Basics
Description
- Non-Hodgkin lymphoma (NHL) arises from the malignant proliferation of developing or mature B or T lymphocytes.
- Extent of disease is determined using the Murphy 's staging system:
- Stage I: single tumor (extranodal) or single nodal area, excluding mediastinum or abdomen
- Stage II: single tumor with regional nodal involvement, 2 or more tumors or nodal areas on the same side of the diaphragm, or a primary GI tract tumor (resected) with or without regional node involvement
- Stage III: tumors or lymph node areas on both sides of the diaphragm, any primary intrathoracic or extensive intra-abdominal disease (unresectable), or any paraspinal or epidural tumors
- Stage IV: bone marrow or CNS disease regardless of other sites; marrow involvement defined as 0.5 " 25% malignant cells
Epidemiology
- 3rd most common childhood malignancy ( ¢ ¼12% cancers in individuals <20 years of age in developed countries)
- Number of cases is increasing in adolescents and young adults.
- Male-to-female ratio: 3:1
Incidence
- 10 " 20 cases per 1 million children/year
- Higher frequency of endemic Burkitt-type in equatorial African countries (10 " 15 per 100,000 children younger than age 5 " 10 years)
- Incidence increases steadily with age; in children, usually seen in 2nd decade of life (unusual in those <3 years of age)
Risk Factors
Environmental factors
- Drugs: immunosuppressive therapy and diphenylhydantoin
- Radiation: atomic bomb survivors and ionizing radiation
- Viruses: Epstein-Barr virus (EBV) present in >95% of cases of endemic Burkitt versus <20% cases of sporadic; HIV
Genetics
Genetic predisposition: increased risk in patients with immunologic defects (e.g., Bruton agammaglobulinemia, ataxia telangiectasia, Wiskott-Aldrich, severe combined immunodeficiency, X-linked lymphoproliferative syndrome [XLP])
Pathophysiology
- Unlike adults, low- and intermediate-grade NHL is uncommon in children ( ¢ ¼7% of cases).
- NHL in children and adolescent can be divided into 3 major categories according to the National Cancer Institute (NCI):
- Mature B-cell NHL (Burkitt and Burkitt-like lymphoma, diffuse large B-cell lymphoma [DLBC], primary mediastinal B-cell lymphoma)
- 50% of childhood NHL
- Express mature B-cell markers (CD20, surface immunoglobulin [Ig])
- Terminal deoxyribonucleotidyl transferase (TdT) negative
- Burkitt lymphoma has characteristic t(8;14), rarely t(8;22) or t(2;8); all chromosomal translocations involve the c-myc proto-oncogene.
- DLBC usually of the germinal center B-cell phenotype. Unlike adults, the t(14:18) translocation is rare.
- Lymphoblastic lymphomas (LL)
- 30% of childhood NHL
- In children, 90% T-cell and 10% B-cell origin
- Morphologically identical to acute lymphoblastic leukemia. TdT positive; express early T (CD5, CD7, cytoplasmic CD3) or B (CD19, CD10) cell markers. Bone marrow involvement of >25% blasts is considered leukemia.
- Early thymic progenitor (ETP) subtype arises earlier in T-cell ontogeny and has a worse prognosis in some studies.
- Anaplastic large cell lymphoma (ALCL) (mature T-cell or null-cell lymphomas):
- 10% of childhood NHL
- Express CD30 (Ki-1)
- Contain chromosomal rearrangement involving the ALK gene (85% t2;5)
- Immunodeficiency-associated NHL usually of B cell origin
Diagnosis
History
- Mature B cell lymphomas
- Systemic manifestation (e.g., fever, weight loss, anorexia, fatigue) if disseminated; less likely if tumor localized
- Abdominal mass with pain, swelling, change in bowel habits, nausea, or vomiting
- Lump in neck unresponsive to antibiotics
- T-cell LL
- Mediastinal mass symptoms include cough, hoarseness, dyspnea, orthopnea and chest pain, anxiety, confusion, lethargy, headache, distorted vision, syncope, and/or a sense of fullness in the ears.
- Marrow involvement: bleeding and/or bruising, bone pain, pallor, fatigue
- B-cell LL
- Tender or painless swelling in neck, axilla, groin or extremities
- Symptoms of marrow involvement
- ALCL
- Painless swelling in neck, axilla, groin
- B type symptoms: fever, night sweats, weight loss
Physical Exam
- Mature B-cell NHL
- Intra-abdominal mass (90%)
- Involving ileocecal region, appendix, ascending colon, or a combination
- Lymphadenopathy may be present in inguinal or iliac region.
- Hepatosplenomegaly may be present.
- Acute abdomen with intussusception, peritonitis, ascites, and acute GI bleeding
- Lymphoma is the most frequent cause of intussusception in children >6 years of age.
- Other sites: testis, unilateral tonsil hypertrophy, peripheral lymph nodes, parotid gland, skin, bone, CNS, and marrow
- In endemic Burkitt lymphoma, jaw tumors are the most frequent. Infants often have orbital involvement.
- Lymphoblastic lymphoma
- T-LL: mediastinal mass (50 " 70%), possibly pleural effusion present with decreased breath sounds, rales, and cough with or without superior vena cava (SVC) syndrome or superior mediastinum syndrome (SMS):
- Signs include swelling, plethora, and cyanosis of the face, neck, and upper extremities; diaphoresis; stridor; and wheezing.
- Lymphadenopathy (50 " 80%); primarily above diaphragm
- Abdominal involvement uncommon: likely to involve only liver, spleen, or kidneys
- Cranial nerve involvement: rare
- B-LL: firm mass in extremity, enlarged LN
- ALCL
- Sites: mediastinum, bone, inguinal nodes, skin
- Bone marrow and CNS involvement: rare at diagnosis
Diagnostic Tests & Interpretation
A diagnosis needs to be made expeditiously, as pediatric lymphomas generally have a rapid growth rate.
- Bone marrow aspirate and biopsy may establish the diagnosis without further testing.
- Fluid from ascites in patients with abdominal disease or pleural fluid should be obtained for cytology, immunophenotyping, and cytogenetics.
- Fine-needle aspirate or biopsy of an enlarged lymph node
Lab
- CBC with differential
- Liver and renal function studies
- Tumor lysis labs: serum lactate dehydrogenase (LDH), potassium, calcium, phosphate, uric acid
- Ascitic, CSF, or pleural fluid
- Cytology
- Immunophenotyping
- Cytogenetics
Imaging
- Abdominal ultrasound
- Chest radiographs: posteroanterior and lateral
- CT scan of chest, abdomen, and pelvis
- PET/CT scan
- MRI (especially for bone involvement)
Diagnostic Procedures/Other
- Adequate surgical biopsy
- Bone marrow aspirate and biopsy
- Lumbar puncture with CSF cytology
Alert
Recumbent positioning, sedation, or positive pressure ventilation may lead to catastrophic respiratory or cardiovascular collapse in patients with partial compromise due to a mediastinal mass. Imaging of airway and consultation with anesthesia, surgeons, and critical care specialists should be obtained prior to any sedation. Procedures may need to be done with local anesthesia only.
Differential Diagnosis
- Abdominal mass (see chapter)
- Newborn: hydronephrosis, renal cysts, Wilms tumor, or neuroblastoma
- Older children: constipation, full bladder, hamartoma, hemangioma, cysts, leukemic or lymphomatous involvement of the liver and/or spleen, Wilms tumor, or neuroblastoma
- Mediastinal mass (see chapter)
- Anterior: masses of thymic origin, teratomas, angiomas, lipomas, or thyroid tumors
- Middle: metastatic or infectious lesions involving the lymph nodes, pericardial or bronchogenic cysts, esophageal lesions, or hernias
- Posterior: neurogenic tumors (e.g., neuroblastoma, ganglioneuroma, neurofibroma), enterogenous cysts, thoracic meningocele, or hernias
Treatment
Medication
- Chemotherapy
- Histology and stage determine therapy
- Because of a high conversion rate of lymphomas to leukemias, prophylactic CNS treatment is given (except in patients with totally excised intra-abdominal tumor).
- Duration: mature B cell lymphomas and ALCL, 1 " 8 months; lymphoblastic lymphomas, 24 months
- Drugs: cyclophosphamide, vincristine, methotrexate (IV and intrathecal [IT]), prednisone, dexamethasone, daunorubicin, asparaginase, cytarabine, thioguanine, hydrocortisone, doxorubicin, mercaptopurine, etoposide, vinblastine
- ALCL: crizotinib (a kinase inhibitor that blocks NPM-ALK fusion protein activity)
- Common side effects: hair loss, myelosuppression with transfusions required, nausea/vomiting
- Immunotherapy
- Rituximab
- A chimeric monoclonal antibody to the CD20 antigen, which is almost universally expressed in B-cell NHL
- Few overlapping side effects with the combination of rituximab and conventional chemotherapeutic agents
- Whether it improves outcome in children is not known.
- Brentuximab vedotin
- Antibody drug conjugate to CD30 that is expressed on all ALCL; currently in clinical trials in children
Additional Therapies
General Measures
A multidisciplinary approach is imperative to ensure the best therapy.
- Prechemotherapy management
- Tumor lysis can be present even before initiation of chemotherapy.
- Allopurinol, hydration, and alkalinization of urine to promote uric acid excretion; may use rasburicase for uric acid >8 mg/dL
- Monitor uric acid, BUN, calcium, creatinine, potassium, and phosphate levels closely.
- Management of relapse
- Relapse indicates extremely poor prognosis.
- No uniform approach to rescue therapy; different chemotherapy combinations may induce a new response.
- For patients with chemosensitive relapse, salvage therapy followed by high-dose therapy with stem cell support
Additional Therapies
Radiotherapy
- Adds no therapeutic benefit in children with limited disease; may be indicated in mediastinal DLBCL
- Used occasionally as emergent treatment for SVC obstruction or CNS or testicular involvement
- Cranial radiotherapy given for CNS-positive children with lymphoblastic lymphoma
- Increases short- and long-term toxicity
Surgery/Other Procedures
- Avoid extensive surgery in patients with NHL.
- Performed in mature B-cell NHL if total resection can be achieved
- Additional indications: intussusception, intestinal perforation, suspected appendicitis, or serious GI bleeding
Ongoing Care
Follow-up Recommendations
- Patient monitoring weekly to monthly with CBC and physical examination
- Radiologic imaging at intervals during and off therapy
Patient Monitoring
Late effects from therapy:
- Cardiomyopathy from anthracyclines
- Impaired reproductive function or infertility from alkylating agents or radiation
- Second malignant neoplasms from etoposide and alkylators
- Psychological consequences of severe illness
Prognosis
- Important prognostic factors for outcome include tumor burden at presentation.
- Favorable
- Stages I and II with primary site head and neck (nonparameningeal), peripheral nodes, or abdomen ( ≥90% 2-year survival)
- Burkitt: >90% 2-year survival
- Less favorable
- Stage III or IV disease; ALCL, LL
- Parameningeal stage II
- Stage IV with CNS involvement
- Incomplete initial remission within 2 months (50 " 80% 2-year survival)
Complications
- Tumor lysis syndrome
- Combination of hyperuricemia, hyperkalemia, and hyperphosphatemia with hypocalcemia, resulting in uric acid nephropathy that leads to renal failure
- GI obstruction, perforation, bleeding, intussusception
- Inferior vena cava obstruction and venous thromboembolism
- Neurologic (e.g., paraplegia, increased intracranial pressure)
- SVC syndrome and SMS: associated with lymphoblastic lymphomas that invade the thymus and nodes surrounding the vena cava and airways
- Massive pleural effusion
- Cardiac tamponade or arrhythmia
Additional Reading
- Abramson SJ, Price AP. Imaging of pediatric lymphomas. Radiol Clin North Am. 2008;46(2):313 " 338. [View Abstract]
- Bollard CM, Lim MS, Gross TG. Children 's Oncology Group 's 2013 blueprint for research: non-Hodgkin lymphoma. Pediatr Blood Cancer. 2013;60(6):979 " 984. [View Abstract]
- Hochberg J, Waxman IM, Kelly KM, et al. Adolescent non-Hodgkin lymphoma and Hodgkin lymphoma: state of the science. Br J Haematol. 2009;144(1):24 " 40. [View Abstract]
- Lones MA, Sanger WG, Le Beau MM, et al. Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children 's Cancer Group Study CCG-E08. J Pediatr Hematol Oncol. 2004;26(3):169 " 178. [View Abstract]
- Pinkerton CR. Continuing challenges in childhood non-Hodgkin 's lymphoma. Br J Haematol. 2005;130(4):480 " 488. [View Abstract]
- Pulte D, Gondos A, Brenner H. Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990 " 2004. J Natl Cancer Inst. 2008;100(18):1301 " 1309. [View Abstract]
Codes
ICD09
- 202.80 Other malignant lymphomas, unspecified site, extranodal and solid organ sites
- 200.20 Burkitt 's tumor or lymphoma, unspecified site, extranodal and solid organ sites
- 200.60 Anaplastic large cell lymphoma, unspecified site, extranodal and solid organ sites
ICD10
- C85.90 Non-Hodgkin lymphoma, unspecified, unspecified site
- C85.10 Unspecified B-cell lymphoma, unspecified site
- C83.70 Burkitt lymphoma, unspecified site
- C84.70 Anaplastic large cell lymphoma, ALK-negative, unsp site
SNOMED
- 118601006 Non-Hodgkin 's lymphoma (disorder)
- 109979007 B-cell lymphoma (disorder)
- 118617000 Burkitt 's lymphoma - disorder
- 277637000 large cell anaplastic lymphoma (disorder)
FAQ
- Q: Did I do something to cause this?
- A: No. Most cases are sporadic and not associated with diet, underlying immune dysfunction, or viral illness.
- Q: Is this contagious?
- A: No. Siblings may have slightly higher inherent risk than the general population, but they are not at risk from the affected child.