Introduction

Myeloid neoplasms have undergone a revision in their classification that has been recently published by the World Health Organization.¹ The reclassification not only involves morphologic and cytochemical findings but in addition includes genetic, immunophenotypic, prognostic, and clinical features to define specific disorders. A significant difference in this revised classification is the number of blast cells used to define acute myeloid leukemias which has been dropped from 30% to 20% based on prognostic information in people.² The nonlymphoid neoplasms occur less frequently than lymphoid neoplasms but are important to properly recognize and treat accordingly. As a result of its clinical importance, an initiative through the American College of Veterinary Pathologists is underway to evaluate myeloid neoplasms and their relevance to the revised human WHO classification.

Four major categories of myeloid neoplasms are currently recognized in veterinary medicine, similar to human medicine. (Table 1) The most recognized category is that of acute myeloid leukemias. The remaining three categories are: myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, and chronic myeloproliferative diseases. Within the latter category are disease entities that are encountered infrequently and may be problematic to diagnose since they are chronic with subtle abnormalities or misdiagnosed as other myeloid neoplasms.

Table 1. Classification of myeloid neoplasms as currently recognized in veterinary medicine.

Definition and Synonyms

Chronic idiopathic myelofibrosis is a chronic myeloproliferative disease that is often accompanied with an intense fibroblastic reaction of the bone marrow. It has several synonyms, such as agnogenic myeloid metaplasia, osteomyelosclerosis, and chronic megakaryocytic-granulocytic myelosis. Myeloid metaplasia refers to those cases in which neoplastic proliferation occurs from predominately granulocytic and megakaryocytic precursors, with or without marrow fibrosis. Some cases were previously misdiagnosed as acute megakaryoblastic leukemia.

Pathogenesis

This is a true stem cell disease with clonal involvement of myeloid precursors including erythroid, granulocytic, monocytic, and megakaryocytic cells and recently both B and T lymphoid cells have been demonstrated to be clonally affected as well. The stromal bone marrow reaction is considered to be reactive and cytokine mediated. This is based on demonstration of polyclonality in bone marrow fibroblasts in human patients with chronic idiopathic myelofibrosis and increased cellular and extracellular concentrations of transforming growth factor-β (TGF-β), basic fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor. The source of the cytokines is likely both monocytes and megakaryocytes.

Diagnosis

Reported clinical signs associated with chronic idiopathic myelofibrosis include a gradual onset of lethargy, exercise intolerance, inappetence, pale mucous membranes, vomiting, diarrhea, fever, weight loss, and splenomegaly.^3-5 A nonregenerative anemia with poikilocytosis, particularly dacryocytosis (tear-dropped shaped erythrocytes) is present in blood smears. Immature erythroid and granulocyte cells appear in the peripheral blood permitting the first clue in the diagnosis, a condition that is termed leukoerythroblastosis. Dysplastic granulocytes and platelets have been observed in the blood. Leukocyte counts may be variable with leukocytosis or leucopenia. Basophilia is sometimes found. Both thrombocytosis and thrombocytopenia occur in veterinary cases. Significant organomegaly of the spleen and/or liver are commonly observed related to intense extramedullary hematopoiesis. Bone marrow histopathology is necessary to support the diagnosis. Blast cell numbers are less than 30% and have been reported to be less than 20%. Intramedullary megakaryocytopoiesis involving variably sized or polymorphic precursors is commonly found associated with the fibroblastic reaction. These dysplastic dwarf megakaryocytes are usually present in clusters. The bone marrow has various degrees of reticulin and collagen fiber deposition as demonstrated by Gomori's reticulin (argyrophilic) and Masson's trichrome stains of histologic material. Evidence of marrow necrosis may be noted. As a result of the connective tissue deposition, aspiration for cytological examination is frequently difficult, referred to as a dry tap.

Biologic Behavior

The abnormal and increased number of erythroid and granulocytic precursors found in the blood and bone marrow arises from intramedullary and extramedullary hematopoiesis particularly of the spleen and liver. Primary myelofibrosis in this disorder involves the replacement of normal hematopoietic tissue with increased numbers of fibroblasts depositing fine reticulin and thick collagen fibers, in response to cytokines released locally by abnormal megakaryocytes and not secondary to bone marrow damage. Pancytopenia may occur as the disease progresses. In humans, this condition may later evolve into other chronic myeloproliferative diseases or acute myeloid leukemia.

Differential Diagnosis

The main differential diagnosis for primary myelofibrosis is secondary myelofibrosis associated with bone marrow damage and necrosis from conditions such as immune-mediated anemia, marrow neoplasia (lymphoproliferative, myeloproliferative, or metastatic), tumors outside the bone marrow, congenital hemolytic anemia, drug-induced marrow damage, ehrlichiosis, and irradiation.

Treatment

Supportive therapy is often given in the form of blood transfusions along with corticosteroids when immune-mediated origin is suspected. Prednisolone 2-3 mg/kg PO SID for 3-4 weeks, then every other day with tapering of the dose as the anemia resolves. Anabolic steroids may be used e.g., nandrolone decanoate 2 mg/kg IM weekly for 3 weeks, then once every 3 weeks. Azathioprine at 2 mg/kg PO every other day is given if the anemia does not respond to initial treatments.

References

1.  Jaffe ES et al.World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001, 15-107.

2.  Vardiman JW et al. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002; 100: 2292-2302

3.  Weiss DJ and Smith SA. A retrospective study of 19 cases of canine myelofibrosis. J Vet Intern Med 2002; 16: 174-178.

4.  Breuer W et al. Idiopathic myelofibrosis in a cat and in three dogs. Comp Haematol Int 1999; 9: 17-24.

5.  Khan et al. Idiopathic myelofibrosis (agnogenic myeloid metaplasia) in a marmoset (Callithrix jacchus): Hematologic and histopathologic changes. Vet Pathol 1997; 34: 341-345.