Pediatric Non-Hodgkin Lymphoma 

Updated: Jun 14, 2018
Author: J Martin Johnston, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

Background

Since the late 1960s, treatment outcomes for pediatric patients with non-Hodgkin lymphoma have steadily improved. Even for patients with advanced disease, event-free survival rates are now 65-90%. (See Prognosis, Treatment, and Medication.)

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. (See Treatment and Medication.)

Lymphomas are malignant neoplasms of lymphoid lineage. Broadly classified as either Hodgkin disease (Hodgkin's disease) or as non-Hodgkin lymphoma, lymphomas are clinically, pathologically, and biologically distinct (see the image below). (See Prognosis and Workup.)[1, 2]

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

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) - Burkitt lymphomas and non-Burkitt lymphomas (Burkittlike lymphomas)

  • Large cell lymphomas (LCLs)

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.

Disease progression

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.(See Etiology.)[3]

Non-Hodgkin lymphoma versus acute leukemia

Childhood non-Hodgkin lymphoma generally manifests as bulky extramedullary (usually extranodal) disease with or without demonstrable dissemination. Particularly in the case of lymphoblastic diseases, the distinction between non-Hodgkin lymphoma and acute leukemia is arbitrary. Therefore, these entities (acute lymphoblastic leukemia and lymphoblastic lymphoma) 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. The term, "leukemia/lymphoma syndrome," which was once in common usage, is no longer valid.

Patient education

For patient education information, see the Cancer Center, as well as Lymphoma (Hodgkin’s Disease and Non-Hodgkin’s Lymphoma) and Cancer of the Mouth and Throat.

Etiology

In industrialized 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.[4, 5]

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.[6, 7]

The epidemiologic association between non-Hodgkin lymphoma and certain paternal occupations (eg, those that increase contact with other individuals) suggests a possible infective etiology for childhood non-Hodgkin lymphoma.[8]

An interesting statistical association exists between high birth weight and the subsequent risk of childhood cancers, including non-Hodgkin lymphoma.[9]

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.[10]

Immunosuppression and viral infection

Immunosuppressed individuals, such as those with human immunodeficiency virus (HIV) infection or those who have undergone solid organ transplantation or bone marrow transplantation, are at increased risk for developing non-Hodgkin lymphoma, particularly small noncleaved cell lymphomas (SNCCL) and large cell lymphomas (LCLs) 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 central nervous system (CNS) lymphoma is more common in these patients than in others.

Previous malignancy

Patients successfully treated for Hodgkin disease are at increased risk for developing non-Hodgkin lymphoma. This phenomenon 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%.[11]

Splenectomy, now rarely performed in patients with Hodgkin disease, is another reported risk factor for secondary malignancies, including non-Hodgkin lymphoma.[12]

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. 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.[13]

Geographic location

In sub-Saharan Africa, the development of endemic Burkitt lymphoma is strongly associated with previous exposures to malaria (with resultant T-cell suppression) and the Epstein-Barr virus. 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.[14, 15]

Genetics

The genetic basis of pediatric non-Hodgkin lymphoma has been studied extensively.[16] 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. Less commonly, 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.[17]

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.[17, 18]

A small portion of T-lymphoblastic lymphomas are also associated with translocations involving one of the TCR loci; either 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 observed in T-lymphoblastic lymphoma 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.[19] 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.[20] 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 p80, an NPM/ALK fusion protein.

Rarely, anaplastic LCLs exhibit rearrangements of c-myc; based on small numbers of patients, this appears to confer a poor prognosis.[21, 22]

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.[23] Patients with non-Hodgkin lymphomas expressing p80 may have a survival advantage over patients whose lymphomas lack p80.[24]

Epidemiology

Occurrence in the United States

Taken collectively, lymphomas are the third most common childhood malignancies after acute leukemias (acute lymphoblastic leukemia, acute myelocytic leukemia) and brain tumors,[25] constituting 10-12% of childhood cancers. In older adolescents, lymphomas surpass brain tumors in incidence, largely because of the increased frequency of Hodgkin disease in this age group.

National cancer 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 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[25] :

  • 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 occurrence

A study reviewing non-Hodgkin lymphoma rates in Canada between 1970 and 1996 found that the incidence of non-Hodgkin lymphoma apparently increased in that nation over the 3 decades of the report.[26] The cause for this rise is unclear.

Burkitt lymphoma is significantly more common in sub-Saharan Africa than in other parts of the world, accounting for approximately one half of all childhood cancers in that region. The disease’s incidence also appears to be higher in Latin America, North Africa, and the Middle East than it is in the United States or Europe.

A retrospective study of pediatric lymphoma in a hospital in Pakistan determined that non-Hodgkin lymphoma accounted for 75% of these cases.

Race- and sex-related demographics

In the United States, the incidence of non-Hodgkin lymphoma is twice as high among whites as it is among blacks, with respective rates of 9.1 and 4.6 cases per million individuals per year.

In addition, the incidence of non-Hodgkin lymphoma in the United States is almost twice as high in males as in females. For 2002-2006, the SEER age-adjusted incidence of non-Hodgkin lymphoma was 1.4 cases per 100,000 males (age 0-19 years) and 0.8 cases per 100,000 females.[25]

Age-related demographics

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 as children age. In adulthood, the risk of non-Hodgkin lymphoma steadily climbs, whereas the age-specific incidence of Hodgkin disease is biphasic.

A study by Mbulaiteye et al of 3,403 cases of Burkitt lymphoma spread over 4 continents found that in all regions and over all periods in the study (which covered 1963-2002), peaks in the rate of Burkitt lymphoma occurred close to the ages of 10 and 70 years. The investigators concluded that their findings—which also included other age-related differences in the disease rate, as well as age-related differences in the male-to-female ratio for the disease’s occurrence—supported their hypothesis that Burkitt lymphoma is multimodal and that the age-related peaks in the disease may aid in determining differences in the disorder’s etiology and/or biology at the peak ages.[27]

Prognosis

The overall prognosis for children with non-Hodgkin lymphoma has steadily improved. Period analysis of SEER data for children under 15 years showed that 5- and 10-year survival increased, respectively, 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%.[28]

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, anaplastic lymphoma kinase (ALK) and/or CD56 in anaplastic large cell lymphoma [LCL]) has additional prognostic significance.[29]

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,[30] and there is increasing recognition that these patients need to be viewed as a unique population in terms of disease biology and treatment tolerance.[31]

Studies have also defined host (ie, nontumoral) prognostic factors for patients with non-Hodgkin lymphoma. For example, polymorphisms of immune-related genes, such as those for interleukin (IL)–10 and tumor necrosis factor, show significant associations with treatment outcomes in adults with non-Hodgkin lymphoma.[32, 33] Similar pediatric data are not yet available.

CNS lymphoma

Pediatric and adolescent patients with CNS lymphoma have better outcomes than do adults with this disease.[34] An Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 is associated with improved survival. Higher dose methotrexate is associated with slightly better response.

Relapsed or refractory disease

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.[35] Even patients who experience relapse after autologous transplantation are potentially salvageable with a second transplant procedure.[36]

Complications

Growth

Linear growth of the pediatric patient often slows during aggressive chemotherapy. Most patients, however, 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.[37]

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 has been thought have little effect on neuropsychological function. Data now suggest, however, that patients with non-Hodgkin lymphoma who survive without irradiation are more likely to require special education classes than are their siblings.

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.[38]

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 can perhaps consider banking their semen before undergoing chemotherapy, if this is feasible.

Ovarian failure after high-dose alkylator therapy has also been described. Nonetheless, a report found that female survivors of non-Hodgkin lymphoma 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 developing permanent gonadal dysfunction.

Secondary malignancies

The oncogenic potential of therapeutic radiation is well documented, but the risk of secondary 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 of less than 1000 mg/m2.

Cyclophosphamide has also been identified as a potential carcinogen. The relative risk of secondary malignancies in children exposed to cyclophosphamide is estimated to be as high as 7.4 if the cumulative exposure is more than 13 g/m2.

In one series, however, only 2 cases of secondary cancer (1 case of malignant melanoma and 1 case of spindle-cell sarcoma, which arose in a radiation field) were found among 86 survivors of pediatric non-Hodgkin lymphoma. The 86 patients were evaluated for a mean period of 11 years after diagnosis.[39] These findings suggest that, despite concerns about the effects of chemotherapy, patients who do not receive irradiation are unlikely to develop a secondary malignancy. However, even longer follow-up is needed to accurately assess the lifelong risk of secondary malignancies.

Fortunately, the risk of secondary cancer appears to be decreasing, due to the recognition (and relative avoidance) of treatment-related risk factors such as radiation and high-dose epipodophyllotoxins.[40]

Cardiotoxicity

At high cumulative doses, doxorubicin is likely to cause delayed myocardial toxicity.[41] Irradiation of the heart exacerbates this effect.

In a recent report, 7 of 29 survivors (aged 2-39 years 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.[42]

Avascular necrosis most commonly affects the femoral heads, and it may be associated with a 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.[43]

Viral transmission by means of blood products

Transmission of cytomegalovirus (CMV) is possible if unscreened blood products are administered without prior leukoreduction. Since leukoreduction reduces the risk of CMV transmission, the role for CMV-seronegative blood products is controversial; arguably, these products should be given to patients who may eventually undergo bone marrow transplantation (BMT), but the benefits of this practice are marginal.

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.

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

Mediastinal involvement

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 the image below.)

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

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 performed 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 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 therapeutic and diagnostic, obviating biopsy. (See the image below.)

Massive left pleural effusion as a complication of Massive left pleural effusion as a complication of an upper anterior mediastinal T-lymphoblastic lymphoma. Note the atelectatic left lung. The diagnosis was established by means of thoracentesis. This patient had presented with bilateral parotid gland enlargement.

Bowel obstruction

In the United States, most patients with small noncleaved cell lymphomas (SNCCLs) present with abdominal involvement, typically in the ileocecal area and arising from Peyer patches. 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. (See the images below.)

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

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.

Other complications

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.

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.

 

Presentation

History

The presentation of patients with non-Hodgkin lymphoma 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 less, with specific complaints varying according to the predominant sites of involvement.

Bone marrow involvement in non-Hodgkin lymphoma may cause generalized or migratory bone pain, but clinically significant cytopenias are uncommon, with their presence suggesting a diagnosis of acute leukemia.

Symptoms of localized disease

Localized disease can manifest as lymphadenopathy (usually with firmness and no tenderness), tonsillar hypertrophy, or a mass in virtually any location. In children, however, 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 [SNCCL] or B-cell large cell lymphoma [LCL]) 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.[44]

Symptoms of large cell lymphomas

Constitutional symptoms are uncommon in non-Hodgkin lymphoma, except in patients with anaplastic large cell lymphoma (LCL). Many of these patients have low-grade fever, malaise, anorexia, and/or weight loss. Because LCLs are biologically disparate, however, 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.

Patients with anaplastic LCLs sometimes present with painful skin lesions, bone lesions, peripheral lymphadenopathy, and hepatosplenomegaly.[45, 46] 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.

Symptoms of CNS involvement

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.

Other

Among the less common lymphomas of childhood, primary cutaneous/subcutaneous involvement can be seen (eg, in cutaneous T-cell lymphoma or blastic plasmacytoid dendritic cell hematodermic neoplasm).

Physical Examination

Patients with non-Hodgkin lymphoma generally 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 industrialized countries, but this finding is particularly common in African patients with endemic Burkitt lymphoma.

Other clinical findings in non-Hodgkin lymphoma include the following:

  • Cervical or supraclavicular masses or adenopathy is/are firm, fixed, and nontender

  • Dyspnea or stridor may occur in patients with a mediastinal mass

  • In patients 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 large cell lymphoma (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:

  • Nasopharyngeal mass

  • Parotid enlargement

  • Nephromegaly

  • Testicular enlargement

 

DDx

 

Workup

Approach Considerations

A complete blood count (CBC) with differential and a platelet count in patients with non-Hodgkin lymphoma should be obtained to assess for possible involvement of the bone marrow and to determine the patient's transfusion requirements. Additional tests, listed in the next section, are run to assess the patient's renal and hepatic function and to monitor for possible tumor lysis syndrome.

Lumbar puncture

Lumbar puncture with determination of the cerebrospinal fluid (CSF) cell count and differential is performed to assess CNS involvement, the presence of which alters therapy.

Airway obstruction

Mediastinal or cervical lymphomas may cause airway compromise. The potential for respiratory arrest must be recognized, particularly if sedation or general anesthesia is administered for a diagnostic procedure.

Consider (1) administering local anesthesia alone for 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.

Laboratory Studies

As previously mentioned, a CBC with differential and a platelet count should be obtained in patients with non-Hodgkin lymphoma 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 the patient has a fever, especially if it is associated with neutropenia. If indicated, also obtain stool and throat cultures.

Analyze the following to assess the patient's renal and hepatic function and to monitor for possible tumor lysis syndrome:

  • Serum electrolytes

  • Blood urea nitrogen (BUN)

  • Creatinine

  • Uric acid

  • Lactate dehydrogenase – The level of lactate dehydrogenase at diagnosis has had prognostic significance in many analyses of treatment outcomes

  • Bilirubin

  • Albumin

  • Total protein

  • Aspartate aminotransferase

  • Alanine aminotransferase

  • Calcium

  • Magnesium

  • Phosphorus

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 ultrasonography helps in assessing the size of the kidneys and the patency of the urinary tract. It is particularly useful before chemotherapy in anticipation of, for example, prolonged excretion and excess toxicity. When symptoms are present, testicular ultrasonography aids in identifying additional sites of disease.

Echocardiography

Perform echocardiography to obtain baseline findings before patients are given chemotherapy with anthracyclines, which can cause cardiomyopathy.

CT scanning

Computed tomography (CT) scans of the chest, abdomen, and pelvis can be used to stage lesions. 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 in individuals with CNS disease.

PET/CT scanning

Positron emission tomography (PET)/CT scanning has largely supplanted gallium-67 (67 Ga) scanning and is highly recommended for patients with non-Hodgkin lymphoma.[47, 48, 49, 50, 51]

Many lymphomas are 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) avid; their response to treatment can be assessed by using this modality. Occult sites of disease may also be identified on PET/CT scans. Many newer "response-based" chemotherapy protocols use PET scanning to assess response and guide subsequent treatments.

Bone scanning and skeletal surveys

When additional symptoms are present, these tests help in identifying additional sites of disease.

Serologic Analyses

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. In addition, these tests may 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. As noted above, however, this is a marginal/arguable recommendation.

Order these tests to confirm previous exposure to a hepatitis virus before blood transfusions are administered.

HIV infection

Non-Hodgkin lymphoma, particularly a primary tumor of the CNS, can be a presenting sign of immunodeficiency, such as that resulting from HIV/acquired immunodeficiency syndrome (AIDS). Perform HIV serologic tests in patients who have risk factors for HIV exposure or in individuals with primary CNS lymphoma.

Biopsy and Paracentesis

A histologic diagnosis must be obtained. Flow cytometric analysis of tumor cell markers has become the standard for lymphoma subtyping.[52] Cytogenetic analysis is sometimes helpful in equivocal cases.

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/peritoneal fluid or involved bone marrow (especially if the CBC is abnormal and/or if imaging studies demonstrate abnormal signal intensity of the marrow). In rare cases, cerebrospinal fluid (CSF) can be used.

Bone marrow aspiration and biopsy

Biopsy is necessary to assess for evidence of bone marrow involvement in patients with lymphomas, with bilateral biopsy being superior to a unilateral procedure. Bone marrow aspiration is potentially less sensitive than a core biopsy.

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.

Polymerase chain reaction (PCR) assays are being used experimentally to detect and monitor minimal residual disease in the marrow.[53, 54] In the future, postinduction measurement of minimal residual disease may improve precision in determining treatment responses and/or treatment assignments.

Histologic Findings

Several classification systems for non-Hodgkin lymphoma are available. Examples are the Kiel classification system and the NCI Working Formulation. At present, the Revised European-American Lymphoma (REAL) classification system 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 and T-cell LCLs. The 3 major classes—lymphoblastic lymphomas, small noncleaved cell lymphomas (SNCCLs), and LCLs—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 lymphomas (SNCCLs) can be classified as 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.[55]

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

Large cell lymphomas

LCLs are a heterogeneous group, with LCL in most cases being classified as the B- or T-cell type. 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. B-cell LCLs can be divided into germinal center and nongerminal center subtypes, a distinction that carries prognostic significance in adult patients; in pediatric patients, germinal-center type B-LCLs predominate, which explains, in part, the overall better outcomes for pediatric patients (versus adults) with B-cell LCL.[56]

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.[57]

Other cell surface markers that may be observed are HLA-DR and the IL-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.[58] 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 gastrointestinal (GI) tumor with or without associated involvement of mesenteric nodes, with gross total resection; or, on the same side of the 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%) involvement

 

Treatment

Approach Considerations

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

Current treatment regimens for lymphoblastic lymphomas (T cell and B cell) are quite similar to protocols for their leukemic counterparts (T-cell ALL and B-cell ALL). In broad terms, these therapies are longer and less intensive (particularly with respect to the use of alkylating agents) than those for small noncleaved-cell lymphoma or LCL, which use relatively high doses of alkylating agents 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.

Antibiotics

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.

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 one 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.

Rapid progression

Non-Hodgkin lymphomas in children typically grow rapidly, in contrast to the more indolent lymphomas often observed in adults.

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.

Tumor Lysis Syndrome Treatment

Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome, a condition that can result from the rapid destruction of a large number of neoplastic cells. This destruction causes intracellular ions and metabolic byproducts to be released into the systemic circulation, which can lead to the rapid development of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. (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 a pH of 5, and 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]).[59]

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.

Chemotherapy for Lymphoblastic Lymphoma

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

LSA2L2 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.[60] 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, below). Their 5-year event-free survival rate was 74%.[61]

Table 1. Modified LSA2 L2 Therapy in Children's Cancer Group Protocol 552 (Open Table in a new window)

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 have demonstrated excellent results in patients with ALL or lymphoblastic lymphoma. (See Table 2, below.)[62]

Unlike the LSA2 L2 protocol, the BFM regimen has a reinduction phase. It also features a less complicated and less intense maintenance phase. In its original report, the BFM protocol included prophylactic cranial irradiation during reinduction. Patients receiving this treatment had a 6-year event-free survival rate of 79%.

Table 2. Therapy for Stage III and IV Non–B-Cell Disease* According to BFM Protocol 86 (Open Table in a new window)

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 large cell lymphomas (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 (1) BFM therapy, (2) a Children's Cancer Group modified version of BFM therapy (which did not include high-dose methotrexate/leucovorin during consolidation), and (3) intensified versions of these 2 protocols (with early introduction of daunomycin and cyclophosphamide). In patients with disseminated disease, there was no statistical difference in outcomes among the 4 groups, with 5-year event-free survival of approximately 81%. Age younger than 10 years and imaging response at 2 weeks were associated with better overall survival.[63]

The Children's Oncology Group is conducting specific protocols to treat T-lymphoblastic lymphoma and T-cell ALL. In particular, current clinical trials 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. In this trial, the 5-year event-free survival rate was 78% ± 4.5%, and the overall survival rate was 85% ± 3.9%. These results suggest that the experimental approach is safe and is just as effective as more prolonged regimens.[64]

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 for lymphoblastic lymphoma is lacking. Treatment options include the LSA2 L2 protocol and BFM protocol 86 for non-Hodgkin lymphoma (with the reinduction phase eliminated).

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. Patients with localized lymphoblastic lymphoma (n=60) were included in Children's Oncology Group protocol A5971; they received a Children's Cancer Group modified version of the BFM protocol (as described above) that included reinduction but had fewer doses of intrathecal chemotherapy during the maintenance phase. Interestingly, most patients (75%) had a B-precursor phenotype. At a median follow-up of 5.9 years, the 5-year event-free survival rate was 90% (95% confidence interval, 78-96%, with an overall survival rate of 96% [84-99%]). There were no relapses among the 15 T-cell lymphoblastic lymphoma subjects.[65]

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; local radiation therapy was not offered routinely. The total duration of therapy was 15 cycles (approximately 60 wk).

Chemotherapy for Small Noncleaved Cell Lymphoma

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

  • Long-term maintenance chemotherapy appears to have no role; therefore, chemotherapy can be short, with the typical duration being 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 an international trial for patients with small noncleaved cell lymphoma (SNCCL); specifically, 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. Patients with B-cell acute lymphoblastic leukemia (ALL) were included in this protocol. Subjects were staged (as described above) and then were assigned to clinical risk groups. (See Tables 3, 4, 5, and 6, below.)

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

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 tumor with no CNS involvement and < 25% marrow blasts

C

25

CNS involvement or >25% marrow blasts

Table 4. Standard Therapy in the International Trial for Patients With SNCCL, Group A* (Open Table in a new window)

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.

With median follow-up of more than 4 years, the 4-year event-free survival rate for group A patients was 98.3%, and the overall survival rate was 99.2%.[66]

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 minimal risk of inducing or exacerbating tumor lysis syndrome. Patients in group B were randomized to 1 of 4 treatment arms: the 3 experimental treatment arms involved incremental decreases 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 days of treatment), outcomes with standard therapy were not superior to outcomes with any of the experimental (reduced therapy) arms. (See Table 5, below.)

The results indicated, therefore, that pediatric patients with intermediate-risk B non-Hodgkin lymphoma who have an early response and achieve a complete remission after the first consolidation course can be effectively treated using a 4-course regimen with a total dose of only 3.3 g/m2 cyclophosphamide and 120 mg/m2 doxorubicin.[67]

Table 5. Standard Therapy in the International Trial for Patients With SNCCL, Group B* (Open Table in a new window)

Phase

Drug

Route

Reduction

Prednisone

PO

 

Vincristine, cyclophosphamide

IV

 

Methotrexate/hydrocortisone

IT

Phase

Cycles

Drug

Route

Induction

2, starting 7 days 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 and/or elimination of maintenance phase 1.

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 rate after randomization was 90% ± 3.1% versus 80% ± 4.2%, respectively, whereas the overall survival rate was 93% ± 2.7% versus 83% ± 4%, respectively. Patients with either combined marrow and CNS disease at diagnosis or a poor response to reduction therapy had significantly inferior event-free survival and overall survival.[68]

Therefore, decreasing therapy in this subgroup of patients appears unwise; standard-intensity therapy is recommended for children with high-risk B non-Hodgkin lymphoma. (See Table 6, below.)

Table 6. Standard Therapy in the International Trial for Patients With SNCCL, Group C* (Open Table in a new window)

Phase

Drug

Route

Reduction

Prednisone

PO

Vincristine, cyclophosphamide

IV

Methotrexate/Ara-C/hydrocortisone

IT

Induction, cycle 1 starting 7 days 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 (BFM) group.[69] 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).

Chemotherapy for Large Cell Lymphoma

B cell ̶ derived LCLs

Patients with B cell ̶ derived large cell lymphomas (LCLs) are treated effectively using regimens for SNCCL.[70, 71, 72] Outcomes are similar between the groups.

An alternative therapy is the APO regimen, consisting of doxorubicin (Adriamycin), prednisone, and vincristine [Oncovin].[73] Methotrexate and 6-mercaptopurine have been added to this regimen.

A randomized study of children with LCLs (including B-cell LCLs) showed no advantage when cyclophosphamide was added to the APO regimen.[74] 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 acute lymphoblastic leukemia (ALL) therapy, whereas others were similar or identical to those used to treat B-cell lymphomas.

The Berlin, Frankfurt, Muenster (BFM) group reported what may be the best results with treatment for Ki-1+ anaplastic LCLs.[75] 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%.

Subsequent modifications have yielded the ALCL99 protocol as shown below and have further demonstrated that: (1) dosing methotrexate at 3 g/m2 over 4 hours appears to be at least as effective (and less toxic) when compared with a dose of 1 g/m2 over 24 hours with the addition of "triple" intrathecal chemotherapy and (2) the addition of vinblastine (both during chemotherapy and continuing weekly until 1 year from diagnosis) delayed but did not ultimately prevent relapses.[76, 77]

Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol (Open Table in a new window)

Drug

Route

Dexamethasone

PO

Cyclophosphamide

IV

Methotrexate/Ara-C/prednisolone

IT

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

Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol (alternating cycles, repeated 3times each) (Open Table in a new window)

Cycle

Drug

Route

A

Dexamethasone

PO

Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-C

IV

B

Dexamethasone

PO

Methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin

IV

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

Good results have been observed with the relatively uncomplicated APO regimen. In addition, a randomized study of children with LCL (including B-cell LCL and anaplastic LCL) showed no apparent advantage when intermediate-dose methotrexate and high-dose cytarabine were added to an APO backbone.[78]

A report from the SFOP described surprising efficacy for monotherapy with vinblastine for relapsing anaplastic LCL, even in patients who previously underwent myeloablative therapy with autologous bone marrow transplantation.[79]

The role of vinblastine in front-line therapy for anaplastic LCL was examined in a Children's Oncology Group protocol (A5941), which compared the standard APO regimen with an experimental therapy that included vinblastine. Myelosuppression was more significant than anticipated and the trial closed early; results have not been published.

The current Children's Oncology Group Phase 2 protocol for anaplastic LCLs uses the ALCL99 regimen (shown above) as a "backbone" and adds (in a randomized fashion) either brentuximab vedotin, an anti-CD30 monoclonal antibody, or crizotinib, a specific small-molecule inhibitor of the ALK pathway.[80]

Radiation Therapy

In general, radiation therapy has a limited role in the treatment of pediatric non-Hodgkin lymphoma, 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 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 daily) offers a theoretic advantage, as does low-dose continuous irradiation. However, the unfeasibility of the latter all but precludes its use.[81]

Finally, consider radiotherapy in any patient with documented residual disease after chemotherapy and in patients with bulky disease at the time of relapse.

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, the anti-CD20 antibody rituximab) may be added to the regimen.[82, 83]

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.

Pembrolizumab is a monoclonal antibody that binds the programmed cell death-1 protein (PD-1) ligands PD-L1 and PL2. In June 2018, it was approved by the FDA for treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. Approval was based on data from the KEYNOTE-170 trial (n=53). The ORR was 45%, with a CRR of 11%, and a PRR of 34% percent. Median duration of response, based on 24 patients who responded, was not reached (range, 1.1+ to 19.2+ months). For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range, 2.1 to 8.5 months).[84]

Lymph Node Excision and Dissection

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.

The chief role for surgery is obtaining tissue for diagnosis. 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 3) 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 the CNS or marrow)

In this situation, the prescribed chemotherapy regimen is far less toxic than it would be otherwise. 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, although second-look procedures require highly individualized approaches. As an alternative, uptake of67 Ga or radiolabeled FDG suggests viability of residual masses in patients whose tumors are gallium or FDG avid.

Consultations

Intensive care specialist

Patients with pediatric 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.

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. As previously discussed, however, radiation therapy generally has a limited role in the treatment of pediatric non-Hodgkin lymphoma, and it is applied almost exclusively in situations deemed to be real or potential emergencies.

Nephrologist

Notify a nephrologist if the patient has substantial tumor lysis syndrome and if dialysis is under consideration.

Long-Term Monitoring

A study of a cohort of 200 childhood non-Hodgkin lymphoma survivors found that common late outcomes in adulthood included obesity (35%), hypertension (9%), and impairment of executive function (13%), attention (9%), and memory (4%). The study also found a prevalence of impaired strength (48%), flexibility (39%), muscular endurance (36%), and mobility (36%) in the cohort.[85]

 

Medication

Medication Summary

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

In addition to the use of chemotherapeutic drugs, treatment also includes the employment of several classes of medications to support patients with non-Hodgkin lymphoma undergoing aggressive chemotherapy. These include the following:

  • Laxatives and stool softeners

  • Prophylactic antibiotics

  • Antiemetics

  • Antimucositic agents

  • Histamine (H2) receptor antagonists

  • Contraceptives

Prophylactic antibiotics

These medications include the following:

  • Trimethoprim-sulfamethoxazole (against Pneumocystis jiroveci [formerly, carinii])

  • Fluconazole (against Candida species)

  • Nystatin (against Candida species)

Antiemetics

Antiemetics include the following:

  • Serotonin (5-hydroxytryptamine type 3 [5-HT3]) receptor antagonists (ondansetron, granisetron, dolasetron)

  • Phenothiazine

  • Lorazepam

  • Metoclopramide

  • Dexamethasone

  • Tetrahydrocannabinol

Antimucositic agents

These agents include the following:

  • Saline or bicarbonate rinse

  • Biotene rinse

  • Peridex rinse

  • 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.

Antineoplastics, Other

Class Summary

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 deoxyribonucleic acid (DNA) synthesis (ie, phase S). The next phase is the premitotic phase (ie, G2), followed by 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 do 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)

Daunorubicin is an anthracycline. Its multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline. Its multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

Cytarabine

Cytarabine is an antimetabolite. A cytotoxic analogue of deoxycytidine, it interferes with DNA replication and repair by incorporating into DNA and inhibiting DNA polymerase.

6-mercaptopurine (6-MP, Purinethol)

This agent is a purine analog. Its metabolites are incorporated into DNA, inhibiting synthesis.

6-thioguanine (Tabloid)

This drug is a purine analogue. Its metabolites are incorporated into DNA, inhibiting synthesis

Methotrexate (Trexall)

Methotrexate is a cytotoxic folate antagonist. It inhibits dihydrofolate reductase.

Vincristine (Vincasar PFS)

Vincristine inhibits microtubule formation in the mitotic spindle, causing metaphase arrest.

Etoposide (VP-16, Toposar)

Etoposide inhibits topoisomerase, causing DNA strand breaks.

Cyclophosphamide

Cyclophosphamide alkylates and cross-links DNA.

Ifosfamide (Ifex)

Ifosfamide alkylates and cross-links DNA.

Carmustine (Gliadel, BiCNU)

Carmustine alkylates DNA and ribonucleic acid (RNA). It may also act by carbamoylation of enzymes.

L-asparaginase (Elspar)

L-asparaginase is an enzyme produced by Escherichia coli that catalyzes the conversion of L-asparagine to aspartic acid. L-asparagine is a nonessential amino acid for most normal tissues. Many lymphoid malignancies have low levels of asparagine synthase and, therefore, depend on the circulating pool of L-asparagine.

Nelarabine (Arranon)

Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). It is converted to active 5'-triphosphate (ara-GTP), a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP, allowing for its incorporation into DNA; the result is inhibition of DNA synthesis and cell death.

Nelarabine has been approved by the US Food and Drug Administration (FDA) as an orphan drug to treat T-cell lymphoblastic lymphoma that is not responsive or is relapsing with at least 2 chemotherapy regimens.

Hydroxyurea (Hydrea, Droxia)

Hydroxyurea apparently inhibits DNA synthesis.

PD-1/PD-L1 Inhibitors

Pembrolizumab (Keytruda)

Indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

Corticosteroids

Class Summary

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

Methylprednisolone (Medrol, A-Methapred, Solu-Medrol)

The mechanism of cytotoxicity for methylprednisolone is unknown, but it is apparently mediated by glucocorticoid receptors.

Dexamethasone (Baycadron)

The mechanism of cytotoxicity for dexamethasone is unknown, but it is apparently mediated by glucocorticoid receptors. The drug's action is apparently enhanced by CNS penetration (relative to prednisone).

Antibiotics, Other

Class Summary

Therapy should cover all likely pathogens in the context of this clinical setting.

Trimethoprim and sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

Trimethoprim/sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. The antibacterial activity of trimethoprim/sulfamethoxazole includes Pneumocystis jiroveci.

Antifungals

Class Summary

These agents may change the permeability of the fungal cell resulting in a fungicidal effect.

Fluconazole (Diflucan)

Fluconazole is a synthetic oral antifungal agent (a broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation.

Nystatin

Nystatin is a fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. It is effective against candidal organisms. It changes the permeability of the fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak.

Antiemetic Agents

Class Summary

Antiemetics are always prescribed before and after the administration of chemotherapy, for the prevention of chemotherapy-induced nausea and vomiting.

Ondansetron (Zofran, Zuplenz)

Ondansetron is a selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Granisetron (Kytril, Granisol, Sancuso)

At the chemoreceptor trigger zone, granisetron blocks serotonin centrally and peripherally on vagal nerve terminals.

Palonosetron (Aloxi)

Palonosetron, is a selective 5-HT3 receptor antagonist with a long half-life (40 h). It is a selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Dolasetron (Anzemet)

At the chemoreceptor trigger zone, granisetron blocks serotonin centrally and peripherally on vagal nerve terminals.

Metoclopramide (Reglan, Metozolv)

The antiemetic effect of metoclopramide appears to be due to its ability to block dopamine receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system (CNS). This agent also enhances gastrointestinal motility and accelerates gastric emptying time.

Lorazepam (Ativan)

Lorazepam is a benzodiazepine used as an antiemetic in patients receiving chemotherapy for non-Hodgkin disease. By increasing the action of gamma-aminobutyric acid (GABA) the major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic system and the reticular formation.

Chlorpromazine

The antiemetic effect of metoclopramide appears to be due to its ability to block dopamine receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system (CNS).

Dronabinol

This agent inhibits endorphins in the brain's emetic center through an unknown mechanism.

Histamine H2 Antagonists

Class Summary

Like antacids, these agents decrease the amount of acid in the refluxate by inhibiting acid production. These agents are used to help prevent gastritis in patients receiving high-dose corticosteroids. All H2 -receptor antagonists are equipotent when used in equivalent doses. H2 -receptor antagonists are considered the drugs of choice for children because pediatric doses are well established and the medications are available in liquid form.

Nizatidine (Axid)

Nizatidine competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reductions in gastric acid secretion, gastric volume, and hydrogen concentrations.

Ranitidine (Zantac)

Ranitidine inhibits histamine stimulation of the H2 receptor in gastric parietal cells, reducing gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at the H2 receptors of gastric parietal cells, reducing gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Progestins

Class Summary

These agents may induce endometrial thinning by inhibiting the secretion of pituitary gonadotropins.

Norethindrone acetate (Aygestin, Camila, Errin)

Norethindrone is a common progestin used in many of the oral contraceptive pills currently available. Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. These agents typically do not stop acute bleeding episode, but they produce normal bleeding episodes following withdrawal.

Medroxyprogesterone (Depo-Provera, Provera)

Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. These agents typically do not stop acute bleeding episode, but they produce normal bleeding episodes following withdrawal.

Medroxyprogesterone is a common progestin available in both an oral and an intramuscular depo form. The efficacy and adverse effects of this drug are similar to those of norethindrone.

Estrogens/Progestins

Class Summary

Oral contraceptives may be used to decrease the amount of bleeding. Topical preparations can be used to help strengthen the mucosa and decrease its susceptibility to bleeding. Before use, screening tests for pulmonary AVMs should be performed because of the risk of complications involving thromboembolism.

Norethindrone acetate and ethinyl estradiol (Aranelle, Balziva, Nortrel, Loestrin 1.5/30)

Norethindrone acetate and ethinyl estradiol are used to decrease mucosal bleeding. The combination probably works by strengthening mucosal tissues and thereby making them more resistant to bleeding.

Uricosuric Agents

Class Summary

These agents control hyperuricemia and are used to attempt to prevent urate nephropathy and subsequent oliguric renal failure.

Allopurinol inhibits xanthine oxidase, thereby reducing uric acid. The IV form (Aloprim) may be used for patients unable to tolerate oral administration.

Caution is necessary because of the high uric acid concentration in the urine. In the presence of allopurinol, the excretion of uric acid, xanthine, and hypoxanthine increases several hundred fold, enough to exceed their solubility limit in the renal tubules even at a urinary pH level of 7. Also, at a urinary pH level higher than 7.5, crystallization of hypoxanthine may occur, which necessitates withdrawal of bicarbonate from IV fluids.

Allopurinol (Zyloprim, Alloprim)

Allopurinol inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine and xanthine, thus decreasing production and excretion of uric acid and increasing the levels of more soluble xanthine and hypoxanthine. The drug reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines. Patient response is measured by serum uric acid levels assessed at 48 hours after the initiation of therapy. Dosage adjustments are made as needed.

Rasburicase (Elitek)

Rasburicase is a recombinant form of the enzyme urate oxidase, which oxidizes uric acid to allantoin. It is indicated for the treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. The elimination half-life for rasburicase is 18 hours.

 

Questions & Answers

Overview

What is pediatric non-Hodgkin lymphoma (NHL)?

What causes disease progression in pediatric non-Hodgkin lymphoma (NHL)?

How is pediatric non-Hodgkin lymphoma (NHL) differentiated from acute leukemia?

What causes pediatric non-Hodgkin lymphoma (NHL)?

What is the role of immunosuppression in the etiology of pediatric non-Hodgkin lymphoma (NHL)?

What are the risk factors for secondary non-Hodgkin lymphoma (NHL)?

What geographic factors increase the risk of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of genetics in the etiology of pediatric non-Hodgkin lymphoma (NHL)?

What is the prevalence of pediatric non-Hodgkin lymphoma (NHL) in the US?

What is the global prevalence of pediatric non-Hodgkin lymphoma (NHL)?

What are the racial predilections of pediatric non-Hodgkin lymphoma (NHL)?

What are the sexual predilections of pediatric non-Hodgkin lymphoma (NHL)?

Which age groups are at highest risk for pediatric non-Hodgkin lymphoma (NHL)?

What is the prognosis of pediatric non-Hodgkin lymphoma (NHL)?

What is the prognosis of pediatric CNS lymphoma?

What is the prognosis of relapsed or refractory pediatric non-Hodgkin lymphoma (NHL)?

What are the possible complications of pediatric non-Hodgkin lymphoma (NHL)?

Presentation

Which clinical history findings are characteristic of pediatric non-Hodgkin lymphoma (NHL)?

What are the signs and symptoms of localized pediatric non-Hodgkin lymphoma (NHL)?

What are the signs and symptoms of large cell pediatric non-Hodgkin lymphoma (NHL)?

What are the signs and symptoms of CNS involvement in pediatric non-Hodgkin lymphoma (NHL)?

When is primary cutaneous involvement seen in pediatric non-Hodgkin lymphoma (NHL)?

Which physical findings are characteristic of pediatric non-Hodgkin lymphoma (NHL)?

DDX

Which conditions are included in the differential diagnoses of pediatric non-Hodgkin lymphoma (NHL)?

What are the differential diagnoses for Pediatric Non-Hodgkin Lymphoma?

Workup

What is the role of lumbar puncture in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of blood tests in the workup of pediatric non-Hodgkin lymphoma (NHL)?

How is the risk of respiratory arrest mitigated when performing diagnostic procedures for suspected pediatric non-Hodgkin lymphoma (NHL)?

What is the role of lab tests in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of chest radiography in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of ultrasonography in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of echocardiography in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of CT scanning in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of PET/CT scanning in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of bone scans in the workup of pediatric non-Hodgkin lymphoma (NHL)?

What is the role of serologic analysis in the workup of pediatric non-Hodgkin lymphoma (NHL)?

When is HIV testing indicated in the workup of pediatric non-Hodgkin lymphoma (NHL)?

How is a histologic diagnosis of pediatric non-Hodgkin lymphoma (NHL) made?

What is the role of bone marrow aspiration in the diagnosis of pediatric non-Hodgkin lymphoma (NHL)?

Which histologic findings are characteristic of pediatric non-Hodgkin lymphoma (NHL)?

Which histologic findings are characteristic of lymphoblastic lymphoma?

Which histologic findings are characteristic of small noncleaved cell lymphoma?

Which histologic findings are characteristic of large cell lymphoma

How is pediatric non-Hodgkin lymphoma (NHL) staged?

Treatment

How is pediatric non-Hodgkin lymphoma (NHL) treated?

What is the role of antibiotics in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

When is central venous access indicated in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

How is rapid progression of pediatric non-Hodgkin lymphoma (NHL) prevented?

How is tumor lysis syndrome treated in pediatric non-Hodgkin lymphoma (NHL)?

How is pediatric lymphoblastic lymphoma treated?

What is the LSA2 L2 protocol for the treatment of pediatric lymphoblastic lymphoma?

What is the modified LSA2 L2 protocol for the treatment of pediatric lymphoblastic lymphoma?

What are the German Berlin, Frankfurt, Muenster (BFM) protocols for the treatment of pediatric lymphoblastic lymphoma?

What are the Children&#39;s Oncology Group protocols for the treatment of pediatric lymphoblastic lymphoma?

How is advanced-stage pediatric lymphoblastic lymphoma treated?

How is pediatric small noncleaved cell lymphoma treated?

What is the Cooperative Group protocol for the treatment of pediatric small noncleaved cell lymphoma?

How are pediatric B cell ? derived large cell lymphomas (LCLs) treated?

How are pediatric anaplastic (T-cell) LCLs treated?

What is the role of radiation therapy in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

How is relapsed pediatric non-Hodgkin lymphoma (NHL) treated?

When is lymph node excision and dissection indicated in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

When is consultation with an intensive care specialist indicated in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

When is consultation with a radiation oncologist indicated in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

When is consultation with a nephrologist indicated in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

What is included in the long-term monitoring of pediatric non-Hodgkin lymphoma (NHL)?

Medications

Which medications are used in the treatment of pediatric non-Hodgkin lymphoma (NHL)?

Which medications in the drug class Uricosuric Agents are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Estrogens/Progestins are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Progestins are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Histamine H2 Antagonists are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Antiemetic Agents are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Antifungals are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Antibiotics, Other are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Corticosteroids are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Pediatric Non-Hodgkin Lymphoma?

Which medications in the drug class Antineoplastics, Other are used in the treatment of Pediatric Non-Hodgkin Lymphoma?