Pediatric Non-Hodgkin Lymphoma Clinical Presentation

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

History

  • The presentation of patients with non-Hodgkin lymphoma (NHL) is acute or subacute, in contrast to the indolent course that characterizes most lymphomas in adults.
  • The duration of symptoms before diagnosis is generally one month or shorter.
  • Specific complaints vary and depend on the predominant sites of involvement.
  • Constitutional symptoms are uncommon, except in patients with anaplastic large cell lymphomas (LCLs). Many of these patients have low-grade fever, malaise, anorexia, and/or weight loss.
  • LCLs are biologically disparate. As a result, these lesions have a varied presentation that may include chest or abdominal complications. In rare cases, an LCL appears as an isolated bone lesion in association with pain, swelling, and a risk of pathologic fracture.
  • Bone marrow involvement may cause generalized or migratory bone pain. However, in individuals with non-Hodgkin lymphoma, clinically significant cytopenias are uncommon, and their presence suggests a diagnosis of acute leukemia.
  • Localized disease can manifest as lymphadenopathy (usually with firmness and no tenderness), tonsillar hypertrophy, or a mass in virtually any location. However, in children, non-Hodgkin lymphoma is primarily an extranodal disease.
  • Patients with supradiaphragmatic disease (eg, lymphoblastic lymphoma) often report having a nonproductive cough, dyspnea, chest pain, and dysphagia.
  • Abdominal tumors (usually small noncleaved cell lymphoma [SNCCLs] or B-cell LCLs) are associated with abdominal pain, constipation, masses, or ascites. An acute abdomen occasionally is observed and may be mistaken for appendicitis. Rare primary non-Hodgkin lymphoma of the pancreas presents with the clinical picture of pancreatitis.[7]
  • Patients with anaplastic LCLs sometimes present with painful skin lesions, bone lesions, peripheral lymphadenopathy, and hepatosplenomegaly.[8, 9] The painful skin lesions may regress spontaneously. A finding less common than these is testicular, lung, or muscle involvement.
  • Anaplastic LCLs may also result in an apparent cytokine storm, with fevers, vascular leakage, and pancytopenia.
  • Patients occasionally develop symptomatic CNS involvement before diagnosis. Headache, meningismus, cranial nerve palsies, and altered sensorium may be observed. Although CNS involvement is uncommon at the time of diagnosis, patients with non-Hodgkin lymphoma (particularly SNCCL) occasionally present with symptoms suggestive of meningoencephalitis.
  • Among the less common lymphomas of childhood, primary cutaneous/subcutaneous involvement can be seen (eg, cutaneous T-cell lymphoma, blastic plasmacytoid dendritic cell hematodermic neoplasm).
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Physical

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

In developed countries, most individuals with non-Hodgkin lymphoma have no known etiology or association.

Epidemiologic data suggest that certain human leukocyte antigen (HLA) types, and even certain blood types, may increase or decrease the likelihood of developing non-Hodgkin lymphoma.[10, 11] Findings from several epidemiologic studies suggest that pesticide exposure may play a role in the development of adult non-Hodgkin lymphoma; the case for its involvement in childhood non-Hodgkin lymphoma is less compelling than the case for adults, but this is still under investigation.[12, 13]

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

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

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

Immunosuppression and viral infection

Immunosuppressed individuals, such as those with HIV infection or those who have undergone bone marrow transplantation, are at increased risk for developing non-Hodgkin lymphoma, particularly SNCCL and LCL of B-cell origin. The Epstein-Barr virus, which causes B-cell proliferation and in vitro immortalization, has been implicated in most of these lymphomas. Primary CNS lymphoma is more common in these patients than in others.

Previous Hodgkin disease

Patients successfully treated for Hodgkin disease are at increased risk for developing non-Hodgkin lymphoma. This effect appears to reflect the combined effects of chemotherapy and radiotherapy, as well as the immunosuppressive effects of Hodgkin disease. Adults older than 40 years who received combined-modality therapy are at particular risk; their 15-year incidence of non-Hodgkin lymphoma is as high as 39%.[17]

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

Secondary non-Hodgkin lymphoma is less common among pediatric patients who survive cancer than among adults.

A cohort of 5484 children was treated for various malignancies at St Jude Children's Research Hospital. Over 30,710 person-years of follow-up care, only 3 had secondary non-Hodgkin lymphoma. The 15-year actuarial risk of non-Hodgkin lymphoma was 0.16% in this group.

However, even among children, patients treated for Hodgkin disease are particularly at risk. In 1991, a literature review revealed 24 incidents of secondary non-Hodgkin lymphoma among patients whose primary malignancy had been diagnosed when they were younger than 20 years. Eighteen (75%) of the patients previously had Hodgkin disease.[19]

Geographic location

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

In addition, exposure to 4-deoxyphorbol ester from the plant Euphorbia tirucalli (by means of goat's milk) is tentatively implicated in the pathogenesis of endemic Burkitt lymphoma.[20, 21]

Genetic causes

The genetic basis of pediatric non-Hodgkin lymphoma has been studied extensively.[22] Each subtype of non-Hodgkin lymphoma is characterized by 1 or more molecular alterations that contribute to the malignant phenotype. Many of these alterations are chromosomal translocations involving genes for immunoglobulin or T-cell receptor (TCR) molecules. During normal lymphocyte development, these loci undergo recombination that enhances immunologic diversification. However, mistargeted recombination leads to translocations with other genes, typically those that regulate cell growth. The resulting dysregulation of these other genes contributes to the transformed phenotype.

For example, the hallmark of Burkitt lymphoma is a t(8;14)(q24;q32) translocation, which is observed in approximately 80% of patients. This translocation juxtaposes c-myc, which encodes a transcription factor important in initiation of the cell cycle, with the locus for the immunoglobulin heavy chain. In a relatively uncommon alteration, c-myc is adjoined to the gene encoding the immunoglobulin kappa light chain [t(2;8)(p11;q24)] or the lambda light chain [t(8;22)(q24;q11)]. In all 3 instances, the result is aberrant expression of the c-MYC protein under the influence of regulatory sequences of immunoglobulin genes. This aberration contributes to the pathogenesis of Burkitt lymphoma.[23]

Aside from the t(8;14) translocation, Burkitt lymphoma frequently involves a gain of chromosomal material that can affect any of a number of chromosomes. Abnormalities of chromosomal arms 1q, 7q, or 13q may portend a poor prognosis.[24, 23]

A small portion of T-lymphoblastic lymphomas are also associated with translocations involving 1 of the TCR loci: TCR alpha delta (14q11) or TCR beta (7q34). The most common example (observed in 7% of children with T-lymphoblastic lymphomas) is the t(11;14)(p13;q11) translocation, which enhances expression of the LMO2 gene on chromosome 11. This gene encodes LIM protein, an apparent modulator of gene transcription. A more common abnormality than this, one observed in approximately 25% of patients with T-lymphoblastic lymphoma/T-cell acute lymphoblastic lymphoma (ALL), is a deletion in a regulatory region of the gene TAL1. This deletion, which is too small to be detected with conventional cytogenetic techniques, leads to aberrant expression of Tal-1, another transcriptional regulator.

Inactivation of the multiple tumor suppressor gene 1 (MTS-1/p16INK4 alpha/CDKN2) on chromosome 16 has been identified as a common genetic event in T-cell ALL; its frequency in T-lymphoblastic lymphoma is likely to be a significant factor. Of interest, the deletions or disruptions responsible for this inactivation are apparently related to illegitimate activity of the same V(D)J recombinase that mediates recombination of the TCR gene.[25] Thus, even in the absence of a TCR translocation, similar molecular mechanisms may be responsible for disrupting other genes involved in normal control of the cell cycle.

Some B-lineage LCLs have the same t(8;14)(q24;q32) translocation observed in Burkitt lymphoma. Compared with adults with B-LCL, this appears to be more common in children and may portend a worse prognosis.[26] Alternatively, most anaplastic (T-lineage) LCLs in children involve a t(2;5)(p23;q35) translocation. This change joins the nucleophosmin gene (NPM) on chromosome 5 to a gene called anaplastic lymphoma kinase (ALK) on chromosome 2 and allows for the expression of an NPM/ALK fusion protein p80. Transcripts of NPM/ALK are also observed in about 20% of individuals with non-Hodgkin lymphoma lacking cytogenetic evidence of t(2;5); this finding reflects an occult or variant translocation.[27] Patients with non-Hodgkin lymphomas expressing p80 may have a survival advantage over patients whose lymphomas lack p80.[28]

For additional reading, see Childhood Cancer, Genetics.

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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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