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Pediatric Non-Hodgkin
Lymphoma
Updated: Feb 06, 2017
Author: J Martin Johnston, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...
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 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
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]
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]
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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]
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
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genes, typically those that regulate cell growth. The resulting dysregulation of these other genes
contributes to the transformed phenotype.
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.
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]
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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] :
Leukemias - 4.5
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.
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
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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.
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
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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.
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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]
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.)
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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 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.)
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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.
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.
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Clinical Presentation
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