Incidence and Risk Factors

Myeloid neoplasms are uncommon or rare in the dog and occur 10 times less frequently than lymphoproliferative disorders.⁵ Accurate information about incidence and other epidemiologic information await consistent use of a uniform classification system (see later discussion). There is no known age, breed, or sex predisposition, although in some retrospective studies, large-breed dogs have been overrepresented.^6-14 In dogs, the etiology of spontaneously occurring leukemia is unknown. It is likely that genetic and environmental factors (including exposure to radiation, drugs, or toxic chemicals) play a role. In humans, acquired chromosomal derangements lead to clonal overgrowth with arrested development.¹⁵ At the end of the last century, chromosomal abnormalities were reported in dogs with AML, chronic myelogenous leukemia (CML), and lymphoid leukemia.^16,17 However, because karyotyping is difficult to perform in dogs because of the large number and morphologic similarity of their chromosomes and their resistance to banding, defining genetic factors in canine myeloid neoplasms has awaited application of molecular technologies and use of the canine genome map.^2,18-21 Certain forms of leukemia in dogs have been produced experimentally following irradiation.^22-24 In contrast to MPDs in cats, no causative viral agent has been demonstrated in dogs, although retrovirus-like budding particles were observed in the neoplastic cells of a dog with granulocytic leukemia.²⁵

Pathology and Natural Behavior

A review of normal hematopoiesis will aid in understanding the various manifestations of MPDs. Hematopoiesis is the process of proliferation, differentiation, and maturation of stem cells into terminally differentiated blood cells. A simplified scheme is presented in Figure 32-17. Pluripotent stem cells differentiate into either lymphopoietic or hematopoietic multipotent stem cells.²⁶ Under the influence of specific regulatory and microenvironmental factors, multipotent stem cells in bone marrow differentiate into progenitor cells committed to a specific hematopoietic cell line, for example, erythroid, granulocytic-monocytic, or megakaryocytic. Maturation results in the production of terminally differentiated blood cells—erythrocytes, granulocytes, monocytes, and platelets—that are delivered to the circulation. In some cases, as in the maturation of reticulocytes to erythrocytes, final development may occur in the spleen.

Proliferation and differentiation of hematopoietic cells are controlled by a group of regulatory growth factors.^26,27 Of these, erythropoietin is the best characterized; it regulates erythroid proliferation and differentiation and is produced in the kidney, where changes in oxygen tension are detected. The myeloid compartment depends on a group of factors, collectively referred to as colony-stimulating factors (CSFs). These factors act at the level of the committed progenitor cells but also influence the functional capabilities of mature cells. Some of these factors have a broad spectrum of activity; others are more restricted in their target cells and actions. CSFs are produced in vitro by a multitude of cell types, including monocytes, macrophages, lymphocytes, and endothelial cells, and these cells likely play a role in the production and regulation of these factors in vivo. The gene for thrombopoietin also has been cloned, and it appears that this hormone alone can induce differentiation of megakaryocytes and platelet production.²⁸ Recombinant forms of many of these hormones are increasingly available.

Clonal disorders of bone marrow include myeloaplasia (usually referred to as aplastic anemia), myelodysplasia, and myeloproliferation. A preleukemic syndrome, characterized by peripheral pancytopenia and bone marrow hyperplasia with maturation arrest, is more correctly termed myelodysplasia because the syndrome does not always progress to overt leukemia. This syndrome has been described in cats, usually in association with FeLV infection but has only rarely been recognized in dogs.^29-32 These clonal disorders may be manifested by abnormalities in any or all lineages because hematopoietic cells share a common stem cell. In addition, transformation from one form to another may occur.³³

Myeloid neoplasms are classified in several ways. The terms acute and chronic refer to the degree of cellular differentiation of the leukemic cells, but these terms also correlate with the biologic behavior of the neoplasm.³⁴ Disorders resulting from uncontrolled proliferation or decreased apoptosis of cells incapable of maturation lead to the accumulation of poorly differentiated or “blast” cells. These disorders are included under the umbrella term, acute myeloid leukemia (AML). Disorders resulting from unregulated proliferation of cells that exhibit progressive, albeit incomplete and defective, maturation lead to the accumulation of differentiated cells. These disorders are termed myeloproliferative neoplasms (MPN) and include polycythemia vera, CML and its variants, essential thrombocythemia, and possibly primary myelofibrosis. Myeloid neoplasms are further classified by the lineage of the dominant cell type(s), defined by Romanowsky stains, special cytochemical stains, ultrastructural features, flow cytometric analysis, and immunologic cell markers, and they have been classified into subtypes (see later discussion).

AML has a more sudden onset and is more aggressive. In both acute and chronic disorders, however, abnormalities in proliferation, maturation, and functional characteristics can occur in any hematopoietic cell line.¹ In addition, normal hematopoiesis is adversely affected. Animals with leukemia usually have decreased numbers of circulating normal cells. The pathogenesis of the cytopenias is complex and may result in part from production of inhibitory factors. Eventually, neoplastic cells displace normal hematopoietic cells, and this is termed myelophthisis. Anemia and thrombocytopenia are particularly common. Neutropenia and thrombocytopenia result in infection and hemorrhage, which may be more deleterious to the animal than the primary disease process.

Acute Myeloid Leukemia

AML is rare and is characterized by aberrant proliferation and/or decreased apoptosis of a clone of cells without maturation. This results in accumulation of immature blast cells in bone marrow and peripheral blood (Figure 32-18, A to E). The WBC count is variable and ranges from leukopenia to counts up to 150,000/µL. Spleen, liver, and lymph nodes are frequently involved, and other tissues, including tonsils, kidney, heart, and the CNS, may be infiltrated as well. There is no characteristic age, and even very young dogs may be affected.³⁵ The clinical course of these disorders tends to be rapid. Production of normal peripheral blood cells is usually diminished or absent, and anemia, neutropenia, and thrombocytopenia are common with infection and hemorrhage occurring as frequent sequelae. Occasionally, neoplastic blasts are present in bone marrow but not in peripheral blood. This is termed aleukemic leukemia, whereas subleukemic suggests a normal or decreased WBC count with some neoplastic cells in circulation.

In 1985 the Animal Leukemia Study Group was formed under the auspices of the American Society for Veterinary Clinical Pathology to develop specific morphologic and cytochemical criteria for classifying acute nonlymphocytic leukemias. Recognition of specific subtypes of leukemia is required to compile accurate and useful information about prognosis and response to treatment, as well as to compare studies from different sites. In 1991, this group proposed a classification system following adaptation of the French-American-British (FAB) system and criteria established by the NCI Workshop.³ Group members examined blood and bone marrow from 49 dogs and cats with myeloid neoplasms. Romanowsky-stained specimens were examined first to identify blast cells and their percentages. Lineage specificity was then determined using cytochemical markers. The percentage of blasts and the information about lineage specificity were used in combination to classify disorders as acute undifferentiated leukemia (AUL), acute myeloid leukemia (AML, subtypes M1 to M5 and M7), and erythroleukemia with or without erythroid predominance (M6 and M6Er). A description of these subtypes is presented in Table 32-12.

Canine karyotyping is difficult, but with advancements in molecular cytogenetic analysis, chromosome painting, and genomic hybridization, AML in dogs can now be analyzed at the base-pair level,^18,19 and missense mutations in FLT3, C-KIT, and RAS sequences have been identified in dogs with AML, similar to what has been found for human AML.³⁶ In addition to serving as diagnostic and prognostic markers, cytogenetic lesions may be therapeutic targets. As cytogenetic abnormalities continue to be identified, this information will need to be incorporated into classification schemes.

With the exception of acute promyelocytic leukemia or M3, all of these subtypes have been described in dogs. However, because this modified FAB system has been adopted only recently, the names given to these disorders in the literature vary considerably. In addition, in the absence of cytochemical staining, immunophenotyping, or electron microscopic evaluation, the specific subtype of leukemia has often been uncertain, making retrospective analysis of epidemiologic information, prognosis, and response to therapy confusing at best. Although defining specific subtypes may seem to be an academic exercise owing to the uniformly poor prognosis of acute leukemias, this information is critical to improving the management of these diseases. Because of the low incidence of AML, national and international cooperative efforts will be required to accumulate information on the pathogenesis and response to different treatment modalities of specific subtypes. Utilization of a uniform classification system is an essential first step.

Different forms of AML are demonstrated in Figure 32-18, A to E. The most frequently reported forms of AML in the dog are acute myeloblastic leukemia (M1 and M2) and acute myelomonocytic leukemia (M4).* Megakaryoblastic leukemia (M7) also is well recognized in dogs^10,47-58 and may be associated with platelet dysfunction.⁵¹ Monocytic leukemias have likely included those with and without monocytic differentiation (M5a and M5b),^11,59 but in some cases the diagnosis may have been chronic myelomonocytic or chronic monocytic leukemia (see later discussion). There are few reports in dogs of spontaneously occurring erythroleukemia (M6) in which the leukemic cells include myeloblasts, monoblasts, and erythroid elements.^60-62 AULs have uncertain lineages because they are negative for all cytochemical markers. These leukemias should be distinguished from lymphoid leukemias by flow cytometric analysis of the leukemic cells for cellular antigens that identify their lineage.⁶³ In addition, examination of blast cells by electron microscopy may reveal characteristic ultrastructural features.

Myeloproliferative Neoplasms

MPNs, previously termed chronic myeloproliferative disorders, are characterized by excessive production of differentiated bone marrow cells, resulting in the accumulation of erythrocytes (polycythemia vera), granulocytes and/or monocytes (CML and its variants), or platelets (essential thrombocythemia). Primary myelofibrosis as a clonal disorder of marrow stromal cells, characterized by proliferation of megakaryocytes and granulocytic precursors with accumulation of collagen in bone marrow, has been recognized only rarely in animals. Myelofibrosis is considered a response to injury and may occur secondary to other neoplasms, systemic inflammation, drug exposure, or FeLV infection in cats.

Other Bone Marrow Disorders

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Multiple Myeloma

History and Clinical Signs

Clinical signs of MM may be present up to a year prior to diagnosis with a median duration of one month reported in dogs.^1,9 In one cat, M-component elevations were detected 9 years prior to clinical presentation. In this latter case, the M-component elevation was consistent with monoclonal gammopathy of unknown significance (MGUS). MGUS (i.e., benign, essential, or idiopathic monoclonal gammopathy) is a benign monoclonal gammopathy that is not associated with osteolysis, bone marrow infiltration, or Bence Jones proteinuria. MGUS has also been reported in dogs.^60,61 Signs of MM can be variable based on the wide range of pathologic effects possible. Tables 32-14 and 32-15 list the relative frequencies of clinical signs observed in the dog and cat, respectively, based on a compilation of several reports.* Bleeding diathesis is usually represented by epistaxis and gingival bleeding. Funduscopic abnormalities may include retinal hemorrhage (see Figure 32-24), venous dilatation with sacculation and tortuosity, retinal detachment, and blindness.^† CNS signs may include dementia, seizure activity, tremors, and deficiencies in midbrain or brain-stem localizing reflexes secondary to HVS or extreme hypercalcemia. Signs reflective of transverse myelopathies secondary to vertebral column infiltration, pathologic fracture, or extradural mass compression can also occur.^1,6,35,62,63 One case of ataxia and seizure activity in a dog with EMP secondary to tumor-associated hypoglycemia has been reported.⁶⁴ Additionally, paraneoplastic polyneuropathy has been reported in a dog with MM.⁶⁵ A history of chronic respiratory infections and persistent fever may also be present in cats. Hepatosplenomegaly and renomegaly can occur due to organ infiltration. Bleeding diathesis due to HVS is less common in the cat; however, epistaxis, pleural and peritoneal hemorrhagic effusions, retinal hemorrhage, and central neurologic signs have been reported.^6,8,49-53 Polydipsia and polyuria can occur secondary to renal disease or hypercalcemia, and dehydration may develop. Hindlimb paresis secondary to osteolysis of lumbar vertebral bodies or extradural compression has been reported in cats.^12,66

Diagnosis and Staging

The diagnosis of MM in dogs usually follows the demonstration of bone marrow plasmacytosis (see Figure 32-20), the presence of osteolytic bone lesions (see Figures 32-22 and 32-23), and the demonstration of serum or urine myeloma proteins (M component) (see Figure 32-21). In the absence of osteolytic bone lesions, a diagnosis can also be made if marrow plasmacytosis is associated with a progressive increase in the M component. In the cat, because the degree of bone marrow infiltration may not be as marked, it has been suggested that consideration of plasma cell morphology and visceral organ infiltration (Figure 32-25) be given in cases with demonstrable M-component disease in the absence of marked (<20%) marrow plasmacytosis.^9,11,24

All animals suspected of plasma cell tumors should receive a minimal diagnostic evaluation including a CBC, platelet count, serum biochemistry profile, and urinalysis. Particular attention should be paid to renal function and serum calcium levels. If clinical hemorrhage is present, a coagulation assessment (e.g., platelet count, PT, PTT) and serum viscosity measurements are indicated. All animals should undergo a careful funduscopic examination. Serum electrophoresis and immunoelectrophoresis are performed to determine the presence of a monoclonal M component (see Figure 32-21) and to categorize the immunoglobulin class involved. Heat precipitation and electrophoresis of urine may be performed to determine presence of Bence Jones proteinuria because commercial urine dipstick methods are not capable of this determination. Definitive diagnosis usually follows the performance of a bone marrow aspiration in the dog. A bone marrow core biopsy or multiple aspirations may be necessary due to the possibility of uneven clustering or infiltration of plasma cells in the bone marrow. Normal marrow contains less than 5% plasma cells, whereas myelomatous marrow often greatly exceeds this level. Current recommendations require more than 20% marrow plasmacytosis to be present, although a 10% cutoff in cats has been recently recommended with special attention to cellular atypia.⁹ Even the 10% threshold is problematic in cats, and cellular atypia and visceral organ involvement (assessed through needle aspiration cytology or tissue biopsy) should be considered equally important in the species.^9,11,24 Rarely, biopsy of osteolytic lesions (i.e., Jamshidi core biopsy; see Chapter 24) is necessary for diagnosis in the dog. In one case of MM in a dog, splenic aspirates were diagnostically helpful.⁶⁷ Overall frequencies of clinical diagnostic abnormalities for dogs and cats with MM are compiled from published series having at least five cases each and are listed in Table 32-16.

Solitary and Extramedullary Plasmacytic Tumors

Solitary collections of monoclonal plasmacytic tumors can originate in soft tissues or bone and are referred to as extramedullary plasmacytoma (EMP) and solitary osseous plasmacytoma (SOP), respectively. The systemic, multicentric, biologically aggressive EMP syndrome encountered in cats^11,24 has been discussed in the MM section and will not be included in this discussion. A number of large case compilations of cutaneous plasmacytoma have been reported in the dog.^17,80-86 The most common locations for EMP in the dog are cutaneous (86%; Figure 32-28), the mucous membranes of the oral cavity and lips (9%; Figure 32-29), and the rectum and colon (4%). The skin of the limbs and head (including the ears) are most frequently reported cutaneous sites. Other sites accounted for only 1% of the remaining cases and can include stomach, spleen, genitalia, eye, uterus, liver, larynx, trachea, third eyelid, sinonasal cavity, and intracranial sites.^87-94 The American cocker spaniel, English cocker spaniel, and West Highland white terrier (and perhaps Yorkshire terriers, Boxers, German shepherds, and Airedale terriers) are at increased risk for developing plasmacytomas and the median age of affected dogs is 9 to 10 years of age.⁸⁶

Cutaneous and oral EMP in dogs are typically benign tumors that are highly amenable to local therapy. There exists, however, a rare form of multiple cutaneous plasmacytomas in dogs that is part of a more generalized biologically aggressive MM process.^95,96 The natural behavior of noncutaneous/nonoral EMP appears to be somewhat more aggressive in the dog. GI EMP have been reported on a number of occasions in the veterinary literature, including the esophagus,⁹¹ stomach,^97,98 and small⁹⁹ and large intestine.^98-101 Metastasis to associated lymph nodes is more common in these cases; however, bone marrow involvement and monoclonal gammopathies are less commonly encountered. Colorectal EMPs tend to be of low biologic aggressiveness, and most do not recur following surgical excision.¹⁰⁰ Conversely, the majority of SOPs eventually progress to systemic MM; however, the time course from local tumor development to systemic MM may be many months to years.^33,102 SOPs have been reported in the dog involving the appendicular skeleton, as well as the zygomatic arch, and ribs.³³

SOPs are less common in cats, and fewer reports exist in the literature.^{11,22,103-107} They occur in older cats (mean ages 9 to 14 years), with no significant sex predilection. The skin is the most common site; however, other sites include the oral cavity, eye, GI tract, liver, subcutaneous tissues, and brain. Reports exist of cutaneous EMP in cats that progressed to systemic MRD.^11,22,105

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