Case Files Pediatrics, (LANGE Case Files) 4th Ed.

CASE 17

A mother brings her previously healthy 6-year-old son to your clinic because he has been limping and complaining of left leg and knee pain for 1 week. He has experienced no recent trauma, and his past medical history is unremarkable. His physical examination reveals a temperature of 100°F (37.8°C) orally with no lower extremity swelling, misalignment, or weakness. He has tenderness over the right knee, hepatosplenomegaly, and petechiae on his cheeks and chest.

Image What is the most likely diagnosis?

Image What is the next step in the evaluation?

ANSWERS TO CASE 17: Acute Lymphoblastic Leukemia

Summary: A 6-year-old boy with a 1-week history of leg pain and limping. He has a low-grade fever, hepatosplenomegaly, and petechiae on his face and chest.

• Most likely diagnosis: Acute lymphoblastic leukemia (ALL).

• Next step in the evaluation: Complete blood count with platelets and differential.

ANALYSIS

Objectives

1. Describe the clinical manifestations of ALL.

2. Describe the laboratory and radiologic tests used in diagnosing ALL.

3. Know the treatment plan for a child with newly diagnosed ALL.

4. Understand the long-term survival and follow-up issues for children with ALL.

Considerations

This patient has several manifestations of ALL, including leg and joint pain, fever, petechiae, and hepatosplenomegaly. Most of the signs and symptoms of ALL result from either replacement of normal bone marrow components with clonal proliferation of a single lymphoblast that has undergone malignant transformation, or from infiltrates of extramedullary sites by these malignant lymphoid cells. Rapid diagnosis and referral to a pediatric cancer center can increase survival.

APPROACH TO:

Acute Lymphoblastic Leukemia

DEFINITIONS

EXTRAMEDULLARY: Areas of the body outside of the bone marrow.

LYMPHOBLAST: A large, primitive, undifferentiated precursor cell not normally seen in the peripheral circulation.

GRANULOCYTOPENIA: A reduction in total circulating leukocytes.

PANCYTOPENIA: A reduction in circulating erythrocytes, leukocytes, and platelets.

THROMBOCYTOPENIA: A reduction in circulating platelets.

CLINICAL APPROACH

Leukemia is the most common childhood cancer, accounting for approximately 40% of all pediatric malignancies. Acute lymphoblastic leukemia affects the lymphoid cell lineand comprises approximately 75% of leukemia cases in children. Acute myeloblastic leukemia (AML) affects the myeloid cell line (granulocytes, monocytes, and can affect erythrocytes or megakaryocytes) and comprises approximately 20% of childhood leukemia. The clinical manifestations of AML and ALL are similar. In the United States, childhood ALL has a peak incidence at age 2 to 4 years and occurs more frequently in boys. Children with certain chromosomal abnormalities, such as Down syndrome and Fanconi anemia, have an increased risk of ALL.

ALL is often called the “great imitator” because of its nonspecific symptoms, including anorexia, irritability, lethargy, pallor, bleeding, petechiae, leg and joint pain, and fever. A physical examination includes the child’s general appearance and energy level, vital signs (note if antipyretics taken), bleeding, bruising, petechiae, pallor, pain upon palpating bones or joints, and hepatosplenomegaly. Differential diagnoses include idiopathic thrombocytopenic purpura (ITP), aplastic anemia, mononucleosis, juvenile rheumatoid arthritis, and leukemoid reaction:

• Idiopathic thrombocytopenic purpura is a common cause of bruising and petechiae because of low platelet levels; however, anemia, leukocyte disturbances, and hepatosplenomegaly are absent.

• Aplastic anemia causes pancytopenia and fever; lymphadenopathy, arthralgias, bone pain, and hepatosplenomegaly are unusual findings.

• Children with infectious mononucleosis (ie, Epstein-Barr virus [EB virus]) or other acute viral illnesses may present with fever, malaise, adenopathy, splenomegaly, and lymphocytosis. Atypical lymphocytes resembling leukemic lymphoblasts are characteristic of these viral illnesses.

• Leukemoid reactions may be observed in bacterial sepsis, pertussis, acute hemolysis, granulomatous disease, and vasculitis. The leukemoid reaction resolves as the underlying disease is treated.

Children with ALL who present with fever, arthralgias, arthritis, or a limp frequently are diagnosed initially with juvenile rheumatoid arthritis (JRA). Anemia, leukocytosis, and mild splenomegaly may also be seen in JRA, causing even more confusion. A bone marrow examination may be required to differentiate ALL from other diagnoses.

Infiltration of the marrow by other types of malignant cells (neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma) occasionally produces pancytopenia. These tumor cells usually are found in clumps in the normal marrow but occasionally replace the marrow completely.

Almost half of the children with newly diagnosed leukemia have total leukocyte counts less than 10,000/mm3. Leukemic blasts may not be seen in the peripheral blood smear. Therefore, the diagnosis of leukemia is established by examination of bone marrow, most commonly aspirated from the posterior iliac crest.

A normal marrow contains less than 5% blasts; a minimum of 25% blasts confirms the diagnosis. Approximately two-thirds of children with ALL have leukemic cell karyotypic abnormalities, including changes in chromosome number (ie, hypodiploidy or hyperdiploidy) or chromosome structure (translocation, deletions, inversions).

A variety of markers can help gauge prognosis. In general, girls have a better prognosis. African-American and Hispanic populations historically have lower remission and higher relapse rates,although newer studies suggest this might be due to factors other than race. Children with ALL who are younger than 1 year and those who are older than 10 years of age have a worse prognosis. Higher leukocyte counts, especially if higher than 50,000/mm3, have an unfavorable prognosis. Patients with T-cell immunophenotype typically have a worse outcome than those with B-precursor ALL. The karyotypes of leukemic cells have diagnostic, prognostic, and therapeutic significance. Patients with hyperdiploidy generally have a more favorable prognosis; those with hypodiploidy and pseudodiploidy do less well. Translocations with a poor outcome include t(9;22) (Philadelphia chromosome) in patients with pre-B ALL, and t(4;11) seen in infants with AML.

Workup includes a lumbar puncture to examine the central nervous system (CNS) for early leukemic involvement; a higher number of blasts in the cerebro-spinal fluid is associated with a worse prognosis. A chest radiograph is performed to detect a mediastinal mass. Bone radiographs may show altered medullary trabeculation, cortical defects, or transverse radiolucent lines; these radiologic findings lack prognostic significance and usually are unnecessary.

Combination chemotherapy is the principal therapy. The therapy involves several phases: remission induction, CNS therapy, consolidation and intensification, and maintenance. Induction therapy, a combination of prednisone, vincristine, and asparaginase, produces remission within 4 weeks in approximately 98% of children with non–high-risk ALL. Intrathecal therapy (± craniospinal irradiation) has decreased the incidence of CNS leukemia as a primary site of relapse from 50% to approximately 3% to 6%. Consolidation treatment, aimed at further reducing residual leukemia, delivers multiple chemotherapies in a relatively short period of time. Maintenance therapy with methotrexate and 6-mercaptopurine, vincristine, and prednisone is given for 2 to 3 years to prevent relapse; therapy is discontinued for children who remain in complete remission for 2 to 3 years.

The 5-year survival rate for childhood ALL has steadily improved over the last 40 years and now is greater than 80%. Late effects to be considered include neuropsychological deficits, seizures, and endocrine disturbances (ie, growth hormone deficiency) related to CNS prophylaxis; spermatogenesis dysfunction related to cyclophosphamide; delayed sexual maturation in boys who received irradiation of gonadal tissue due to leukemic invasion of the testes; leukoencephalopathy and neurodevelopmental problems (especially in post–CNS radiation patients); and secondary malignancies.

COMPREHENSION QUESTIONS

17.1 A mother brings her 3-year-old son with Down syndrome to the clinic because his gums have been bleeding for 1 week. She reports that he has been less energetic than usual. Examination reveals that the child has an oral temperature of 100°F (37.8°C), pallor, splenomegaly, gingival bleeding, and bruises on the lower extremities. Which of the following is most likely?

A. Aplastic anemia

B. Idiopathic thrombocytopenic purpura (ITP)

C. Leukemia

D. Leukemoid reaction

E. Megaloblastic anemia

17.2 A father brings to the clinic his 6-year-old son who currently is undergoing induction chemotherapy for ALL. The school will not allow the child to register until his immunizations are up-to-date. Which of the following is the best course of action?

A. Call the school nurse or principal to inform him or her that this child should not receive immunizations while he is taking chemotherapy.

B. Update all immunizations except for measles-mumps-rubella (MMR) and varicella.

C. Update all immunizations except for oral polio vaccine.

D. Update all immunizations.

E. Call the school nurse or principal to inform him or her that this child will never receive immunizations because of the alteration in his immune system.

17.3 A mother brings to the clinic her 4-year-old son who began complaining of right knee pain 2 weeks ago, is limping slightly, is fatigued, and has had a fever to 100.4°F (38°C). Which of the following laboratory tests is most important?

A. Antinuclear antibodies

B. Complete blood count (CBC) with differential and platelets

C. Epstein-Barr virus titer

D. Rheumatoid factor

E. Sedimentation rate

17.4 Two weeks after a viral syndrome, a 2-year-old develops bruising and generalized petechiae that is more prominent over the legs. He has neither hepatosplenomegaly nor lymph node enlargement. Laboratory testing reveals a normal hemoglobin, hematocrit, and white blood cell count and differential. The platelet count is 15,000/mm3. Which of the following is the most likely diagnosis?

A. Acute lymphoblastic leukemia

B. Aplastic anemia

C. Immune thrombocytopenic purpura

D. Thrombotic thrombocytopenic purpura

E. von Willebrand disease

ANSWERS

17.1 C. A high susceptibility to leukemia is associated with certain heritable diseases (Klinefelter syndrome, Bloom syndrome, Fanconi syndrome, ataxia telangiectasia, neurofibromatosis) and chromosomal disorders such as Down syndrome. Children with Down syndrome have a 10- to 15-fold increased risk for developing leukemia. Siblings of an ALL patient have a two- to fourfold increased risk for ALL, and the monozygotic twin of a child who develops ALL in the first year of life has a >70% chance of also developing ALL. A few cases of ALL are associated with p53 gene aberrations. Overall, these genetic links account for a small number of total ALL cases.

17.2 A. Live virus vaccines are contraindicated for the child with ALL (and all members of the household) during chemotherapy and for at least 6 months after completion of treatment. Although the viruses in the vaccine are attenuated, immunosuppression from treatment can be profound and viral disease can result. Immunizations without live virus (diphtheria, tetanus, inactivated poliovirus vaccine, hepatitis A and B) are not absolutely contraindicated in this case, but the immunosuppression with chemotherapy often inhibits antibody responses.

17.3 B. This child has symptoms consistent with both JRA and leukemia. The CBC with differential and platelets is the best initial screening test. The leukocyte and platelet counts are normal to increased in JRA, and no blast cells are present. Frequently, blast cells are found on the peripheral smear with ALL. The child in the question ultimately may require a bone marrow aspiration.

17.4 C. Immune (or idiopathic) thrombocytopenic purpura (ITP) is common in children. In most cases, a preceding viral infection can be documented. The platelet count frequently is less than 20,000/mm3, but other laboratory test results are normal, including the bone marrow aspiration (which may show an increase in megakaryocytes). Treatment consists of observation or possibly intravenous immunoglobulin (IVIG), intravenous anti-D (in Rh-positive patients), immunosuppressives, or steroids. The history must be reviewed for other possible causes of thrombocytopenia, including recent MMR vaccination, drug ingestion, and human immunodeficiency virus.


CLINICAL PEARLS

Image Leukemias are the most common childhood cancers, and acute lymphoblastic leukemia (ALL) represents approximately 75% of all leukemia cases in children.

Image Acute lymphoblastic leukemia has a peak incidence at the age of 2 to 4 years, and boys are affected more frequently.

Image Acute lymphoblastic leukemia is often called the “great imitator” because of its nonspecific symptoms of anorexia, irritability, lethargy, pallor, bleeding, petechiae, leg and joint pain, and fever.

Image Combination chemotherapy is the principal therapy for childhood acute lymphoblastic leukemia. Induction therapy produces remission within 4 weeks in approximately 98% of children with average-risk acute lymphoblastic leukemia.


REFERENCES

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Mahoney DH. Acute lymphoblastic leukemia. In: McMillan JA, Feigin RD, DeAngelis CD, Jones MD, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:1750-1758.

Maloney K, Foreman NK, et al. Neoplastic disease. In: Hay WW, Levin MJ, Sondheimer JM, Deter-ding RR, eds. Current Diagnosis & Treatment Pediatrics. 20th ed. New York, NY: McGraw-Hill; 2011:882-885.

Nachman JB. Acute lymphoblastic leukemia. In: Rudolph CD, Rudolph AM, Lister GE, First LR, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:1620-1625.

Neunert CE, Yee DL. Immune thrombocytopenic purpura (ITP). In: Rudolph CD, Rudolph AM, Lister GE, First LR, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:1582-1583.

Tubergen DT, Bleyer A, Ritchey AK. The leukemias. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, and Behrman RE, eds. Nelson Textbook of Pediatrics, 19th ed. Philadelphia, PA: Elsevier; 2011:1732-1737.

Wallace CA, Cabral DA, Sundel RP. Juvenile idiopathic arthritis. In: Rudolph CD, Rudolph AM, Lister GE, First LR, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:800-806.