase deficiency requires dosage adjustment
Interactions	Increases busulfan toxicity; empty stomach enhances absorption
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; mucositis; hepatotoxicity (eg, venoocclusive disease, unsteady gait, photosensitivity)

Drug Name	Methotrexate (Folex PFS) -- Cytotoxic folate antagonist that inhibits dihydrofolate reductase.
Pediatric Dose	10 mg/m2 to 8 g/m2 PO/IV/IM 8-15 mg IT
Contraindications	Documented hypersensitivity; caution in patients with chronic liver disease; severe pre-existing bone marrow depression
Interactions	NSAIDs may cause increased or prolonged levels of MTX; may decrease clearance of theophylline; penicillins may decrease renal excretion of MTX; broad-spectrum PO antibiotics may decrease MTX bioavailability; additional folate antagonists (eg, TMP/SMX) may have additive myelosuppression
Pregnancy	X - Contraindicated in pregnancy
Precautions	Myelosuppression; nausea; mucositis; high doses require leucovorin rescue

Drug Name	Vincristine (Oncovin) -- Inhibits microtubule formation in mitotic spindle, causing metaphase arrest.
Pediatric Dose	1.5-2 mg/m2 IV; not to exceed 2 mg
Contraindications	Documented hypersensitivity; severe constipation and/or peripheral neuropathy are relative contraindications
Interactions	Acute pulmonary reaction may occur when taken concurrently with mitomycin-C
Pregnancy	D - Unsafe in pregnancy
Precautions	Peripheral neuropathy; constipation; alopecia; tissue damage with extravasation

Drug Name	Etoposide (VP-16, Toposar) -- Inhibits topoisomerase, causing DNA strand breaks.
Pediatric Dose	150-200 mg/m2 IV
Contraindications	Documented hypersensitivity
Interactions	May prolong effects of warfarin and increase clearance of methotrexate; cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; alopecia; mucositis; hypersensitivity reaction

Drug Name	Cyclophosphamide (Cytoxan) -- Alkylates and cross-links DNA.
Pediatric Dose	0.2-1.2 g/m2 IV
Contraindications	Documented hypersensitivity; severe hemorrhagic cystitis
Interactions	Metabolic activation may be enhanced by coadministration of phenobarbital and phenytoin; inhibits cholinesterase, thereby potentiating effect of succinylcholine
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; alopecia; hemorrhagic cystitis; impaired fertility

Drug Name	Ifosfamide (Ifex) -- Alkylates and cross-links DNA.
Pediatric Dose	800 mg/m2 IV
Contraindications	Documented hypersensitivity; severe hemorrhagic cystitis
Interactions	Metabolic conversion to active metabolites may be enhanced by coadministration of phenobarbital and phenytoin; phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P-450 activity may alter effects of ifosfamide
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; nausea; alopecia; hemorrhagic cystitis; impaired fertility

Drug Name	Carmustine (BCNU, BiCNU) -- Alkylates DNA and RNA; also may act via carbamoylation of enzymes.
Pediatric Dose	30 mg/m2 IV
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cimetidine may increase toxicity; coadministration with etoposide may cause severe hepatic dysfunction (hyperbilirubinemia ascites, thrombocytopenia)
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression (delayed); nausea; nephrotoxicity; pulmonary toxicity; impaired fertility

Drug Name	L-asparaginase (Elspar) -- Enzyme produced by Escherichia coli, which catalyzes conversion of L-asparagine to aspartic acid. The former is a nonessential amino acid for most normal tissues, but many lymphoid malignancies have low levels of asparagine synthase and, thus, depend on circulating pool of L-asparagine.
Pediatric Dose	6,000-10,000 IU/m2 IM
Contraindications	Documented hypersensitivity; history of pancreatitis
Interactions	May inhibit effect of methotrexate on neoplastic cells; toxicity may increase with vincristine or prednisone
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pancreatitis; hyperglycemia; coagulopathy; hypersensitivity reaction; occasional myelosuppression

--

Drug Name	Nelarabine (Arranon)- Prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). Converted to the active 5’-triphosphate, ara-GTP, a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death. Approved by FDA as orphan drug to treat persons with T-cell lymphoblastic lymphoma (a type of non-Hodgkin lymphoma [NHL]) whose disease has not responded to or has relapsed with at least 2 chemotherapy regimens.
Adult Dose	1500 mg/m2 IV (infuse over 2 h) on days 1, 3, and 5; repeat q21d
Pediatric Dose	650 mg/m2 IV (infuse over 1 h) qd for 5 consecutive days; repeat q21d
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	D - Fetal risk shown; may use if benefits outweigh risk to fetus.
Precautions	Common adverse effects include hematologic toxicity (eg, leukopenia, thrombocytopenia, anemia, neutropenia), hypokalemia, hypoalbuminemia, hyperbilirubinemia, fatigue, nausea, vomiting, and diarrhea; severe neurologic events reported and include extreme somnolence, convulsions, demyelination, ascending peripheral neuropathies similar to Guillain-Barré syndrome, and peripheral neuropathy ranging from numbness and paresthesia to motor weakness and paralysis; do not dilute prior to administration; preventive measures for hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, allopurinol prophylaxis) must be taken

Drug Name	Hydroxyurea (Hydrea) -- Apparently inhibits DNA synthesis.
Pediatric Dose	2.4 g/m2/d PO
Contraindications	Documented hypersensitivity; severe anemia and bone marrow depression
Interactions	Coadministration with fluorouracil can increase neurotoxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression; megaloblastic anemia; nausea; mucositis; impaired fertility

FOLLOW-UP

Section 8 of 12

In/Out Patient Meds:

• Several medications are used to support the patient undergoing aggressive chemotherapy.


• • Laxatives and stool softeners
  
  
  
  • Prophylactic antibiotics
    • Trimethoprim/sulfamethoxazole (Pneumocystis carinii)

    • Fluconazole (Candida species)

    • Nystatin (Candida species)
  
  
  
• Antiemetics
  • 5HT3-receptor antagonists (ondansetron, granisetron, dolasetron)

  • Phenothiazine

  • Lorazepam

  • Metoclopramide

  • Dexamethasone

  • Tetrahydrocannabinol



• Antimucositics
  • Saline or bicarbonate rinse

  • Biotene rinse

  • Peridex rinse

  • Glutamine suspension



• Histamine (H2)-receptor antagonists - Famotidine and ranitidine to help prevent gastritis in patients receiving high-dose corticosteroids



• Contraceptives - Oral or injectable contraceptives (can be used to suppress menses in adolescent females at risk for menorrhagia due to thrombocytopenia)

Complications:

• Acute complications of NHL and its treatment are discussed in the Mortality/Morbidity section. With increasing survival rates, late effects of therapy are a growing concern and are described here.


• • Growth: Linear growth often slows during aggressive chemotherapy. Most patients exhibit catch-up growth and eventually attain heights within the normal range. Significant long-term growth retardation essentially is confined to patients who receive cranial irradiation. Interestingly, a significant minority of children treated for lymphoma eventually becomes obese; the basis for this is unclear.
  
  
  
  • Neuropsychological sequelae: Neurotoxicity from the combination of cranial radiation and intrathecal chemotherapy is well described in patients with ALL. Neurotoxicity ranges from mild learning disabilities to a profound necrotizing leukoencephalopathy. Patients with CNS lymphoma are at risk for the same complications. In the absence of radiation, intrathecal chemotherapy appears to have little effect on neuropsychological function. However, a recent study suggests that nonirradiated survivors of NHL are more likely to require special education classes than their siblings. The peripheral neuropathy associated with vincristine occasionally may leave permanent deficits, particularly lower extremity weakness.
  
  
  
  • Fertility: In particular, alkylating agents have been implicated in acute gonadal dysfunction. The long-term effects of these agents among survivors of childhood cancer are less clear. Younger (prepubertal) males appear to be at low risk of eventual azoospermia or failure of sexual maturation. Older adolescent males are at some risk for temporary azoospermia and may consider banking semen before chemotherapy, if feasible. Ovarian failure following high-dose alkylator therapy also has been described; however, in a recent report, female survivors had little or no apparent deficit in pregnancies. Patients who experience a relapse, particularly those treated with myeloablative chemotherapy and/or total body irradiation, are at much higher risk of permanent gonadal dysfunction.
  
  
  
  • Second malignancies: The oncogenic potential of therapeutic radiation is well documented. However, the risk of second malignancies associated with chemotherapy is less obvious. One clearly implicated antineoplastic agent is etoposide; however, the risk of secondary AML from this drug appears to be insignificant at cumulative doses less than 1000 mg/m². Cyclophosphamide also has been identified as a potential carcinogen; the relative risk of second malignancies in children exposed to cyclophosphamide is estimated to be as high as 7.4 if the cumulative exposure is greater than 13 g/m².

    Among a series of 86 survivors of pediatric NHL evaluated an average of 11 years after diagnosis, only 2 cases of secondary cancer were observed (ie, 1 malignant melanoma, 1 spindle-cell sarcoma [the latter arising within a radiation field]). This study suggests that, in spite of concerns about chemotherapy effects, patients who do not receive radiation therapy are unlikely to develop a second malignancy. Longer periods of follow-up care are necessary to assess accurately the life-long risk of second malignancies.

  
  
  
  • Cardiotoxicity: At very high cumulative doses, doxorubicin is likely to cause delayed myocardial toxicity. Irradiation of the heart exacerbates this effect. In a recent report, 7 of 29 NHL survivors (aged 2-39 y at diagnosis) who had received 240-560 mg/m² of doxorubicin eventually developed left ventricular dysfunction, on average approximately 10 years later. However, other reports have described anthracycline cardiotoxicity after a cumulative dose as small as 100 mg/m². Indefinitely continue screening echocardiograms every 2-4 years in patients who have received more than 300 mg/m² of doxorubicin. Lower this threshold if mediastinal irradiation also was employed.
  
  
  
  • Skeletal toxicity: Chronic high-dose steroid therapy is associated with osteoporosis and with avascular necrosis of bone. The latter most commonly affects the femoral heads, may be associated with slipped capital femoral epiphysis, and is observed more often in adolescent and female patients. The spectrum of disease ranges from asymptomatic x-ray findings to incapacitating joint destruction requiring restorative surgery. Radiation therapy also is associated with osteopenia, which may occur locally or, interestingly, may be observed diffusely following cranial irradiation.
  
  
  
  • Viral transmission via blood products: Transmission of CMV is likely if unscreened blood products are administered. Exposed patients who eventually require myeloablative therapies are then at substantial risk of disseminated CMV. Thus, CMV-negative products are ideal for patients who eventually may undergo bone marrow transplantation. With modern transfusion practices, exposure to hepatitis B or hepatitis C virus is rare. Nonetheless, patients occasionally demonstrate serologic evidence of exposure. Chronic active hepatitis and hepatocellular carcinoma are potential sequelae of this exposure. Exposure to HIV is even less likely but nevertheless is possible. Explain these risks to patients, parents, and/or caregivers prior to transfusions.
  
  
  

Patient Education:

• For excellent patient education resources, visit eMedicine’s Blood and Lymphatic System Center and Cancer and Tumors Center. Also, see eMedicine’s patient education articles Lymphoma and Cancer of the Mouth and Throat.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Airway obstruction: Mediastinal or cervical lymphomas may cause airway compromise. The potential for respiratory arrest must be recognized, particularly if sedation or general anesthesia is administered for a diagnostic procedure. Consider (1) administering local anesthesia alone for a lymph node biopsy, (2) establishing a diagnosis with pleural or peritoneal fluid or a bone marrow aspiration, and (3) performing local radiation therapy to stabilize the airway prior to obtaining a diagnostic specimen from a site outside the radiation field.



• Tumor lysis syndrome: Non-Hodgkin lymphomas typically respond briskly to induction chemotherapy. With initial supportive treatment, include aggressive hydration, close monitoring of serum chemistries, and administration of allopurinol. Consider consulting a nephrologist as dialysis ultimately may be necessary.



• Human immunodeficiency virus: Non-Hodgkin lymphoma (particularly, a primary tumor of the CNS) can be a presenting sign of immunodeficiency, such as HIV/AIDS.



• Rapid progression: Non-Hodgkin lymphomas in children typically grow rapidly, in contrast to the more indolent lymphomas often observed in adults. To avoid tumor regrowth and an increased short-term risk of complications, keep any delay between diagnosis and initiation of chemotherapy (eg, to allow healing after an abdominal procedure) to an absolute minimum.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is more likely in children with non-Hodgkin lymphoma (NHL) than in adults with NHL?

A: Presenting with an indolent course
B: Exhibiting nodular disease on histologic examination
C: Having a tumor characterized by the t(8;14) translocation
D: Presenting with thrombocytopenia
E: Requiring involved-field radiation therapy

The correct answer is C: The t(8;14) translocation is a hallmark of Burkitt lymphoma, which constitutes approximately 40-50% of childhood NHLs. This subtype of NHL is uncommon in adults. In general, childhood NHL progresses rapidly, whereas adult NHL is more likely to be indolent. Histologically, childhood NHL is usually diffuse, not nodular. Abnormal blood counts are not typical of NHL, in which fewer than 25% marrow blasts are present. Cytopenias suggest more extensive bone marrow involvement, thus acute leukemia is the proper diagnosis. Radiation therapy plays a very limited role in the treatment of children with NHL.

CME Question 2: Which of the following is accurate regarding the epidemiology of childhood lymphomas?

A: Collectively, lymphomas are the most common solid tumors of childhood.
B: Among preschool-aged children, Hodgkin disease is more common than non-Hodgkin lymphoma (NHL).
C: Incidence of childhood NHL has decreased slightly over the last 3 decades.
D: Among children, the incidence of NHL increases substantially with older age.
E: Collectively, lymphomas account for 10-12% of childhood malignancies.

The correct answer is E: Lymphomas (non-Hodgkin lymphoma, Hodgkin disease) account for approximately 10-12% of childhood malignancies. Collectively, brain tumors are the most common solid tumor among children (20%), and lymphomas are second. In younger children, NHL is somewhat more common than Hodgkin disease, but the incidence of the latter increases markedly in older adolescents. The incidence of NHL is relatively steady across pediatric age groups but rises markedly in elderly adults. During the last 2-3 decades, incidence of childhood NHL has risen somewhat, primarily as a consequence of immunodeficiencies and combined modality therapy for other cancers, especially Hodgkin disease.

Pearl Question 1 (T/F): Non-Hodgkin lymphoma is the most common cause of a rapidly progressive mediastinal mass and dyspnea in a child.

The correct answer is True: Lymphoblastic lymphoma (anaplastic T cell) is the most common cause of a rapidly progressive mediastinal mass and dyspnea in a child. This is an uncommon presentation for a B-cell malignancy. Hodgkin disease usually presents more insidiously, thus even a large mediastinal mass is unlikely to cause pronounced respiratory symptoms. Other less common anterior mediastinal masses (teratoma, thymoma, cystic hygroma) eventually may cause airway obstruction but usually progress slowly. Neuroblastoma may present with a posterior thoracic mass, thus respiratory symptoms are usually absent.

Pearl Question 2 (T/F): For patients with advanced stage Burkitt lymphoma (ie, bone marrow or CNS involvement), the probability of being cured with current therapies is approximately 60%.

The correct answer is False: The 2-year event-free survival is approximately 90%, with little or no likelihood of relapse after that time.

Pearl Question 3 (T/F): An aggressive surgical resection is critical for the successful treatment of abdominal Burkitt lymphoma.

The correct answer is False: The complete resection of an intestinal Burkitt lymphoma (along with any involved lymph nodes) may allow clinical down-staging, thus significantly less chemotherapy can be administered. However, no role exists for heroic attempts at resection. With aggressive chemotherapy, even large unresected tumors exhibit a complete response, and these patients have a high cure rate. Recovery from an aggressive surgical procedure may postpone chemotherapy and compromise care. In particular, if evidence is present of widespread dissemination (eg, CNS symptoms, bone pain, cytopenias [suggesting diagnosis of B-cell acute lymphoblastic lymphoma]) and the patient does not have an acute abdomen (ie, peritoneal signs, high-grade obstruction), a resection and/or biopsy may not be necessary. The diagnosis can be established using cerebrospinal fluid, pleural fluid, or bone marrow.

Pearl Question 4 (T/F): Metabolic derangements (ie, tumor lysis syndrome) seldom are observed in patients with non-Hodgkin lymphoma.

The correct answer is False: Rapid tumor cell turnover often is present when the physician diagnoses non-Hodgkin lymphoma and is reflected by elevations in serum lactate dehydrogenase, potassium, phosphorus, and uric acid. These abnormalities are likely to worsen with the initial doses of chemotherapy. Renal involvement with lymphoma may exacerbate the situation. Hyperuricemia can lead to renal failure, requiring dialysis. Aggressive intravenous hydration (ie, bicarbonate, without potassium) and allopurinol are important interventions prior to chemotherapy. Serum chemistries should be monitored at least twice daily for the first 2-3 days of treatment.

PICTURES

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Caption: Picture 1. Lymphoma incidence as a function of age (US Surveillance, Epidemiology, and End Results [SEER] data, 1990-94, per 100,000 population)
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Caption: Picture 2. Massive mediastinal T-lymphoblastic lymphoma. Note compression of the left mainstem bronchus and pulmonary atelectasis.
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Caption: Picture 3. Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign (ie, intraluminal contrast surrounded by a grossly thickened bowel wall). The appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type).
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Caption: Picture 4. Malignant pleural effusion. This patient was diagnosed with non-Hodgkin lymphoma of the terminal ileum; the doughnut sign (ie, intraluminal contrast surrounded by a grossly thickened bowel wall) was present. A diagnosis of stage 3 Burkitt lymphoma was established by pleurocentesis (bone marrow was normal). The patient was treated successfully and never required an abdominal procedure.
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Caption: Picture 5. Massive left pleural effusion complicating an upper anterior mediastinal T-lymphoblastic lymphoma. Note the atelectatic left lung. The diagnosis was established by thoracentesis. This patient also had bilateral parotid gland involvement.
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BIBLIOGRAPHY

Section 12 of 12

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• Brugieres L, Quartier P, Le Deley MC, et al: Relapses of childhood anaplastic large-cell lymphoma: treatment results in a series of 41 children--a report from the French Society of Pediatric Oncology. Ann Oncol 2000 Jan; 11(1): 53-8[Medline].
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