NON-HODGKIN LYMPHOMA

Introduction
Background

Lymphomas are malignant neoplasms of lymphoid lineage. Broadly classified as either Hodgkin disease (Hodgkin's disease) or as non-Hodgkin lymphoma (NHL), lymphomas are clinically, pathologically, and biologically distinct.1,2

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

* Lymphoblastic lymphomas
* Small noncleaved cell lymphomas (SNCCLs), or Burkitt lymphomas (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 childhood lymphoma (some of which are much more common in adults) are not discussed.

Since the late 1960s, treatment outcomes for children with non-Hodgkin lymphoma have steadily improved. Even for patients with advanced disease, event-free survival rates are now 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 non-Hodgkin lymphoma, surgical resection and radiation therapy are also key components of definitive treatment. Newer therapies that target immunologic and biologic aspects of the lymphoma are still under development but 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, non-Hodgkin lymphoma 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. The role of lymphoma stem cells in the genesis and maintenance of B cell lymphomas remains speculative.3

Childhood non-Hodgkin lymphoma generally manifests as bulky extramedullary (usually extranodal) disease with or without demonstrable dissemination. The distinction between non-Hodgkin lymphoma 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 some threshold (typically, a blast count of >25%) irrespective of the presence of bulky extramedullary disease. In contrast, an extramedullary tumor accompanied by marrow involvement below 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.4 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 2002-2006 are shown below. In children, non-Hodgkin lymphoma is somewhat less common than Hodgkin disease. However, the incidence of non-Hodgkin lymphoma appears to be rising in the United States. This trend largely reflects the occurrence of non-Hodgkin lymphoma in patients who are immunocompromised (eg, patients with human immunodeficiency virus [HIV]) and in patients who were previously exposed to chemotherapy and irradiation as treatment for an unrelated cancer.

Age-adjusted incidences of selected cancers per 100,000 individuals aged 0-19 years are as follows:4

* All sites - 16.6
* Leukemias - 4.5
* Brain and other nervous tissues - 2.9
* Hodgkin disease - 1.2
* Non-Hodgkin lymphoma - 1.1
* Soft tissue - 1.1
* Bone and joint - 0.9
* Kidney and renal pelvis - 0.6

International

Over the last 3 decades, the incidence of non-Hodgkin lymphoma appears to have increased in Canada, as it has in the United States.5 The cause for this rise is unclear. Burkitt lymphoma 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, in North Africa, and in the Middle East than in the United States or Europe.

A recent review of pediatric lymphoma from Pakistan was notable for a greater proportion of non-Hodgkin lymphoma (75% of cases) and for a male-to-female ratio of 5.8:1.6
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 extent of involvement. These in turn 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 below). 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).

Massive mediastinal T-lymphoblastic lymphoma. No...
Massive mediastinal T-lymphoblastic lymphoma. Note compression of the left mainstem bronchus and the pulmonary atelectasis.

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Massive mediastinal T-lymphoblastic lymphoma. No...

Massive mediastinal T-lymphoblastic lymphoma. Note compression of the left mainstem bronchus and the pulmonary atelectasis.

Mediastinal tumors may cause compression of the great vessels (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 below). 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.

Non-Hodgkin lymphoma of the terminal ileum. Note ...
Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type).

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Non-Hodgkin lymphoma of the terminal ileum. Note ...

Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type).

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, non-Hodgkin lymphomas 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 non-Hodgkin lymphoma is twice as high among whites compared with blacks, with respective rates of 9.1 and 4.6 cases per million individuals per year.
Sex

In the United States, the incidence is almost twice as high in male individuals as in females. For 2002-2006, the SEER age-adjusted incidence of non-Hodgkin lymphoma was 1.4 per 100,000 males (age 0-19 years) and 0.8 per 100,000 females.4
Age

In the United States, the age-specific incidence of non-Hodgkin lymphoma only slightly increases over the first 2 decades of life. By comparison, the incidence of Hodgkin disease increases more dramatically than this as children age (see image below). In adulthood, the risk of non-Hodgkin lymphoma steadily climbs, whereas the age-specific incidence of Hodgkin disease is biphasic.

Incidence of lymphoma as a function of age per 10...
Incidence of lymphoma as a function of age per 100,000 population. Data are from the Surveillance, Epidemiology, and End Results (SEER) for 1990-1994.

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Incidence of lymphoma as a function of age per 10...

Incidence of lymphoma as a function of age per 100,000 population. Data are from the Surveillance, Epidemiology, and End Results (SEER) for 1990-1994.

Clinical
History

* The presentation of patients with non-Hodgkin lymphoma (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 one month or shorter.
* Specific complaints vary and depend on the predominant sites of involvement.
* Constitutional symptoms are uncommon, except in patients with anaplastic large cell lymphomas (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 non-Hodgkin lymphoma, 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, non-Hodgkin lymphoma 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 small noncleaved cell lymphoma [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. Rare primary non-Hodgkin lymphoma of the pancreas presents with the clinical picture of pancreatitis.7
* Patients with anaplastic LCLs sometimes present with painful skin lesions, bone lesions, peripheral lymphadenopathy, and hepatosplenomegaly.8,9 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 pancytopenia.
* 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 non-Hodgkin lymphoma (particularly SNCCL) occasionally present with symptoms suggestive of meningoencephalitis.
* Among the less common lymphomas of childhood, primary cutaneous/subcutaneous involvement can be seen (eg, cutaneous T-cell lymphoma, blastic plasmacytoid dendritic cell hematodermic neoplasm).

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. The less common forms of cutaneous lymphoma (T-cell, blastic plasmacytoid dendritic) are typically nontender.
* 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:
o Nasopharyngeal mass
o Parotid enlargement
o Nephromegaly
o Testicular enlargement

Causes

In developed countries, most individuals with non-Hodgkin lymphoma 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 non-Hodgkin lymphoma.10,11 Findings from several epidemiologic studies suggest that pesticide exposure may play a role in the development of adult non-Hodgkin lymphoma; the case for its involvement in childhood non-Hodgkin lymphoma is less compelling than the case for adults, but this is still under investigation.12,13

The epidemiologic association between non-Hodgkin lymphoma and certain paternal occupations (eg, those that increase contact with other individuals) suggest a possible infective etiology for childhood non-Hodgkin lymphoma.14

An interesting statistical association exists between high birth weight and the subsequent risk of childhood cancers, including non-Hodgkin lymphoma.15

Regarding protective factors, results of one case-control study suggested that exposure to sunlight may protect individuals against non-Hodgkin lymphoma, presumably because of enhanced vitamin D synthesis.16

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 non-Hodgkin lymphoma, 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 non-Hodgkin lymphoma. 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 non-Hodgkin lymphoma is as high as 39%.17

Splenectomy, now rarely performed in patients with Hodgkin disease, is another reported risk factor for second malignancies, including non-Hodgkin lymphoma.18

Secondary non-Hodgkin lymphoma 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 non-Hodgkin lymphoma. The 15-year actuarial risk of non-Hodgkin lymphoma 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 non-Hodgkin lymphoma among patients whose primary malignancy had been diagnosed when they were younger than 20 years. Eighteen (75%) of the patients previously had Hodgkin disease.19

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.20,21

Genetic causes

The genetic basis of pediatric non-Hodgkin lymphoma has been studied extensively.22 Each subtype of non-Hodgkin lymphoma 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.23

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.24,23

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.25 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. Compared with adults with B-LCL, this appears to be more common in children and may portend a worse prognosis.26 Alternatively, 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 non-Hodgkin lymphoma lacking cytogenetic evidence of t(2;5); this finding reflects an occult or variant translocation.27 Patients with non-Hodgkin lymphomas expressing p80 may have a survival advantage over patients whose lymphomas lack p80.28

For additional reading, see Childhood Cancer, Genetics.Differential Diagnoses
Acute Lymphoblastic Leukemia
Lymphoproliferative Disorders
Acute Myelocytic Leukemia
Mononucleosis and Epstein-Barr Virus Infection
Appendicitis
Neuroblastoma
Atypical Mycobacterial Infection
Rhabdomyosarcoma
Catscratch Disease
Sarcoidosis
Hodgkin Disease
Toxoplasmosis
Intussusception
Tuberculosis
Lymphadenitis
Wilms Tumor
Workup
Laboratory Studies

* Obtain a CBC count with differential and a platelet count in patients with non-Hodgkin lymphoma (NHL) 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.
o Serum electrolytes
o BUN
o Creatinine
o Uric acid
o Lactate dehydrogenase
o Bilirubin
o Albumin
o Total protein
o Aspartate aminotransferase
o Alanine aminotransferase
o Calcium
o Magnesium
o 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
o Abdominal sonography helps in assessing the size of the kidneys and the patency of the urinary tract.
o Abdominal sonography is useful particularly before chemotherapy in anticipation of prolonged excretion and excess toxicity, for example.
o When symptoms are present, testicular ultrasonography aids in identifying additional sites of disease.
* Computed tomography
o CT scans of the chest, abdomen, and pelvis can be used to stage lesions (see Staging).
o If the patient is stable, chest CT scan is indicated to assess for the degree of tracheal compression.
o 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.
* Positron emission tomography/computerized tomography (PET/CT) has largely supplanted67 Gal scanning and is highly recommended for patients with NHL.29,30,31,32
o Many lymphomas are 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) avid; their response to treatment can be assessed by using this modality.
o Occult sites of disease may also be identified on PET/CT scans.

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.
o Perform these tests to document susceptibility in patients who will be receiving immunosuppressive therapy.
o These tests might provide evidence of the cause (eg, Epstein-Barr virus).
o 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.
o 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
o Biopsy is necessary to assess for evidence of bone marrow involvement in patients with lymphomas.
o A finding of more than 25% marrow blasts is generally regarded as diagnostic of acute leukemia. Levels of lymphoma involvement lower than this indicate stage 4 disease.
o Polymerase chain reaction assays are being used experimentally to detect and monitor minimal residual disease in the marrow.33,34 In the future, postinduction measurement of minimal residual disease may improve precision in determining treatment responses and/or treatment assignments.
* Biopsy
o A histologic diagnosis must be obtained. Flow cytometric analysis of tumor cell markers has become the standard for lymphoma subtyping.35 Cytogenetic analysis is sometimes helpful in equivocal cases.
o For patients with an abdominal tumor, tissue is generally available from resection or intraoperative biopsy.
o Patients with mediastinal disease frequently have enlarged supraclavicular or cervical nodes, which can enable diagnosis without thoracotomy.
o As an alternative, a diagnosis may be made by using pleural fluid (see following image) or by using involved bone marrow (especially if CBC counts are abnormal and/or if imaging studies demonstrate abnormal signal intensity of the marrow). In rare cases, cerebrospinal fluid (CSF) can be used.
o

Malignant pleural effusion. Non-Hodgkin lymphoma ...
Malignant pleural effusion. Non-Hodgkin lymphoma of the terminal ileum was diagnosed; the doughnut sign (ie, intraluminal contrast material surrounded by a grossly thickened bowel wall) was present. A diagnosis of stage 3 Burkitt lymphoma was established by means of pleurocentesis. (The bone marrow was normal.) The patient was treated successfully and never required an abdominal procedure.

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Malignant pleural effusion. Non-Hodgkin lymphoma ...

Malignant pleural effusion. Non-Hodgkin lymphoma of the terminal ileum was diagnosed; the doughnut sign (ie, intraluminal contrast material surrounded by a grossly thickened bowel wall) was present. A diagnosis of stage 3 Burkitt lymphoma was established by means of pleurocentesis. (The bone marrow was normal.) The patient was treated successfully and never required an abdominal procedure.
* 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
o For most patients, a central venous access device is necessary to manage chemotherapy.
o If feasible, multiple procedures (eg, line placement, biopsy, lumbar puncture, bone marrow aspiration) can be performed during one session of anesthesia.
o 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 non-Hodgkin lymphoma 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 non-Hodgkin lymphoma. For classifying childhood non-Hodgkin lymphoma, this system is overly complicated because it includes numerous diagnoses that are rarely or never observed in children.

Adult non-Hodgkin lymphomas are characterized as low, intermediate, or high grade, and they can have a diffuse or nodular appearance. In contrast, childhood non-Hodgkin lymphomas 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 large cell lymphomas (LCLs), B-cell 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 acute lymphoblastic leukemia (ALL). The cells are monotonous and associated with a high nuclear-to-cytoplasmic ratio. Their nuclei are often convoluted and contain finely stippled chromatin. Nucleoli are usually visible but 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 human leukocyte antigen (HLA)-DR.

Small noncleaved cell lymphomas

Small noncleaved cell lymphoma (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.36

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-cell 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. Aberrant expression of myeloid markers CD13 and CD33 has more recently been reported as a sensitive (but not specific) marker of ALK+ anaplastic LCL.37

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 non-Hodgkin lymphomas have been proposed. The St Jude system (ie, the Murphy system) has gained the widest acceptance.38 This system is as follows:

* Stage I - Single extranodal tumor or single anatomic area (nodal), excluding the mediastinum or abdomen
* Stage II - Single extranodal tumor with regional node involvement; primary GI tumor with or without associated involvement of mesenteric nodes, with gross total resection; or, on same side of diaphragm, 2 or more nodal areas, or 2 single (extranodal) tumors with or without regional node involvement
* Stage III - Any primary mediastinal, pleural, or thymic intrathoracic tumor; any extensive and unresectable abdominal tumor; 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 with or without regional node involvement
* Stage IV - Any of the above with initial CNS or marrow (<25%) involvementTreatment Medical Care Proper care of non-Hodgkin lymphoma (NHL) 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). 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 than it is at pH 5, 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. In high-risk situations (extreme elevations of lactate dehydrogenase [LDH] and/or uric acid or evidence of impaired renal function at presentation), consider administration of recombinant urate oxidase (rasburicase [Elitek]).39 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. LSA2 L2 protocol The LSA2 L2 protocol evolved from ALL protocols used at the Memorial Sloan-Kettering Cancer Center in the early 1960s. The LSA2 L2 protocol features 3 phases of therapy—namely, induction, consolidation, and repeated cycles of maintenance—given over a total of 2-3 years.40 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 LSA2 L2 regimen in a Children's Cancer Group trial (see Table 1). Their 5-year event-free survival was 74%.41 Table 1. Modified LSA2 L2 Therapy in Children's Cancer Group Protocol 552 Open table in new window [ CLOSE WINDOW ] Table Phase Drug Route Induction Cyclophosphamide, vincristine, daunorubicin IV Ara-C, methotrexate IT Prednisone PO Consolidation Ara-C IV or SC 6-thioguanine PO Methotrexate IT L-asparaginase IM BCNU IV Phase Cycle Drug Route Maintenance* 1 6-thioguanine PO Cyclophosphamide IV 2 Hydroxyurea PO Daunorubicin IV 3 Methotrexate PO BCNU IV 4 Ara-C IV or SC Vincristine IV Phase Drug Route Induction Cyclophosphamide, vincristine, daunorubicin IV Ara-C, methotrexate IT Prednisone PO Consolidation Ara-C IV or SC 6-thioguanine PO Methotrexate IT L-asparaginase IM BCNU IV Phase Cycle Drug Route Maintenance* 1 6-thioguanine PO Cyclophosphamide IV 2 Hydroxyurea PO Daunorubicin IV 3 Methotrexate PO BCNU IV 4 Ara-C IV or SC Vincristine IV 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) are noted. 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 non-Hodgkin lymphoma (see the Children's Oncology Group protocols below) received treatment, as shown in Table 2.42

Compared with the LSA2 L2 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 2. Therapy for Stage III and IV non–B-Cell Disease* According to BFM Protocol 86

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Table
Phases Drug Route
Induction Prednisone, 6-mercaptopurine PO
Vincristine, daunorubicin, cyclophosphamide, Ara-C 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, Ara-C IV
L-asparaginase IM
Methotrexate IT
Maintenance† 6-mercaptopurine, methotrexate PO
Phases Drug Route
Induction Prednisone, 6-mercaptopurine PO
Vincristine, daunorubicin, cyclophosphamide, Ara-C 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, Ara-C IV
L-asparaginase IM
Methotrexate IT
Maintenance† 6-mercaptopurine, methotrexate PO

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, Children's Cancer Group protocol 5941 examined an aggressive, 11-month multiagent regimen. Results of this trial were recently published: the 5-year event-free survival was 78% ± 4.5% and overall survival was 85% ± 3.9%. These results suggest that the experimental approach is safe and just as effective as more prolonged regimens.43

Localized lymphoblastic lymphoma is unusual. In the previously mentioned BFM study, 6 of 77 subjects with non–B-cell non-Hodgkin lymphoma 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 LSA2 L2 protocol and the BFM protocol 86 for non-Hodgkin lymphoma (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 3). 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 3.

Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961)

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Table
Clinical Group Subjects,
Estimated % Definition
A 10 All resected stage I or abdominal stage II tumors
B 65 Unresected stage I or II tumor, stage III, tumor, or stage IV with no CNS involvement and <25% marrow blasts C 25 CNS involvement or >25% marrow blasts
Clinical Group Subjects,
Estimated % Definition
A 10 All resected stage I or abdominal stage II tumors
B 65 Unresected stage I or II tumor, stage III, tumor, or stage IV with no CNS involvement and <25% marrow blasts C 25 CNS involvement or >25% marrow blasts

Table 4. Standard Therapy for Subjects in the International Trial for Patients With SNCCL, Group A*

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Table
Drug Route
Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Filgrastim (G-CSF), to enhance neutrophil recovery SC or IV
Drug Route
Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Filgrastim (G-CSF), to enhance neutrophil recovery SC or IV

G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO = oral; SC = subcutaneous.
* See Table 3 for the definition of group A. All subjects received 2 cycles.

The results of the international trial were recently published; with median follow-up of more than 4 years, the 4-year event-free survival for group A subjects was 98.3%, and overall survival was 99.2%.44

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. For patients in group B with an "early response" to therapy (at least 20% tumor decrease after 7 d of treatment), outcomes with standard therapy were not superior to outcomes on any of the experimental (reduced therapy) arms. Thus, pediatric patients with intermediate-risk B-non-Hodgkin lymphoma who have an early response and achieve a complete remission after the first consolidation course are effectively treated using a 4-course regimen with a total dose of only 3.3 g/m2 cyclophosphamide and 120 mg/m2 doxorubicin.45

Table 5. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group B*

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Table
Phase Drug Route
Reduction Prednisone PO
Vincristine, cyclophosphamide IV
Methotrexate/hydrocortisone IT
Phase Cycles Drug Route
Induction 2, starting 7 d after reduction Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Consolidation 2 Methotrexate with leucovorin rescue, Ara-C
Methotrexate/hydrocortisone, Ara-C/hydrocortisone
Filgrastim (G-CSF)
Maintenance 1 Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Phase Drug Route
Reduction Prednisone PO
Vincristine, cyclophosphamide IV
Methotrexate/hydrocortisone IT
Phase Cycles Drug Route
Induction 2, starting 7 d after reduction Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
Consolidation 2 Methotrexate with leucovorin rescue, Ara-C
Methotrexate/hydrocortisone, Ara-C/hydrocortisone
Filgrastim (G-CSF)
Maintenance 1 Prednisone PO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV
Methotrexate/hydrocortisone IT

Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous.
* See Table 3 for the definition of group B.

Based on published results from this trial, equivalent outcomes are expected with a reduced (50%) dose of cyclophosphamide in induction phase 2, elimination of maintenance phase 1, or both.

Group C patients in remission after 3 cycles were randomized to standard versus reduced-intensity therapy (omitting the last 3 cycles of maintenance). The 4-year event-free survival after randomization was 90% ± 3.1% versus 80% ± 4.2%, whereas survival was 93% ± 2.7% versus 83% ± 4%. Patients with either combined marrow and CNS disease at diagnosis or a poor response to reduction therapy had significantly inferior event-free survival and survival (P <0.001).46 Therefore, decreasing therapy in this subgroup of patients appears unwise; standard-intensity therapy is recommended for children with high-risk B-non-Hodgkin lymphoma. Table 6. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group C* Open table in new window [ CLOSE WINDOW ] Table Phase Drug Route Reduction Prednisone PO Vincristine, cyclophosphamide IV Methotrexate/Ara-C/hydrocortisone IT Induction, cycle 1 starting 7 d after reduction Prednisone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/hydrocortisone IT Filgrastim (G-CSF) SC or IV Induction, cycle 2 Prednisone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/hydrocortisone IT Filgrastim (G-CSF) SC or IV Consolidation, 2 cycles† High-dose Ara-C, etoposide (VP-16) IV Filgrastim (G-CSF), days 7-21 SC or IV High-dose methotrexate with leucovorin rescue IV Methotrexate/Ara-C/hydrocortisone IT Maintenance 1 Prednisone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/hydrocortisone IT Maintenance 2 Ara-C, etoposide (VP-16) IT Maintenance 3 Prednisone PO Vincristine, cyclophosphamide, doxorubicin IV Maintenance 4 Ara-C, etoposide (VP-16) IV Phase Drug Route Reduction Prednisone PO Vincristine, cyclophosphamide IV Methotrexate/Ara-C/hydrocortisone IT Induction, cycle 1 starting 7 d after reduction Prednisone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/hydrocortisone IT Filgrastim (G-CSF) SC or IV Induction, cycle 2 Prednisone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/hydrocortisone IT Filgrastim (G-CSF) SC or IV Consolidation, 2 cycles† High-dose Ara-C, etoposide (VP-16) IV Filgrastim (G-CSF), days 7-21 SC or IV High-dose methotrexate with leucovorin rescue IV Methotrexate/Ara-C/hydrocortisone IT Maintenance 1 Prednisone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/hydrocortisone IT Maintenance 2 Ara-C, etoposide (VP-16) IT Maintenance 3 Prednisone PO Vincristine, cyclophosphamide, doxorubicin IV Maintenance 4 Ara-C, etoposide (VP-16) IV Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous. * See Table 3 for the definition of group C. † For patients with CNS involvement, during consolidation cycle 1 only. An alternative treatment approach has been developed over a series of randomized trials by the German Berlin, Frankfurt, Muenster group.47 In particular, the role of intermediate-dose or high-dose methotrexate has been investigated among the different clinical risk groups. Pilot protocols for patients with B-cell non-Hodgkin lymphoma 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).48,49,50 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].51 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.52 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.53 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 7. Prephase Therapy for Ki-1+ Anaplastic LCLs in All Patients According to the BFM-90 Protocol Open table in new window [ CLOSE WINDOW ] Table Drug Route Prednisone PO Cyclophosphamide IV Methotrexate/Ara-C/prednisolone IT Drug Route Prednisone PO Cyclophosphamide IV Methotrexate/Ara-C/prednisolone IT 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 8. * 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 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the BFM-90 Protocol Open table in new window [ CLOSE WINDOW ] Table Cycle Drug Route A Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-C IV Methotrexate/Ara-C/prednisolone IT B Dexamethasone PO Methotrexate with leucovorin rescue, Ara-C, doxorubicin IV Methotrexate/Ara-C/prednisolone IT AA Dexamethasone PO Vincristine, high-dose methotrexate with leucovorin rescue, ifosfamide, Ara-C, etoposide (VP-16) IV Methotrexate/Ara-C/prednisolone IT BB Dexamethasone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/prednisolone IT CC Dexamethasone PO Vindesine, high-dose Ara-C, etoposide (VP-16) IV Methotrexate/Ara-C/prednisolone IT Cycle Drug Route A Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-C IV Methotrexate/Ara-C/prednisolone IT B Dexamethasone PO Methotrexate with leucovorin rescue, Ara-C, doxorubicin IV Methotrexate/Ara-C/prednisolone IT AA Dexamethasone PO Vincristine, high-dose methotrexate with leucovorin rescue, ifosfamide, Ara-C, etoposide (VP-16) IV Methotrexate/Ara-C/prednisolone IT BB Dexamethasone PO Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin IV Methotrexate/Ara-C/prednisolone IT CC Dexamethasone PO Vindesine, high-dose Ara-C, etoposide (VP-16) IV Methotrexate/Ara-C/prednisolone IT 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%.54 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.55 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.56 The role of vinblastine in front-line therapy for anaplastic LCL was examined in a recent Children's Oncology Group protocol (A5941), which compared the standard APO regimen with an experimental therapy that includes vinblastine. A final report is not yet available. Treatment of Relapsed Disease As front-line therapies for pediatric non-Hodgkin lymphoma 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.57,58 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 non-Hodgkin lymphoma, debulking surgery is not crucial to effective therapy. For example, chemotherapy is effective in relieving partial airway or bowel obstruction. In rare instances, resection may be required for this purpose. Non-Hodgkin lymphoma of the terminal ileum. Note ... Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type). [ CLOSE WINDOW ] Non-Hodgkin lymphoma of the terminal ileum. Note ... Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type). Malignant pleural effusion. Non-Hodgkin lymphoma ... Malignant pleural effusion. Non-Hodgkin lymphoma of the terminal ileum was diagnosed; the doughnut sign (ie, intraluminal contrast material surrounded by a grossly thickened bowel wall) was present. A diagnosis of stage 3 Burkitt lymphoma was established by means of pleurocentesis. (The bone marrow was normal.) The patient was treated successfully and never required an abdominal procedure. [ CLOSE WINDOW ] Malignant pleural effusion. Non-Hodgkin lymphoma ... Malignant pleural effusion. Non-Hodgkin lymphoma of the terminal ileum was diagnosed; the doughnut sign (ie, intraluminal contrast material surrounded by a grossly thickened bowel wall) was present. A diagnosis of stage 3 Burkitt lymphoma was established by means of pleurocentesis. (The bone marrow was normal.) The patient was treated successfully and never required an abdominal procedure. 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 non-Hodgkin lymphoma. 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 non-Hodgkin lymphoma 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 of67 Ga suggests viability of residual masses in patients whose tumors are gallium avid. Consultations * Intensive care specialist o Patients with childhood non-Hodgkin lymphoma 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. o 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 o Consider consultation with a radiation oncologist. In general, radiation therapy has a limited role in the treatment of childhood non-Hodgkin lymphoma, and it is applied almost exclusively in situations deemed to be real or potential emergencies. o 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. o 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). o 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.59
o 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

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.
Corticosteroids

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

Methylprednisolone (Medrol)

Mechanism of cytotoxicity unknown but apparently mediated by glucocorticoid receptors.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

5-25 mg/m2/d PO/IV
4-10 mg IT

* Dosing
* Interactions
* Contraindications
* Precautions

Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases risk of hypokalemia; may alter response to warfarin (Coumadin) anticoagulants (usually inhibitory, but unsubstantiated reports describe potentiation)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; avascular necrosis of bone; systemic fungal infection (relative contraindication)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Immunosuppression; weight gain; hypertension; osteopenia; myositis; striae; cataracts; poor linear growth; gastritis can be reduced with coadministration of antacids or inhibitors of gastric acid secretion

Dexamethasone (Decadron)

Mechanism of cytotoxicity unknown, but apparently mediated by glucocorticoid receptors; apparently enhanced CNS penetration (relative to prednisone).

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

8-10 mg/m2/d PO/IV

* Dosing
* Interactions
* Contraindications
* Precautions

Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases risk of hypokalemia; may alter response to warfarin (Coumadin) anticoagulants (usually inhibitory, but unsubstantiated reports describe potentiation)

* Dosing
* Interactions
* Contraindications
* Precautions

Avascular necrosis of bone; systemic fungal infection (relative contraindication)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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
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.

Daunorubicin (Cerubidine)

Anthracycline. Multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

30-60 mg/m2 IV

* Dosing
* Interactions
* Contraindications
* Precautions

Increased risk of cardiotoxicity when combined with cardiac irradiation

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; myocardial damage; cumulative anthracycline dose >450 mg/m2 (relative contraindication)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; diarrhea; alopecia; cardiotoxicity; tissue damage with extravasation

Doxorubicin (Adriamycin)

Anthracycline. Multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

25-60 mg/m2 IV

* Dosing
* Interactions
* Contraindications
* Precautions

Increased risk of cardiotoxicity when combined with cardiac irradiation; may potentiate toxicity of other chemotherapeutic agents, including cyclophosphamide and mercaptopurine

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; myocardial damage; cumulative anthracycline dose >450 mg/m2 (relative contraindication)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; diarrhea; alopecia; cardiotoxicity; tissue damage with extravasation

Cytarabine (Cytosine arabinoside, Ara-C, Cytosar-U)

Antimetabolite. Cytotoxic analog of deoxycytidine. Interferes with DNA replication and repair by incorporating into DNA and inhibiting DNA polymerase.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

75-100 mg/m2 IV
16-30 mg IT

* Dosing
* Interactions
* Contraindications
* Precautions

Steady-state digoxin levels may decrease if coadministered with beta-acetyldigoxin (not digitoxin)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; diarrhea; mucositis; alopecia; ocular toxicity; neurotoxicity

6-mercaptopurine (6-MP, Purinethol)

Purine analog. Metabolites incorporated into DNA, inhibiting synthesis.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

25-60 mg/m2 PO

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration of allopurinol substantially enhances absorption of 6-MP PO; after pretreatment with allopurinol, reduce dose by 75%; food decreases bioavailability

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe liver disease and bone marrow depression

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; mucositis; hepatotoxicity; adjust dose in thiopurine methyltransferase deficiency

6-thioguanine (Purinethol)

Purine analog. Metabolites are incorporated into DNA, inhibiting synthesis

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

50-60 mg/m2 PO

* Dosing
* Interactions
* Contraindications
* Precautions

Increases busulfan toxicity; empty stomach enhances absorption

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; hepatic venoocclusive disease

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; mucositis; hepatotoxicity (eg, venoocclusive disease, unsteady gait, photosensitivity); adjust dose in thiopurine methyltransferase deficiency

Methotrexate (MTX, Folex PFS)

Cytotoxic folate antagonist. Inhibits dihydrofolate reductase.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

10 mg/m2 to 8 g/m2 PO/IV/IM
8-15 mg IT

* Dosing
* Interactions
* Contraindications
* Precautions

NSAIDs may increase or prolong levels; may decrease clearance of theophylline; penicillins may decrease renal excretion; broad-spectrum PO antibiotics may decrease bioavailability; additional folate antagonists (eg, trimethoprim-sulfamethoxazole) may cause additive myelosuppression

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; caution with chronic liver disease; severe pre-existing bone marrow depression

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk
Precautions

Myelosuppression; nausea; mucositis; leucovorin rescue required with high doses

Vincristine (Oncovin)

Inhibits microtubule formation in mitotic spindle, causing metaphase arrest.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

1.5-2 mg/m2 IV; not to exceed 2 mg/dose

* Dosing
* Interactions
* Contraindications
* Precautions

Acute pulmonary reaction may occur with concurrent mitomycin-C

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe constipation and/or peripheral neuropathy (relative contraindications)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Peripheral neuropathy; constipation; alopecia; tissue damage with extravasation

Etoposide (VP-16, Toposar)

Inhibits topoisomerase, causing DNA strand breaks.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

150-200 mg/m2 IV

* Dosing
* Interactions
* Contraindications
* Precautions

May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine on cytotoxicity of tumor cells

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; alopecia; mucositis; hypersensitivity reaction

Cyclophosphamide (Cytoxan)

Alkylates and cross-links DNA.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

0.2-1.2 g/m2 IV

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration of phenobarbital and phenytoin may enhance metabolic activation; inhibits cholinesterase, potentiating effect of succinylcholine

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe hemorrhagic cystitis

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; alopecia; hemorrhagic cystitis; impaired fertility

Ifosfamide (Ifex)

Alkylates and cross-links DNA.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

800 mg/m2 IV

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration of phenobarbital and phenytoin may enhance metabolic conversion to active metabolites; phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P450 activity may alter effects

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe hemorrhagic cystitis

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Myelosuppression; nausea; alopecia; hemorrhagic cystitis; impaired fertility

Carmustine (BCNU, BiCNU)

Alkylates DNA and RNA; may also act by carbamoylation of enzymes.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

30 mg/m2 IV

* Dosing
* Interactions
* Contraindications
* Precautions

Coadministration with cimetidine may increase toxicity; coadministration with etoposide may cause severe hepatic dysfunction (hyperbilirubinemia ascites, thrombocytopenia)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Delayed myelosuppression; nausea; nephrotoxicity; pulmonary toxicity; impaired fertility

L-asparaginase (Elspar)

Enzyme produced by Escherichia coli, which catalyzes conversion of L-asparagine to aspartic acid; former is nonessential amino acid for most normal tissues. Many lymphoid malignancies have low levels of asparagine synthase and, therefore, depend on circulating pool of L-asparagine.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

6,000-10,000 IU/m2 IM

* Dosing
* Interactions
* Contraindications
* Precautions

May inhibit effect of methotrexate on neoplastic cells; vincristine or prednisone may increase toxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; history of pancreatitis

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Pancreatitis; hyperglycemia; coagulopathy; hypersensitivity reaction; occasional myelosuppression

Nelarabine (Arranon)

Prodrug of deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (Ara-G). Converted to active 5'-triphosphate (ara-GTP), a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP, allowing for incorporation into DNA; result is inhibition of DNA synthesis and cell death.
Approved by US Food and Drug Administration as orphan drug to treat T-cell lymphoblastic lymphoma not responding to or relapsing with at least 2 chemotherapy regimens.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

1500 mg/m2 IV infusion over 2 h on days 1, 3, and 5; repeat q21d
Pediatric

650 mg/m2/d IV infusion over 1 h for 5 consecutive days; repeat q21d

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

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 before administration; must take preventive measures for hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, allopurinol prophylaxis)

Hydroxyurea (Hydrea)

Apparently inhibits DNA synthesis.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Pediatric

2.4 g/m2/d POFollow-up
Inpatient & Outpatient Medications

Several classes of medications are used to support patients with non-Hodgkin lymphoma (NHL) undergoing aggressive chemotherapy. These are listed below.

* Laxatives and stool softeners
* Prophylactic antibiotics
o Trimethoprim-sulfamethoxazole (against Pneumocystis carinii)
o Fluconazole (against Candida species)
o Nystatin (Candida species)
* Antiemetics
o Serotonin (5-hydroxytryptamine type 3 [5-HT3]) receptor antagonists (ondansetron, granisetron, dolasetron)
o Phenothiazine
o Lorazepam
o Metoclopramide
o Dexamethasone
o Tetrahydrocannabinol
* Antimucositic agents
o Saline or bicarbonate rinse
o Biotene rinse
o Peridex rinse
o Glutamine suspension
* Histamine (H2) receptor antagonists: Famotidine and ranitidine help to prevent gastritis in patients receiving high-dose corticosteroids.
* Contraceptives: Oral or injectable contraceptives can be used to suppress menses in female adolescents at risk for menorrhagia due to thrombocytopenia.

Complications

Acute complications of non-Hodgkin lymphoma and its treatment are discussed in Mortality/Morbidity. 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 have catch-up growth and eventually achieve a height in the normal range. Clinically significant long-term growth retardation is essentially confined to patients who receive cranial irradiation. Of interest, a notable minority of children treated for lymphoma eventually becomes obese; the basis for this effect is unclear.60

Neuropsychological sequelae

Neurotoxicity due to combined cranial irradiation and intrathecal chemotherapy is well described in patients with acute lymphoblastic leukemia (ALL). Neurotoxic effects range from mild learning disabilities to a profound necrotizing leukoencephalopathy. Patients with CNS lymphoma are at risk for developing these same complications.

In the absence of radiation, intrathecal chemotherapy appears to have little effect on neuropsychological function. However, recent data suggest that patients with non-Hodgkin lymphoma who survive without irradiation are more likely to require special education classes than their siblings are.

In a recent report from Finland, scholastic achievement was particularly impaired in survivors of childhood non-Hodgkin lymphoma and not in patients with Wilms tumor or Hodgkin disease.61

The peripheral neuropathy associated with vincristine occasionally leaves permanent deficits, particularly lower extremity weakness.

Fertility

Alkylating agents have particularly been implicated in acute gonadal dysfunction. The long-term effects of these agents among survivors of childhood cancer are somewhat unclear.

Prepubertal boys appear to be at low risk for eventually developing azoospermia or failure of sexual maturation. Older male adolescents are at some risk for developing temporary azoospermia; they might consider banking their semen before undergoing chemotherapy, if this is feasible.

Ovarian failure after high-dose alkylator therapy has also been described. However, in a recent report, female survivors had little or no apparent deficit in pregnancies.

Patients who have a relapse, particularly those treated with myeloablative chemotherapy and/or total body irradiation, have a particularly elevated risk of having permanent gonadal dysfunction.

Second malignancies

The oncogenic potential of therapeutic radiation is well documented, but the risk of second malignancies associated with chemotherapy is less obvious. One clearly implicated antineoplastic agent is etoposide. However, the risk of secondary acute myelocytic leukemia (AML) due to this drug appears to be insignificant at cumulative doses less than 1000 mg/m2.

Cyclophosphamide has also 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 more 13 g/m2.

In one series, 86 survivors of pediatric non-Hodgkin lymphoma were evaluated for a mean of 11 years after diagnosis. Only 2 cases of secondary cancer were observed: 1 malignant melanoma and 1 spindle-cell sarcoma, which arose in a radiation field.62 These findings suggest that, despite concerns about the effects of chemotherapy, patients who do not receive irradiation are unlikely to develop a second malignancy. Follow-up longer than this is needed to accurately assess the life-long risk of second malignancies. Fortunately, the risk appears to be decreasing over time, due to the recognition (and relative avoidance) of treatment-related risk factors such as radiation and high-dose epipodophyllotoxins.63

Cardiotoxicity

At high cumulative doses, doxorubicin is likely to cause delayed myocardial toxicity.64 Irradiation of the heart exacerbates this effect.

In a recent report, 7 of 29 survivors (aged 2-39 y at diagnosis) who received doxorubicin 240-560 mg/m2 eventually developed left ventricular dysfunction approximately 10 years later. However, other reports have described anthracycline-related cardiotoxicity after cumulative doses as small as 100 mg/m2.

If patients have received more than 300 mg/m2 of doxorubicin, perform screening echocardiography every 2-4 years on an indefinite basis. Lower this threshold if mediastinal irradiation was also administered.

Skeletal toxicity

Long-term, high-dose steroid therapy is associated with osteoporosis and avascular necrosis of bone. In one report, long-term survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma exhibited low bone mineral density in roughly two thirds of men and one third of women. The effects of dexamethasone therapy, cranial radiation, and bone marrow transplantation appeared to be additive.65 Avascular necrosis most commonly affects the femoral heads, and it may be associated with slipped capital femoral epiphysis. Avascular necrosis of bone is most often observed in adolescents and in female patients. The spectrum of disease ranges from asymptomatic radiographic findings to incapacitating joint destruction requiring restorative surgery.

Radiation therapy is associated with osteopenia. This may occur locally or, of interest, it may be observed diffusely after cranial irradiation.66

Viral transmission by means of blood products

Transmission of cytomegalovirus (CMV) is likely if unscreened blood products are administered. Patients who receive such products and who eventually require myeloablative therapies are then at substantial risk of acquiring disseminated CMV. Therefore, the use of CMV-negative products is ideal for patients who may eventually undergo bone marrow transplantation.

With modern transfusion practices, exposure to hepatitis B or 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 relatively unlikely but nevertheless possible.

Explain the risks of viral transmission to patients, their parents, and/or caregivers before transfusions are given.
Prognosis

The overall prognosis for children with non-Hodgkin lymphoma has continued to steadily improve over the last two decades. Period analysis of SEER data for children less than 15 showed that 5-year and 10-year survival increased from 76.6% and 73.0% in 1990-1994 to 87.7% and 86.9% in 2000-2004. The projected 10-year survival rate for children diagnosed in 2005-2009 was 90.6%.67

Among patients with non-Hodgkin lymphoma, the major determinants of prognosis are histology and disease stage. The presence or absence of particular molecular markers (eg, ALK and/or CD56 in anaplastic large cell lymphoma [LCL]) has additional prognostic significance.68

Age at diagnosis is a significant prognostic factor when one considers the older pediatric patient (adolescent or young adult) with non-Hodgkin lymphoma. Broadly speaking, older patients have poorer outcomes.69 There is increasing recognition that these patients need to be viewed as a unique population, in terms of disease biology and treatment tolerance.70

More recent studies have defined host (ie, nontumor) prognostic factors for patients with non-Hodgkin lymphoma. For example, polymorphisms of immune-related genes such as interleukin (IL)-10 and tumor necrosis factor show significant associations with treatment outcomes in adults with non-Hodgkin lymphoma.71,72 Similar data are not yet available in children.

Patients with relapsed or refractory non-Hodgkin lymphoma are candidates for salvage therapy, which often includes autologous or allogeneic hematopoietic stem cell transplantation. The likelihood of cure depends on diagnosis, initial therapy, and length of first remission.73 Even patients who experience relapse after autologous transplantation are potentially salvageable with a second transplant procedure.74
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
Medicolegal Pitfalls

* Airway obstruction
o Mediastinal or cervical lymphomas may cause airway compromise.
o The potential for respiratory arrest must be recognized, particularly if sedation or general anesthesia is administered for a diagnostic procedure.
o Consider (1) administering local anesthesia alone for lymph node biopsy; (2) establishing a diagnosis with pleural fluid, peritoneal fluid, or bone marrow aspiration; and (3) performing local irradiation to stabilize the airway before obtaining a diagnostic specimen from a site outside the radiation field.
* Tumor lysis syndrome
o Non-Hodgkin lymphomas (NHLs) typically respond briskly to induction chemotherapy.
o With initial supportive treatment, include aggressive hydration, close monitoring of serum chemistry results, and administration of allopurinol.
o Consider consulting a nephrologist because dialysis may ultimately be necessary.
* HIV infection: Non-Hodgkin lymphoma (NHL), particularly a primary tumor of the CNS, can be a presenting sign of immunodeficiency, such as HIV/AIDS.
* Rapid progression
o Non-Hodgkin lymphoma in children typically grow rapidly, in contrast to the more indolent lymphomas often observed in adults.
o To prevent tumoral regrowth and to avoid increasing the short-term risk of complications, absolutely minimize any delay (eg, to allow healing after an abdominal procedure) between diagnosis and the start of chemotherapy.