Pediatric Acute Myelocytic Leukemia Workup
- Author: Mark E Weinblatt, MD; Chief Editor: Jennifer Reikes Willert, MD more...
Imaging studies are not required for the diagnosis of acute myeloid leukemia in children or evaluation of the disease’s extent in these patients. Such studies, however, can be helpful in managing complications that arise.
Blood Counts and Blood Smears
The hallmark of acute myeloid leukemia is a reduction or absence of normal hematopoietic elements. Anemia is usually normocytic, with a reticulocyte count lower than expected for the level of the hemoglobin. The decrease in hemoglobin levels can range from minimal to profound.
Platelet counts are usually low and generally commensurate with the degree of bleeding. Patients with spontaneous petechiae usually have platelet counts of less than 20 X 109/L (< 20,000/μL).
WBC counts may be decreased or elevated. Hyperleukocytosis with WBC counts of more than 100 X 109/L (>100,000/μL) are occasionally observed; with high numbers, the blood specimen appears white. The WBC differential is usually the key to evaluating suspected leukemia; primitive granulocyte or monocyte precursors are observed on peripheral smears. Numbers of mature neutrophils are usually diminished.
Upon careful examination of the blood smears, Auer rods (thin, needle-shaped, eosinophilic cytoplasmic inclusions) are revealed in specimens of circulating blood obtained from many patients acute myelocytic leukemia. They are particularly prominent in children with APL.
Blood Chemistries and Other Blood Work
Serum uric acid and lactic dehydrogenase levels are frequently elevated as a consequence of increased cell proliferation and destruction.
Serum muramidase (lysozyme) levels are usually increased in patients with monocytic leukemias.
Other signs of tumor lysis, including hyperkalemia, hypocalcemia, and lactic acidosis, may be present.
Blood and urine cultures should always be obtained in a child with fever and leukemia.
Coagulation tests should also be performed during initial diagnosis to look for evidence of disseminated intravascular coagulation that might suggest APL.
Routine chest radiography should be performed to rule out mediastinal masses, particularly in patients with respiratory symptoms or suspected superior vena cava syndrome.
If the patient has abdominal pain and distention, abdominal images often depict free air suggestive of a perforation.
Radiographic examination of the extremities may reveal findings such as metaphyseal bands at the distal femurs (most commonly observed in young children with ALL), periosteal new bone formation, focal lytic lesions, or pathologic fractures.
CT Scanning and MRI
If the patient has abdominal pain and possible infection of the large bowel, computed tomography (CT) scanning may reveal thickening and edema of the bowel wall suggestive of typhlitis.
If a patient has neurologic symptoms, CT scanning or magnetic resonance imaging (MRI) of the head, spine, or other involved region is mandatory to rule out intracranial hemorrhage or infiltrative disease.
CT scanning may also allow early detection of asymptomatic sinusitis that might cause persistent, unexplained fevers.
Because serious infections that affect heart function are routinely observed in this patient population, periodic cardiac monitoring is important.
Perform echocardiography before chemotherapy and periodically when high cumulative doses of anthracyclines are administered.
Most treatment regimens include anthracyclines, such as daunomycin and idarubicin, which may cause clinically significant cardiomyopathy.
Radionuclide imaging is often used to detect occult infection that cultures and other imaging modalities do not reveal. For example, technetium-99m (99m Tc) bone scans often help in localizing an occult osteomyelitis.
Whole-body gallium or indium scanning often reveals an occult deep-tissue infection and can help with appropriate antibiotic management.
In addition to standard Wright-Giemsa stains, histochemical stains help in differentiating the various acute leukemias. Positive periodic acid-Schiff stains indicate acute biphenotypic leukemia or undifferentiated leukemia with lymphoblastic features. Most acute myeloid leukemia cells have strong positive reactions to myeloperoxidase and Sudan black stains. Esterase stain findings usually help in differentiating myeloid (specific esterase positive) from monocytic (nonspecific esterase positive) leukemia.
Monoclonal antibodies specific for different cell lineages and stages of development are routinely used to further characterize the leukemic cells. The most common myeloid markers are CD13, CD14, CD15, and CD33, with more than 90% of leukemic cells demonstrating positivity to some of these antigens. CD34 is frequently found in acute myeloid leukemia blasts.
Analysis of the chromosome changes in the leukemic cell is often performed to confirm the diagnosis and for prognostic purposes. If patients have the 9;22 translocation, this would indicate an underlying chronic myelogenous leukemia that would necessitate treatment with tyrosine kinase inhibitors and possibly stem cell transplantation. FLT3 would likewise be an important prognostic marker.
Human leukocyte antigen (HLA)–matched family donors should be identified because bone marrow transplantation (or hematopoietic stem cell transplantation) may be considered in high-risk patients.
At the time of diagnosis, the donor screening process should be started by obtaining blood for HLA matching from the patient and immediate family members.
Bone Marrow Examination
Bone marrow examination is necessary to establish the diagnosis of acute myeloid leukemia. The sample is examined under the microscope, at which time the percentage of different cells is tabulated. The hallmark of leukemia is the presence of a high proportion of primitive cells and a paucity of normal hematopoietic elements.
Bone marrow aspirates and biopsy samples demonstrate the characteristic replacement of normal marrow elements with the monotonous sheets of leukemic blasts.
The preferred site for retrieving marrow is the iliac crest, either anterior or posterior. The tibia may be an alternative source of marrow for diagnostic purposes in infants, although it is rarely required as a preferred site. In rare cases, a sternal biopsy is necessary; this can sometimes be required in children with extensive marrow fibrosis. The sternal site is generally more painful and entails the risk of heart damage if the needle penetrates deeply beyond the sternal bone.
Although bone marrow aspiration is usually sufficient to establish the diagnosis and to follow up on the progress of the disease, a core biopsy may be necessary if one encounters a "dry tap." This can happen when a marrow is heavily infiltrated or when significant fibrosis of the bone marrow is present.
Biopsy is necessary to gauge the cellularity of a marrow specimen and was the former standard during follow-up to aid subsequent therapeutic decisions. However, biopsy is now less commonly used, since the disease status can usually be evaluated with marrow aspirations and immunologic and cytogenetic testing.
Bone marrow examination usually reveals characteristic hyperplastic marrow with monotonous replacement with leukemia cells.
Patients with low blast count t(8;21) can also present a diagnostic challenge, sometimes considered a myelodysplastic syndrome, and often require multiple marrow examinations before the diagnosis of leukemia is confirmed. Other patients with myelodysplasia have less than 20% of blast cells, megaloblastic features, and a decrease in the normal hematopoietic cell population.
Pronounced fibrosis is often observed, particularly in the acute megakaryoblastic subtype (M7).
Lumbar Puncture and Cerebrospinal Fluid Examination
Lumbar puncture is necessary for diagnostic and therapeutic reasons.
Even if the marrow is not involved at the time of diagnosis, CNS seeding can occur later. Therefore, periodic surveillance lumbar puncture with the administration of intrathecal chemotherapy is necessary.
Although the cerebrospinal fluid (CSF) is less frequently involved in acute myeloid leukemia than in ALL, leukemic infiltration has been reported in 5-20% of patients with acute myeloid leukemia, depending on the study. The greatest risk is seen in patients with monocytic subtypes, in infants, and in children with hyperleukocytosis on presentation.
CSF samples should be obtained before any therapy is begun. Fluid should be sent for cytologic evaluation in addition to the usual cell counts and chemical tests.
Intrathecal chemotherapy is administered simultaneously and repeated intermittently to treat or prevent CNS involvement.
Gurney JG, Ross JA, Wall DA, Bleyer WA, Severson RK, Robison LL. Infant cancer in the U.S.: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol Oncol. 1997 Sep-Oct. 19(5):428-32. [Medline].
Bhatia S, Neglia JP. Epidemiology of childhood acute myelogenous leukemia. J Pediatr Hematol Oncol. 1995 May. 17(2):94-100. [Medline].
Matasar MJ, Ritchie EK, Consedine N, Magai C, Neugut AI. Incidence rates of acute promyelocytic leukemia among Hispanics, blacks, Asians, and non-Hispanic whites in the United States. Eur J Cancer Prev. 2006 Aug. 15(4):367-70. [Medline].
[Guideline] Tomizawa D, Tabuchi K, Kinoshita A, Hanada R, Kigasawa H, Tsukimoto I, et al. Repetitive cycles of high-dose cytarabine are effective for childhood acute myeloid leukemia: long-term outcome of the children with AML treated on two consecutive trials of Tokyo Children's Cancer Study Group. Pediatr Blood Cancer. 2007 Aug. 49(2):127-32. [Medline].
Imamura T, Iwamoto S, Kanai R, Shimada A, Terui K, Osugi Y, et al. Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia Study. Br J Haematol. 2012 Aug 28. [Medline].
Gamis AS, Woods WG, Alonzo TA, Buxton A, Lange B, Barnard DR, et al. Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol. 2003 Sep 15. 21(18):3415-22. [Medline].
Ortega JJ, Madero L, Martín G, Verdeguer A, García P, Parody R, et al. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol. 2005 Oct 20. 23(30):7632-40. [Medline].
Klco JM, Miller CA, Griffith M, et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. JAMA. 2015 Aug 25. 314 (8):811-22. [Medline].
[Guideline] Children's Oncology Group. Chemotherapy. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Mar 2006.
Harding A. One-third cure rate in first-ever pediatric relapsed AML trial. Medscape Medical News. January 18, 2013. Available at http://www.medscape.com/viewarticle/777872. Accessed: January 28, 2013.
Kaspers GJ, Zimmermann M, Reinhardt D, et al. Improved Outcome in Pediatric Relapsed Acute Myeloid Leukemia: Results of a Randomized Trial on Liposomal Daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Jan 14. [Medline].
Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L, et al. Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials. Br J Haematol. 2003 Jul. 122(2):217-25. [Medline].
Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009 Feb 26. 113(9):1875-91. [Medline].
[Guideline] Children's Oncology Group. Hematopoetic cell transplant. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Mar 2006.
Klingebiel T, Reinhardt D, Bader P. Place of HSCT in treatment of childhood AML. Bone Marrow Transplant. 2008 Oct. 42 Suppl 2:S7-9. [Medline].
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Jan 29. [Medline]. [Full Text].
Bucaneve G, Micozzi A, Menichetti F, Martino P, Dionisi MS, Martinelli G, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005 Sep 8. 353(10):977-87. [Medline].
Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, Graf N, et al. Randomized trial comparing liposomal daunorubicin with idarubicin in induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood. 2013 May 23. [Medline].
Johnson K. Less cardiotoxicity in pediatric AML. Medscape Medical News. May 30, 2013. [Full Text].