Pediatric Non-Hodgkin Lymphoma 

  • Author: J Martin Johnston, MD; Chief Editor: Max J Coppes, MD, PhD, MBA   more...
 
Updated: Apr 8, 2011
 

Background

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

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

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

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

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

The mainstay of conventional therapy is multiagent chemotherapy tailored to the histologic subtype and the clinical stage of disease. In certain individuals with non-Hodgkin lymphoma, surgical resection and radiation therapy are also key components of definitive treatment. Newer therapies that target immunologic and biologic aspects of the lymphoma are still under development but beginning to appear in the clinical arena.

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Pathophysiology

Most malignancies arise as disease localized in the organ or tissue of origin. They may then secondarily spread by means of local extension or distant metastases. In contrast, non-Hodgkin lymphoma is best regarded as a systemic disease because of the unique anatomy of the lymphoid system and because of the physiology of lymphoid cells, which tend to migrate whether they are normal or malignant. The role of lymphoma stem cells in the genesis and maintenance of B cell lymphomas remains speculative.[3]

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

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

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Epidemiology

Frequency

United States

Taken collectively, lymphomas are the third most common childhood malignancies after acute leukemias and brain tumors.[4] Lymphomas constitute 10-12% of childhood cancers (see Childhood Cancer, Epidemiology). In older adolescents, lymphomas surpass brain tumors in incidence largely because of the increased frequency of Hodgkin disease in this age group.

Data from the NCI Surveillance, Epidemiology, and End Results (SEER) program for 2002-2006 are shown below. In children, non-Hodgkin lymphoma is somewhat less common than Hodgkin disease. However, the incidence of non-Hodgkin lymphoma appears to be rising in the United States. This trend largely reflects the occurrence of non-Hodgkin lymphoma in patients who are immunocompromised (eg, patients with human immunodeficiency virus [HIV]) and in patients who were previously exposed to chemotherapy and irradiation as treatment for an unrelated cancer.

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

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

International

Over the last 3 decades, the incidence of non-Hodgkin lymphoma appears to have increased in Canada, as it has in the United States.[5] The cause for this rise is unclear. Burkitt lymphoma is significantly more common in sub-Saharan Africa, where it accounts for approximately one half of childhood cancers. Its incidence also appears to be higher in Latin America, in North Africa, and in the Middle East than in the United States or Europe.

A recent review of pediatric lymphoma from Pakistan was notable for a greater proportion of non-Hodgkin lymphoma (75% of cases) and for a male-to-female ratio of 5.8:1.[6]

Mortality/Morbidity

Rapidly growing or bulky tumors can cause severe metabolic derangement, which may be life threatening. One indicator of the potential for tumor lysis syndrome is an elevated plasma lactate dehydrogenase level or hyperuricemia at the time of diagnosis. The start of effective chemotherapy acutely increases the risk of complications, including hyperkalemia, hyperphosphatemia, hypocalcemia, oliguria, and renal failure.

Other immediate risks depend on the site and extent of involvement. These in turn vary according to the histologic subtype of disease.

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

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

Mediastinal tumors may cause compression of the great vessels (superior vena cava syndrome), with swelling of the neck, face, and upper extremities. Esophageal compression may lead to dysphagia. Pleural effusion is sometimes observed and may be large enough to cause symptoms. In affected individuals, thoracentesis may be both therapeutic and diagnostic, obviating biopsy.

In the United States, most patients with SNCCLs present with abdominal involvement, typically in the ileocecal area and arising from Peyer patches (see image below). A potential complication at the time of diagnosis is bowel obstruction due to direct compression, torsion, or intussusception. Because of bowel perforation, some patients have ascites or present with a clinical picture of acute appendicitis or peritonitis.

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

In equatorial Africa, SNCCL (ie, endemic Burkitt lymphoma) classically appears as a mass in the jaw, nasopharynx, or orbit. These masses grow rapidly and can be disfiguring.

With current treatments, non-Hodgkin lymphomas in most children are apparently curable. The results depend on achieving a precise histologic diagnosis, thorough staging of the disease, and applying complex multiagent (and sometimes multimodal) treatment. The short-term morbidity of chemotherapy regimens is considerable, but the effects are usually manageable. Late effects of treatment are a growing concern, as survival rates are increasing (see Complications).

Race

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

Sex

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

Age

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

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

J Martin Johnston, MD  Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital

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

Disclosure: Nothing to disclose.

Specialty Editor Board

Kathleen M Sakamoto, MD, PhD  Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Co-Associate Program Director of the Signal Transduction Program Area, Jonsson Comprehensive Cancer Center, California Nanosystems Institute and Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, Society for Pediatric Research, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Timothy P Cripe, MD, PhD  Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training, University of Cincinnati College of Medicine

Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Samuel Gross, MD  Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University

Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA  Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

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Incidence of lymphoma as a function of age per 100,000 population. Data are from the Surveillance, Epidemiology, and End Results (SEER) for 1990-1994.
Massive mediastinal T-lymphoblastic lymphoma. Note compression of the left mainstem bronchus and the pulmonary atelectasis.
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 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.
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.
Table 1. Modified LSA2 L2 Therapy in Children's Cancer Group Protocol 552
PhaseDrugRoute
InductionCyclophosphamide, vincristine, daunorubicinIV
Ara-C, methotrexateIT
PrednisonePO
ConsolidationAra-CIV or SC
6-thioguaninePO
MethotrexateIT
L-asparaginaseIM
BCNUIV
PhaseCycleDrugRoute
Maintenance*16-thioguaninePO
CyclophosphamideIV
2HydroxyureaPO
DaunorubicinIV
3MethotrexatePO
BCNUIV
4Ara-CIV or SC
VincristineIV
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.



Table 2. Therapy for Stage III and IV non–B-Cell Disease* According to BFM Protocol 86
PhasesDrugRoute
InductionPrednisone, 6-mercaptopurinePO
Vincristine, daunorubicin, cyclophosphamide, Ara-CIV
L-asparaginaseIM
MethotrexateIT
Consolidation6-mercaptopurinePO
Methotrexate with leucovorin rescueIV
MethotrexateIT
Re-inductionDexamethasone, 6-thioguaninePO
Vincristine, doxorubicin, cyclophosphamide, Ara-CIV
L-asparaginaseIM
MethotrexateIT
Maintenance†6-mercaptopurine, methotrexatePO
Source.—Berlin-Frankfurt-Munster Group.



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



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



† Continued until 24 months after diagnosis.



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



Estimated %



Definition
A10All resected stage I or abdominal stage II tumors
B65Unresected stage I or II tumor, stage III, tumor, or stage IV with no CNS involvement and < 25% marrow blasts
C25CNS involvement or >25% marrow blasts
Table 4. Standard Therapy for Subjects in the International Trial for Patients With SNCCL, Group A*
DrugRoute
PrednisonePO
Vincristine, cyclophosphamide, doxorubicinIV
Filgrastim (G-CSF), to enhance neutrophil recoverySC 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.



Table 5. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group B*
PhaseDrugRoute
ReductionPrednisonePO
Vincristine, cyclophosphamideIV
Methotrexate/hydrocortisoneIT
PhaseCyclesDrugRoute
Induction2, starting 7 d after reductionPrednisonePO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicinIV
Methotrexate/hydrocortisoneIT
Filgrastim (G-CSF)SC or IV
Consolidation2Methotrexate with leucovorin rescue, Ara-C
Methotrexate/hydrocortisone, Ara-C/hydrocortisone
Filgrastim (G-CSF)
Maintenance1PrednisonePO
Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicinIV
Methotrexate/hydrocortisoneIT
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.



Table 6. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group C*
PhaseDrugRoute
ReductionPrednisonePO
Vincristine, cyclophosphamideIV
Methotrexate/Ara-C/hydrocortisoneIT
Induction, cycle 1 starting 7 d after reductionPrednisonePO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicinIV
Methotrexate/Ara-C/hydrocortisoneIT
Filgrastim (G-CSF)SC or IV
Induction, cycle 2PrednisonePO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicinIV
Methotrexate/Ara-C/hydrocortisoneIT
Filgrastim (G-CSF)SC or IV
Consolidation, 2 cycles†High-dose Ara-C, etoposide (VP-16)IV
Filgrastim (G-CSF), days 7-21SC or IV
High-dose methotrexate with leucovorin rescueIV
Methotrexate/Ara-C/hydrocortisoneIT
Maintenance 1PrednisonePO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicinIV
Methotrexate/Ara-C/hydrocortisoneIT
Maintenance 2Ara-C, etoposide (VP-16)IT
Maintenance 3PrednisonePO
Vincristine, cyclophosphamide, doxorubicinIV
Maintenance 4Ara-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.



Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs in All Patients According to the BFM-90 Protocol
DrugRoute
PrednisonePO
CyclophosphamideIV
Methotrexate/Ara-C/prednisoloneIT
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.
Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the BFM-90 Protocol
CycleDrugRoute
AMethotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-CIV
Methotrexate/Ara-C/prednisoloneIT
BDexamethasonePO
Methotrexate with leucovorin rescue, Ara-C, doxorubicinIV
Methotrexate/Ara-C/prednisoloneIT
AADexamethasonePO
Vincristine, high-dose methotrexate with leucovorin rescue, ifosfamide, Ara-C, etoposide (VP-16)IV
Methotrexate/Ara-C/prednisoloneIT
BBDexamethasonePO
Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicinIV
Methotrexate/Ara-C/prednisoloneIT
CCDexamethasonePO
Vindesine, high-dose Ara-C, etoposide (VP-16)IV
Methotrexate/Ara-C/prednisoloneIT
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.
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