Myelofribrosis and myelodysplasia in the dog and cat

MYELOFIBROSIS

Myeolofibrosis (Fig. 1) is characterized by the progressive replacement of haematopoietic tissue with connective tissue. The condition may be:

1. PRIMARY: chronic idiopathic myelofibrosis
2. SECONDARY

1. Chronic idiopathic myelofibrosis is a rare clonal disorder of haematopoietic cells the aetiology of which is unknown. It is characterized by bone marrow fibrosis, myeloid metaplasia with extramedullary haematopoiesis and splenomegaly. Fibroblasts do not belong to the neoplastic clone. The fibrosis is accompanied by an increased production of transforming growth factor β (TGF-β) and thrombopoietin by megacaryocytes and/or platelets.

The initial stages of the disorder are characterized by hyperplasia of the three haematopoietic lineages, with a particular increase in the megakaryocyte component. The progression of the disorder is accompanied by a reduction in cellularity, in view of the substitution of haematopoietic lacunae with fibrous tissue. In advanced stages of myelofibrosis the cellularity of bone  marrow  cytology is from scarce to absent (punctio sicca).

Anaemia is typically present in peripheral blood smears, with morphological alterations caused by bone marrow dysplasia (dacryocytes, elliptocytes and nucleated red blood cells). Myeloid and erythroid precursors may be found in circulation (leucoerythroblastosis)). The platelet and leukocyte count is variable and a marked splenomegaly is present.

2. Secondary myelofibrosis is a  bone  marrow  disorder characterized by the proliferation of fibroblasts, collagen and reticulin fibres within the haematopoietic spaces. The condition is relatively frequent, 4.2% in the dog and 9% in the cat. It is associated with a moderate to severe nonregenerative anaemia and less frequently with leucopenia and thrombocytopenia. In the dog, myelofibrosis has been associated with immune mediated haemolytic anaemia (IMHA), acute leukaemia/lymphoma (myelophthisis), nonhaematopietic tumours, pharmacological treatments (e.g. phenobarbital, phenylbutazone) and exposure to radiation.

In the cat, the most likely causes of myeolofibrosis are myelodisplasia, acute myeloid leukaemia, immune mediated haemolytic anaemia, FIP and chronic renalfailure.

It has been hypothesized that fibrosis may be the result of an acute bone marrow damage, the expression of a reparative event similar to what happens in other tissues; bone marrow fibrosis is in fact often associated with conditions of sub-acute/chronic bone marrow necrosis (Fig. 2). Chronic inflammation may be the cause of myelofibrosis via the release of fibrogenic cytokines (TGF-β, platelet-derived GF, epidermal GF) from megakaryocytes and macrophages. In case of early removal of the triggering factors the fibrosis may be reversible.

MYELODYSPLASIA

Myelodysplasia is a condition characterized by the anomalous development of haematopoietic cells, with consequent morphological atypia and/or alterations in cell number, with associated severe peripheral cytopaenia. The paradoxical nature of myelodysplasia is evidenced by the presence of bone marrow hypercellularity combined with peripheral cytopaenia caused by ineffective haematopoiesis  (Fig. 3). Blasts are usually not present in the peripheral blood, if not in small percentages; in the  bone marrow, even when increased, they never exceed 20% of total nucleated cells, a percentage necessary for the diagnosis of acute myeloid leukaemia (AML).

Myelodysplasia may be classified as follows:

• primary dysplasia: MYELODYSPLASIA or PRIMARY MYELODYSPLASTIC SYNDROME (MDS)
• secondary dysplasia: MYELODYSPLASIA or SECONDARY MDS or DYSMYELOPOIESIS
• CONGENITAL MYELODYSPLASIA.

Primary myelodysplasia consists in a group of acquired haematological clonal disorders consequent to a mutation of haematopoietic cells. The bone marrow is hypercellular, with dysplastic morphological alterations associated with multiple episodes of cytopaenia, which result from a combination of defects in the development, differentiation and increased apoptosis of haematopoietic cells. The condition is considered preleukaemic.

In human medicine, the current classification of primary MDS is based on the WHO (World Health Organization) classification system, which combines the existing morphological characteristics with information on cytogenetics, molecular genetics and on immunological markers in order to allow for a more accurate prognostic assessment:

• refractory anaemia (RA)
• refractory anaemia with ring  sideroblasts (RARS)
• refractory cytopaenia with multilineage dysplasia (RCMD)
• RA with excess of blasts (5-10%) [RAEB I]
• RA with excess of blasts (10-20%) [RAEB II]
• MDS with isolated chromosome 5q abnormality
• nonclassifiable MDS
• acute myeloid leukaemia (blasts >20%)

The WHO classification system has been adjusted to veterinary medicine. In veterinary literature, two recent retrospective clinical trials have specifically used the WHO classification for bone marrow cytology in both the dog and cat.

The clinical characteristics of primary MDS in the dog and cat have been summarized in tables 1 and 2.

With regard to signs of dysplasia involving the erythroid lineage it is possible to identify the presence of megaloblasts (nuclear:cytoplasmic asynchrony) (Fig. 4), binucleation and nuclear  fragmentation (Fig. 5). Sideroblasts are in fact metarubricytes containing iron deposits in perinuclear position.

Myeloid dysplasia may manifest itself with maturation asynchrony, giant metamyelocytes, small size myeloblasts and promyelocytes, ringed nuclei (Fig. 6) and nuclear hypersegmentation (Fig. 7).

Dismegakariopoiesis includes characteristics such as maturation asynchrony and cell types with hypolobulated or dispersed nuclei.

  Table 1. Primary myelodysplasia in the dog (4%)

Table 2. Primary myelodysplasia in the cat (11,6%)

In FeLV+ cats a clonal origin of MDS has been documented. Scientific publications report that in FeLV+ cats MDS is a pathological manifestation resulting from a clonal proliferation of haematopoietic cells and can be considered as a preleukaemic stage of AML.

Peripheral blood cytopaenia is a common finding in FeLV+ cats; the virus, in particular, induces severe myelosuppression, which is the frequent cause of macrocytic ANAEMIA (especially in subgroup C). This important haematological alteration results from the fact that:

• the virus blocks erythroid precursors, interfering with the transduction signal which regulates erythropoiesis;
• a dysfunction in the support function of stromal cells is present;
• T helper cells are inhibited from promoting erythroid differentiation.

In the dog, myelodysplasia is considered as primary in the absence of concomitant disorders and of exposure to toxic agents or drugs.

With regard to therapeutic strategies, the following options are available as palliative care:

• chemotherapeutic agents(hydroxyurea, cytosine arabinoside, cyclophosphamide);
• supportive therapy (antibiotics, transfusions);
• growth factors (CSF-GF, EPO).

Bonemarrow transplantation could clearly be a resolutive therapeutic option.

With regard to prognosis, in the presence of RAEB a progression into AML has been reported in 25% of described cases, with variable survival times ranging from days to months; in the presence of RA survival times vary from months to years.

Secondary myelodysplasia consists of a collection of non-clonal haematologic disorders associated with a variety of conditions which include specific pathological processes (e.g. infectious disorders, tumours and immune disorders), the administration of drugs (chemotherapeutic agents, extrogens, phenobarbital) and exposure to heavy metals (lead, zinc). Bone marrow cytology ranges from normo- to hypercellular, with variable dysplastic morphological alterations combined with mono or multiple cytopaenia. The underlying mechanism of action is typically immune mediated, supported by chronic inflammation.

In the cat, FIV is among the causes of secondary MDS, with the additional common finding of peripheral cytopaenia, and more commonly of neutropenia. Such cytopaenia is the consequence of the integration of the virus within haematopoietic and stromal cells, with secondary myelosuppression, myelodysplastic alterations and immune mediated destruction of infected and non-infected cells. The above-mentioned mechanisms overlap with those reported for HIV, in which a clonal mutation of haematopoietic cells (HIV myelopathy) is excluded.

Scientific publications report that morphology alone does not allow to distinguish primary from secondary myelodysplastic syndromes. Particularly in the dog, haematological alterations typical of non-neoplastic syndromes of ineffective haematopoiesis are common in the presence of primary myelodysplastic syndromes.

With regard to therapy, when possible it is indispensable to remove the cause  (ex. phenobarbital, hyperoestrogenism, etc.). It is then possible to start with an immunosuppressive therapy (corticosteroids, cyclosporine) combined possibly with support therapy (antibiotics, transfusions) and growth factors (CSF-GF, EPO). Removal of the cause and an immunosuppressive therapy usually allow for the resolution of the clinical condition.

CONGENITAL MYELODYSPLASIA mainly includes:

• Poodle macrocytosis;
• dyserythropoiesis, polymyopathy and cardiomyopathy of English Springer Spaniels;
• macrocytosis of the Giant Schnauzer due to selective congenital malabsorption of vitamin B₁₂ (cobalamin).

In Poodle macrocytosis the peripheral blood smear is characterized by the presence of macrocytosis, Howell-Jolly bodies (at times multiple) and nucleated erythroid cells (metarubricytes), occasionally with signs of dysplasia caused by an asynchronous nucleus:cytoplasm ratio (megaloblastosis); a potential neutropenia and neutrophylic hypersegmentation is also present. Concomitantly, bone marrow cytology is characterized by megaloblastosis associated with atypical mitosis, binucleation, abnormal nuclear forms of the erytrhoid series as well as by some giant metamyelocytes. The abnormal concentration of vitamin B12 and folates has not been reported.

With reference to English Springer Spaniels, three cases have been described with the presence of diserythropoiesis, polymyopathy associated with megaesophagus and cardiomegaly. Dogs present a non-regenerative, mild to moderate normochromic microcytic anaemia associated with marked metarubricytosis. Peripheral alterations of erythrocyte morphology include spherocytes, schistocytes, dacryocytes and codocytes. Marked erythroid hyperplasia and dyserythropoiesis are present in the bone marrow (e.g. atypical mitosis, binucleation). The prevalence, aetiology and the underlying pathogenetic mechanisms are still unknown.

Subjects with congenital vitamin B12 malabsorption develop a chronic normochromic normocytic anaemia with poikilocytosis, neutropenia with nuclear hypersegmentation and megaloblastic alterations of the bone marrow, accompanied by reduced serum concentrations of cobalamin.

Suggested readings

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3. Holland CT [21], Canfield PJ [22], Watson AD [23], Allan GS [24]. - Dyserythropoiesis, polymyopathy, and cardiac diseasein three related English springer spaniels. J Vet Intern Med. [25]1991 May-Jun;5(3):151-9.
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6. Valli VE.  Veterinary comparative Hematophatology, 1° edition, ed. Wiley Blackwell Publishing, 2007.
7. Weiss DJ, Aird B. Cytologic Evaluation of Primary and Secondary Myelodysplastic Syndromes in the Dog. Vet Clin Path 2001;30(2).
8. Weiss DJ, Smith SA. A Retrospective Study of 19 Cases of Canine Myelofibrosis. J Vet Intern Med 2002;16:174–178.
9. Weiss DJ [39]. A retrospective study of the incidence and the classification of bone marrow disorders in the dog at a veterinary teaching hospital (1996-2004). J Vet Intern Med [40]2006Jul-Aug;20(4):955-61.
10. Weiss DJ [41].  Evaluation of dysmyelopoiesis in cats: 34 cases (1996-2005). J Am Vet Med Assoc [42]2006Mar 15;228(6):893-7.
11. Weiss DJ, Wardrop KJ. Schalm’s Veterinary haematology, 6° edition, ed. Wiley Blackwell Publishing, 2010.
12. Weiss DJ. A retrospective study of the incidence and classification of bone marrow disorder in cats (1996–2004) Comp Clin Path. [43]2012;14(4):179-185.