Many pathologic disorders of bone marrow have

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1 J Vet Intern Med 2006;20: A Retrospective Study of the Incidence and the Classification of Bone Disorders in the Dog at a Veterinary Teaching Hospital ( ) Douglas J. Weiss Background: An 8-year retrospective study was conducted to evaluate the prevalence and the classification of canine bone marrow disorders in a clinical pathology service at a university referral hospital. Animals: Dogs evaluated for bone marrow disorders at a veterinary teaching hospital. Hypothesis: A better understanding of the spectrum and the prevalence of canine bone marrow disorders can be achieved with a multiyear retrospective study. Methods: Bone marrow aspirate smears, core biopsy specimens, and case records from 717 dogs were reviewed. Results: Bone marrow specimens were first categorized based on the presence or the absence of a primary bone marrow disorder. Nondysplastic and nonmalignant pathologic changes were placed into 14 subcategories. Frequently observed pathologic disorders included nonregenerative immune-mediated anemia, pure red cell aplasia, bone marrow necrosis, myelofibrosis, and hemophagocytic syndrome. Dysmyelopoiesis (n 5 61) was subcategorized into myelodysplastic syndromes (n 5 27), and congenital (n 5 1) and secondary (n 5 33) dysmyelopoiesis. One hundred twenty-six cases of neoplasia were divided into acute leukemia (n 5 46), chronic leukemia (n 5 7), stage 5 malignant lymphoma (n 5 28), multiple myeloma (n 5 25), malignant histiocytosis (n 5 11), metastatic mast-cell tumor (n 5 3), sarcoma (n 5 5), and carcinoma (n 5 1). Conclusions and Clinical Importance: This study provides a general indication of the spectrum and the prevalence of canine bone marrow disorders at a referral center in North America. Key words: Aplastic pancytopenia; Immune-mediated anemia; Leukemia; Malignant lymphoma; Myelofibrosis; Necrosis. Many pathologic disorders of bone marrow have been described for the dog, but the prevalence of these disorders is unknown. 1 3 In the present report, I conducted an 8-year retrospective study of bone marrow disorders at the University of Minnesota Veterinary Medical Center. This study provides a relatively large cohort from which to describe pathologic changes in bone marrow. The sample population also provides some indication of the spectrum and the prevalence of canine bone marrow disorders, but it is biased in several ways. First, it is limited by geographic location. Several infectious diseases, including monocytic ehrlichiosis and leishmaniasis, are not endemic in this area. Second, the hospital is a referral hospital located in a large metropolitan area. As such, most dogs are not allowed to roam free, decreasing the likelihood of exposure to infectious diseases. Third, the hospital has a large oncology service. This feature increased the number of bone marrow samples collected for staging lymphosarcoma and mast-cell tumors. Given these limitations, this study provides a general indication of the spectrum and the prevalence of canine clinical bone marrow disorders seen at referral centers in North America. Materials and Methods Canine bone marrow specimens submitted between July 1, 1996, and June 30, 2004, were reviewed. Bone marrow reports from 717 From the Department of Veterinary Biomedical Sciences, University of Minnesota, St Paul, MN. Reprint requests: Douglas J. Weiss, DVM, PhD, Department of Veterinary Biomedical Sciences, University of Minnesota, 1971 Commonwealth Avenue, St Paul, MN, 55108; weiss005@umn.edu. Submitted August 2, 2005; Revised December 13, 2005, October 17, 2005, October 10, 2005; Accepted January 9, Copyright E 2006 by the American College of Veterinary Internal Medicine /06/ /$3.00/0 dogs were identified. All dogs had blood smears evaluated, which were collected within 24 hours of bone marrow collection, and 609 dogs (85%) had concurrent bone marrow core biopsy specimens collected; 699 bone marrow aspirate smears, and 591 bone marrow core biopsy specimens were available for review. Most of these were evaluated to confirm the original findings and to place disorders into pathologic or disease categories. Bone marrow aspirates and core biopsy specimens that were not reviewed included nondiagnostic specimens, those with no cytologic abnormalities, and hyperplastic bone marrow specimens (Table 1). Case records or computerized case files also were reviewed, and the clinical, clinicopathologic, or histopathologic diagnosis was determined. Disease prevalence was listed as a percentage of the total number of diagnostic bone marrow samples evaluated or as a percentage of bone marrow samples in which core biopsy samples were obtained if histopathologic evaluation was considered essential for establishing the diagnosis. Results Of the 717 bone marrow samples evaluated, 12 (1.6%) were nondiagnostic samples. Of the remaining samples, 21.8% had no cytologic abnormalities, 26.1% had conditions in which bone marrow alterations occurred secondary to another primary disease process, 24.3% had nondysplastic and nonneoplastic conditions, 8.7% had dysplastic conditions, and 17.9% had malignant conditions (Tables 1 4). Nonspecific Conditions Associated with Other Primary Disease Conditions or Drug Treatments Hyperplastic marrow was defined as marrow in which more than 75% of the hematopoietic space consisted of hemic cells (Table 1). 4 In this group, erythroid hyperplasia was defined as a granulocyte-toerythroid (G : E) ratio, 1:1. 4 Myeloid hyperplasia was defined as a G : E ratio. 2:1. 4 Megakaryocytic hyperplasia was defined as.3 megakaryocytes/lowpower field. 5

2 956 Weiss Table 1. Diagnostic categories for nonspecific conditions of bone marrow occurring secondary to other primary disease conditions or drug treatments. % Bone Normal Hyperplastic marrow Panhyperplasia Erythroid hyperplasia Granulocytic hyperplasia Megakaryocytic hyperplasia Granulocytic and erythroid hyperplasia Granulocytic and megakaryocytic hyperplasia Erythroid and megakaryocytic hyperplasia Hypoplasia Panhypoplasia Erythroid hypoplasia Granulocytic hypoplasia Megakaryocytic hypoplasia Granulocytic and erythroid hypoplasia Lymphocytosis Plasma cell hyperplasia Diagnoses most frequently associated with panhyperplasia included mast-cell tumors (n 5 8), malignant lymphoma (n 5 4), and blood-loss anemia (n 5 3). The most frequently encountered diagnoses for dogs with erythroid hyperplasia, included blood-loss anemia (n 5 10), malignant lymphoma (n 5 8), mast-cell tumor (n 5 8), and nonhemic neoplasia (n 5 3). Diagnoses most frequently encountered for dogs with granulocytic hyperplasia included infectious diseases (n 5 9), immune-mediated arthritis (n 5 6), and nonhemic neoplasia (n 5 3). Hypoplastic marrow was defined as marrow in which 5 to 25% of the hematopoietic space consisted of hemic cells (Table 1). Erythroid hypoplasia was defined as a G : E ratio. 2:1. 4 Myeloid hypoplasia was defined as a G : E ratio, 1:1. 4 Megakaryocytic hypoplasia was defined as,1 megakaryocytes/low-power field. The most frequently encountered diagnoses for panhypoplasia were chronic renal failure (n 5 3) and chemotherapy (n 5 2). The most frequently encountered diagnoses for erythroid hypoplasia were chronic renal failure (n 5 6) and nonhemic neoplasia (n 5 3). The most frequently encountered diagnoses for granulocytic hypoplasia were chemotherapy (n 5 3) and septicemia (n 5 3). Relatively few dogs had lymphocytosis or plasma-cell hyperplasia as the only finding in their bone marrow. However, 48 dogs had plasma-cell hyperplasia or lymphocytosis associated with other primary conditions, most notably, immune-mediated anemia (IMA), pure red cell aplasia (PRCA), and immune-mediated thrombocytopenia (IMT). Two dogs had small lymphoid aggregates present in core biopsy specimens. IMA Twenty-nine of 31 dogs with a diagnosis of IMA had nonregenerative anemia at the time of bone marrow Table 2. Nondysplastic and nonneoplastic bone marrow conditions associated with primary bone marrow disorders. % Bone IMA with erythroid hyperplasia IMA with maturation arrest Pure red cell aplasia Immune-mediated thrombocytopenia Idiopathic aplastic pancytopenia Estrogen-induced aplastic pancytopenia Drug-induced aplastic pancytopenia Ehrlichia canis induced aplastic pancytopenia Myelonecrosis Secondary myelofibrosis Hemophagocytic syndrome Toxic change Inflammation Iron deficiency IMA, immune-mediated anemia. collection (Table 2). Bone marrow evaluation indicated that 18 dogs had erythroid hyperplasia, and 13 dogs had maturation arrest in the erythroid lineage. Few polychromatophilic erythrocytes were observed in the marrow of dogs with erythroid hyperplasia, indicating that erythropoiesis was ineffective. Plasma-cell hyperplasia was present in 19 dogs and lymphocytosis was present in 6 dogs. Mild to moderate collagen fibrosis was observed in 7 dogs (22.6%). Focal or multifocal areas of necrosis were present in core biopsy specimens of 3 dogs (9.7%). PRCA PRCA was defined as the presence of a severe nonregenerative anemia in the blood and a G : E ratio. 75 : 1 in bone marrow (some of these cases have been previously reported; 6 Table 2). 7 9 Spherocytes were observed in 3 dogs, but direct Coombs test results were positive in only 1 of 13 dogs tested. Bone marrow cellularity was normal in 21 dogs and hyperplastic in 3 dogs. Immune-Mediated Thrombocytopenia Dogs with a diagnosis of IMT had severe thrombocytopenia. Twenty-five dogs had megakaryocyte hyperplasia (ie,.3 megakaryocytes/low-power field) in bone marrow aspiration smears; however, 3 dogs had no megakaryocytes in bone marrow aspiration smears or core biopsy specimens consistent with megakaryocyte aplasia. All 3 dogs with megakaryocyte aplasia tested negative for Ehrlichia canis and Rickettsia rickettsii. Two of the 3 dogs recovered after immunosuppressive therapy, which was consistent with an immune-mediated cause for the disease. Idiopathic Aplastic Pancytopenia Idiopathic aplastic pancytopenia was defined as pancytopenia in the blood bone marrow in which

3 Bone Disorders in the Dog % of the hematopoietic space was occupied by adipose tissue and cases in which known causes of marrow aplasia had been ruled out Bone marrow specimens with evidence of myelonecrosis or myelofibrosis were excluded (Table 2). Dogs were young, with a median age of 2.9 years. A review of the clinical history and the physical examination findings identified no common factor, such as recent viral infection, recent vaccination, or toxin or drug exposure that may have induced the aplasia. The anemia was moderate to severe, the median total neutrophil count was,1,000/ml, and the median platelet count was,10,000/ml. Secondary Aplastic Pancytopenia Four dogs had aplastic-pancytopenia associated disease conditions or drug treatments. These included combination chemotherapy for lymphosarcoma, an estrogen-secreting Sertoli cell tumor, and chronic monocytic ehrlichiosis (Table 2). Bone Necrosis Bone marrow necrosis consisted of focal or multifocal areas of coagulation-type necrosis or individual cell necrosis (Table 2). 13,14 Chronic necrosis frequently was accompanied by variable degrees of myelofibrosis. 15 The most frequently encountered diagnoses for dogs with bone marrow necrosis included sepsis (n 5 3), IMA (n 5 3), and systemic lupus erythematosus (n 5 2; these cases have been previously reported 13 ). Sixteen of the dogs had prior drug therapy that may have contributed to the necrosis. Drug treatments associated with bone marrow necrosis included carprofen (n 5 3), phenobarbital (n 5 3), metronidazole (n 5 3), mitotane (n 5 2), cyclophosphamide (n 5 1), vincristine (n 5 1), colchicine (n 5 1), and fenbendazole (n 5 1). Ten dogs had idiopathic bone marrow necrosis. Secondary Myelofibrosis Myelofibrosis was defined as proliferation of fibroblasts in bone marrow that was associated with various degrees of collagen deposition. 15 Reticulin fibrosis was not included in the definition, because most core biopsy sections had not been stained to detect reticulin fibers. The severity of the fibrosis was graded as mild, moderate, or marked as previously described. 15 Myelofibrosis was the only pathologic lesion identified in 9 dogs (Table 2). Myelofibrosis was also seen in association with other disease processes in 36 cases. All dogs had a moderate to severe nonregenerative anemia, and a few were neutropenic or thrombocytopenic. Other frequent blood findings included ovalocytosis, dacryocytosis, and metarubricytosis. Dysplastic changes in hematopoietic cell lineages were not observed; therefore, these cases were determined to be a secondary type of myelofibrosis. Hemophagocytic Syndrome Criteria for diagnosis of hemophagocytic syndrome consisted of the presence of bicytopenia or pancytopenia in the blood and.3% macrophages in bone marrow, with the majority of these cells being phagocytic (Table 2) Increased numbers of phagocytic macrophages also were observed in the spleen or the liver of 6 dogs. Secondary causes of hemophagocytic disorders (n 5 22), including IMA, IMT, myelodysplastic syndrome (MDS), and myelonecrosis, were excluded. Clinical signs associated with hemophagocytic syndrome included weakness, lethargy, and fever (some of these cases have been previously reported 17 ). Macrophages varied between 9% and 24% of all nucleated bone marrow cells. Based on the paucity of reported cases of hemophagocytic syndrome in dogs, the incidence appears to be greater than previously suspected. 18,19 Toxic Changes Toxic changes were observed in metamyelocyte, band, and segmented neutrophils. In 3 dogs, toxic changes consisted of cytoplasmic basophilia and granularity (Table 2). These changes were similar to those associated with bacterial sepsis. 19 All 3 dogs had a history of diarrhea, and 2 of the 3 dogs had oral ulcers. A diagnosis of sepsis was suspected or confirmed for all 3 dogs. Toxic changes in 3 dogs were characterized by distinct round cytoplasmic vacuoles. Two of these dogs were being treated with therapeutic doses of metronidazole, and the other dog was being treated with a therapeutic dose of cyclophosphamide. Similar cytoplasmic vacuolization has been associated with chloramphenicol administration. 20 Therefore, these vacuoles may represent drug-induced degenerative changes. Inflammation Bone marrow from 2 dogs had evidence of a purulent inflammatory response (Table 2). Both dogs had a history of acute lameness and a reluctance to walk, suggesting that the condition caused pain. Bone marrow was characterized by dilatation of sinusoids, fibrin deposits, and multifocal infiltrates of segmented neutrophils. One dog had multifocal areas of coagulation necrosis present, and the other dog had mild myelofibrosis. Septicemia was suspected in 1 dog. Iron Deficiency Iron deficiency was a relatively infrequent finding in this study. Blood smears were characterized by a microcytic, hypochromic, regenerative or nonregenerative anemia. All dogs lacked stainable iron in bone marrow. Three dogs had erythroid hyperplasia, with increased numbers of rubricytes and metarubricytes in bone marrow specimens. Four dogs had rubricytes and metarubricytes, with scant cytoplasm and patchy basophilia. All dogs had a histopathologic diagnosis of stomach or intestinal neoplasia, which presumably led to chronic intestinal blood loss. Dysmyelopoiesis Dysmyelopoiesis was defined as a hematologic disorder characterized by the presence of morphologic

4 958 Weiss Table 3. Diagnostic categories for 61 canine bone marrow specimens with a diagnosis of dysmyelopoiesis. % Bone MDS MDS with refractory cytopenia MDS with sideroblastic differentiation MDS with excess myeloblasts Variant form a Congenital dysmyelopoiesis b Secondary dysmyelopoiesis MDS, myelodysplastic syndrome. a From Ref. 29. b From Ref. 30. abnormalities (ie, dysplasia) in 1 or more hematologic cell lines in the blood or bone marrow In this and a previous study, dysmyelopoiesis was divided into myelodysplastic syndromes, secondary dysmyelopoiesis, and congenital dysmyelopoiesis. 21 Myelodysplastic syndromes were subclassified as MDS with refractory cytopenias (MDS-RC), MDS with sideroblastic differentiation (MDS-SD), and MDS with excess (ie, 6 30%) myeloblasts (MDS-EB; some of these cases have been previously reported 27,28 ). Hematologic alterations in dogs with MDS-RC consisted of moderate to severe normocytic, normochromic nonregenerative anemia (Table 3). Bone marrow was normocellular or hypercellular, with a normal or decreased G : E ratio. Dysplastic features were restricted to the erythroid series in all dogs. Features of dyserythropoiesis included megaloblastosis, binucleation, nuclear fragmentation, and asynchronous maturation. Rubriblasts varied between 7 and 18% of all nucleated cells. Myeloblasts were,6% of all nucleated bone marrow cells. MDS-SD was characterized by a microcytic or hypochromic nonregenerative anemia with large numbers of siderocytes in peripheral blood. Variable numbers of ringed sideroblasts were present in bone marrow. Rubriblasts were increased in bone marrow of most dogs, and dysplastic features were present in all cell lines. All dogs with MDS-EB had bicytopenia or pancytopenia. Bone marrow was normocellular or hypercellular with an increased G : E ratio and 8 20% myeloblasts. Dysgranulopoiesis was present in all dogs, and dyserythropoiesis and dysmegakaryopoiesis was present in the majority of dogs. Three dogs had erythroid hypoplasia. Secondary dysmyelopoiesis was associated with potentially causative disease processes or administration of drugs. Six dogs had sideroblastic anemia and 27 dogs had nonsideroblastic anemia. Conditions frequently associated with nonsideroblastic anemia include IMA, IMT, lymphosarcoma, and treatment with chemotherapeutic agents. Dysplastic features in bone marrow were generally similar to those associated with MDS; however, the percentage of rubriblasts and myeloblasts were rarely increased. Most dogs with secondary sideroblastic anemia had acute inflammatory diseases. Affected dogs had moderate to severe microcytic or hypochromic anemia. Dysplastic features were similar to those associated with MDS-SD; however, the percentage of blast cells in bone marrow was not increased. Acute Leukemia Acute leukemias were classified according to the French-American-British classification scheme (Table 4) Leukemias were evaluated by various combinations of cytology, cytochemistry, and immunophenotyping (some cases have been previously reported 32 ). Four bone marrow specimens had.90% poorly differentiated blast cells. Three bone marrow specimens lacked features that permitted them to be classified and were termed unclassified leukemias. One bone marrow was classified as undifferentiated leukemia. Many blast cells had cytoplasmic pseudopodia similar to those described in acute undifferentiated leukemia Of the cases of acute myelogenous leukemia (AML), 5 were categorized as M1, and 11 were classified as M2. Nonblast cells present in M2 AML were mostly differentiated granulocytes. Immunophenotyping was performed in 7 cases. All cases were CD11b-positive, CD18-positive, and CD14-negative, consistent with a granulocyte lineage. Dogs with a diagnosis of acute myelomonocytic leukemia had cells that resembled myeloblasts and monoblasts, which exceeded 30% of all nucleated cells. Immunophenotyping of 2 dogs determined that the blast-cell population consisted of a subpopulation of cells that was CD11b-positive and CD14-negative (ie, granulocyte origin) and a subpopulation that was CD11b- and CD14-positive (ie, monocyte origin). Four dogs had a diagnosis of acute monocytic leukemia. Immunolabeling of cells with CD14 supported the diagnosis in 3 dogs. Based on the maturity of the monocytes, 3 cases were classified as M5b and 1 was classified as M5a. Two cases of erythroleukemia were diagnosed. These cases were characterized by increased numbers of myeloblasts and rubriblasts. Rubriblasts exceeded 30% of all nucleated cells, and both cases were classified as M6Er. Dogs with a diagnosis of acute lymphocytic leukemia were differentiated from stage 5 malignant lymphoma. In the present cases, stage 5 malignant lymphoma was characterized by lack of evidence of enlargement of internal or external lymph nodes, liver, spleen, or intestinal tract. All dogs had.30% blast cells in bone marrow. Cells in all dogs resembled lymphoblasts or prolymphocytes. Lymphoblasts were present in blood smears of 9 dogs. Immunophenotyping was performed in 5 dogs. Two dogs had a T-cell phenotype, 1 dog had a B-cell phenotype, and 2 dogs were negative for T- and B-cell markers. Chronic Leukemia Chronic myelogenous leukemia was characterized by total leukocyte counts of.100,000/ml, with leukocytes consisting mostly of band and segmented neutrophils (Table 4). Occasional atypical blast cells were identified

5 Bone Disorders in the Dog 959 Table 4. Diagnostic categories for 126 canine bone marrow specimens with a diagnosis of neoplasia. % Total Bone Specimens Acute leukemia Unclassified leukemia Undifferentiated leukemia (AUL) Myelogenous leukemia (M1, M2) Myelomonocytic leukemia (M4) Monocytic leukemia (M5) Erythroleukemia (M6) Megakaryoblastic leukemia (M7) a Lymphocytic leukemia Chronic leukemia Myelogenous leukemia Lymphocytic leukemia Primary erythrocytosis Idiopathic myelofibrosis b Others Malignant lymphoma Multiple myeloma Malignant histiocytosis Metastatic mast-cell tumor Sarcoma Carcinoma a From Ref. 29. b From Ref. 17. in blood smears. Bone marrow was characterized by hypercellularity and an increased G : E ratio, and myeloblasts were 16% of all nucleated cells in 1 dog, and 12% of all nucleated cells in the other dog. The diagnosis was supported by lack of toxic changes in blood or bone marrow, failure to identify a site of inflammation, and failure to identify a site of neoplasia in nonhemic tissue. Chronic lymphocytic leukemia was characterized by marked lymphocytosis in blood and bone marrow. The percentage of lymphocytes in bone marrow varied between 47% and 72% of all nucleated cells. Lymphocytes were slightly larger than normal small lymphocytes and frequently had cleaved or lobulated nuclei. 31 Two of the dogs had splenomegaly and hepatomegaly, and 1 dog had a monoclonal gammopathy. Primary erythrocytosis was characterized by an absolute increase in erythrocyte mass, an erythropoietin concentration that was undetectable, and a recurrence of polycythemia after phlebotomy. Morphologic abnormalities were not observed in blood or bone marrow aspiration smears. Other Neoplastic Conditions Malignant lymphoma was the most frequently diagnosed neoplastic condition in canine bone marrow samples (Table 4). The diagnosis of malignant lymphoma was based on the presence of lymphoblasts in bone marrow, identification of lymphoblasts in multiple lymph nodes or organs, relatively low blast-cell numbers in the blood, and lack of severe cytopenias in the blood. The percentage of malignant cells in bone marrow varied between 6 and 68%. Multiple myeloma was the second most frequently diagnosed neoplastic condition in canine bone marrow. The diagnosis of multiple myeloma was based on increased numbers of plasma cells and the presence of atypical plasma cells. Malignant plasma cells were characterized by large size, anisocytosis, anisokaryosis, and frequent binucleation. Features most helpful in differentiating malignant plasma cells from reactive plasma-cell hyperplasia included anisocytosis, anisokaryosis, high nuclear-to-cytoplasmic ratio, binucleation, and clustering of plasma cells. Dogs with malignant histiocytosis had multiple cytopenias in the blood (some of these cases have been reported previously 17 ). All dogs had more than 30% histiocytic cells in bone marrow, but features of malignancy were variable. Features that were useful in differentiating malignant histiocytosis from hemophagocytic syndrome included histiocytic cells.30% of all nucleated cells, high nuclear-to-cytoplasmic ratio, large size (as determined by flow cytometry), and multinuclearity. Cytophagia was present in all bone marrow aspiration smears but was a prominent feature in only 3 dogs. In 3 dogs, mast-cell tumors in bone marrow were associated with cutaneous mast-cell tumors. In 2 dogs, mast cells appeared immature being characterized by anisocytosis, prominent nucleoli, and variable numbers of granules. In the other dog, mast cells appeared mature but represented 12% of all nucleated cells. Six dogs had carcinomas or sarcomas. These were present as clusters of cells in bone marrow aspiration smears or core biopsy specimens. Of the 5 sarcomas, 4 were metastatic osteosarcomas. The carcinoma was suspected to be a metastatic mammary carcinoma. Discussion Bone marrow disorders in dogs were classified based on clinical and cytologic findings and, in some instances, ancillary testing modalities. Primary hematologic conditions included 14 nondysplastic and nonneoplastic, 7 dysplastic, and 18 neoplastic conditions. Several conditions occurred more frequently than expected based on the paucity of reported cases. These conditions include idiopathic aplastic pancytopenia, hemophagocytic syndrome, PRCA, and myelonecrosis. Although MDS-EB was the most frequently identified form of myelodysplastic syndrome, secondary dysmyelopoiesis was the most frequent cause of dysmyelopoiesis. As reported previously, nonregenerative IMA was a frequent cause of marrow failure. 33 In that study, erythroid hyperplasia was the most frequent finding in bone marrow. The combined results of these 2 studies indicate that the nonregenerative anemia associated with IMA may result from a combination of immune-mediated destruction of precursor cells within the marrow and bone marrow stromal disorders that limit erythropoiesis. Other poorly described conditions identified in this study included acute inflammation of bone marrow that was associated

6 960 Weiss Fig 1. Diagnostic algorithm for major bone marrow disorders in the dog that result in bicytopenia or pancytopenia. Initial evaluation should include a search for drug or toxin exposure; evaluation for immune-mediated diseases, including immune-mediated anemia (IMA), immune-mediated thrombocytopenia (IMT), and systemic lupus erythematosus (SLE); and serology, virus detection, and bacterial culture for detection of infectious agents. Thereafter, bone marrow aspiration and core biopsy examination is indicated. Conditions that cause hypocellular bone marrow include aplastic pancytopenia (defined as.95% of marrow space replaced by adipose tissue), myelofibrosis, and necrosis. Conditions associated with normocellular or hypercellular bone marrow include leukemia (defined as.30% blast cells), benign (ie, hemophagocytic syndrome) and malignant (ie, malignant histiocytosis) macrophage proliferation disorders, and dysmyelopoiesis. Dysmyelopoiesis is differentiated into myelodysplastic syndrome with excess myeloblasts (MDS-EB), myelodysplastic syndrome with refractory cytopenia (MDS-RC), and secondary dysmyelopoiesis. with acute lameness, drug-associated toxic changes in late stage granulocyte precursors, and idiopathic aplastic pancytopenia in young adult dogs. The results of this and previous studies provide an indication of the spectrum and the prevalence of clinical bone marrow disorders seen in dogs at referral centers in North America. Based on these studies, a diagnostic algorithm was developed to define major bone marrow disorders in dogs that result in bicytopenia or pancytopenia (Fig 1). References 1. Shelly SM. Causes of canine pancytopenia. Compend Contin Educ Pract Vet 1988;10:9 16.

7 Bone Disorders in the Dog Tyler RD, Cowell RL. Classification and diagnosis of anemia. Comp Haematol Int 1996;6: Weiss DJ, Evanson OA, Sykes J. A retrospective study of canine pancytopenia. Vet Clin Pathol 1999;28: Harvey JW. Canine bone marrow: Normal hematopoiesis, biopsy techniques, and cell identification and evaluation. Compend Continu Ed Pract Vet 1984;6: Mischke R, Busse L, Bartels D, et al. Quantification of thrombopoietic activity in bone marrow aspirates of dogs. Vet J 2002;164: Weiss DJ. Primary pure red cell aplasia in dogs: 13 cases ( ). J Am Vet Med Assoc 2002;221: Gilmour M, Lappin MR, Thrall MA. Investigating primary acquired pure red cell aplasia in dogs. 1991;86: Weiss DJ. Antibody-mediated suppression of erythropoiesis in dogs with red blood cell aplasia. Am J Vet Res 1986;47: Weiss DJ, Miller ML, Crawford MA, et al. Primary-acquired red cell aplasia in a dog: Response to glucocorticoid and cyclophosphamide therapy. J Am Anim Hosp Assoc 1984;20: Sherding RG, Wilson GP, Kociba GJ. Bone marrow hypoplasia in eight dogs with Sertoli cell tumor. J Am Vet Med Assoc 1981;178: Weiss DJ, Klausner JS. Drug-associated aplastic anemia in dogs: Eight cases ( ). J Am Vet Med Assoc 1990;196: Weiss DJ, Christopher MM. Idiopathic aplastic anemia in a dog. Vet Clin Pathol 1985;14: Weiss DJ. Bone marrow necrosis in dogs: 34 cases ( ). J Am Vet Med Assoc 2005;227: Hoenig M. Six dogs with features compatible with myelonecrosis and myelofibrosis. J Am Anim Hosp Assoc 1989;25: Weiss DJ, Smith SA. A retrospective study of 19 cases of canine myelofibrosis. J Vet Intern Med 2002;16: Walton RM, Modaino JF, Thrall MA, et al. Bone marrow cytologic findings in 4 dogs and a cat with hemophagocytic syndrome. J Vet Intern Med 1996;10: Weiss DJ. Cytologic evaluation of benign and malignant hemophagocytic disorders in canine bone marrow. Vet Clin Pathol 2001;30: Brown DE, Thrall MA, Getzy DM, et al. Cytology of canine malignant histiocytosis. Vet Clin Pathol 1994;23: Aroch I, Klement E, Segev G. Clinical, biochemical, and hematologic characteristics, disease prevalence, and prognosis of dogs presenting with neutrophil cytoplasmic toxicity. J Vet Intern Med 2005;19: Penny RHC, Carlisle CH, Prescott CW, et al. Further observations on the effect of chloramphenicol on the haematopoietic system of the cat. Br Vet J 1970;126: Weiss DJ. Recognition and classification of dysmyelopoiesis in the dog: A review. J Vet Intern Med 2005;19: Blue JT. Myelodysplastic syndromes and myelofibrosis. In: Feldman BF, Zinkl JG, Jain NC, eds. Schalm s Veterinary Hematology, 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2000: Raskin RE. Myelopoiesis and myeloproliferative disorders. Vet Clin North Am Small Anim Pract 1996;26: Weiss DJ, Lulich J. Myelodysplastic syndrome with sideroblastic differentiation in a dog. Vet Clin Pathol 1999;28: Weiss DJ. Selective dysmegakaryopoiesis in thrombocytopenic dogs ( ). Compar Clin Pathol 2004;13: Smedile LE, Houston DM, Taylor SM, et al. Idiopathic, asymptomatic thrombocytopenia in Cavalier King Charles Spaniels: 11 cases ( ). J Am Anim Hosp Assoc 1997;33: Weiss DJ, Aird B. Cytologic evaluation of primary and secondary myelodysplastic syndromes in the dog. Vet Clin Pathol 2001;30: Weiss DJ. Sideroblastic anemia in 7 dogs ( ). J Vet Intern Med 2005;19: Jain NC, Blue JT, Grindem CB, et al. Proposed criteria for classification of acute myeloid leukemia in dogs and cats. Vet Clin Pathol 1991;20: Grindem CB, Stevens JB, Perman V. Morphological classification and clinical and pathological characteristics of spontaneous leukemia in 17 dogs. J Am Anim Hosp Assoc 1985;21: Raskin RE. Myelopoiesis and myeloproliferative disorders. Vet Clin North Am Small Anim Pract 1996;26: Weiss DJ. Evaluation of proliferative disorders in canine bone marrow by use of flow cytometric scatter plots and monoclonal antibodies. Vet Pathol 2001;38: Stokol T, Blue JT, French TW. Idiopathic pure red cell aplasia and nonregenerative immune-mediated anemia in dogs: 43 cases ( ). J Am Vet Med Assoc 2000;216: