Pediatrics

Non-Hodgkins

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Non-Hodgkins Lymphoma? What are the typical findings for this disease?

Pediatric Non-Hodgkins Lymphoma (NHL) includes a group of malignancies arising from lymphoid cells and organs. NHL can affect children at any age. Children generally present with adenopathy and systemic symptoms such as fever and weight loss. NHL can progress very rapidly and must be evaluated and managed urgently.

Pediatric NHL includes Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, Lymphoblastic Lymphoma, Anaplastic Large Cell Lymphoma, and other more unusual lymphomas which should be histologically confirmed prior to treatment whenever possible. Each type of NHL requires different treatment and has variable outcomes. Treatment includes multiagent systemic chemotherapy and central nervous system prophylaxis. Newly diagnosed patients are at high risk for tumor lysis syndrome.

NHL is a diverse collection of malignancies arising from lymphoid cells and organs.

  • B-cell, T-cell, or NK cell origin

  • Differentiated by morphology, flow cytometry, and cytogenetics

  • Typically high grade in children

  • Variety of therapy depending on histologic type

  • Variety of outcomes

Pediatric NHL is distinct from NHL that occur in adults.

  • Different subtypes, staging, biology, treatment, and prognosis

Typical findings:

  1. Painless lymphadenopathy

  2. Abdominal pain or swelling

  3. Breathing problems

  4. Fever

  5. Bleeding

  6. Bruising

  7. Weight loss

Symptoms can progress very rapidly. In general, lymph nodes that are in unusual locations (beyond cervical and inguinal), larger than 2 cm, rapidly increasing in size, or matted together are more concerning for malignancy including NHL.

What subtypes of NHL occur in children?

Mature B-cell orgin

  • Burkitt Lymphoma

  • Diffuse Large B-cell Lymphoma (DLBCL)

  • Primary Mediastinal B-cell Lymphoma

Lymphoblastic Lymphoma

  • Presursor T-cell

  • Precursor B-cell

Anaplastic Large Cell Lymphoma (ALCL)

  • ALK positive

  • ALK negative

Rare Lymphomas in pediatrics

  • Mature (Peripheral) T-cell Lymphoma

  • Follicular Lymphoma

  • Primary cutaneous lymphoma

  • Marginal zone lymphoma (MZL)

  • Nodal MZL

  • Mucosa Associated Lympoid Tumor (MALT) Lymphoma

  • Post transplant Lymphoproliferative Disease (PTLD)

  • Primary Central Nervous System (CNS) Lymphoma

What is the difference between lymphoma and leukemia?

Lymphoma and leukemia arise from the same group of hematopoietic cells.

Defined by percentage of bone marrow involvement at the time of diagnosis.

  1. >25% involvement = leukemia

  2. May not identify biologically different diseases

  3. Frequently treated as the same disease

    • Burkitt Leukemia requires lymphoma-like treatment (similar to Burkitt Lymphoma)

    • Lymphoblastic Lymphoma requires leukemia-like treatment (similar to Lymphoblastic Leukemia)

What other disease/condition shares some of these symptoms?

Infection

  • Lymphadenitis

  • Tuberculosis

  • Histoplasmosis

  • HIV/AIDS

  • Cat Scratch Disease (Bartonella infection)

  • Infectious Mononucleosis (EBV or CMV primary infection)

Rheumatologic Conditions

  • Juvenile Rheumatoid Arthritis

  • Systemic Lupus Erythematosus (SLE)

  • Sarcoidosis

  • Autoimmune Lymphoproliferative Syndrome (ALPS)

Other malignancies

  • Acute Lymphoblastic Leukemia (ALL)

  • Acute Myeloblastic Leukemia (AML)

  • Hodgkin Lymphoma

  • Neuroblastoma

  • Rhabdomyosarcoma

What caused this disease to develop at this time?

  • Rarely known predisposing factors.

  • Family history and past medical history may provide insight to potential etiology.

  • Viral infection may contribute to pathogenesis.

    • EBV

    • HIV

  • Immune compromised states increase risk of NHL

    • Congenital

      • Wiskott-Aldrich syndrome

      • Common variable immune deficiency

      • Ataxia-Telangectasia

      • Bloom syndrome

      • Nijmegen breakage syndrome

    • Acquired

      • HIV infection

      • Solid organ transplant

      • Bone marrow transplant

  • Autoimmune disease

    • Autoimmune lymphoproliferative syndrome

      • Apoptotic defect allowing abnormal lymphocytes to accumulate

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Complete blood count - evaluates bone marrow involvement

    • Anemia

    • Thrombocytopenia

    • Neutropenia

    • Sometimes tumor blast on differential

  • Chemistries - evaluates for tumor lysis syndrome

    • Order sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen (BUN), glucose, calcium, magnesium, phosphorus, uric acid, and lactate dehydrogenase (LDH)

    • Hyperkalemia

    • Hyperphosphatemia

    • Hyperuricemia

    • Renal insufficiency

    • Hypocalcemia (secondary)

    • Elevated LDH

  • Infectious studies - evaluates for alternative diagnosis

    • Order Monospot, EBV titers

    • If febrile: Order blood culture (secondary infection are often found)

    • If HIV risk factors: Order HIV

    • If cat exposure: Order Bartonella titers

    • If TB risk factors: Place PPD

  • Biopsy of suspicious lesion

    • Morphology

    • Flow cytometry

    • Cytogenetics

  • Staging evaluation after diagnosis confirmed

    • Bone marrow aspiration and biopsy

    • Lumbar puncture for CSF cytology

      • Frequently intrathecal chemotherapy administered during this procedure

Would imaging studies be helpful? If so, which ones?

  • Initial studies - lowest radiation exposure and cost

    • Ultrasound of involved lymph node area

    • Ultrasound of abdomen

      • Obtain for abdominal pain and persistent vomiting

      • Evaluate for intussusception or mass lesion

    • Chest X-Ray to evaluate for mediastinal mass

      • Should be completed prior to anesthesia for biopsy procedure

  • Confirmatory studies

    • CT neck, chest, abdomen, pelvis

      • Assess extent of disease

      • Indicated for all patients with highly suspicious adenopathy or biopsy proved Non-Hodgkin Lymphoma.

    • Positron Emission Tomography (PET)/CT - no data currently for using PET for staging

      • Allows identification of active tumor

        • Uptake of FDG-labeled glucose

      • Can be followed for response to therapy - no data currently on prognostic value of response evaluated by PET in pediatric NHL

      • Can be expensive

      • Indicated in the setting of clinical trial for treatment of NHL.

      • May be useful in other clinical scenarios on a case by case basis. Recommend discussion with treating oncologist.

    • Bone scan

      • Identifies metastatic bone sites

      • Useful if primary tumor is not PET-avid

      • Indicated if patient complains of bone pain and bone lesions have not been identified by previous imaging.

    • Gallium scan

      • No longer routinely used (in favor of PET)

  • Echocardiogram useful to assess baseline cardiac function prior to chemotherapy.

How do you stage pediatric Non-Hodgkins Lymphoma?

Ann Arbor staging system (used in adult NHL) not routinely used in pediatric NHL.

-Has not been shown to be prognostically relevant.

Murphy staging system typically used:

-Stage I: One tumor or nodal area. Excludes disease in the mediastinum or abdomen.

-Stage II: One tumor with regional nodal involvement OR 2 or more tumors on the same side of the diaphragm OR primary gastrointestinal tract tumor that is completely resected.

-Stage III: Two or more tumors on opposite sides of the diaphragm OR any intrathoracic tumor OR any unresectable intraabdominal disease OR any paraspinal or epidural disease.

-Stage IV: Involvement of central nervous syndrome or bone marrow.

Confirming the diagnosis

Pathologic evaluation of tumor tissue or cells (blood, marrow, CSF, pleural or ascitic fluid) is required to make the diagnosis.

If you are able to confirm that the patient has Non-Hodgkins Lymphoma, what treatment should be initiated?

  • Immediate management

    • All children suspected of having NHL should be referred to a pediatric oncology specialist.

      • If available, all children should be offered participation in a therapeutic clinical trial.

    • Children with suspected NHL should be admitted to the hospital for rapid evaluation and treatment.

    • Preventative treatment for tumor lysis syndrome should be started immediately.

    • If the patient is febrile or ill-appearing, empiric treatment for infection should be started immediately.

    • Avoid administration of corticosteroids until after diagnosis is confirmed.

  • Disease-directed treatment depends on subtype and stage

    • Typically includes multiagent systemic and intrathecal chemotherapy.

    • Treatment lasts between 2 months and 3 years depending on subtype and stage.

    • Radiation reserved for active CNS disease in lymphoblastic lymphoma patients only.

How is tumor lysis syndrome (TLS) prevented and treated?

Tumor lysis syndrome results from breakdown of tumor cells

  • Laboratory triad of hyperuricemia, hyperphophatemia, and hyperkalemia.

  • Clinical manifestations include renal insufficiency or failure, cardiac dysrhythmia, seizures, or death.

  • Children with NHL are particularly susceptible to TLS

    • Typically have large tumor burden at the time of diagnosis

    • Malignant cells are highly susceptible to chemotherapy

    • Malignant cells have high concentration of phosphorus

All children with suspected NHL should be monitored for possible TLS prior to starting and during initial chemotherapy.

  • TLS can occur spontaneously prior to starting chemotherapy

Hydration

  • Goal is large volume of dilute urine

  • Achieved with IV fluids at two times the maintenance rate with D5 1/2NS adjusted as needed for electrolyte abnormalities.

  • No supplemental potassium unless symptomatic hypokalemia develops

  • No supplemental calcium unless symptomatic hypocalcemia develops

  • Alkalinization of the urine is controversial

    • Typically no longer used for NHL due to treatment with raspuricase and concern for calcium phosphate deposition in the kidneys at high urine pH.

    • If desired, tight control of urine pH between 7 and 8 is necessary to prevent deposition of urate crystals or calcium phosphate in the kidneys

    • Achieved with IV fluids containing HCO3. If aklalinization is desired, start hydration with D5 1/4 NS plus NaHCO3 30mEq/L and titrate NaHCO3 concentration up or down as needed to obtain desired urine pH. Monitoring of urine pH necessary with every void.

Frequent laboratory monitoring for potassium, phosphorus, calcium, uric acid, BUN, and creatinine initially every 6 hours starting prior to chemotherapy. Wean frequency of laboratory monitoring if electrolytes and renal function remain stable.

Uric acid processing

  • Allopurinol

    • Inhibits further uric acid production by inhibiting xanthine oxidase

    • Does not eliminate uric acid already present

    • Dose: 10mg/kg PO or IV divided two times per day

  • Raspuricase

    • Directly breaks down uric acid

    • Considered standard of care in patients at very high risk for TLS

      • Particular tumors: advanced stage Burkett's Lymphoma and DLBCL

      • Renal insufficiency prior to chemotherapy

      • Hyperuricemia prior to chemotherapy

    • Dose: 0.2mg/kg IV once daily while uric acid remains elevated or as per protocol

    • Uric acid must be sent to lab on ice after raspuricase is given.

    • Do not use allpurinol or urine alkalinization with raspuricase.

Modern protocol treated Burkitt lymphoma use a prephase (prophase) of less intense chemotherapy that has greatly reduced incidence of mortality due to TLS in Burkitt lymphoma patients.

How are mature B cell lymphomas treated?

Children with Burkett's Lymphoma and DLBCL are treated with the same protocols.

Mature B-cell lymphomas are divided into three clinical groups.

A: Completely resected stage I tumors or stage II abdominal tumors

B: All other patients without CNS disease and without evidence of leukemia

C: Any CNS disease or bone marrow involvement >25% (leukemia)

Therapy is dependent on the clinical group.

Group A patients have an excellent prognosis with minimal therapy.

  • Typically receive 2 or 3 cycles (6 to 9 weeks) of multiagent chemotherapy.

  • No therapeutic radiation.

  • No maintenance therapy.

Group B patients have an excellent prognosis with more intensive therapy.

  • Typically receive 4 or 5 cycles (4 to 5 months) of multiagent chemotherapy.

  • Increased use of high dose infusional methotrexate compared to Group A.

  • Increased use of prophylactic intrathecal chemotherapy.

Group C patients have a moderate prognosis with more intensive therapy.

  • Typically receive 7 or 8 cycles (approximately 6 months) of multiagent chemotherapy.

  • Increased dose intensity compared to Group A and B.

  • Increased use of high dose infusional methotrexate compared to Group B.

  • Increased use of prophylactic intrathecal chemotherapy compared to Group B.

Rituximab is new agent with potential to improve treatment for mature B-cell NHL.

  • Monoclonal antibody targeted at CD20.

  • Routinely used in some adult patients with NHL.

  • Ongoing pediatric studies address adding rituximab to intensive chemotherapy.

How are lymphoblastic lymphomas treated?

Lymphoblastic lymphomas are treated similarly, often on the same clinical trial, as lymphoblastic leukemia of the same cell type (precursor B-cell or T-cell).

  • Risk stratification is not as well established as for lymphoblastic leukemia

  • Therapy is the same for all stages of disease

Therapy is 2 or 3 years depending on therapeutic protocol.

  • May be longer for boys

Three phases of therapy

  • Remission induction (1 month)

    • Intensive cytoreductive chemotherapy

  • Consolidation (6 to 9 months)

    • Intensive cytoreductive chemotherapy

    • Intensive CNS prophylaxis with intrathecal chemotherapy

    • Cranial radiation typically not indicated - unless there is CNS disease at diagnosis

  • Maintenance (1 to 2 years)

    • Lower dose antimetabolite based chemotherapy

How is anaplastic large cell lymphoma treated?

Treatment is more variable than for other subtypes of pediatric NHL.

Grossly resected low stage disease

  • Typically can be treated with short term pulsed therapy similar to mature B-cell NHL.

  • Isolated cutaneous disease may be able to be treated with surgical resection only if ALK-negative.

Disseminated disease

  • Currently, in the United States, most often treated with APO regimen.

  • Anthracycline, prednisone, and vincristine based chemotherapy

    • 5 weeks of induction therapy

    • 45 weeks of consolidative therapy in 3 week cycles

  • New protocol in the United States will transition to approach more similar to German group.

  • Interest in new agents

    • New anti-CD30 monoclonal antibody

    • Development of specific ALK inhibitor

How is recurrent or refractory NHL treated?

The optimal strategy for how to treat children with recurrent disease or refractory to initial chemotherapy is not clear. As no standard treatment currently exists, all children should be considered for participation in a clinical trial if one is available.

Vineblastine has shown good single agent activity in relapsed ALCL.

Hematopoietic stem cell transplant

  • Should be considered for all patients who achieve remission.

  • Appears to approve event free survival if patient has chemotherapy sensitive disease.

  • Relative benefit of allogenic or autologous transplant is currently unclear.

    • Data suggests that allogenic transplant is preferred for relapsed lymphoblastic lymphoma.

Ongoing clinical trials and laboratory investigations are looking for new agents and therapeutic approaches.

  • Particular interest in investigation into small-molecule inhibitors of intracellular targets.

What are the adverse effects associated with each treatment option?

Tumor Lysis Syndrome

  • See previous section on prevention and treatment of tumor lysis syndrome.

Immediate effects of chemotherapy

  • Common side effects of chemotherapy include nausea/vomiting, alopecia, and hematologic suppression. Hematologic suppression can result in fatigue (anemia), bleeding (thrombocytopenia), and risk for infection (neutropenia).

  • Other short-term effects of these agents include peripheral neuropathy, constipation, mucositis, hypertension, hyperglycemia, allergy, pancreatitis, thrombosis, and seizures.

  • Rituximab treatment is specifically associated with reactivation of latent hepatitis B virus and B-cell depletion requiring IV gammaglobulin replacement in some cases.

Long term effects of chemotherapy

  • Complications of therapy which can occur years after therapy is completed.

  • Highly dependent on exact agent and cumulative dose of agent received.

  • Doxorubicin -- cardiac dysfunction or failure.

  • Cyclophosphamide -- hematuria, electrolyte wasting, secondary malignancy (acute myeloid leukemia, bladder carcinoma).

  • Etoposide -- secondary malignancy (acute meyloid leukemia).

  • Corticosteroids -- osteonecrosis, obesity.

With modern regimens, serious late effects are rare in pediatric NHL survivors.

What are the possible outcomes of Non-Hodgkins Lymphoma?

Overall 80% of children with NHL will have long-term survival from their disease.

Prognosis varies by subtype and stage.

  • With modern chemotherapy including CNS prophylaxis, 5-year event free survival will be approximately:

    • Low-stage Burkitt Lymphoma and DLBCL >95%

    • High-stage Burkitt Lymphoma and DLBCL 90%

    • Lymphoblastic Lymphoma 85%

    • ALCL 75%

The outcome after recurrent disease is currently still very poor.

  • Better for ALCL than other subtypes of NHL.

    • ALCL approximately 60%

    • Burkitt Lymphoma, DLBCL, Lymphoblastic Lymphoma 10%-20%

What causes this disease and how frequent is it?

  • Epidemiology

    • Lymphoma is the third most common type of cancer in childhood and adolescents.

    • NHL accounts for 7% of malignancy in people under the age of 20 in the United States.

      • Burkitt lymphoma is most common childhood NHL 30%-40%

      • Lymphoblastic lymphoma 20%-30%

      • DLBCL 10%

      • ALCL 10%

    • Incidence is variable across geographic regions.

      • In equatorial Africa, Burkitt Lymphoma is the most common childhood cancer (approximately 70%).

    • Incidence increases with age throughout childhood.

    • Incidence is greater in boys than girls (approximately factor of 2).

    • NHL before age 3 is most likely to be associated with congenital immune deficiency.

  • c-myc oncogene rearrangements is seen in all Burkitt lymphoma

    • Required for diagnosis

    • Most common translocation is between c-myc and immunoglobulin heavy chain gene [t(8;14)]

    • Other translocations involving c-myc and immunoglobulin chains also occur

  • ALCL typically involve ALK oncogene expression

    • 90% of pediatric cases

    • t(2;5)

Other clinical manifestations that might help with diagnosis and management

Abdominal presentation

  • NHL can present as an acute abdomen including symptoms consistent with appendicitis, intussusception, or small bowel obstruction.

  • Presentation can be indistinguishable from other cases of appendicitis or intussusception until mass is noted at the time of surgery or on pathology.

Mediastinal mass presentation

  1. NHL can present as superior mediastinal syndrome

    • Airway compression, vena cava compression, cardiac tamponade

    • Symptoms include facial swelling and plethora, syncope, cough or progressive respiratory distress

    • Can be life-threatening

    • Need to obtain diagnosis by quickest and least invasive method possible

  2. In extreme situations, empiric treatment (most commonly with corticosteroids) may be indicated prior to obtaining tissue for pathology.

Are additional laboratory studies available; even some that are not widely available?

N/A

How can Non-Hodgkins Lymphoma be prevented?

There are no known preventive strategies for pediatric NHL.

What is the evidence?

Gross, TG, AM Termuhlen. "Pediatric Non-Hodgkin's Lymphoma". Current Oncology Reports. vol. 9. 2007. pp. 459-465..

(This is an overview of pediatric NHL focusing on the differences from adult and pediatric disease and discussing in detail current recommendations for treatment for common pediatric subtypes.)

Howard, SC, Jones, DP, Pui, C. "The Tumor Lysis Syndrome". New England Journal of Medicine. vol. 364. 2011. pp. 1844-54..

(This is a review of the biology, definition, and management of tumor lysis syndrome written from the pediatric perspective. TLS is an important complication during early treatment for NHL that may need to be recognized and managed by non-oncology physicians.)

Link, MP, Shuster, JJ, Donaldson, SS. "Treatment of children and young adults with early-stage non-Hodgkin's lymphoma". New England Journal of Medicine,. vol. 337. 1997. pp. 1259-66..

(This article presents the rational for currently recommended treatment approaches for pediatric patients with low stage NHL stressing that minimal therapy is likely to be adequate for disease control with few late effects. This article demonstrates no benefit of radiation to tumor sites. This article also reviews the important finding that lymphoblastic lymphoma requires longer therapy similar to lymphoblastic leukemia.)

Laver, JH, Kraveka, JM, Hutchison, RE. "Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial". Journal of Clinical Oncology. vol. 23. 2005. pp. 541-547..

(This article presents the results of the most recent United States therapeutic trial for ALCL. The results suggest that the addition of methotrexate and cytarabine does not improve results when compared to standard chemotherapy with APO regimen.)

Gross, TG, Hale, GA, He, W. "Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents". Biology of Blood and Marrow Transplant. vol. 16. 2010. pp. 223-30..

(This study reviewed all stem cell transplants for refractory or recurrent pediatric NHL that were reported to the Center for International Blood and Marrow Transplant Research. Data on 182 transplants worldwide was reviewed for transplant characteristics and outcomes. Transplant appears to be an effective salvage therapy for relapsed and refractory NHL.)

Mahadevan, D, Fisher, RI. "Novel Therapeutics for Aggressive Non-Hodgkin's Lymphoma". Journal of Clinical Oncology,. vol. 29. 2011. pp. 1876-1884.

(This is a review of the development of new targeted therapeutic agents for NHL focusing on potential small-molecule inhibitors of intracelluar targets. These approaches may be relevant to both children and adults with NHL particularly those with relapsed or refractory disease.)

"Childhood Non-Hodgkin Lymphoma Treatment, Physician Data Query, National Cancer Institute,". http://www.cancer.gov/cancertopics/pdq/treatment/child-non-hodgkins/HealthProfessional.

(This is a website maintained by the National Cancer Institute to provide up-to-date information on pediatric NHL and its treatment written for both patients and health professionals. Information on this site is updated monthly by national experts in the field.)

Ongoing controversies regarding etiology, diagnosis, treatment

Clinical trials to optimally treat pediatric NHL are ongoing through the Children's Oncology Group and other international pediatric oncology cooperative groups. Work continues on better risk stratification, development on new chemotherapy agents and strategies particularly for recurrent or refractory disease, and minimization of long-term effects of therapy.

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