AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

ALCLs, anaplastic LCLs, anaplastic large cell lymphomas, Ki-1+ lymphoma, Ki 1+ lymphoma, malignant anaplastic lymphoma, histiocytic lymphoma, immunoblastic lymphoma, myeloid lymphoma, lymphosarcoma, reticulum cell sarcoma, acute lymphoblastic lymphoma, ALL, common ALL antigen, CALLA, diffuse large cell lymphoma

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Lymphomas are malignant neoplasms of lymphoid lineage. Broadly classified as either Hodgkin disease or as non-Hodgkin lymphoma (NHL), lymphomas are clinically, pathologically, and biologically distinct.

According to the National Cancer Institute (NCI) formulation, most childhood NHLs can be classified as one of the following types:

• Lymphoblastic lymphomas
• Small noncleaved cell lymphomas (SNCCLs), ie, Burkitt lymphomas or Burkittlike lymphomas (non-Burkitt lymphomas)
• Large cell lymphomas (LCLs)

In recent years, B-cell LCLs and anaplastic (usually T-cell) LCLs (ie, Ki-1+ lymphomas) have come to be viewed as distinct entities. In this article, these categories are considered separately. Other, less common forms of lymphoma are not discussed.

Since the late 1960s, treatment outcomes for children with NHL have improved steadily. Even for patients with advanced disease, event-free survival rates are 65-90%.

The mainstay of conventional therapy is multiagent chemotherapy tailored to the histologic subtype and the 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 disease localized in the organ or tissue of origin. They may then secondarily spread by means of local extension or distant metastases. In contrast, NHL is best regarded as a systemic disease because of the unique anatomy of the lymphoid system and because of the physiology of lymphoid cells, which tend to migrate whether they are normal or malignant.

Childhood NHL generally manifests as bulky extramedullary (usually extranodal) disease with or without demonstrable dissemination. The distinction between NHL and acute leukemia is arbitrary. Therefore, these entities are best considered in terms of a spectrum ranging from clinically localized disease to overt leukemia.

In most treatment protocols, acute leukemia is now defined on the basis of marrow involvement above than some threshold (typically a blast count of >25%) irrespective of the presence of bulky extramedullary disease. In contrast, a tumor accompanied by marrow involvement below than this threshold constitutes stage 4 lymphoma.

Frequency

United States

Taken collectively, lymphomas are the third most common childhood malignancies after acute leukemias and brain tumors. Lymphomas constitute 10-12% of childhood cancers (see Childhood Cancer, Epidemiology). In older adolescents, lymphomas surpass brain tumors in incidence largely because of the increased frequency of Hodgkin disease in this age group.

Data from the NCI Surveillance, Epidemiology, and End Results (SEER) program for 1994-1998 are shown in Table 1. In children, NHL is somewhat less common than Hodgkin disease. However, the incidence of NHL appears to be rising in the United States. This trend largely reflects the occurrence of NHL in patients who are immunocompromised (eg, patients who are HIV positive) and in patients who were previously exposed to chemotherapy and irradiation as treatment for an unrelated cancer.

Table 1. Age-Adjusted Incidences of Selected Cancers per 100,000 Individuals Aged 0-19 Years

Source.—SEER data for 1994-1998.

International

Over the last 3 decades, the incidence of NHL appears to have increased in Canada, as it has in the United States. The cause for this rise is unclear. Burkitt lymphoma is significantly most 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, in North Africa, and in the Middle East than in the United States or 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 the time of diagnosis. The start 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 the 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 Image 2). Even in the absence of symptomatic airway compromise, sudden obstruction may be a risk if the patient undergoes anesthesia for biopsy or placement of a central line. In these individuals, consider biopsy done under local anesthesia or immediate radiation therapy to the airway, provided that another site of disease is outside the radiation field (to allow for subsequent histologic confirmation of the diagnosis).
• Mediastinal tumors may cause compression of the great vessel (superior vena cava syndrome), with swelling of the neck, face, and upper extremities. Esophageal compression may lead to dysphagia. Pleural effusion is sometimes observed and may be large enough to cause symptoms. In affected individuals, thoracentesis may be both therapeutic and diagnostic, obviating biopsy.
• In the United States, most patients with SNCCLs present with abdominal involvement, typically in the ileocecal area and arising from Peyer patches (see Image 3). A potential complication at the time of diagnosis is bowel obstruction due to direct compression, torsion, or intussusception. Because of bowel perforation, some patients have ascites or present with a clinical picture of acute appendicitis or peritonitis.
• In equatorial Africa, SNCCL (ie, endemic Burkitt lymphoma) classically appears as a mass in the jaw, nasopharynx, or orbit. These masses grow rapidly and can be disfiguring.
• With current treatments, NHLs in most children are apparently curable. The results depend on achieving a precise histologic diagnosis, thorough staging of the disease, and applying complex multiagent (and sometimes multimodal) treatment. The short-term morbidity of chemotherapy regimens is considerable, but the effects are usually manageable. Late effects of treatment are a growing concern, as survival rates are increasing (see Complications).

Race

In the United States, the incidence of NHL is twice as high among Caucasians as among African Americans, with respective rates of 9.1 and 4.6 cases per million individuals per year.

Sex

In the United States, the incidence is 2-3 times higher in male individuals than in female individuals.

Age

In the United States, 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 than this as children age (see Image 1). In adulthood, the risk of NHL climbs steadily, whereas the age-specific incidence of Hodgkin disease is biphasic.

CLINICAL

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History

• The presentation of patients with NHL is acute or subacute, in contrast to the indolent course that characterizes most lymphomas in adults.
• The duration of symptoms before diagnosis is generally 1 month or shorter.
• Specific complaints vary and depend on the predominant sites of involvement.
• Constitutional symptoms are uncommon, except in patients with anaplastic LCLs. Many of these patients have low-grade fever, malaise, anorexia, and/or weight loss.
• LCLs are biologically disparate. As a result, these lesions have a varied presentation that may include chest or abdominal complications. In rare cases, an LCL appears as an isolated bone lesion in association with pain, swelling, and a risk of pathologic fracture.
• Bone marrow involvement may cause generalized or migratory bone pain. However, in individuals with NHL, clinically significant cytopenias are uncommon, and their presence suggests a diagnosis of acute leukemia.
• Localized disease can manifest as lymphadenopathy (usually with firmness and no tenderness), tonsillar hypertrophy, or a mass in virtually any location. However, in children, NHL is primarily an extranodal disease.
• Patients with supradiaphragmatic disease (eg, lymphoblastic lymphoma) often report having a nonproductive cough, dyspnea, chest pain, and dysphagia.
• Abdominal tumors (usually SNCCLs or B-cell LCLs) are associated with abdominal pain, constipation, masses, or ascites. An acute abdomen occasionally is observed and may be mistaken for appendicitis.
• Patients with anaplastic LCLs sometimes present with painful skin lesions, bone lesions, peripheral lymphadenopathy, and hepatosplenomegaly. The painful skin lesions may regress spontaneously. A finding less common than these is testicular, lung, or muscle involvement.
• Anaplastic LCLs may also result in an apparent cytokine storm, with fevers, vascular leakage, and altered blood counts that indicate anemia, thrombocytopenia, leukopenia, and leukocytosis.
• Patients occasionally develop symptomatic CNS involvement before diagnosis. Headache, meningismus, cranial nerve palsies, and altered sensorium may be observed. Although CNS involvement is uncommon at the time of diagnosis, patients with NHL (particularly SNCCL) occasionally present with symptoms suggestive of meningoencephalitis.

Physical

• In general, patients often appear mildly to moderately ill. They occasionally have a low-grade fever. Patients may present with pallor, respiratory distress, pain, and discomfort.
• A jaw or orbital mass is present in as many as 10% of patients in developed countries. It is particularly common in African patients with endemic Burkitt lymphoma.
• Cervical or supraclavicular masses or adenopathy is firm, fixed, and nontender.
• Dyspnea or stridor may occur in patients with a mediastinal mass. In those with superior vena cava syndrome, distended neck veins and plethora may be observed.
• Decreased breath sounds are secondary to bronchial obstruction or pleural effusion.
• Thoracic dullness to percussion may be present with pleural effusion.
• Abdominal distention or a mass may be present with or without tenderness, rebound tenderness, and/or shifting dullness.
• Painful skin lesions suggest an anaplastic LCL.
• Obtundation, agitation, and meningismus may be observed in individuals with CNS involvement.
• Focal pain or swelling in the extremity may be present in patients with primary bone lymphoma.
• Relatively uncommon physical findings include the following:
• • Nasopharyngeal mass
  • Parotid enlargement
  • Nephromegaly
  • Testicular enlargement

Causes

In developed countries, most individuals with NHL have no known etiology or association.

Epidemiologic data suggest that certain human leukocyte antigen (HLA) types, and even certain blood types, may increase or decrease the likelihood of developing NHL. Findings from several epidemiologic studies suggest that pesticide exposure may play a role in the development of adult NHL; the case for its involvement in childhood NHL is less compelling than the case for adults, but this is still under investigation.

The epidemiologic association between NHL and certain paternal occupations (eg, those that increase contact with other individuals) suggest a possible infective etiology for childhood NHL.

Regarding protective factors, results of one case-control study suggested that exposure to sunlight may protect individuals against NHL, presumably because of enhanced vitamin D synthesis.

Immunosuppression and viral infection

Immunosuppressed individuals, such as those with HIV infection or those who have undergone bone marrow transplantation, are at increased risk for developing NHL, particularly SNCCL and LCL of B-cell origin. The 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 than in others.

Previous Hodgkin disease

Patients successfully treated for Hodgkin disease are at increased risk for developing NHL. This effect appears to reflect the combined effects of chemotherapy and radiotherapy, as well as the immunosuppressive effects of Hodgkin disease. Adults older than 40 years who received combined-modality therapy are at particular risk; their 15-year incidence of NHL is as high as 39%.

Splenectomy, now rarely performed in patients with Hodgkin disease, is another reported risk factor for second malignancies, including NHL.

Secondary NHL is less common among pediatric patients who survive cancer than among adults.

A cohort of 5484 children was treated for various malignancies at St Jude Children's Research Hospital. Over 30,710 person-years of follow-up care, only 3 had secondary NHL. The 15-year actuarial risk of NHL was 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 among patients whose primary malignancy had been diagnosed when they were younger than 20 years. Eighteen (75%) of the patients previously had Hodgkin disease.

Geographic location

In sub-Saharan Africa, the development of endemic Burkitt lymphoma is strongly associated with previous exposures to both malaria (with resultant T-cell suppression) and the Epstein-Barr virus. Recent speculation suggests that mosquito-borne arboviruses may also play a role in the development of Burkitt lymphoma in this part of the world.

In addition, exposure to 4-deoxyphorbol ester from the plant Euphorbia tirucalli (by means of goat's milk) is tentatively implicated in the pathogenesis of endemic Burkitt lymphoma.

Genetic causes

The genetic basis of pediatric NHL has been studied extensively. Each subtype of NHL is characterized by 1 or more molecular alterations that contribute to the malignant phenotype. Many of these alterations are chromosomal translocations involving genes for immunoglobulin or T-cell receptor (TCR) molecules. During normal lymphocyte development, these loci undergo recombination that enhances immunologic diversification. However, mistargeted recombination leads to translocations with other genes, typically those that regulate cell growth. The resulting dysregulation of these other genes contributes to the transformed phenotype.

For example, the hallmark of Burkitt lymphoma is a t(8;14)(q24;q32) translocation, which is observed in approximately 80% of patients. This translocation juxtaposes c-myc, which encodes a transcription factor important in initiation of the cell cycle, with the locus for the immunoglobulin heavy chain. In a relatively uncommon alteration, c-myc is adjoined to the gene encoding the immunoglobulin 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 regulatory sequences of immunoglobulin genes. This aberration contributes to the pathogenesis of Burkitt lymphoma.

Aside from the t(8;14) translocation, Burkitt lymphoma frequently involves a gain of chromosomal material that can affect any of a number of chromosomes. Abnormalities of chromosomal arms 1q, 7q, or 13q may portend a poor prognosis.

A small portion of T-lymphoblastic lymphomas are also associated with translocations involving 1 of the TCR loci: TCR alpha delta (14q11) or TCR beta (7q34). The most common example (observed in 7% of children with T-lymphoblastic lymphomas) is the t(11;14)(p13;q11) translocation, which enhances expression of the LMO2 gene on chromosome 11. This gene encodes LIM protein, an apparent modulator of gene transcription. A more common abnormality than this, one observed in approximately 25% of patients with T-lymphoblastic lymphoma/T-cell acute lymphoblastic lymphoma (ALL), is a deletion in a regulatory region of the gene TAL1. This deletion, which is too small to be detected with conventional cytogenetic techniques, leads to 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-lymphoblastic lymphoma is likely to be a significant factor. Of interest, the deletions or disruptions responsible for this inactivation are apparently related to illegitimate activity of the same V(D)J recombinase that mediates recombination of the TCR gene. Thus, even in the absence of a TCR translocation, similar molecular mechanisms may be responsible for disrupting other genes involved in normal control of the cell cycle.

Some B-lineage LCLs have the same t(8;14)(q24;q32) translocation observed in Burkitt lymphoma. In the converse, most anaplastic (T-lineage) LCLs in children involve a t(2;5)(p23;q35) translocation. This change joins the nucleophosmin gene (NPM) on chromosome 5 to a gene called anaplastic lymphoma kinase (ALK) on chromosome 2 and allows for the expression of an NPM/ALK fusion protein p80. Transcripts of NPM/ALK are also observed in about 20% of individuals with NHLs lacking cytogenetic evidence of t(2;5); this finding reflects an occult or variant translocation. Patients with NHLs expressing p80 may have a survival advantage over patients whose lymphomas lack p80.

For additional reading, see Childhood Cancer, Genetics.

DIFFERENTIALS

Section 4 of 11  

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WORKUP

Section 5 of 11  

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• Differentials
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• Follow-up
• Miscellaneous
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Lab Studies

• Order a CBC with differential and a platelet count to assess for possible involvement of the bone marrow and to determine the patient's transfusion requirements.
• Measure the prothrombin time, the activated partial thromboplastin time, fibrinogen, and the D-dimer level if the patient is febrile or if he or she has evidence of sepsis. The purpose is to assess for possible disseminated intravascular coagulation, which may require specific therapy.
• Obtain blood and urine cultures if patient has a fever, especially if it is associated with neutropenia. If indicated, also obtain stool and throat cultures.
• Analyze the measures listed below to assess the patient's renal and hepatic function and to monitor for possible tumor lysis syndrome. Of note, the level of lactate dehydrogenase at diagnosis had prognostic significance in many analyses of treatment outcomes.
  • Serum electrolytes
  • Blood urea nitrogen
  • Creatinine
  • Uric acid
  • Lactate dehydrogenase
  • Bilirubin
  • Albumin
  • Total protein
  • Aspartate aminotransferase
  • Alanine aminotransferase
  • Calcium
  • Magnesium
  • Phosphorus
• Perform HIV serologic tests in patients who have risk factors for HIV exposure or in those with primary CNS lymphoma to exclude these possible predisposing factors.

Imaging Studies

• Chest radiography: Obtain posteroanterior and lateral views to assess for possible mediastinal masses, to evaluate the airway, and to exclude pulmonary parenchymal lesions and associated pneumonia.
• Ultrasonography
• • Abdominal sonography helps in assessing the size of the kidneys and the patency of the urinary tract.
  • Abdominal sonography is useful particularly before chemotherapy in anticipation of prolonged excretion and excess toxicity, for example.
  • When symptoms are present, testicular ultrasonography aids in identifying additional sites of disease.
• Computed tomography
• • CT scans of the chest, abdomen, and pelvis can be used to stage lesions (see Staging).
  • If the patient is stable, chest CT scan is indicated to assess for the degree of tracheal compression.
  • Head CT scans assist in excluding mass lesions and possible meningeal involvement among individuals with CNS disease.
• Bone scanning and skeletal surveys: When additional symptoms are present, these tests help in identifying additional sites of disease.
• Gallium-67 scanning
• • ⁶⁷67 scanning is highly recommended.
  • Some tumors are gallium avid, and their response to treatment can be assessed by using this modality.
  • Occult sites of disease also may be identified on ⁶⁷67 scans.
• Positron emission tomography: Positron emission tomography (PET) has recently been used for purposes similar to those for ⁶⁷67 scanning.

Other Tests

• Other tests may include serologic analyses for varicella, measles, herpes simplex virus, Epstein-Barr virus, cytomegalovirus (CMV), hepatitis A, hepatitis B, and hepatitis C.
• • Perform these tests to document susceptibility in patients who will be receiving immunosuppressive therapy.
  • These tests might provide evidence of the cause (eg, Epstein-Barr virus).
  • Serologic results can help in identifying patients who may benefit from transfusion with CMV-negative blood products, especially if bone marrow transplantation is eventually offered.
  • Order these tests to confirm previous exposure to a hepatitis virus before blood transfusions are administered.
• Perform echocardiography to obtain baseline findings before patients are given chemotherapy with anthracyclines, which can cause cardiomyopathy.

Procedures

• Bilateral (superior to unilateral) bone marrow aspiration and biopsy
• • Biopsy is necessary to assess for evidence of bone marrow involvement in patients with lymphomas.
  • A finding of >25% marrow blasts is generally regarded as diagnostic of acute leukemia. levels of involvement lower than this with lymphoma indicate stage 4 disease.
  • Polymerase chain reaction assays are being used experimentally to detect and monitor minimal residual disease in the marrow. In the future, postinduction measurement of minimal residual disease may improve precision in determining treatment responses and/or treatment assignments.
• Biopsy
• • A histologic diagnosis must be obtained.
  • For patients with an abdominal tumor, tissue is generally available from resection or intraoperative biopsy.
  • Patients with mediastinal disease frequently have enlarged supraclavicular or cervical nodes, which can enable diagnosis without thoracotomy.
  • As an alternative, a diagnosis may be made by using pleural fluid (see Image 4) or by using involved bone marrow (especially if CBCs are abnormal and/or if imaging studies demonstrate abnormal signal intensity of the marrow). In rare cases, CSF can be used.
• Lumbar puncture with determination of the CSF cell count and differential: This test is done to assess CNS involvement, the presence of which alters therapy.
• Acquisition of central venous access
• • For most patients, a central venous access device is necessary to manage chemotherapy.
  • If feasible, multiple procedures (eg, line placement, biopsy, lumbar puncture, bone marrow aspiration) can be performed during 1 session of anesthesia.
  • As noted previously, patients with mediastinal disease must be treated cautiously if the use of general anesthesia is being considered. Unrecognized airway compression can lead to obstruction, with disastrous consequences.

Histologic Findings

Several classification systems for NHL are available. Examples are the Kiel classification and the NCI Working Formulation. At present, the Revised European-American Lymphoma (REAL) classification is gaining acceptance as the criterion standard for classifying adult NHL. For classifying childhood NHL, this system is overly complicated because it includes numerous diagnoses that are rarely or never observed in children.

Adult NHLs are characterized as low, intermediate, or high grade, and they can have a diffuse or nodular appearance. In contrast, childhood NHLs are almost always high grade and diffuse. In general, they can be divided into 3 major classes, or even 4 classes if one differentiates the 2 most common types of LCLs (B- or T-cell LCLs). The 3 major classes are described below.

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

Lymphoblastic lymphomas

Lymphoblastic lymphoma cells are indistinguishable from the lymphoblasts of ALL. The cells are monotonous and associated with a high nuclear-to-cytoplasmic ratio. Their nuclei often are convoluted and contain finely stippled chromatin. Nucleoli are usually visible, but they are not prominent.

Immunohistochemical analysis usually reveals T-cell markers, including CD5 and CD7. Common ALL antigen (CALLA) is occasionally observed.

A minor subset of lymphoblastic lymphomas expresses the precursor B-cell phenotype typical of childhood ALL. This phenotype includes the surface antigens CALLA and B4 and the HLA-DR.

Small noncleaved cell lymphomas

SNCCLs can be classified Burkitt or non-Burkitt (Burkittlike) lymphomas. The distinction may be subtle, and its clinical significance is unclear.

Burkitt lymphoma cells are notably uniform in size and shape, and they usually contain multiple prominent nucleoli. In contrast, extensive cellular pleomorphism, or occasionally the presence of a single nucleolus in most cells, suggests a diagnosis of Burkittlike lymphoma. SNCCL cells have slightly more cytoplasm than do lymphoblastic lymphoma cells. The cytoplasm is basophilic and usually contains lipid-filled vacuoles.

Macrophages often infiltrate the tumors, lending the classic starry-sky appearance. However, this observation is not pathognomic of Burkitt lymphoma.

The tumor cells are mature B cells, as evidenced by the surface expression of immunoglobulin (usually immunoglobulin M), CD19, CD20, and HLA-DR. CALLA is usually present.

Immunophenotyping results suggest that Burkittlike lymphoma cells are more likely than Burkitt lymphoma cells to express the BCL-6 oncogene, and they exhibit relatively low levels of apoptosis.

Because of the features described, Burkittlike lymphoma appears to be biologically distinct from Burkitt lymphoma, and it is perhaps most closely related to the B-cell LCLs.

Large cell lymphomas

LCLs are a heterogeneous group. Most cases can be classified as B- or T-cell LCLs.

The B cell—derived LCLs histologically merge with the SNCCLs. In terms of the expression of cell-surface proteins, these tumors are currently indistinguishable. If infiltrating macrophages are present, these cells can serve as a reference by which the tumor cells are measured. In B-cell LCLs, many or most of the tumoral nuclei are larger than those of the macrophages.

Anaplastic LCLs are more common than B-cell LCLs and are derived from T cells, as evidenced by their TCR gene rearrangements. However, anaplastic LCLs 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.

Staging

Several systems for classifying NHLs have been proposed. The St Jude system (ie, the Murphy system) has gained the widest acceptance. This system is presented in Table 2.

Table 2. Staging for NHL According to the St Jude System

Source.—St Jude Children's Research Hospital.

TREATMENT

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Medical Care

Proper care requires a referral to a comprehensive tertiary care center. The current intense treatment regimens, particularly those for advanced stages of disease, necessitate inpatient administration of chemotherapy, as well as aggressive support by a team experienced in the care of children with immunosuppression.

Before 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 relatively gentle cytoreductive chemotherapy designed to avoid these metabolic complications.

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

Follow up the patient's laboratory values to monitor tumor lysis syndrome throughout initial therapy. Testing may be needed as often as 2-4 times per day. This follow-up 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 beginning empiric broad-spectrum antibiotic coverage until sepsis or focal infection (eg, due to bowel perforation) is excluded.

Current treatment regimens are primarily based on the immunophenotype of the particular lymphoma (B cell vs T cell). In broad terms, T-cell therapies are longer and less intensive (particularly with respect to the use of alkylating agents) than B-cell therapies. Treatments for B-cell lymphomas involve relatively high doses of alkylators and antimetabolites.

Current survival rates for patients with advanced disease are 65-75% for T-cell (lymphoblastic) lymphomas and 80-90% for those with B-cell lymphomas.

Lymphoblastic lymphoma

The most successful treatment protocols for advanced-stage lymphoblastic lymphoma feature chemotherapy combinations designed to treat ALL.

LSA₂L₂ protocol

The LSA₂L₂ protocol evolved from ALL protocols used at the Memorial Sloan-Kettering Cancer Center in the early 1960s. The LSA₂L₂ protocol features 3 phases of therapy—namely, induction, consolidation, and repeated cycles of maintenance—given over a total of 2-3 years. Methotrexate is administered intrathecally for CNS prophylaxis throughout treatment. When this protocol was first described, it included irradiation of sites of bulky disease; however, radiation is no longer routinely applied.

Children's Cancer Group protocol 552

Between 1986 and 1989, 143 subjects with lymphoblastic lymphoma (10% with localized disease) received treatment with a modified LSA₂L₂ regimen in a Children's Cancer Group trial (see Table 3). Their 5-year event-free survival was 74%.

Table 3. Modified LSA₂L₂ Therapy in Children's Cancer Group Protocol 552

Source.—Children's Cancer Group.
Ara-C = cytarabine; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea, or carmustine; IM = intramuscular; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous.
^*A minimum of 5 repeated courses (total duration of therapy >18 mo) exist. Each course of intrathecal methotrexate (day 0 of each course) consists of 4 cycles of rotating drug pairs that are administered every 2 weeks after blood counts have recovered.

German Berlin, Frankfurt, Muenster treatment protocol

The German Berlin, Frankfurt, Muenster (BFM) protocols demonstrated excellent results in patients with ALL or lymphoblastic lymphoma. As reported in 1995, 71 subjects with stage III or IV non–B-cell NHL (see the Children's Oncology Group protocols below) received treatment, as shown in Table 4.

Compared with the LSA₂L₂ protocol, the BFM regimen adds a re-induction phase and features a less complicated and less intense maintenance phase. In its original report, the BFM protocol included prophylactic cranial irradiation during re-induction. Patients receiving this treatment had a 6-year event-free survival of 79%.

Table 4. Therapy for Stage III and IV non–B-Cell Disease^* According to BFM Protocol 86

Source.—Berlin-Frankfurt-Munster Group.
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous.
^*Diagnoses included lymphoblastic lymphoma of the T-cell or precursor B-cell type, immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients with Ki-1+ anaplastic LCLs were not included.
^† Continued until 24 months after diagnosis.

Children's Oncology Group protocols

The most recent Children's Oncology Group phase 3 protocol (A5971) for children with advanced-stage T-cell lymphoblastic lymphoma featured a 4-way randomization between BFM therapy, a Children's Cancer Group modified version of BFM therapy (which did not include high-dose methotrexate/leucovorin during consolidation), and intensified versions of these 2 protocols (with early introduction of daunomycin and cyclophosphamide). Results from this comparison are still pending.

The Children's Oncology Group is developing specific protocols to treat T-cell diseases—both T-lymphoblastic lymphoma and T-cell ALL. In particular, researchers will examine the role of nelarabine (previously known as compound 506U78), a prodrug of the deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (Ara-G) that has shown efficacy in T-cell malignancies.

Additional treatment details

For advanced-stage lymphoblastic lymphoma, as for ALL, relatively long intervals of treatment have been most successful. The maintenance phase typically lasts 18-30 months. Protocols shorter than this have also been investigated. For example, in the Children's Cancer Group protocol 5941, investigators examined an aggressive, 11-month multiagent protocol; final results are pending.

Localized lymphoblastic lymphoma is unusual. In the previously mentioned BFM study, 6 of 77 subjects with non–B-cell NHL had stage I or II disease.

When results from several series were combined, patients appeared to have an excellent prognosis. Long-term survival was approximately 80%.

Despite these findings, a consensus about optimal therapy is lacking. Treatment options include the LSA₂L₂ protocol and the BFM protocol 86 for NHL (with the re-induction phase eliminated). Patients with localized lymphoblastic lymphoma are included in Children's Oncology Group protocol A5971; they receive a Children's Cancer Group modified version of the BFM protocol (as described above) that includes re-induction but with fewer doses of intrathecal chemotherapy during the maintenance phase.

Regimens simpler than these 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 as rescue therapy). Aggressive intrathecal prophylaxis with cytarabine and methotrexate was included. However, local radiation therapy was not offered routinely. The total duration of therapy is 15 cycles (approximately 60 wk).

Small noncleaved cell lymphoma

Since the mid-1980s, survival rates for patients with Burkitt or Burkittlike lymphomas have increased dramatically. In general terms, several lessons have been learned, as summarized below:

• Long-term maintenance chemotherapy appears to have no role. Therefore, chemotherapy can be short. A typical duration is 2-6 cycles, each lasting 3-4 weeks. However, the intensity of treatment is high for most patients, and inpatient treatment is required.
• When observed, relapses occur early, either during therapy or within 6-12 months of its completion. Salvage rates for patients with relapse have been disappointing.
• Even patients with widely disseminated disease (eg, bone marrow involvement) have a long-term survival rate of 90%.
• Involvement of the CNS at diagnosis continues to be an adverse prognostic indicator.

Treatment protocol from a Cooperative Group trial

Three cooperative groups conducted a recent international trial for patients with SNCCL: the French Society of Pediatric Oncology (SFOP) in France, Belgium, and the Netherlands; the Children's Cancer Group in the United States, Canada, and Australia; and the United Kingdom Children's Cancer Study Group (UKCCSG) in the United Kingdom and Ireland.

Chemotherapy was based on the SFOP LMB-89 study, in which event-free survival rates ranged from 100% in group A to 87.5% in group C (see Table 5). Patients with B-cell ALL were included in this protocol. Subjects were staged (as described above), then assigned to clinical risk groups, as presented in Table 5.

Table 5. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961)

Table 6. Standard Therapy for Subjects in the International Trial for Patients With SNCCL, Group A^*

G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO = oral; SC = subcutaneous.
^*See Table 5 for the definition of group A. All subjects received 2 cycles.

In this trial, patients with advanced disease (groups B and C) received an initial moderately intensive reduction phase of chemotherapy. This was intended to reduce the tumor burden with a minimal risk of inducing or exacerbating tumor lysis syndrome. The experimental treatment arms for these patients involved incremental reductions in the intensity and/or duration of chemotherapy. In Group C, early analysis of the results suggested that the reduced-intensity, experimental treatment arms yielded inferior outcomes. Therefore, it appears unwise to decrease therapy in this subgroup of patients.

Table 7. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group B^*

Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous.
^*See Table 5 for the definition of group B.

Table 8. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group C^*

Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous.
^*See Table 5 for the definition of group C.
^† For patients with CNS involvement, during consolidation cycle 1 only.

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

Large cell lymphoma

B cell–derived LCLs

Patients with B cell-derived LCLs are treated effectively by using the regimens for SNCCL (discussed above). In fact, the recent international protocol allowed clinicians to enroll of subjects with LCL, as well as those with SNCCL. Outcomes are similar between the groups.

An alternative therapy is the APO regimen consisting of doxorubicin (Adriamycin), prednisone, vincristine [Oncovin]. Methotrexate and 6-mercaptopurine were later added. A randomized study of children with LCLs (including B-cell LCLs) showed no advantage when cyclophosphamide was added to this regimen. Therefore, this therapy has the advantage of avoiding exposure to an alkylating agent. However, the cumulative dose of doxorubicin is 450 mg/m².

Anaplastic (T cell–derived) LCLs

The therapy for anaplastic (T-cell) LCLs is somewhat controversial. Good results (event-free survival rates of 65-80%) have been reported with a number of protocols. Some were based on ALL therapy, whereas others were similar or identical to those used to treat B-cell lymphomas.

The BFM group reported what may be the best results with treatment for Ki-1+ anaplastic LCLs. The group administered a regimen for B-cell lymphomas that did not include local radiation therapy. Among 62 patients (none with bone marrow disease and 1 with CNS involvement), 4 did not achieve remission, 1 died from infection, and 7 had a relapse. At the time of the report, 50 patients remained in a continuous first episode of complete remission, and 56 were alive. The calculated event-free survival rate at 9 years was 83%.

Table 9. Prephase Therapy for Ki-1+ Anaplastic LCLs in All Patients According to the BFM-90 Protocol

Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

Subsequent therapy is based on the stage, which is determined by using a modified St Jude system. Treatments are listed below, and cycles A, B, AA, BB, and CC are defined in Table 10.

• 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 Ki-1+ Anaplastic LCLs According to the BFM-90 Protocol

Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

A recent report of 89 children described the results of virtually identical therapy in which dexamethasone was used instead of prednisone in the prephase. The overall event-free survival rate at 5 years was 76%.

As noted previously, good results have also been observed with the relatively uncomplicated APO regimen.

A recent randomized study of children with LCL (including both B-cell 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 SFOP described surprising efficacy of monotherapy with vinblastine for relapsing anaplastic LCL, even in patients who previously underwent myeloablative therapy with autologous bone marrow transplantation. The role of vinblastine in front-line therapy for anaplastic LCL is being examined in a Children's Oncology Group protocol. Investigators are comparing the standard APO regimen with an experimental therapy that includes vinblastine.

Treatment of relapsed disease

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

Reinduction regimens use novel chemotherapy combinations, such as ifosfamide, carboplatin, and etoposide (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 option for curative consolidative therapy.

Surgical Care

Even for patients with bulky NHL, debulking surgery is not crucial to effective therapy. For example, chemotherapy is effective in relieving partial airway or bowel obstruction (see Image 3, Image 4). In rare instances, 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 a potential therapeutic dilemma, involves abdominal B-cell NHL. The patient can be assigned to clinical group A (see Table 5 above), if the following conditions are met:

• An intestinal primary lesion can be resected along with all involved adjacent lymph nodes
• The marginal lymph nodes are free of disease
• The patient has no evidence of further dissemination (eg, to CNS or marrow)

In this situation, the prescribed chemotherapy regimen is far less toxic than it otherwise is.

Therefore, a surgeon treating a reasonably small abdominal NHL is advised to perform lymph node dissection and to try to excise all visible areas of tumor. However, this surgery is performed only if it can be accomplished without causing clinically significant morbidity. Heroic attempts at resection are best avoided because unresected disease can still be cured in most patients. Furthermore, prolonged postoperative recovery may delay the start of chemotherapy and potentially compromise its effectiveness.

Second-look surgery may be helpful for assessing the viability of residual masses. Second-look procedures require highly individualized approaches. As an alternative, uptake of ⁶⁷Ga suggests viability of residual masses in patients whose tumors are gallium avid.

Consultations

• Intensive care specialist
• • 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, the patient's condition may be unstable or deteriorating. Therefore, the support of a pediatric intensive care unit 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.
• Radiation oncologist
• • 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 the use of general anesthesia is being contemplated for biopsy or central line placement.
  • For patients with lymphoblastic lymphoma, low-dose radiation therapy is often is used to treat neurologic involvement (eg, cranial nerve palsies, intracerebral extension of tumor, paraplegia).
  • Irradiation has minimal efficacy in patients with SNCCL, presumably because of the rapid growth of these cells. Although a dose of radiation may result in significant cell kill, rapid regrowth of surviving cells between doses largely negates the benefit. Hyperfractionated radiotherapy (ie, > 1 dose per day) offers a theoretic advantage, as does low-dose continuous irradiation; however, the unfeasibility of the latter all but precludes its use.
  • Finally, consider radiotherapy in any patient with documented residual disease after chemotherapy and in patients with bulky disease at the time of relapse.
• Nephrologist: Notify a nephrologist if the patient has substantial tumor lysis syndrome and if dialysis is under consideration.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

As discussed Medical Care, the agents described below are used in combination regimens, and doses are tailored to the histologic subtype of lymphoma and stage of disease present.

Drug Category: Corticosteroids

Corticosteroids elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Drug Category: Antineoplastic Agents

Cancer chemotherapy is based on an understanding of tumoral cell growth and on 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 the premitotic phase (ie, G2), then finally mitotic cell division (ie, phase M).

Cell division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the growth rate may further decrease in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant cells, and is the rationale for current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific.

Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.