Case studies and literature review (Table 1)

Case 1:

A 14-year old boy presented with headache, nausea, vomiting and nose bleeding. Physical examination was unremarkable. Complete blood counts showed: Hb 9.4 g/dL, WBC 32 X 10⁹/L (89% blasts, leucoerythroblastic picture, dysplastic neutrophils), and platelets 35 X 10⁹/L. The marrow was markedly hypercellular showing replacement of normal haemopoietic elements by sheets of blasts (73%) with rather heterogeneous morphology. They were medium to large in size showing variable N:C ratio, round to irregular nucleus, basophilic cytoplasm and prominent round to irregularly shaped vacuoles. Auer rod was not seen. Very occasional blasts showed phagocytosis of other haemopoietic elements. Both erythroid and myeloid activities were reduced and morphologically dysplastic. Micromegakaryocytes were frequently encountered.

Blast cells showed marginal SBB (3%) and negative MPO staining on cytochemistry. Flow cytometric analysis of blast population showed expression of myeloid markers CD33, CD117, CD13 (weak) and anti-MPO (weak). Stem cell antigen CD34 was positive. A diagnosis of acute myeloblastic leukaemia, minimally differentiated, was made. Karyotype showed: 46,XY,t(16;21)(p11;q22)[10] (Figure 1).

The patient was treated with HKPHOSG 1996 protocol and attained complete remission.

Case 2:

A 23-year old man presented with fever and anaemic symptoms. Complete blood counts showed: Hb 7.9 g/dL, WBC 96.8 X 10⁹/L (95% blasts) and platelets 19 X 10⁹/L. The marrow was hypercellular showing 80% blasts and marked depression of normal haemopoietic elements. Myeloid cells of promyelocyte stage and beyond were scarce (5%). The blast cells were medium in size showing fine chromatin, weakly basophilic cytoplasm and scattered azurophilic granules in occasional ones. Auer rod was not seen. The blast population was positive for MPO (12%) and SBB (56%). A diagnosis of acute myeloblastic leukaemia without maturation was made. Karyotype showed: 46,XY,t(16;21)(p11;q22)[10] (Figure 2).

The patient attained complete remission after 7:3 induction and high dose ara-C consolidation. He received an allograft from a HLA-matched sibling and was complicated by severe GVHD that necessitated significant immunosuppression. The clinical course was further complicated by occurrence of post-transplant lymphoproliferative disorder for which he succumbed five months after transplantation.

Case 3:

An 18-year old boy presented with skin infections (boils) and petechiae. Complete blood counts showed: Hb 8.2 g/dL, WBC 44.2 X 10⁹/L (68% blasts, 10% basophils), and platelet 66 X 10⁹/L. The marrow was hypercellular showing an obvious increase in blasts (66%). They were medium to large in size with relatively low N:C ratio, multiple prominent nucleoli and finely granular cytoplasm. Some blasts showed monocytoid features whereas a few others bear strongly basophilic granules. Auer rod was not seen. Granulocytic maturation was evident but dysplastic. There was marrow basophilia (14%). Blast cells were positive for MPO (25%) and SBB (95%) on cytochemistry. A diagnosis of acute myeloblastic leukaemia with maturation was made. Karyotype showed: 46,XY,t(16;21)(p11;q22)[2]/ 46,idem,del(6)(q14q22)[8] (Figure 3).

Discussion

Translocation (16;21)(p11;q22) is a uncommon but recurrent cytogenetic abnormality described in acute myeloid leukaemia (AML) and one case of chronic myeloid leukaemia in blastic crisis. To date, around 30 cases of AML with t(16;21) are reported in the literature. There is a preponderance of young adults (median age at diagnosis = 30) and childhood cases are described. Both sexes are affected equally. Blasts show myeloid or monocytic morphology. Erythrophagocytosis by blast population may be encountered. Bone marrow may show increased eosinophils including abnormal forms. Interestingly most of the reported cases were from Japan and a predilection for Orientals cannot be excluded. While many aspects of this disease remain uncertain, the prognosis seems to be poor. In one study (Kong et al 1997), 18 of the 19 patients died of disease with a median overall survival of 16 months.

This translocation is rarely found as a sole abnormality and most often associated with other numerical or structural abnormalities. The translocation breakpoint in t(16;21)(p11;q22) has been cloned (Ichikawa et al 1994) and involves ERG on chromosome 21 and TLS/FUS on chromosome 16. The translocation results in TLS/FUS-ERG gene fusion and produces a chimeric transcript on der(21). The ERG gene located at 21q22 is a member of the ets oncogene family. The TLS/FUS gene at chromosome 16p11, first identified in myxoid liposarcoma, encodes an RNA-binding protein with extensive amino acid sequence homology to the EWS gene product involved in Ewing's and related tumours. Four isoforms of TLS/FUS-ERG fusion transcript may be identified.

Finally, t(16;21)(p11;q22) must be distinguished from another translocation associated with myeloid disorders, t(16;21)(q24;q22) that involves AML1-MTG16 gene fusion.

References

• Berkowicz M, Rosner E, resnitzky P, Mamon Z, Ben-Bassat I, Ramot B (1990). Acute nonlymphocytic leukemia with t(16;21). Cancer Genet Cytogenet 47:139-140.

• Ferro MR, Cabello P, Garcia-Sagredo JM, Resino M, San Roman C,Larana JG (1992). t(16;21) in a Ph positive CML. Cancer Genet Cytogenet 60:210-211.

• Hiyoshi M, Koh K-R, Yamane T, Tatsumi N (1995). Acute non-lymphoblastic leukemia with t(16;21): case report with a review of the literature. Clin Lab Haem 17:243-246.

• Ichikawa H, Shimizu K, Hayashi Y, Ohki M (1994). An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res 54:2865.

• Kong X-T, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yangagisawa M, Hayashi Y (1997). Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript. Blood 90:1192-1199.

• Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M, Kaneko Y (1993). The 8;21 chromosome translocationin acute myeloid leukemia is always detectable by molecular analysis using AML1. Blood 81:1573-1579.

• Mecucci C, Bosly A, Michaux J-L, Broeckaert-Van Orshoven, Van Den Berghe H (1985). Acute nonolymphoblastic leukemia with bone marrow eosinophilia and structural anomaly of chromosome 16. Cancer Genet Cytogenet 17:359-363.

• Minamihisamatsu M, Ishihara T (1988). Translocation (8;21) and its variants in acute nonlymphocytic leukemia. The relative importance of chromosome 8 and 21 to the genesis of the disease. Cancer Genet Cytogenet 33:161-173.

• Morgan R, Riske CB, Meloni A, Ries CA, Johnson CH, Lemons RS, Sandberg AA (1991). t(16;21)(p11.2;q22): A recurrent primary rearrangement in ANLL. Cancer Genet Cytogenet 53:83-90.

• Sadamori N, Yao E, Tagawa M, Nakamura H, Sasagawa I, Itoyama T, Tokunaga S, Ichimaru M, Nakamura I, Kamei T, Yokoyama Y (1990). 16;21 translocation in acute nonolymphocytic leukemia with abnormal eosinophils: A unique subtype. Acta Haematol 84:212-216.

• Sharma P, Watson N, Robson L, Gallo J, Smith A (1999). Novel chromosome 16 abnormality-der(16)del(16)(q13)t(16;21)(p11.2;q22)-associated with acute myeloid leukemia. Cancer Genet Cytogenet 113:25-28.

• Tamura S, Kanamaru A, Takemoto Y, Kakishita E, Nagai K (1993). Clonal evolution during long-term cultures of bone marrow from de novo acute myeloid leukemia with trilineage myelodysplasia and with myelodysplastic remission marrow. Br J Haematol 84:219-226.