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

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


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]


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.

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