Pediatric Non-Hodgkin Lymphoma
- Author: J Martin Johnston, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...
Background
Lymphomas are malignant neoplasms of lymphoid lineage. Broadly classified as either Hodgkin disease (Hodgkin's disease) or as non-Hodgkin lymphoma (NHL), lymphomas are clinically, pathologically, and biologically distinct.[1, 2]
According to the National Cancer Institute (NCI) formulation, most childhood non-Hodgkin lymphomas can be classified as one of the following types:
- Lymphoblastic lymphomas
- Small noncleaved cell lymphomas (SNCCLs), or Burkitt lymphomas (Burkittlike lymphomas) (non-Burkitt lymphomas)
- Large cell lymphomas (LCLs)
In recent years, B-cell LCLs and anaplastic (usually T-cell) LCLs (ie, Ki-1+ lymphomas) have come to be viewed as distinct entities. In this article, these categories are considered separately. Other, less common forms of childhood lymphoma (some of which are much more common in adults) are not discussed.
Since the late 1960s, treatment outcomes for children with non-Hodgkin lymphoma have steadily improved. Even for patients with advanced disease, event-free survival rates are now 65-90%.
The mainstay of conventional therapy is multiagent chemotherapy tailored to the histologic subtype and the clinical stage of disease. In certain individuals with non-Hodgkin lymphoma, surgical resection and radiation therapy are also key components of definitive treatment. Newer therapies that target immunologic and biologic aspects of the lymphoma are still under development but beginning to appear in the clinical arena.
Pathophysiology
Most malignancies arise as disease localized in the organ or tissue of origin. They may then secondarily spread by means of local extension or distant metastases. In contrast, non-Hodgkin lymphoma is best regarded as a systemic disease because of the unique anatomy of the lymphoid system and because of the physiology of lymphoid cells, which tend to migrate whether they are normal or malignant. The role of lymphoma stem cells in the genesis and maintenance of B cell lymphomas remains speculative.[3]
Childhood non-Hodgkin lymphoma generally manifests as bulky extramedullary (usually extranodal) disease with or without demonstrable dissemination. The distinction between non-Hodgkin lymphoma and acute leukemia is arbitrary. Therefore, these entities are best considered in terms of a spectrum ranging from clinically localized disease to overt leukemia.
In most treatment protocols, acute leukemia is now defined on the basis of marrow involvement above some threshold (typically, a blast count of >25%) irrespective of the presence of bulky extramedullary disease. In contrast, an extramedullary tumor accompanied by marrow involvement below this threshold constitutes stage 4 lymphoma.
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. 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 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 100,000 population. Data are from the Surveillance, Epidemiology, and End Results (SEER) for 1990-1994. Shad A, Magrath I. Malignant non-Hodgkin's lymphomas in children. In: Principles and Practice of Pediatric Oncology. 1997:545-87.
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- Table 1. Modified LSA2 L2 Therapy in Children's Cancer Group Protocol 552
- Table 2. Therapy for Stage III and IV non–B-Cell Disease* According to BFM Protocol 86
- Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961)
- Table 4. Standard Therapy for Subjects in the International Trial for Patients With SNCCL, Group A*
- Table 5. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group B*
- Table 6. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group C*
- Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs in All Patients According to the BFM-90 Protocol
- Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the BFM-90 Protocol
| 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. | |||
| Phases | Drug | Route |
| Induction | Prednisone, 6-mercaptopurine | PO |
| Vincristine, daunorubicin, cyclophosphamide, Ara-C | IV | |
| L-asparaginase | IM | |
| Methotrexate | IT | |
| Consolidation | 6-mercaptopurine | PO |
| Methotrexate with leucovorin rescue | IV | |
| Methotrexate | IT | |
| Re-induction | Dexamethasone, 6-thioguanine | PO |
| Vincristine, doxorubicin, cyclophosphamide, Ara-C | IV | |
| L-asparaginase | IM | |
| Methotrexate | IT | |
| Maintenance† | 6-mercaptopurine, methotrexate | PO |
| Source.—Berlin-Frankfurt-Munster Group. Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous. * Diagnoses included lymphoblastic lymphoma of the T-cell or precursor B-cell type, immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients with Ki-1+ anaplastic LCLs were not included. † Continued until 24 months after diagnosis. | ||
| Clinical Group | Subjects, Estimated % | Definition |
| A | 10 | All resected stage I or abdominal stage II tumors |
| B | 65 | Unresected stage I or II tumor, stage III, tumor, or stage IV with no CNS involvement and < 25% marrow blasts |
| C | 25 | CNS involvement or >25% marrow blasts |
| 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. | |
| Phase | Drug | Route | |
| Reduction | Prednisone | PO | |
| Vincristine, cyclophosphamide | IV | ||
| Methotrexate/hydrocortisone | IT | ||
| Phase | Cycles | Drug | Route |
| Induction | 2, starting 7 d after reduction | Prednisone | PO |
| Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin | IV | ||
| Methotrexate/hydrocortisone | IT | ||
| Filgrastim (G-CSF) | SC or IV | ||
| Consolidation | 2 | Methotrexate with leucovorin rescue, Ara-C | |
| Methotrexate/hydrocortisone, Ara-C/hydrocortisone | |||
| Filgrastim (G-CSF) | |||
| Maintenance | 1 | Prednisone | PO |
| Vincristine, methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin | IV | ||
| Methotrexate/hydrocortisone | IT | ||
| Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous. * See Table 3 for the definition of group B. | |||
| Phase | Drug | Route | |
| Reduction | Prednisone | PO | |
| Vincristine, cyclophosphamide | IV | ||
| Methotrexate/Ara-C/hydrocortisone | IT | ||
| Induction, cycle 1 starting 7 d after reduction | Prednisone | PO | |
| Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin | IV | ||
| Methotrexate/Ara-C/hydrocortisone | IT | ||
| Filgrastim (G-CSF) | SC or IV | ||
| Induction, cycle 2 | Prednisone | PO | |
| Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin | IV | ||
| Methotrexate/Ara-C/hydrocortisone | IT | ||
| Filgrastim (G-CSF) | SC or IV | ||
| Consolidation, 2 cycles† | High-dose Ara-C, etoposide (VP-16) | IV | |
| Filgrastim (G-CSF), days 7-21 | SC or IV | ||
| High-dose methotrexate with leucovorin rescue | IV | ||
| Methotrexate/Ara-C/hydrocortisone | IT | ||
| Maintenance 1 | Prednisone | PO | |
| Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin | IV | ||
| Methotrexate/Ara-C/hydrocortisone | IT | ||
| Maintenance 2 | Ara-C, etoposide (VP-16) | IT | |
| Maintenance 3 | Prednisone | PO | |
| Vincristine, cyclophosphamide, doxorubicin | IV | ||
| Maintenance 4 | Ara-C, etoposide (VP-16) | IV | |
| Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous. * See Table 3 for the definition of group C. † For patients with CNS involvement, during consolidation cycle 1 only. | |||
| Drug | Route |
| Prednisone | PO |
| Cyclophosphamide | IV |
| Methotrexate/Ara-C/prednisolone | IT |
| Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral. | |
| Cycle | Drug | Route |
| A | Methotrexate with leucovorin rescue, ifosfamide, etoposide (VP-16), Ara-C | IV |
| Methotrexate/Ara-C/prednisolone | IT | |
| B | Dexamethasone | PO |
| Methotrexate with leucovorin rescue, Ara-C, doxorubicin | IV | |
| Methotrexate/Ara-C/prednisolone | IT | |
| AA | Dexamethasone | PO |
| Vincristine, high-dose methotrexate with leucovorin rescue, ifosfamide, Ara-C, etoposide (VP-16) | IV | |
| Methotrexate/Ara-C/prednisolone | IT | |
| BB | Dexamethasone | PO |
| Vincristine, high-dose methotrexate with leucovorin rescue, cyclophosphamide, doxorubicin | IV | |
| Methotrexate/Ara-C/prednisolone | IT | |
| CC | Dexamethasone | PO |
| Vindesine, high-dose Ara-C, etoposide (VP-16) | IV | |
| Methotrexate/Ara-C/prednisolone | IT | |
| Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral. | ||

