Clinical Management of the Cancer Patient

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Laboratory Abnormalities in Patients with Cancer Stephen A. Kruth, DVM*, and Ronald F. Carter, DVM, PhDt

Animals with cancer are often presented to the veterinarian because of vague or nonspecific signs. Anorexia, weight loss, or fever may be the only problems identified at the time of the initial examination, and a data base consisting of a complete blood count, serum biochemistry panel, and urinalysis is often obtained. Abnormal values for these tests may occur due to the direct effect of a tumor on involved organs and/or due to paraneoplastic disorders. The purpose of this article is to identify laboratory abnormalities that should alert the clinician to the possibility of cancer, and to present a rational diagnostic approach to these patients.

ABNORMALITIES OF THE COMPLETE BLOOD COUNT Tests performed on peripheral blood may reveal abnormalities of cell counts, morphology, or function. These abnormalities may reflect primary diseases of the hemic-lymphatic system or perturbations secondary to other diseases. Interpretation of the complete blood count has been extensively reviewed recently. 23 • 31 • 34 · 37 · 52 · 63 We will discuss the diagnostic approach to abnormalities caused by cancer. Reference values for peripheral blood are commonly available, 31 but values received from a laboratory should be evaluated in the context of that particular laboratory's reference ranges. Basic laboratory tests available for blood include morphologic assessment, cell counts, and derived indices. ~Iarrow aspiration and core biopsy are required to confirm many diseases. :\ wide range of ancillary tests are available, such as special stains, iron status (total iron binding capacity, serum iron, percent saturation), antibody •Diplomate, American College of Veterinary Internal Medicine; Associate Professor, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada 7 Postdoctoral Fellow, Department of Pathology, University of Toronto, Toronto, Ontario, Canada \'eterinary Clinics of North America: Small Animal Practice-Yo!. 20, No. 4, July 1990

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tests, parasitology, hormone assays, cell function tests, and coagulation tests. Erythron Anemia. Anemia represents a deficiency of red cells due to either decreased cell production or increased cell loss. Determination of responsiveness, as indicated primarily by reticulocyte count relative to the degree of anemia, will suggest a further restriction of possible causes. Morphologic abnormalities and values of calculated indices, such as hypochromia and low mean corpuscular hemoglobin concentration, are useful clues which Sl!ggest more specific causes. The diagnostic approach to anemia has recently been reviewed. 31 • 34• 63 Responsive anemia occurs when there is a functional response to a peripheral demand for red cells communicated by erythropoietin. Response requires usable iron, stem cell capacity, functional differentiation, marrow microenvironment, eythropoietin and other specific growth factors, and time. The differential diagnosis for responsive anemias would include any situation where these requirements are not limiting (Table 1). Nonresponsive anemia occurs when one or more required capacities for functional red cell production are limiting. Frequent limiting requirements are stem cells, marrow space, and usable iron. The differential diagnosis for nonresponsive anemias is outlined in Table l. Anemia is commonly associated with cancer. The association may result

Table 1. Differential Diagnoses for Anemia and Polycythemia RESPONSIVE ANEMIA Blood loss Acute or chronic internal blood loss Acute external blood loss (chronic external blood loss may appear nonresponsive), including blood loss secondary to thrombocytopenia Hemolysis: intravascular or extravascular Immune hemolytic anemia Parasites Drug-induced hemoglobin denaturation, eg, acetaminophen Mechanical fragmentation secondary to vascular shunting, vascu)opathy, DIC, parasites, enzyme deficiencies NONRESPONSIVE ANEMIA Anemia of chronic disease Chronic renal failure (erythropoietin deficiency) Primary marrow problem: myelophthisis, myelodysplasia, erythroid aplasia/dysplasia/ leukemia (especially, FeLV-related marrow abnormalities in cats); drug/chemical marrow toxicity Secondary to decreased metabolic rate: thyroid, pituitary endocrine hypofunction Iron deficiency, including severe chronic external blood loss POLYCYTHEMIA Primary Polycythemia vera Secondary Tissue hypoxia: arteriovenous shunting, pulmonary disease Primary renal carcinoma, benign renal lesion, or other tumors causing increased erythropoietin activity

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directly from cancer of the hemic-lymphatic system, or indirectly through systemic effects of cancer. Anemia caused by hemopoietic cancer will be detectable by examination of hemopoietic tissues: blood, bone marrow, spleen, thymus, and lymph nodes. Erythroid malignancy can cause severe anemia if there is an early block in differentiation. Erythremic myelosis (relatively common in the cat) and the more rare erythroleukemia are acute leukemias of the red cell series whic;h paradoxically result in severe, nonresponsive anemias. Defective maturation of red cells causes decreased release of cells from the marrow, decreased circulation time, and defective red cell function. Diagnosis is based upon finding marked peripheral rubricytosis without polychromasia or reticulocytosis, marked size variation of red cells (anisocytosis), circulating erythroid blasts, and a hypercellular marrow packed with immature erythroid precursors. Myelodysplastic syndromes, such as refractory anemia with excess blasts (RAEB, more common in the cat) can also cause anemia with marrow abnormalities such as hyperplasia or hypoplasia with increased blasts and defective cell maturation. 63 Nonerythroid leukemias, as well as lymphoma, can cause severe nonresponsive anemias. Usually, the anemia is caused by the malignant cell mass physically displacing the erythroid precursors from preferred microenvironments in the marrow; this process is called phthisis or myelophthisis and is a common cause of deficient cell production secondary to marrow cancer. In cases of acute leukemias, severe anemia is often present as a direct result of phthisis and also secondary to hemorrhage due to phthisic thrombocytopenia. Diagnosis of phthisic anemia is confirmed by finding erythroid hypoplasia and significant malignant infiltration in aspirates or core biopsies of marrow. Anemia associated with marrow abnormalities (such as myelodysplasia, aplasia, or leukemia) secondary to feline leukemia virus or feline immunodeficiency virus infection is common in cats. 53 Mild to moderately severe normochromic normocytic nonresponsive anemia is a common finding in patients with cancer. Anemia as a systemic sign secondary to cancer is usually anemia of chronic disease. Pathogenetic mechanisms include the following: physiologic sequestration of iron into unusable forms (increased marrow hemosiderin deposits, decreased serum iron, decreased percent iron saturation, and shortened red cell lifespan due to tissue-associated destruction), decreased serum erythropoietin activity, and subnormal response to circulating erythropoietin. Anemia and decreased red cell circulation time may occur after fragmentation caused by disseminated intravascular coagulation (DIC), \'ascular anomalies, or microangiopathy in tumors such as splenic lymphoma or hemangiosarcoma. Schistocytes (torn red cells) and thrombocytopenia may be detectable. 25 · 31• 63 Where cancer is the cause, there may be further exacerbation of the anemia due to chronic hemorrhage (common for gastrointestinal, cutaneous, bladder, and hemangiomatous tumors), circulating toxins, autoantibodies, or deficits of function in organs which help maintain functional red cell mass. Examples of the latter are decreased serum erythropoietin activity due to chronic renal failure, excessive red cell sequestration due to splenic enlargement and hypersplenism, or decreased synthesis of hemoglobin due

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to protein deficiency caused by gastrointestinal insufficiency, all secondary to malignancies of the affected·organs. Diagnosis is based upon recognition of the anemia on screening and then determination of the primary cause through further examination and testing. Life-threatening anemia can be treated by transfusion of whole blood or fractionated red cells, but eventually management of anemia is based upon finding the cause. In anemia secondary to malignancy, effective anticancer therapy is indicated regardless of the actual mechanism of anemia (e.g., differentiation block, phthisis, anemia of chronic disease, hemorrhage, . red cell fragmentation, organ function deficit). Response to therapy can be aided by symptomatic treatment with hematinics and anabolic steroids. However, iron supplementation' may lead simply to iron overload if it is unnecessary, excessive, or essentially unusable due to sequestration mechanisms. Also, estrogen, chloramphenicol, and other drugs have been associated with drug-induced marrow aplasia. Polycythemia. Polycythemia is a true increase in circulating red cells. Spurious causes of polycythemia such as excitation upon sampling, dehydration, clotted samples, or erroneous counts should be ruled out. True polycythemia can be caused by erythroid malignancy (polycythemia vera) or can be secondary to other diseases including tumors. The differential diagnosis of polycythemia has been recently reviewed 31 • 63 and is outlined in Table l. Polycythemia vera is a chronic myeloproliferative disease characterized by autonomous production of red cells independent of serum erythropoietin levels. Diagnosis is based upon the demonstration of very high peripheral red cell count and a hypercellular marrow with extreme erythroid hyperplasia despite normal or reduced serum erythropoietin. Given the rarity of this tumor, a concerted effort should be made to rule out secondary polycythemia. Secondary polycythemia is caused by a functional marrow response to a perceived requirement for increased red cell mass. The pathogenesis is usually increased erythropoietin secondary to tissue hypoxygenation, but increased secretion of erythropoietin by renal carcinoma or other tumors may occur. 55 Diagnosis is based upon an increase in peripheral red cell count, increased serum or urinary erythropoietin activity, low blood oxygen saturation and a causal lesion (e. g., arteriovenous shunting), or renal lesion. The polycythemic patient may require emergency phlebotomy and hydration if the packed cell volume is high enough to cause vascular sludging. Further management is aimed at the primary cause. Abnormal Red Cell Morphology. Alterations of red cell morphology frequently provide important clues to the presence of tumor. Red cells with abnormal shape are referred to as poikilocytes in a general sense. Types of poikilocytosis associated with tumor include (1) schistocytes due to DIC, hemangiosarcoma, arteriovenous shunting, vasculopathy, or valvular stenosis; (2) ovalocytes due to marrow fibrosis or phthisis, and (3) poikilocytes, Howell-Jolly bodies, and rubricytes due to splenic hypofunction. Increased rubricytes may also indicate extreme peripheral demand or defective release of immature red cells from the marrow. Splenic heman-

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giosarcoma in dogs is frequently associated with recurring bouts of responsive anemic crisis, Howell-Jolly bodies, poikilocytes, and rubricytes. Leukon

Leukopenia. Leukopenia is defined as an abnormally low number of circulating white cells, often specifically defined by cell type (neutropenia, lymphopenia, and so on). The differential diagnosis of leukopenia has recently been reviewed31 • 37• 63 and is outlined in Table 2. Leukopenia may be caused by marrow cancer, systemic response to cancer, or therapy for cancer. Any tmnor of the hemic-lymphatic system can cause leukopenia. Most commonly, the pathogenesis is deficient production of normal cells due to malignant infiltration of the marrow (phthisis). Acute myelogenous leukemia may cause leukopenia of even the affected cell type due to a block in differentiation, resulting in impaired release of cells from the marrow and decreased circulating time. Chronic myelogenous leukemia usually causes a massive increase in the specific affected cell lineage while causing phthisic decreases in other cell lineages. Diagnosis is based upon examination of peripheral blood and bone marrow. Demonstration of hemopoietic malignancy with coexisting reduction of benign myeloid series is diagnostic. Chronic or cyclic leukopenia is associated with FeLV infection in the cat, often predating eventual marrow aplasia, myelodysplasia, or frank Table 2. Differential Diagnoses for Leukopenia '\EUTROPENIA Excessive consumption Diffuse or localized inflammation, especially viral or bacterial Steroid responsive neutropenias (presumably immune related) Deficient production (primary marrow problem) Stem cell insufficiency: viral or rickettsial disease (eg, parvovirus, FeLV, FIV, Ehrlichia canis), drug toxicity or idiosyncratic reaction (eg, anticancer drugs, chronic estrogen therapy, chloramphenicol in cats) :\lyelophthisis, leukemia, myelodysplasia, myelofibrosis, myelosclerosis Cyclic hematopoiesis (gray collie syndrome) \largination Endotoxin or interleukin related LHIPHOPENIA Redistribution and decreased production Corticosteroid therapy or acute endogenous release Endocrine disease (pituitary, adrenal) Deficient production \lyelophthisis, leukemia Toxicity of hemic-lymphatic system including chemotherapy, radiotherapy Stem cell insufficiency: viral infection, congenital deficiency Excessive consumption: chylothorax or other chronic losses of lymph, diffuse inflammation (especially body surfaces) EOSINOPENIA Hyperadrenocorticism (pituitary, adrenal) Corticosteroid therapy or acute endogenous release Chemotherapy or other toxicity

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leukemia. Lymphopenia and overt malignancy have been associated with feline immunodeficiency virus. 28 Leukopenia secondary to systemic cancer is usually caused by consumption in excess of supply, or toxic depression of the marrow (eg, estrogen-secreting Sertoli cell tumors in the dog). Diagnosis is based upon demonstrating a site of excessive loss or consumption, detection of the tumor, and failure to find detectable metastasis to the marrow. Leukopenia is often the major complication limiting cancer therapy. Several anticancer agents are myelosuppressive (see Dr. Couto's article in this issue). Leukocytosis. Leukocytosis is defined as an abnormally high increase in circulating leukocytes, usually specifically identified by cell type (eg, neutrophilia, lymphocytosis, and so on). The differential diagnosis of leukocytosis has been recently rev1ewed 31 · 37• 63 and is outlined in Table 3. Leukocytosis associated with cancer may be caused by hemopoietic malignancy or myelodysplastic syndromes, nonhemopoietic tumors, and certain antitumor therapies. Chronic myeloid leukemias are recognized by marked to extreme leukocytosis of the affected cell type. Acute myeloid leukemias may cause anything from marked leukopenia to marked leukocytosis of the affected Table 3. Differential Diagnoses for Leukocytosis NEUTROPHILIA Redistribution Physiologic Drugs (corticosteroids, epinephrine) Infection: viruses, bacteria, rickettsia, parasites, fungi Inflammation, necrosis, tumor (release of interleukins, tissue pyrogens) Crossover response to stimulation of other lineages, e.g., in ITP, IHA Immune-related disease, e.g., SLE Stem cell stimulation by drugs, e. g., early phase of estrogen response, hemopoietic factors Myeloid malignancy Compensatory in state of neutrophil dysfunction LYMPHOCYTOSIS Endocrine Physiologic in the cat Hypoadrenocorticism (minority) Chronic antigenic stimulation: sepsis, inflammation, autoimmune disease, tumor Lymphoid malignancy (leukemia, lymphoma, thymoma) MONOCYTOSIS Infection: inflammation, tissue necrosis of almost any cause including tumor Leukemia: myelomonocytic or monocytic Cyclic hematopoiesis (gray collie syndrome) EOSINOPHILIA, BASOPHILIA, MASTOCYTEMIA Benign eosinophilia, basophilia Parasitism Inflammation of body surface, especially allergic etiologies Tumor Eosinophilic leukemia (rare) H ypereosinophilia syndromes Basophilic malignancy (rare) Mast cell tumor; mast cell leukemia (rare)

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cell type, but usually are associated with a mild to moderate increase in cell count. Leukocytosis is directly related to the malignant proliferation of a developmentally arrested and clonal cell population. Diagnosis is confirmed by finding marked myeloid hyperplasia with a marked increase of blasts, maturation arrest, and abnormal differentiation of the affected cell line in the bone marrow. Myelodysplastic syndromes may cause increased cell counts early in the course of disease but usually terminate with reduced marrow output. Hypereosinophilia syndromes must be distinguished from allergic reactions or inflammation caused by parasites. Consideration must also be given to other conditions which mimic myeloid malignancy, such as extreme benign reactive leukocytosis, Chediak-Higashi syndrome, Pelger Huet anomaly, and cyclic hematopoiesis. In particular, differentiating severe immune hemolytic anemia with myeloid response from acute myelogenous leukemia may be difficult. Leukocytosis may be secondary to nonhemopoietic malignancy, reflecting systemic inflammatory response or production of cytokines by the tumor. Increases in neutrophils, lymphocytes, and monocytes may be associated with release of pyrogens, endogenous corticosteroids, specific and nonspecific antitumor responses, or sepsis secondary to tumor. Diagnosis is based upon finding the inciting cause, appropriate inflammatory response, and absence of marrow metastases. Leukocytosis may occur secondary to therapy for cancer. The outstanding example is mature neutrophilic leukocytosis (often with hypersegmented neutrophils) caused by redistribution of neutrophils to circulation after prednisone therapy. Lymphocytotoxic dosage with prednisone for lymphocytic malignancies or immune disorders may cause lymphopenia as well. Surgical or radiotherapeutic eradication of tumor may cause inflammatory responses. Diagnosis is usually obvious upon consideration of clinical history. Management of leukocytosis depends on the cause. Leukocytosis due to myeloid malignancy will respond only to appropriate cytotoxic therapy. Extreme leukocytosis, as seen in chronic myeloid and lymphocytic leukemia, may cause vascular sludging and diffuse intravascular coagulation related to cell count or abnormal function. Emergency therapy may consist of phlebotomy or leukopheresis and fluid therapy. Inflammatory leukocytosis secondary to nonhemopoietic malignancy or therapy rarely requires anything other than periodic assessment. Thrombon

There are detailed reviews of diagnosis and management of coagulopathies and platelet disorders in recent issues of this series 19 · ·52 and elsewhere. 31 • 63 Thrombocytopenia. Thrombocytopenia is defined as an abnormally low number of circulating platelets. The differential diagnosis of thrombocytopenia has been reviewed 20· 31 · 32 and is outlined in Table 4. Thrombocytopenia may be associated with hemopoietic malignancy, nonhemopoietic malignancy, and cancer therapy. 8· 25· 51 Functional clotting and vascular hemostasis depend upon tissue and blood clotting factors, platelet function, and platelet number. Thrombocytopenia alone, even with counts as low as 5000 per

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Table 4. Differential Diagnoses for Platelet Disorders THROMBOCYTOPENIA Increased loss or sequestration: Immune-mediated Primary: idiopathic, associated with SLE, concurrent with IHA Secondary to exposure to many drugs, lymphoid tumors Modified live virus vaccination Hemorrhage Chronic infection

DIC Microangiopathy Splenic lesions, hypersplenism (increased sequestration) Decreased production:

Primary marrow problem Myelophthisis due to leukemia or metastatic tumor Megakaryoblastic myelosis (rare), chronic phase of myelodysplastic syndrome Marrow toxicity/stem cell death, e.g., drugs, irradiation, infection, Sertoli cell tumor THROMBOCYTOSIS Primary marrow problem Secondary to marrow response to anemia, neutropenia Megakaryocytic myelosis (rare), early phase of myelodysplastic syndrome Reactive, secondary to inflammation, infection, hemopoietic or other tumors Chronic hemorrhage Iron deficiency ABNORMAL PLATELET FUNCTION Secondary or acquired: Drug-induced, e.g., nonsteroidal anti-inflammatory drugs, heparin, many others Leukemia or myeloproliferative disease Immune-mediated thrombocytopenia Systemic lupus erythematosus Liver, renal disease Abnormal plasma proteins Pancreatitis, diabetes, hyperadrenocorticism, tumor Congenital (rare)

liter, 52 may be insufficient to cause significant hemorrhagic diathesis if the few platelets which are circulating are well granulated and functional. Recognition of a clotting disorder should prompt consideration of all possible causes. Acute leukemias classically come to attention because of acute, severe, and diffuse hemorrhage secondary to thrombocytopenia. In the case of acute leukemias, the primary mechanism is phthisis of marrow megakaryocytes. Malignant infiltration is so rapid that the megakaryocytes do not have time to respond to crowding by expanding into less appropriate marrow microenvironments. Chronic leukemias and lymphoma metastatic to bone marrow may also cause thrombocytopenia due to paraneoplastic immune mechanisms. 25 Phthisis in myelodysplasia, chronic leukemia, or metastatic lymphoma occurs in late-stage disease, because the megakaryocytes have sufficient time to expand into free marrow space and thus develop functional

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accommodation until late in the course of disease. 63 Diagnosis of thrombocytopenia secondary to marrow malignancy is based upon finding peripheral thrombocytopenia, adequate clotting factors, leukemia or lymphoma or other tumor metastatic to marrow, and reduction in marrow megakaryocytes. Thrombocytopenia may occur, paradoxically, due to megakaryoblastic myelosis (acute leukemia of platelets). Developmental arrest causes failure of cytoplasmic maturation of megakaryocytes, resultin'g in functionally deficient as well as decreased numbers of platelets (thrombocytosis has also been reported). Diagnosis is based on thrombocytopenia, circulating giant platelets and megakaryocytic blasts, and marrow hypercellularity with markedly increased megakaryocytic blasts, developmental arrest of megakaryocytes, phthisis of other lineages, and myelofibrosis. 31 • 63 Thrombocytopenia may occur secondary to other tumors. Major mechanisms are consumption or sequestration due to such causes as DIC, hemorrhage, hypersplenism, clotting factor deficiencies, microangiopathy, vasculitis, and marrow toxicity. 25 · 31 • 51 • 63 Diagnosis is based upon finding the primary cause and demonstrating a functional marrow megakaryocytic response. A wide variety of cancer drugs can cause thrombocytopenia, including cyclophosphamide, dacarbazine, vincristine, and doxorubicin. 23 • 24 • 51 Diagnosis is suggested by clinical history, and withdrawal of the inciting drug is usually sufficient treatment. 24 Management of thrombocytopenia depends upon the primary cause. In life-threatening situations, the immediate action should be to restore vascular integrity by supplying fresh platelets or whole blood. 46 Thrombocytopenia secondary to marrow malignancy will respond to cytotoxic therapy. Thrombocytopenia secondary to systemic cancer will respond to treatment appropriate for the mechanism. For example, thrombocytopenia secondary to DIC may respond to emergency treatment for DIC, but upon survival of the crisis, the inciting tumor must still be treated. Thrombocytosis. Thrombocytosis is defined as an abnormal increase in circulating platelets. Again, it should be noted that vascular integrity is dependent upon functional as well as numerical platelet capacity. The differential diagnosis of thrombocytosis has been reviewed recently20 and is outlined in Table 4. Thrombocytosis may be caused by hemopoietic malignancy, myelodysplastic syndromes in early phase, and a variety of other tumors. Megakaryocytic myelosis is a rare chronic leukemia of the megakaryocytic lineage. Diagnosis is made upon finding extreme thrombocytosis with shift platelets, a hypercellular marrow with markedly increased megakaryocytic blasts exhibiting asynchrony of nuclear and cytoplasmic differentiation, and phthisis of other lineages. The immediate danger is hemorrhage, thrombosis, vascular sludging, or DIC due to the circulating abnormal platelets. Phlebotomy, rehydration, transfusion with separated blood products, and cytotoxic therapy are possible actions. Subsequently, there is a risk of widespread hemorrhage due to platelet functional deficits. Myelodysplastic syndromes may also cause thrombocytosis early in the course of disease, but less severe in degree. A variety of hemopoietic and nonhemopoietic tumors may induce a

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reactive thrombocytosis, 20• 25 including chronic myelogenous leukemia, polycythemia vera, and carcinomas. Thrombocytosis may also occur due to chronic bleeding and iron deficiency anemia associated with the presence of tumor. Increased, small platelets are produced due to a cross-over effect of hemopoietic factors released in response to the anemia. Platelet Function Defects. Platelets may be deficient in function, resulting in hemorrhage or thrombosis. The differential diagnosis of platelet function defects has been reviewed recentlyB· 25 • 31 • 32 · 51 • 63 and is outlined in Table 4. Abnormal platelet activity due to cancer may be caused by megakaryocytic malignancy, or may be secondary to other tumors. The most direct association of platelet function defects with cancer occurs with megakaryocytic and. megakaryoblastic myelosis. Defective cytoplasmic maturation results in poor platelet granulation. For megakaryoblastic myelosis, the functional defects compound a situation already made severe by the possible decrease in platelets released from the marrow. Functional defects in megakaryocytic myelosis may be masked by the extreme thrombocytosis present until effective therapy is instituted. Management is aimed at addressing the deficiency with platelet-rich plasma while treating the primary problem. Monoclonal gammopathies and various tumors can cause acquired defects of platelet function. 8 • 25 • 46 · 51 Decreased platelet adhesion leading to thrombosis is one mechanism. Diagnosis is based primarily on excluding other possible causes of hemorrhage and finding the tumor. Treatment of coagulation disorders secondary to platelet defects has been reviewed. 46

ABNORMALITIES OF THE SERUM BIOCHEMISTRY PANEL Hypercalcemia The value for serum calcium reported by the laboratory represents the total plasma calcium concentration, which is composed of calcium bound to albumin and other molecules, and ionized, biologically active calcium. Alterations in albumin concentration may be associated with changes in measured calcium. Formulas have been derived which correct the total calcium value when abnormalities in albumin or total protein are present47 : Corrected calcium (mg/dL) Corrected calcium (mg/dL)

=

measured calcium (mg/dL) - albumin (g/dL) + 3.5 measured calcium (mg/dL) - 0.4[total serum protein (g/dL)]

+ 3.3

If the animal is hypoalbuminemic and the calcium value is not corrected, the diagnosis of hypercalcemia may be missed. Corrected values of calcium greater than 12 mg/dL are considered diagnostic of hypercalcemia; however, the normal range varies among laboratories, and the clinician should always interpret the value with respect

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to the specific reference values for that laboratory. 65 The most common cause of hypercalcemia in dogs is malignancy-associated hypercalcemia 1\IAHC). 44 Malignancy-associated hypercalcemia has been reported in the cat, although infrequently. A variety of malignancies are associated with \IAHC, including lymphoma, apocrine cell adenocarcinoma of the anal sac, adenocarcinoma of the mammary gland, thyroid carcinoma, epidermoid carcinoma, thymoma, fibrosarcoma, gastric carcinoma, adenocarcinoma of the exocrine pancreas, primary bone tumors, metastatic bone tumors, squamous cell carcinoma, bladder tumors, interstitial cell tumor, and seminoma. 65 The initial, and most common, clinical signs of MAHC are polyuria and polydypsia. These result from a reversible reduction in cAMP levels in antidiuretic hormone-responsive. renal distal tubular cells, and the development of a form of nephrogenic diabetes insipidus. Additionally, a decrease in renal sodium and chloride resorption resulting in medullary washout may occur. 44 Hypercalcemia may also cause vasoconstriction, decreased renal blood flow, and decreased glomerular filtration rate. 2 The most important consequences of hypercalcemia are associated with decreased neuromuscular function and soft-tissue mineralization. Eventual calcification of the nephron causes proximal and distal tubular degeneration and necrosis. Depression, anorexia, dehydration, and vomiting occur when azotemia and renal insufficiency develop. Other neuromuscular signs may appear at this time, including weakness, cardiac arrhythmias, and coma. Two mechanisms are currently understood to lead to the development of MAHC. The first, local osteolytic hypercalcemia, is caused by direct infiltration of bone by tumor cells, which release locally acting substances that stimulate osteoclastic bone resorption. These substances are collectively termed osteoclast activation factor (OAF), and include interleukin-1, tumor necrosis factor, and lymphotoxin. 29 Prostaglandin E 2 also appears to be involved in local osteolytic hypercalcemia. 21 In dogs, this form of hypercalcemia has been associated with lymphoma, leukemias, and myeloma. It is less commonly associated with nonlymphoid solid tumors, but has been reported in dogs with mammary gland adenocarcinoma with bone metastases. 44 The second mechanism of MAHC is termed humoral hypercalcemia of malignancy (HHM). This is caused by the release of parathormone-like peptides or transforming growth factor-like peptides from the tumor. These factors stimulate osteoclastic bone resorption in bone remote from the neoplasm. Malignancy-associated hypercalcemia occurs in approximately 20% of canine lymphoma cases. 44 Conflicting data exist regarding the mechanism of MAHC in these dogs. Meuten et al48 reported increased osteoclastic bone resorption in hypercalcemic dogs, which was not associated with increased immunoreactive PTH or 1,25-dihydroxyvitamin D levels, but was associated with tumor infiltration of marrow and presumably the local production of a bone resorption-stimulating factor. More recently, however, Weir et al64 studied a series of dogs with lymphoma and MAHC and found increased bone resorption with no evidence of tumor at the site, and increased fractional phosphorus and nephrogenic cAMP (a marker of para-

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thyroid hormone bioactivity) excretion. Additionally, tumor extracts contained a PTH-like protein. The~e findings suggest that lymphoma-associated MAHC is mediated by HHM mechanisms. Apocrine cell adenocarcinoma of the anal sac occurs predominantly in female dogs and is associated with MAHC in approximately 80 to 90% of cases. 44 Complete tumor resection results in normocalcemia, whereas recurrence of the tumor is associated with hypercalcemia. A PTH-like peptide has been isolated from these tumors, suggesting a humorally mediated mechanism for the MAHC. 49 Hypercalcemia may occur with several other disorders (Table 5), including primary hyperparathyroidism (hyperplasia, adenoma, or carcinoma). The diagnosis is confirmed by demonstrating increased immunoreactive PTH levels; however, the interpretation of these assays has been complicated by the presence of normally occurring multiple, inactive fragments of PTH in plasma. Immunoreactive PTH assays are invalid in the presence of azotemia. A two-site intact human PTH assay has recently been validated for dogs, which may increase the utility of the test. 62 It is essential that proper blood sampling and handling be observed for these assays. The differential diagnoses of hypercalcemia also include mild hypercalcemia in young, growing animals, hypervitaminosis D (from diet or from cholecalciferol-containing rodenticides), acute and chronic renal insufficiency, hypoadrenocorticism, osteomyelitis, disuse osteoporosis, blastomycosis, and spurious elevations due to hyperlipidemia. 16· 22 • 50 The diagnostic approach to the animal with hypercalcemia includes a review of the history for vitamin D supplementation and clinical signs associated with hypercalcemia. A physical examination should be repeated, searching for hepatosplenomegaly, lymphadenopathy, lameness, bone pain, respiratory abnormalities, and masses associated with the anal sacs. The serum biochemistry panel should be repeated to verify the finding. Increases in both calcium and phosphorus concentrations are consistent with renal insufficiency, vitamin D toxicosis, and osteolytic lesions. The phosphorus concentration may be low, normal, or increased in primary hyperparathyroidism.3 The calcium concentration in MAHC may vary from day to day. 44 A CBC should be evaluated for evidence oflymphoma or leukemia. Table 5. Differential Diagnoses for Hypercalcemia Malignancy-associated hypercalcemia Lymphoma, apocrine cell adenocarcinoma of the anal sac, adenocarcinoma of the mammary gland, many other tumors Primary hyperparathyroidism Growing animals Hypervitaminosis D Dietary Cholecalciferol-containing rodenticides Acute and chronic renal insufficiency H ypoadrenocorticism Osteomyelitis Disuse osteoporosis Blastomycosis Spurious increase due to hyperlipidemia

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Thoracic radiographs may show signs consistent with neoplasia or blastomycoses. A radiographic bone survey can be evaluated for neoplastic osteolysis, myeloma, and demineralization (mild in MARC and primary hyperparathyroidism, moderate to severe in chronic renal disease and nutritional hyperparathyroidism). 67 Abdominal ultrasonography may show evidence of a liver mass. Lymph node and bone marrow biopsy may reveal neoplastic infiltration. Biopsies should be taken from any mass lesions. Finally, serum immunoreactive PTR levels can be determined. Malignancy-associated hypercalcemia is ultimately managed by appropriate management of the underlying neoplasm. The indications for management of hypercalcemia per se are not clear in veterinary medicine. In the authors' experience, nonazotemic animals with a Ca X P0 4 product less than 60 (below which soft-tissue mineralization is unlikely) do not require emergency management of the hypercalcemia .. We have observed dogs with apocrine cell adenocarcinoma of the anal sac that have had hypercalcemia for months, with an inability to concentrate urine and mild polyuria and polydipsia; the dogs did not develop azotemia within this period. We attempt to reduce calcium concentrations in animals with a Ca X P0 4 product greater than 60; and animals with azotemia, cardiac arrhythmias, or neurologic signs should be managed aggressively. The initial management of MARC is the restoration of intravascular volume with 0.9% saline. This reduces calcium concentrations by dilution, increases renal perfusion, and induces a sodium-dependent calciuresis. Once hydration has been established, furosemide (2 mg/kg body weight IV bid to tid) can be given to maintain the calciuresis. 44 The fluid rate can be increased to one and one-half to two times maintenance rates, and maintained until normocalcemia is achieved. Prednisone, given at a dose of 2 to 3 mg/kg body weight daily, is usually listed as adjunctive therapy for hypercalcemia. 22 • 65 Proposed mechanisms of action include antagonism of vitamin D metabolities and PTR, interference with calcium absorption from the gut, increasing renal excretion of calcium, and, in lymphoreticular malignancies, a direct tumor effect. 65 We do not administer prednisone to animals in which the underlying cause of hypercalcemia is not obvious, because the antineoplastic effect may make the diagnosis of lymphoma more difficult. Diphosphonates are synthetic analogues of inorganic pyrophosphate which inhibit hydroxyapatite crystal growth and dissolution. Dichloromethylene diphosphate, an investigational drug, may prove to be helpful in the management of hypercalcemia at a dose of 10 to 30 mg/kg body weight PO bid to tid. Diphosphate etidronate (Didronel, Norwich-Eaton Pharmaceuticals, Norwich, NY) is commercially available but has not been evaluated in dogs. 21, 44 Several other management approaches to MARC have been reported, but are probably not as useful as the ones previously described. Prostaglandin inhibitors (aspirin, indomethacin, piroxicam) have been used in humans to manage hypercalcemia; however, they have not been critically evaluated in veterinary medicine. 21 Prostaglandins may not be the primary mediator of MARC in dogs, except in metastatic carcinoma to bone. 44 Mithramycin inhibits bone resorption, and is associated with a rapid fall in serum calcium concentration. 21 A dose of 25 g/kg body weight IV once daily for 2 to 4 days

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with fluid therapy has been suggested for dogs, but is associated with thrombocytopenia, hepatic and renal necrosis, and hypocalcemia. 44 Mithramycin should be used only in cases refractory to other forms of therapy. Calcitonin transiently inhibits bone resorption, and the action may be prolonged by the concurrent administration of glucocorticoids. 21 The use of calcitonin has not been reported in dogs. Hypoproteinemia

Abnormalities in protein concentration may initially be identified either as a decrease in total proteins on the complete blood count, or as low globulin and/or albumin concentration on the serum chemistry panel. Hypoproteinemia can be caused by either decreased synthesis or increased loss of albumin and, in some disorders, by increased loss of globulins. A decrease in globulin synthesis leading to hypoproteinemia is rare in adult animals. The plasma half-life of albumin is approximately 23 days; thus, synthetic failure must persist for several weeks before hypoalbuminemia occurs. 9 More than 70% of liver function must be lost before synthetic failure occurs. 18 Hypoalbuminemia was reported in 34% of dogs with metastatic liver disease, and hypoalbuminemia and hyperglobulinemia were reported in 83% of dogs with hepatocellular carcinoma. 45 • 59 Cancer cachexia is associated with decreased albumin synthesis and hypoalbuminemia. 60 Hypoproteinemia is commonly due to increased loss of proteins. This may occur secondary to blood loss from the tumor, or with protein-losing gastrointestinal malignancies. Hypoalbuminemia was also identified in a dog with pancreatic adenocarcinoma and secondary maldigestion. 6 Non-neoplastic causes of hypoalbuminemia include failure of albumin synthesis associated with a variety of chronic liver diseases, and increased loss associated with inflammatory and severe malabsorptive gastrointestinal disease, lymphangectasia, glomerular disease, severe cutaneous injury, and starvation. Differential diagnoses of hypoproteinemia are summarized in Table 6. The clinician should attempt to localize the cause of hypoproteinemia with the initial diagnostic approach, beginning with the determination of serum albumin and globulin levels. Hypoalbuminemia with normal globulin levels is often seen with glomerular loss; hypoalbuminemia with hypoglobTable 6. Differential Diagnoses for Alterations in Plasma Protein Levels HYPOPROTEINEMIA Liver failure of any cause Protein-losing enteropathies of any cause Glomerulonephritis or amyloidosis Cancer cachexia Blood loss MONOCLONAL GAMMOPATHIES Myeloma, plasma cell leukemia, lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia Ehrlichia canis Amyloidosis Benign hyperglobulinemia

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ulinemia is usually seen with gastrointestinal loss; and hypoalbuminemia with hyperglobulinemia may be associated with chronic liver disease. Urine protein, sediment, and protein:creatinine ratio should localize the problem further to the urinary system. Gastrointestinal losses are usually associated with a history of diarrhea. Liver enzyme activity, serum bile acid levels, and liver radiographs or ultrasound should localize the disorder in hepatic disease. The management of hypoproteinemia is dependent upon controlling the primary disorder. Hyperalimentation with low-carbohydrate, highprotein solutions may benefit animals with cancer cachexia. 13 Plasma transfusions (ire not usually effective for albumin replacement in animals with chronic disease, due to the massive total body deficit of albumin. 56 Hyperproteinemia

Pathologic hyperproteinemia is due to increased globulin concentrations. Albumin concentration is only increased by dehydration. Serum protein electrophoresis allows the differentiation of a general increase of globulins from increased concentration of a single immunoglobulin or immunoglobulin fragment. Polyclonal gammopathies are increases of all globulins, and have been associated with bacterial and mycotic infections, heartworm disease, feline infectious peritonitis, infection with FeLV, a variety of neoplasms, chronic active liver disease, granulomatous disease, amyloidosis, and immune-mediated disorders. 68 Monoclonal gammopathies are increased concentration of the secretory product (M-protein) of a single monoclonal line of immunoglobulin-producing cells, and are most commonly associated with a neoplastic process. The .M-proteins have limited electrophoretic mobility and are identified by electrophoresis as a single peak. Monoclonal proteins are sometimes identified in urine as Bence-Jones proteins; a specific assay is required, however, because Bence-Janes proteins are not identified by urine dipstick methods. Urine electrophoresis can also be used to identify urine M-proteins. Tumors associated with monoclonal gammopathies are myeloma, plasma cell leukemia, lymphoma, chronic lymphocytic leukemia, and primary macroglobulinemia. 12• 42 The type of secretory product can be determined by immunoelectrophoresis. Myeloma is associated with increased monoclonal IgG or IgA, whereas macroglobulinemia is due to increased lgM. Non-neoplastic disorders have also been associated with monoclonal gammopathies (Table 6), and include Ehrlichia canis infection, amyloidosis, and benign hyperglobulinemia. 5· 27· 58 Bleeding is a relatively common consequence of hyperproteinemia. Impairment of platelet aggregation results from the coating of platelets with ~1-protein. These proteins also coat the vascular endothelium and may interfere with clotting protein activity. 4 Signs include epistaxis, gingival bleeding, ecchymosis, petechiation, and gastrointestinal bleeding. M-protein coating of red blood cells has rarely been associated with immunemediated anemia. 61 Extreme increases in M-protein concentration may cause plasma hyperviscosity and microvascular stasis. Clinical signs ofhyperviscosity include depression, ataxia, coma, dementia, fundic venous tortuosity and retinal

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hemorrhage or detachment, and rarely, congestive heart failure. 40 Hyperviscosity is usually associated with IgM or IgA gammopathies; approximately 30% of dogs with myeloma have this syndrome. 42 The measurement of serum viscosity is required to document hyperviscosity syndrome. The management of hyperviscosity syndrome requires plasmapheresis. 43 The diagnostic approach to an animal with hyperproteinemia includes evaluation of serum albumin and globulin levels, serum protein electrophoresis, determination of Bence-Jones proteinuria, bone marrow biopsy, and radiographic bone survey for osteolytic lesions associated with multiple myeloma. Hypoglycemia

Hypoglycemia can be seen in animals with a variety of tumors. Clinical signs of hypoglycemia depend upon the rate of fall, duration, and absolute value of blood glucose. Concentrations below 50 mg/dL are usually clinically significant. Signs include weakness, hunger, disorientation, seizures, ataxia, muscle fasciculations, posterior paresis, and behavioral abnormalities. Tumor-associated hypoglycemia is seen most frequently in dogs with functional beta cell tumors of the pancreas. Hyperinsulinemia results from unregulated secretion of insulin from neoplastic cells. Hypoglycemia has been documented in non-islet cell tumors, most frequently liver tumors, including hepatomas, hepatocellular carcinoma, and hepatic hemangiosarcoma and leiomyosarcoma. 39 Non-hepatic malignancies associated with hypoglycemia include metastatic oral melanoma, metastatic hemangiosarcoma, salivary gland adenocarcinoma, lymphocytic leukemia, plasma cell tumors, mammary adenocarcinoma, and primary pulmonary carcinoma. 15• 39· 66 With these tumors, hypoglycemia is due to the release of insulin-like peptides or growth factors. 39 These peptides have been called non-suppressible insulin-like activity, or somatomedins, and are normally produced in the liver under growth hormone regulation. Other mechanisms of hypoglycemia include massive destruction of the liver by tumor, or the release of factors which inhibit the release of insulin and glucagon. The ectopic release of insulin from these tumors is extremely rare. 39 Non-neoplastic causes of hypoglycemia in the adult animal include hypoadrenocorticism, hepatic lipidosis, cachexia, sepsis, ketotic hypoglycemia in the pregnant bitch, and hunting dog hypoglycemia. 17• 26 • 35 Differential diagnoses for hypoglycemia are outlined in Table 7. The work-up of an adult animal with hypoglycemia includes a complete Table 7. Differential Diagnoses for Hypoglycemia in the Adult Animal Insulin-secreting islet cell tumors, liver tumors, miscellaneous other neoplasms H ypoadrenocorticism Hepatic failure of any cause Sepsis Ketotic hypoglycemia in the pregnant bitch Hunting-dog hypoglycemia Spurious hypoglycemia due to delay in processing sample

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blood count, urinalysis, serum biochemistry panel, thoracic radiographs, and abdominal radiographs or ultrasound. The demonstration of increased insulin activity during hypoglycemia is diagnostic for an islet cell tumor. Immunoreactive insulin (IRI) should be determined on a sample obtained when the animal is hypoglycemic. If the IRI level is not increased, the "appropriateness" of the IRI value with respect to glucose concentration can be determined by using the amended insulin glucose ratio: IRI J.LU/mL X 100 serum glucose (mg/dL) - 30 The normal ratio is less than 30. 36 This ratio may give false-positive results in dogs with liver disease, sepsis, and non-islet cell tumors. 38 These disorders should be ruled out before applying the calculation. The management of hypoglycemic crisis involves the infusion of glucose-containing solutions (1 to 10 mL 25% glucose given into a large vein to minimize phlebitis). Once the animal is stable, it should be fed small meals four to six times daily that are high in protein, fat, and complex carbohydrates. Simple sugars and semimoist foods may provoke insulin release and should be avoided. Increased Liver Enzyme Activities Primary and metastatic liver tumors may be associated with an increase of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Alterations in bilirubin concentration are less common. There is no correlation between the magnitude of increase and the extent of tumor involvement. Clinical and biochemical abnormalities cannot differentiate between neoplastic and non-neoplastic liver disease. Increased serum alkaline phosphatase (SAP) activities result from enzyme induction caused by tumor-induced cholestasis, or an isoenzyme may be secreted by neoplastic tissue. 41 N onhepatic tumors associated with increased SAP activity include adrenocortical adenocarcinoma, mixed mammary tumor, hemangiosarcoma, lymphoma, and oral carcinoma. 57 Small increases may occur with osteosarcoma. 33 Non-neoplastic causes for elevated SAP activity include cholestasis of any etiology and drugs (corticosteroids, primidone, phenobarbital). 1• 7 Small increases may occur with bone healing and hyperparathyroidism. 17 In a case series reported by Strombeck, 59 100% of dogs with hepatocellular carcinoma had increases of serum ALT and SAP activity. Dogs with metastatic disease had elevated ALT in 46%, and elevated SAP in 50% of cases. McConnell and Lumsden45 reviewed 47 dogs with metastatic liver disease and found increased ALT in 62%, AST in 87%, SAP in 51%, and total bilirubin in 45% of cases. Seventy percent of cases had increased ALT or SAP. Extensive infiltration can also occur without alteration of enzyme activities. The approach to the animal with increased liver enzymes includes assay of serum bile acids and hepatic radiographs and ultrasound. A liver biopsy is required to confirm the disorder.

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Other Abnormalities Found on the Serum Biochemistry Panel

Increases of urea nitrogen and creatinine may occur in animals with malignancy. Prerenal azotemia is common in debilitated animals. Azotemia of renal origin has been reported with renal cell carcinoma, nephroblastoma, renal sarcoma, adenocarcinoma, papillary adenoma, and lymphoma. 10 Postrenal azotemia will occur if both ureters are obstructed by a trigonal mass. Increased serum lipase and amylase activity have been reported in dogs with pancreatic adenocarcinoma. 11 These dogs also had increases of ALT and SAP. The SAP level may be markedly increased when obstruction of the common bile duct by tumor occurs. ABNORMALITIES ON URINALYSIS

Inadequate urine concentrating ability may be observed in dogs with hypercalcemia or renal insufficiency from any cause. Gross and microscopic hematuria is a hallmark of neoplasia of the urinary tract. Proteinuria, pyuria, and bacteriuria often accompany hematuria in these patients. The differential diagnoses for hematuria should include bacterial infection of the urinary tract, urolithiasis, renal amyloidosis, strenuous exercise, trauma, parasites (Capillaria plica, Dioctophyma renale, Dirofilaria immitis), coagulopathies, glomerulonephritis, renal cysts, and idiopathic renal hematuria. The initial work-up of a mature animal with hematuria should include urine culture, plain and contrast radiographs, and ultrasonographic evaluation of the kidneys and bladder. Examination of the urine sediment may reveal neoplastic cells which exfoliate from bladder tumors, or from renal tumors that invade the renal pelvis or ureter. Squamous cell carcinoma and transitional cell carcinoma are tumors most likely to exfoliate cells. 54 Atypical cells can also be seen in urine from patients with bacterial or sterile cystitis. 14 Single atypical cells are not a significant indicator of malignancy; however, clusters of cells are highly suggestive of malignancy. Exfoliated cells may undergo alterations while floating in urine. Cellular detail may be optimized by emptying the bladder and collecting newly formed urine, or by washing the bladder with saline. 54 SUMMARY

In this problem-oriented review of abnormalities associated with cancer, we have emphasized distinctive diagnostic points related to pathogenesis for each condition and outlined how the approach to management is determined by pathogenesis. For abnormalities of the complete blood count, it is important to distinguish between abnormalities directly related to marrow malignancy and abnormalities associated with extramarrow malignancy. Hemopoietic tumors consist of developmentally deficient blood cells produced by a clonal population of malignant stem cells. Tumors infiltrating marrow cause

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overcrowding in the limited marrow microenvironment. Extramarrow malignancies cause blood abnormalities, but the potential for normal marrow function is present. Abnormalities of blood cells secondary to therapy are usually clearly identified by consideration of clinical history. The initial differential diagnosis for hypercalcemia is malignancy. An aggressive diagnostic approach may be needed to identify the neoplasm, and therapy should incorporate measures to prevent renal failure. Hypoproteinemia and hyperproteinemia may be caused by neoplasia. Monoclonal gammopathies should be identified and may be associated with hyperviscosity syndrome. Hypoglycemia in the adult animal is most frequently caused by insulin-secreting tumors, but it has also been associated with hepatic and other tumors. Increased blood urea nitrogen, creatinine, lipase, amylase, and liver enzyme activities may also be caused by malignancy. Inadequate urine concentrating ability may be caused by hypercalcemia or malignancy-associated renal insufficiency. Hematuria in older animals is suggestive of urinary tract neoplasia. Exfoliated tumor cells may be identified in the urine sediment of these patients.

REFERENCES l. Badylak SF, Van Vleet JF: Sequential morphologic and clinicopathologic alterations in

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 1.5. 16.

dogs with experimentally induced glucocorticoid hepatopathy. Am J Vet Res 42:1310, 1981 Benabe JE, Martinez-Maldonado M: Hypercalcemic nephropathy. Arch Intern Med 138:777, 1978 Berger B, Feldman EC: Primary hyperparathyroidism in dogs: 21 cases (1976-1986). J Am Vet Med Assoc 191:350, 1987 Bergsagel DE, Rider WD: Plasma cell neoplasms. In DeVita Vf, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology. Philadelphia, JB Lippincott, 1985, p 1776 Breitschwerdt EB, Woody BJ, Zerbe CA, et a!: Monoclonal gammopathy associated with naturally occurring canine ehrlichiosis. J Vet Intern Med 1:2, 1987 Bright JM: Pancreatic adenocarcinoma in a dog with a maldigestion syndrome. JAm Vet Med Assoc 187:420, 1985 Bunch SE, Castleman WL, Baldwin BH: Effects of long-term primidone and phenytoin administration on canine hepatic function and morphology. Am J Vet Res 46:105, 1985 Catalfamo JL, Dodds WJ: Hereditary and acquired thrombopathias. Vet Clin North Am [Small Anim Pract]18:185, 1988 Center SA: The biochemical evaluation of liver function in the dog and cat. In Kirk RW (ed): Current Veterinary Therapy IX, Small Animal Practice. Philadelphia, WB Saunders, 1986 Clein MK, Cockerell GL, Harrie CK, et a!: Canine primary renal neoplasms: A retrospective review of 54 cases. J Am Anim Hasp Assoc 24:443, 1988 Cornelius LM: Laboratory diagnosis of acute pancreatitis and pancreatic adenocarcinoma. Vet Clin North Am 6:671, 1976 Couto CG, Ruehl W, Muir S: Plasma cell leukemia and monoclonal (IgG) gammopathy in a dog. JAm Vet Med Assoc 184:90, 1984 Crow SE: Cancer cachexia. Camp Cont Ed 3:681, 1981 Crow SE: Urinary tract neoplasms in dogs and cats. Comp Cont Ed 7:607, 1985 DiBartola SP, Reynolds HA: Hypoglycemia and polyclonal gammopathy in a dog with plasma cell dyscrasia. JAm Vet Med Assoc 180:1345, 1982 Dow SW, Legendre AM, Stiff M, et a!: Hypercalcemia associated with blastomycosis in dogs. JAm Vet Med Assoc 188:706, 1986

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17. Duncan JR, Prasse KW: Veterinary Laboratory Medicine, ed 2. Ames, Iowa, Iowa State University Press, 1986, p 116 18. Duncan JR, Prasse KW: Veterinary Laboratory Medicine, ed 2. Ames, Iowa, Iowa State University Press, 1986, p 136 19. Feldman BF (ed): Hemostasis. Vet Clin North Am [Small Anim Pract], 18, 1988 20. Feldman BF: Quantitative platelet disorders. Vet Clin North Am [Small Anim Pract] 18:35, 1988 21. Fields ALA, Josse RG, Bergsagel DE: Metabolic emergencies. In DeVita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology. Philadelphia, JB Lippincott, 1985, p 1869 22. Finco DR: Interpretations of serum calcium concentration in the dog. Comp Cont Ed 5:778, 1983 23. Grindem CB: Bone marrow biopsy and evaluation. Vet Clin North Am [Small Anim Pract] 19:669, 1989 24. Handagama P, Feldman BF: Thrombocytopenia and drugs. Vet Clin North Am [Small Anim Pract] 18:51, 1988 • 25. Helfand SC: Platelets and neoplasia. Vet Clin North Am [Small Anim Pract]18:131, 1988 26. Hardie EM: Septic shock. Part I. Pathophysiology. Comp Cont Ed 5:369, 1983 27. Hoenig M, O'Brien JA: A benign hypergammaglobulinemia mimicking plasma cell myeloma. J Am Anim Hosp Assoc 24:688, 1988 28. Hopper CD, Sparkes AH, Gruffydd-Jones TJ, et a!: Clinical and laboratory findings in cats infected with feline immunodeficiency virus. Vet Rec 125:341, 1989 29. Insogna KL, Broadus AE: Hypercalcemia of malignancy. Annu Rev Med 38:241, 1987 30. Jacobs RM, Valli YEO: Bone marrow biopsies: Principles and perspectives of interpretation. Semin Vet Med Surg Small Anim 3:176, 1988 31. Jain NC: Schalm's Veterinary Hematology, ed 4. Philadelphia, Lea & Febiger, 1986 32. Johnstone IB: Clinical and laboratory diagnosis of bleeding disorders. Vet Clin North Am [Small Anim Pract] 18:21, 1988 33. Jongeward SJ: Primary bone tumors. Vet Clin North Am [Small Anim Pract]15:609, 1985 34. Kociba GJ: Erythrocytes. Vet Clin North Am [Small Anim Pract] 19:627, 1989 35. Kruth SA: Hypoglycemia. In Morgan RV (ed): Handbook of Small Animal Practice. New York, Churchill Livingstone, 1988, p 554 36. Kruth SA, Feldman EC, Kennedy PC: Insulin-secreting islet cell tumors: Establishing a diagnosis and the clinical course for 25 dogs. JAm Vet Med Assoc 181:53, 1982 37. Latimer KS, Rakich PM: Clinical interpretations of leukocyte responses. Vet Clin North Am [Small Anim Pract] 19:637, 1989 38. Leifer CE, Peterson ME, Matus RE: Insulin-secreting tumor: Diagnosis and medical and surgical management in 55 dogs. JAm Vet Med Assoc 188:60, 1986 39. Leifer CE, Peterson ME, Matus RE, et a!: Hypoglycemia associated with nonislet cell tumor in 13 dogs. JAm Vet Med Assoc 186:53, 1985 40. MacEwen EG, Hurvitz AI: Diagnosis and management of monoclonal gammopathies. Vet Clin North Am 7:119, 1977 41. Magne ML, Withrow SJ: Hepatic neoplasia. Vet Clin North Am [Small Anim Pract] 15:243, 1985 42. Matus RE, Leifer CE: Immunoglobulin-producing tumors. Vet Clin North Am [Small Anim Pract] 15:741, 1985 43. Matus RE, Leifer CE, Gordon BR: Plasmapheresis and chemotherapy of hyperviscosity syndrome associated with monoclonal gammopathy in the dog. J Am Vet Med Assoc 183:215, 1983 44. Matus RE, Weir EC: Hypercalcemia of malignancy. In Kirk RW (ed): Current Veterinary Therapy X, Small Animal Practice. Philadelphia, WB Saunders, 1989, p 988 45. McConnell MF, Lumsden JH: Biochemical evaluation of metastatic liver disease in the dog. JAm Anim Hosp Assoc 19:173, 1983 46. Meric SM: Drugs used for disorders of coagulation. Vet Clin North Am [Small Anim Pract]18:1217, 1988 47. Meuten DJ, Chew DJ, Capen CC, eta!: Relationship of serum total calcium to albumin and total protein in dogs. JAm Vet Med Assoc 180:63, 1982 48. Meuten DJ, Kociba GJ, Capen CC, et a!: Hypercalcemia in dogs with lymphosarcoma. Lab Invest 49:553, 1983 49. Meuten DJ, Segre GV, Capen CC, et a!: Hypercalcemia in dogs with adenocarcinoma derived from apocrine glands of the anal sac. Lab Invest 48:428, 1983

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50. Moore FM, Kudisch M, Richter K, et a!: Hypercalcemia associated with rodenticide poisoning in three cats. J Am Vet Med Assoc 193:1099, 1988 51. O'Keefe DA, Couto CG: Coagulation abnormalities associated with neoplasms. Vet Clin North Am [Small Anim Pract] 18:157, 1988 52. Parry BW: Laboratory evaluation of hemorrhagic coagulopathies in small animal practice. Vet Clin North Am [Sm Anim Pract]19:729, 1989 53. Parry BW, Holloway SA, Studdert MJ: Diagnosis of feline leukemia virus and feline immunodeficiency virus infections. Vet Clin North Am [Sm Anim Pract]19:719, 1989 54. Perman V, Alsaker RD, Riis RC: Cytology of the Dog and Cat. South Bend, Indiana, Am Anim Hasp Assoc, 1979, p 23 55. Peterson ME, Zanjani ED: Inappropriate erythropoietin production from a renal carcinoma in a dog with polycythemia. JAm Vet Med Assoc 179:995, 1981 56. Pichler ME, Turnwald GH: Blood transfusion in the dog and cat. Part l. Physiology, collection, storage, and indications for whole blood therapy. Camp Cant Ed 7:64, 1985 57. Schall WD: Laboratory diagnosis of hepatic disease. Vet Clin North Am 6:679, 1976 .58. Schwartzman RM: Cutaneous amyloidosis associated with a monoclonal gammopathy in a dog. JAm Vet Med Assoc 185:102, 1984 .59. Strombeck DR: Clinicopathologic features of primary and metastatic neoplastic disease of the liver in dogs. JAm Vet Med Assoc 173:267, 1978 60. Tayek JA, Bistrian BR, Hehir DJ, eta!: Improved protein kinetics and albumin synthesis by branched chain amino acid-enriched total parenteral nutrition in cancer cachexia. Cancer 58:147, 1986 61. Thrall MA: Lymphoproliferative disorders. Vet Clin North Am [Small Anim Pract]ll:321, 1981 62. Torrance AG, Nachreiner R: Intact parathyroid hormone assay and total calcium concentration in the diagnosis of disorders of calcium metabolism in dogs. J Vet Intern Med 3:86, 1989 63. Valli VEO: The hemopoietic system. In Jubb KVF, Kennedy PC, Palmer N (eds): Pathology of Domestic Animals, val 3, ed 3. New York, Academic Press, 1985 64. Weir EC, Norrdin RW, Matus RE: Humoral hypercalcemia of malignancy in canine lymphosarcoma. Endocrinology 122:602, 1988 6.5. Weller RE: Cancer-associated hypercalcemia in companion animals. Camp Cant Ed 6:639, 1984 66. Weller RE: Paraneoplastic disorders in companion animals. Camp Cant Ed 4:423, 1982 67. Weller RE: Paraneoplastic syndromes. In Morgan RV (ed): Handbook of Small Animal Practice. New York, Churchill Livingstone, 1988, p 821 68. Werner LL: Immunologic diseases affecting internal organ systems. In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1983

:\ddress reprint requests to Stephen A. Kruth, DVM Department of Clinical Studies Ontario Veterinary College l'niversity of Guelph Guelph, Ontario N1G 2W1 Canada