Case presentation:

A 52-year old Indonesian Chinese presented with lumps over the axilla, and physical examination showed bilateral axillary lymphadenopathy, tonsillar enlargement and splenomegaly.

Peripheral blood showed leucocytosis. Complete blood counts were: haemoglobin 11.2 g/dL, white cell count 41.5 X 10⁹/L, and platelet count 163 X 10⁹/L. Examination of the blood film (Figure 1) showed circulating immature granulocytes and normoblasts, constituting a leucoerythroblastic blood picture. There is also monocytosis, eosinophilia and basophilia. The differential count was: neutrophils 26%, lymphocytes 7%, monocytes 27%, eosinophils 20% basophils 4%, myelocytes 14% and blasts 2%. Neutrophils showed abnormal nuclear segmentation. Red cells were hypochromic microcytic, compatible with thalassaemia trait. Platelets were normal in number and morphologically unremarkable.

The marrow aspirate yielded markedly hypercellular particles. Myeloid series was hyperplastic showing obvious marrow eosinophilia (20%) (Figure 2). Blasts and promyelocytes accounted for 3% and 4% of all nucleated cells respectively. Erythroid activity was reduced but maturation was normoblastic. Megakaryocytes were increased in numbers and showed some pleomorphism although not frankly dysplastic. Stainable iron was present and ringed sideroblast was not detected.

Trephine biopsy (Figure 3) confirmed the increased cellularity and the hyperplastic myeloid series. Marrow eosinophilia was present
.

Cytogenetics study on bone marrow cells showed a karyotype of 46,XX,t(8;9)(p11;q34)[3]/47,idem,+t(8;9)(p11;q34)[2] (Figure 4). The Ph chromosome was not detected and fluorescence in-situ hybridization analysis did not reveal any cryptic BCR-ABL gene fusion. Therefore this case qualifies for a 8p11 myeloproliferative disorder with t(8;9).

Biopsy of the tonsil (Figure 5) showed tissue infiltration by immature granulocytes admixed with eosinophilic myelocytes. In view of the propensity of these patients to develop T cell malignancies that might coincide with the myeloproliferative process, T cell receptor gene rearrangement study was performed on DNA extracted from tonsillar biopsy using three sets of primers for the TCR g-gene. No clonal rearrangement band was detected.

The patient subsequently sought treatment abroad.

Diagnosis

8p11 myeloproliferative disorder with t(8;9), presenting as atypical chronic myeloid leukaemia

Discussion

Atypical chronic myeloid leukaemia (aCML), as described by the FAB group in 1994 [1], should be considered under the spectrum of chronic myeloid leukaemias and is by definition negative for the Ph chromosome and BCR gene rearrangement. In this condition, there is obvious granulocytic dysplasia, circulating immature granulocytes of 10 - 20%, monocytosis of 3 - 10% and no or borderline basophilia.

More recently, this designation is endorsed by the World Health Organization in the classification of haematopoietic and lymphoid tumours [2]. The characteristic features of aCML, which is considered under myelodysplastic / myeloproliferative diseases, are described as follows:

1. Leucocytosis due to increase in mature and immature granulocytes.
2. Prominent dysgranulopoiesis.
3. No Ph chromosome or BCR-ABL fusion gene.
4. Neutrophilic precursors >= 10% of white cells.
5. No or minimal absolute basophilia.
6. No or minimal absolute monocytosis (monocytes < 10% of white cells).
7. Hypercellular marrow biopsy with granulocytic proliferation and dysplasia.
8. Blasts < 20% in the blood or bone marrow.

On morphological grounds, the present case fits into the diagnostic category of aCML. Cytogenetic abnormalities, including +8, +13, del(20q), i(17q) and del(12p) are found in up to 80% of patients with this disorder, but none is specific. A single case of aCML with t(5;10)(q33;q22), resulting in PDGFbR/D10S170 gene fusion, has been described [3].

Our case is unusual in harbouring the balanced translocation t(8;9)(p11;q34), involving the breakpoint at 8p11. Two distinct syndromes have been associated with 8p11 abnormality:

1. Acute myeloid leukaemia, predominantly acute myelomonocytic and monocytic leukaemia, associated with erythrophagocytosis. These translocations, namely t(8;16)(p11;p13), t(8;14)(p11;q11.1), t(8;19)(p11;q13) and t(8;22)(p11;q13), fuses the MOZ gene at 8p11 to respective partner genes on the other chromosome.

2. Myeloproliferative disorder associated with myeloid hyperplasia, B cell or T cell lymphoblastic leukaemia / lymphoma, peripheral blood eosinophilia, and tendency to progress into acute myeloid leukaemia [4]. Due to multi-lineage involvement, this disorder most probably originates from a haemopoietic stem cell.

The latter condition involves chromosomal translocations including t(6;8)(q27;p11), t(8;9)(p11;q34) and t(8;13)(p11;q12), which fuses the FGFR1 (fibroblast growth factor receptor 1) gene on 8p11 to respective partner genes on the other chromosome. Recently, the fusion partner of FGFR1 gene in t(8;9)(p11;q34) has been cloned [5] and is shown to be the centrosome associated protein CEP110 at 9q34.

In conclusion, our case shows that 8p11 syndrome may present as aCML, and vice versa 8p11 abnormality may be considered a cytogenetic subgroup under the designation of aCML.

References

1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick H, Sultan C, Cox C. The chronic myeloid leukaemias: guideline for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposal by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87: 746 - 754, 1994.
2. Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissue. IARC Press, Lyon, 2001.
3. Kulkarni S, Heath C, Parker S, Chase A, Iqbal S, Pocock CF, Kaeda J, Cwynarski K, Goldman JM, Cross NC. Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorder with a t(5;10)(q33;q21). Cancer Res 60: 3592 - 3598, 2000.
4. MacDonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC. A new proliferative disorder associated with chromosomal translocations involving 8p12: a review. Leukemia 9: 1628 - 1630, 1995.
5. Guasch G, Mack GJ, Popovici C, Dastugue N, Birnbaum D, Rattner JB, Pebusque M-J. FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33). Blood 95: 1788 - 1796, 2000.