Hematopathology Case 03

Final Diagnosis & Discussions:

FINAL DIAGNOSIS: Juvenile myelomonocytic leukemia



Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm/mylodysplastic syndrome occurring with an incidence of 1.2 in 1 million [1]. Initial presentation is usually non-specific and typically includes rash, bleeding, infections, developmental delay, lymphadenopathy and hepatosplenomegaly. Allogeneic bone marrow transplantation has been the most effective therapeutic option with 50% of patients achieving long term survival [1, 2]. Splenectomy may be performed prior transplantation to decrease overall load of leukemic cells. The mortality is most often attributed to disease recurrence and leukemic spread to organs with secondarily induced damage.

The initial diagnosis is challenging due to limited findings on the bone marrow biopsy and broad differential including acute myeloid leukemia, chronic myelomonocytic leukemia and infectious agents such as Epstein-Barr virus, cytomegalovirus, human herpes virus 6, histoplasmosis, and mycobacterial infections [3]. Typically, JMML predominantly affects children less than 3 years of age, whereas chronic myelomonocytic leukemia most often affects an older population. Flow cytometric studies may help to rule out acute leukemia. Additionally, patients with a past medical history of malignancies may be prone to developing adult type myeloproliferative neoplasm or mylodysplastic syndrome, which may also be considered in the differential diagnosis. Ruling out infectious agents is challenging because patients with JMML are predisposed to infections and two processes may be taking place at the same time. Molecular and cytogenetic abnormalities are important diagnostic evidence in cases with prolonged illness and high clinical suspicion.

The 2008 WHO diagnostic criteria include, monocytosis with benign appearance (>1x 109 /L), less than 20% blasts, and no BCR/ABL fusion gene [4]. Additionally, two of the following are required for the diagnosis: increased Hemoglobin F, left shift and nucleated red blood cells in the peripheral blood, white blood cell count >10x109 /L, clonal chromosomal abnormality or GM-CSF hypersensitivity of myeloid progenitors in vitro. Mild decrease in number of megakaryocytes can be seen in a bone marrow biopsy. Typically, there is myeloid hyperplasia with increased myeloid to erythroid ratio. Flow cytometry may help to enumerate monocytes but otherwise shows no diagnostic abnormalities. Immunohistochemical stains for CD68, NSE, or lysozyme, can also be used to highlight population of monocytes, particularly in evaluation of liver or spleen. Molecular analysis has been utilized to support the diagnosis and molecular abnormality can be documented in approximately 85-90% of cases [5]. These include mutation of PTPN11, NRAS and KRAS or NF1 inactivation [5, 6].

A molecular alternation currently thought to be implicated in pathogenesis of JMML is overstimulation of receptor tyrosine kinases leading to myeloid cells proliferation or hyperplasia (Figure 1) [5-6].


  1. Niemeyer, C.M. and C.P. Kratz, Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. British Journal of Haematology, 2008. 140(6): p. 610-624.
  2. Luna-Fineman, S., et al., Myelodysplastic and Myeloproliferative Disorders of Childhood: A Study of 167 Patients. Blood, 1999. 93(2): p. 459-466.
  3. McKenna, R.W., Myelodysplasia and Myeloproliferative Disorders in Children. American Journal of Clinical Pathology. Pathology Patterns Reviews., 2004. 122(Suppl 1): p. S58-S69.
  4. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., Vardiman, J.W, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. 2008, Lyon, France: International Agency for Research on Cancer, p. 82-84.
  5. Loh, M.L., Childhood Myelodysplastic Syndrome: Focus on the Approach to Diagnosis and Treatment of Juvenile Myelomonocytic Leukemia. ASH Education Program Book, 2010. 2010(1): p. 357-362.
  6. Chan, R.J., et al., Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium. Leukemia research, 2009. 33(3): p. 355-362.