Final Diagnosis -- Simultaneous Hematolymphoid Disorders

DIAGNOSES AND DISCUSSION

The peripheral blood and bone marrow findings are most concerning for a chronic myeloproliferative syndrome, such as polycythemia vera. Although a specific diagnosis could not be rendered based on the bone marrow findings at the time of examination, the most worrisome findings included the rare circulating blasts and the prominent morphologic abnormalities of the megakaryocytes, along with erythrocytosis, panmyelosis, and moderate reticulin fibrosis. The iron stain performed on the bone marrow aspirate was negative for iron stores, and so iron-deficiency was suggested as an explanation for the patient's microcytosis. Follow-up examination after iron repletion was also recommended.

The histologic and flow cytometric findings in the excised left axillary lymph node are diagnostic of precursor T-lymphoblastic lymphoma. The diagnostic features include lymphoblast-like morphology and the characteristic immunophenotype, with expression of TdT and numerous T-cell-associated antigens. There was no evidence of this population of T-lymphoblasts in the bone marrow, by morphology or flow cytometry.

This patient has concurrent diagnoses of precursor T-lymphoblastic lymphoma and a probable myeloproliferative syndrome, along with the balanced translocation between the short arm of chromosome 8 and the long arm of chromosome 13. These findings, together with peripheral blood eosinophilia, are best explained by what has been referred to as 8p11 myeloproliferative syndrome (EMS) or stem cell leukemia-lymphoma syndrome (SCLL). EMS is a distinct hematologic disorder characterized by myeloid hyperplasia, eosinophilia, and lymphoblastic lymphoma.^{1, 2} The myeloid hyperplasia is characterized by overproduction of myeloid cells that retain the capacity to differentiate. The myeloproliferative component of the syndrome tends to progress to acute myeloid leukemia within 1 to 2 years of diagnosis.¹ About 70% of patients present with or develop high-grade non-Hodgkin's lymphoblastic lymphoma, predominantly of a primitive T-cell phenotype.³

Translocations described in this syndrome involve fusion of the tyrosine kinase domain of the FGFR1 gene to another gene. In the t(8;13)(p11;q12), as was shown in the bone marrow of this patient, the FGFR1 gene is fused to the ZNF198 gene, resulting in constitutive tyrosine kinase activation. ^{4, 5} Six distinct fusions involving FGFR1 have been identified in association with this syndrome. The partner genes (ZNF198, FOP, CEP110, BCR, HERV-K, and FGFR1OP2) are believed to promote dimerization and ligand-independent activation of the FGFR1 tyrosine kinase, deregulating hematopoiesis in a manner analogous to BCR-ABL.⁶ The different fusions are associated with different disease phenotypes. Most patients with t(8;13), the most commonly associated translocation, present with or develop T-cell non-Hodgkin's lymphoma in addition to having a myeloproliferative disorder, as was the case with this patient.⁷ Where reported, the same clonal karyotypic abnormality is seen in both the lymphoma and myeloid cells, suggesting a common lymphoid/myeloid stem cell as the target for the original transforming event.⁸ Consistent with this hypothesis, the disease cannot be eradicated by chemotherapy alone, although there is a potential for cure with allogeneic bone marrow transplantation.⁹

This patient's translocation has not been characterized further by molecular studies in order to identify the patient's fusion gene. It would be of interest to study the patient's precursor T-lymphoblastic lymphoma for the presence of the translocation. However, the constellation of clinical findings, together with the characteristic translocation, t(8;13)(p11;q12), are consistent with this distinctive clonal stem cell disorder, and suggest an aggressive disease course and probable need for allogeneic stem cell transplantation.

REFERENCES

1. Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC. A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review. Leukemia. 1995;9:1628-30.
2. Inhorn RC, Aster JC, Roach SA et al. A syndrome of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia/malignancy associated with t(8;13)(p11;q11): description of a distinctive clinicopathologic entity. Blood. 1995;85:1881-7.
3. Roumiantsev S, Krause DS, Neumann CA et al. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. Cancer Cell. 2004;5:287-98.
4. Smedley D, Demiroglu A, Abdul-Rauf M et al. ANF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5. Neoplasia. 1999;1:349-55.
5. Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D, Pebusque MJ. Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation. J Biol Chem. 1999;274:26922-30.
6. Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 2002;16:1207-12.
7. Walz C, Chase A, Schoch C et al. The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1. Leukemia. 2005;19:1005-9.
8. Reiter A, Sohal J, Kulkarni S et al. Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome. Blood. 1998;92:1735-42.
9. Macdonald D, Reiter A, Cross NC. The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol. 2002;107:101-7.

Contributed by Beth Z Clark, MD, Sara A Monaghan, M.D., Sarangarajan Ranganathan, MD and Lydia Contis, MD