handbook of small animal practice || paraneoplastic diseases

726 SECTION 9 | Hemolymphatic System

Paraneoplastic Diseases

| Armando R. Irizarry-Rovira

C H A P T E R 73

726

III. Mechanisms of hypercalcemia secondary to tumor metas-tases to bone are unknown, but a variety of cytokines, tumor products, and infl ammatory mediators are impli-cated.

IV. Hypercalcemia has deleterious effects on multiple organs.A. Kidneys

1. Decreased urine concentrating ability2. Interference with the effects of antidiuretic hormone

(ADH)3. Secondary to renal tubular injury, mineralization,

and ischemiaB. Muscles of the skeleton and gastrointestinal (GI) tract:

inter ference with muscle contractilityC. Cardiovascular system

1. Vasoconstriction2. Interference with contractility, rhythm and excita-

bility of the myocardiumD. Nervous system

1. Interference with normal brain function2. Polydipsia from stimulation of the central nervous

system (CNS) thirst centerE. Metastatic mineralization in various organs

Clinical Signs

I. Clinical signs related to the primary neoplastic process II. Clinical signs associated with hypercalcemia

A. Most severe: calcium >16 mg/dLB. Polyuria, polydipsiaC. Renal failureD. Vomiting, constipation, and anorexiaE. Muscle weakness and twitchingF. Bone pain, lamenessG. Seizures, coma, stupor and/or depression, changes in

behaviorH. Cardiac arrhythmias and abnormalities in the electro-

cardiogram (e.g., shortened Q-T interval, prolongation of P-R interval, arrhythmias)

Diagnosis

I. Persistently increased ionized calcium or total calcium concentrationsA. Because most calcium in blood is bound to albumin/

proteins, correction formulas may be used in dogs to obtain an estimated total calcium concentration

CANCER-ASSOCIATED HYPERCALCEMIA

Defi nition I. Hypercalcemia is defi ned as a value greater than the upper

limit of the reference interval (generally ≥12.0 mg/dL) (Bergman, 2002).

II. It is the most common cause of persistent hypercalcemia in animals (Capen, 2002).

Causes

I. It is described most often in the dog and less frequently in the cat (Morrison, 2002).

II. In dogs, the tumors most often responsible include lym-phoma, anal sac apocrine gland adenocarcinoma, and myeloma (Capen, 2002; Morrison, 2002).

III. In cats, the tumors most often responsible include lym-phoma, squamous cell carcinoma, and some hematological malignancies (Capen, 2002; Morrison, 2002).

IV. Lymphoma is the leading cause in both dogs and cats (Capen, 2002).

Pathophysiology

I. Endocrine-mediated hypercalcemia (humoral) arises when tumor-derived products reach the bloodstream and have a systemic effect (uncontrolled hypercalcemia).A. Parathyroid hormone (PTH) is produced by a func-

tional parathyroid tumor.B. Products of tumors mimic the effects of PTH or other

hormones.1. PTH-like product called parathyroid hormone-

related protein (PTHrP): most common mechanism2. Possible inappropriately increased circulating con-

centrations of 1,25(OH)2–vitamin D3. Transforming growth factor (TGF), tumor necrosis

factor (TNF), and interleukin (IL)-1 possibly act with PTHrP (Sellers et al., 2002)

II. Paracrine-mediated hypercalcemia is associated with bone marrow neoplasms, such as myeloma.A. Tumors of the bone marrow may secrete products that

act locally to cause resorption of calcium from bone and result in hypercalcemia (Teske, 2004; Capen, 2002).

B. Implicated products include PTHrP, TGF, TNF, IL-1, and IL-6.

Ch073-X3949.indd 726 8/8/07 11:13:03 AM

CHAPTER 73 | Paraneoplastic Diseases 727

to compensate for the effects of hyperproteinemia (Stockham and Scott, 2002a).1. Adjusted total calcium concentration (estimated)

= measured total calcium concentration − measured albumin concentration + 3.5

2. Adjusted, estimated total calcium concentration = measured total calcium concentration − (measured total protein concentration μ 0.4) + 3.3

B. In a hyperproteinemic and hypercalcemic animal, a corrected total calcium concentration or an ionized calcium concentration that is normal supports the con clusion that hypercalcemia is secondary to changes in protein concentrations.

C. The acid-base status must also be considered, as acidemia increases the concentration of ionized calcium in the blood.

D. Inorganic phosphorus concentration is normal to decreased unless complicated by renal failure and in-appropriately increased concentration of 1,25(OH)2–vitamin D.

II. Increased serum PTHrP concentrationA. Assays are available in commercial and university

diagnostic laboratoriesB. PTHrP concentration in normal dogs is low (<0.2 pmol/

L) (Foley et al., 2000). III. Serum PTH concentration: decreased to normal, unless

hypercalcemia is secondary to parathyroid adenoma IV. Azotemia and renal failure possible with extensive renal

injury V. Diagnostic tests for underlying neoplasia

A. Diagnostic imagingB. Laboratory testing: complete blood count (CBC),

serum biochemical profi le, protein electrophoresisC. Fine-needle aspirates, biopsy, and histopathology

Differential Diagnosis

I. Primary hyperparathyroidism II. Intoxication from ingestion of vitamin D3 or vitamin D3

analogues, rodenticides, or nutritional supplements III. Granulomatous infl ammation (Stockham and Scott,

2002a): blastomycosis, cryptococcosis, histoplasmosis IV. Adrenocortical insuffi ciency V. Thiazide diuretics VI. Iatrogenic hypercalcemia: administration of calcium-

containing intravenous products. VII. Urine acidifying diets in cats (McClain et al., 1999) VIII. Primary renal failure

Treatment

I. The primary goal is treatment or elimination of the asso-ciated neoplasm; however, hypercalcemia must be controlled promptly to avoid detrimental effects on other organs.

II. Fluid therapy is used to induce diuresis and correct elec-trolyte abnormalities (Bergman, 2002).A. NaCl 0.9% supplemented with potassium chloride if

animal is hypokalemicB. Dose: 50 to 70 mL/kg/day IV for mild (12 to 14 mg/dL)

to moderate (14 to 16 mg/dL) hypercalcemia

C. ≥80 mL/kg/day IV for severe hypercalcemia (>16 mg/dL calcium concentration)

III. Correct acid-base disturbances. IV. Diuretics such as furosemide at 1 to 2 mg/kg IV SID to BID,

may be useful in well-hydrated animals (Bergman, 2002). V. Prednisone 1 to 2 mg/kg PO SID to BID may be given after

a diagnosis is reached in cases of moderate hypercalcemia (14 to 16 mg/dL [Bergman, 2002]) or when other therapies fail (Kirby et al., 2000).

VI. Other treatments for hypercalcemia (bisphosphonates, calcitonin, mithramycin) may be helpful but require further investigation.

VII. See Chapter 48 for treatment of renal failure.

Monitoring of Animal

I. Monitor serum calcium, acid-base status, and kidney function SID.

II. Repeat electrocardiographic evaluations if cardiac failure or arrhythmias were diagnosed initially.

III. Monitor for secondary infections owing to immunosup-pression from chemotherapy or glucocorticoid therapy.

CANCER-ASSOCIATED HYPOGLYCEMIA

Defi nition I. Decreased serum/plasma glucose concentration occurs in

association with neoplastic disease. II. Blood glucose concentration is <60 to 70 mg/dL (Ogilvie,

2000; Bergman, 2002).

Causes and Pathophysiology

I. Pancreatic beta-cell tumors (insulinoma) may produce hypoglycemia by inappropriate secretion of insulin.

II. Tumors other than pancreatic beta cell tumors may also result in hypoglycemia.A. Examples include leiomyosarcoma, renal adenocarci-

noma, hepatocellular neoplasms, hemangiosarcoma, salivary gland adenocarcinoma, melanoma, mammary carcinoma, primary pulmonary adenocarcinoma, and lymphoid leukemia (Morrison, 2002; Braund, 2003; Battaglia et al. 2005).

B. Tumors may produce an insulin-like substance, such as insulin-like growth factor (IGF) II.

C. Excessive consumption of glucose by the tumor occurs rarely.

D. Hepatic dysfunction or failure from destruction by the neoplasm may result in hypoglycemia.

E. Combinations of the preceding causes also occur.

Clinical Signs

I. Clinical signs are secondary to low glucose concentrations or to counterregulatory mechanisms mediated by the sympathetic system and adrenal gland (Braund, 2003).

II. Neurological signs are most common and typically occur if glucose is <45 to 50 mg/dL.

III. Neurological signs may arise from polyneuropathy (Dyer, 2004).

Ch073-X3949.indd 727 8/8/07 11:13:03 AM


IV. Clinical signs worsen with precipitous drops in the con-centration of glucose.A. SeizuresB. Confusion, ataxiaC. Weakness, lethargy, fatigue, collapseD. Muscle twitching

V. Clinical signs may also be related to the primary tumor.

Diagnosis

I. Decreased serum/plasma glucose concentrationA. Persistently low fasting glucose concentrationB. May need to fast for 24 to 48 hours to have reproducible

results II. ± Increased blood insulin concentration

A. It is measured concurrently with glucose concentra-tions.

B. Increased insulin concurrent with fasting hypoglycemia (<60 mg/dL) is strong evidence of an insulinoma.

III. Increased insulin to glucose ratio (I:G ratio) (Stockham and Scott, 2002)A. I:G ratio (mU insulin/mg glucose) = insulin concen-

tration (mU/mL) μ100 ÷ glucose (mg/dL).B. Normal values must be determined by each laboratory.C. Increased I:G ratio with hypoglycemia suggests insulin

is contributing to the hypoglycemia.D. Increased I:G ratio with hyperglycemia or normo-

glycemia suggests insulin resistance.E. Amended I:G ratio is not considered valid in dogs and

cats (Stockham and Scott, 2002; Braund, 2003). IV. To detect the causative neoplastic disease: diagnostic

imaging, laboratory testing, biopsy, and histopathology


I. Iatrogenic hypoglycemia: insulin overdose II. Malnutrition III. Gastrointestinal disease IV. Liver insuffi ciency V. Adrenocortical insuffi ciency VI. Sepsis

Treatment

I. Treat or eliminate the associated neoplasm. II. Institute frequent feeding (3 to 6 meals daily) of a high

complex carbohydrate, protein, and fat diet. III. Prednisone 0.5 to 1 mg/kg PO BID may be used to increase

glucose concentrations in dogs. IV. Diazoxide 5 to 13 mg/kg PO BID may be useful in dogs

with inoperable or metastatic insulinoma, but it is expensive (Nelson, 2000).

V. Intravenous infusion of a 5% dextrose solution imme-diately increases glucose concentrations, but infusion of more concentrated solutions may result in rebound hyper-insulinemia and profound hyperglycemia.


I. Regularly monitor the animal for clinical signs of hypo-glycemia.

II. Monitor blood glucose concentration initially every 2 weeks, and then every 4 to 6 weeks once glucose concen-trations are normal.

III. Prognosis is guarded to poor in dogs with insulinoma because of the high risk for recurrence and metastasis.

CANCER-ASSOCIATED HYPERGLYCEMIA

Defi nition I. Increased serum/plasma glucose concentration occurs in

association with neoplastic disease. II. Blood glucose concentration is greater than the upper limit

of normal (generally >110 to 130 mg/dL).


I. Tumors that may be associated with hyperglycemia in -clude growth hormone-secreting pituitary tumors, adreno -cortical tumors, glucagonomas, and vascular hamartomas (Padgett et al., 1997; Stockham and Scott, 2002b; Capen, 2002; Zerbe and Washabau, 2000; Feldman, 2000).

II. Hyperglycemia is caused by the production of hormones that stimulate release and synthesis of glucose, or by resistance to insulin.

Clinical Signs

I. Clinical signs are usually secondary to the primary tumor or hormone produced by the tumor.

II. Animals with growth hormone-producing acidophil adenomas may have acromegalic features.

III. Animals with functional adrenocortical tumors may have clinical signs of hyperadrenocorticism.

IV. Animals with glucagonomas may have cutaneous changes (superfi cial necrolytic dermatitis).

Diagnosis

I. Increased serum/plasma glucose concentrations are suspi-cious.A. Persistently increased fasting glucose concentrations

(>130 mg/dL)B. Hyperglycemia refractory to insulin therapy

II. Diagnostic imaging, laboratory testing, biopsy, and histo-pathologic analysis assist in the detection of the underlying neoplastic disease.

III. Hormone determinations (glucagon, cortisol, growth hor-mone) may reveal a direct hormonal cause for the hyper-glycemia.


I. Diabetes mellitus secondary to pancreatic islet injury or destruction

II. Insulin resistance unassociated with neoplastic disease III. Iatrogenic hyperglycemia: glucocorticoids, megestrol ace -

tate, dextrose, glucagon, ketamine, xylazine, streptozocin IV. Stress or excitement: transient hyperglycemia

Treatment and Monitoring

I. The primary goal is treatment and/or elimination of the associated neoplasm.

Ch073-X3949.indd 728 8/8/07 11:13:04 AM


II. Monitor blood glucose concentrations SID after elimina-tion of the primary neoplasm, then every 2 weeks after concentrations stabilize.

MAST CELL-ASSOCIATED SYNDROMES

Defi nition I. Mast cell-associated syndromes arise from increased con-

centrations of histamine and other products of mast cell tumors (Fox et al., 1990; Morrison, 2002; Kraegel and Madewell, 2000; Misdrop, 2004; Teske, 2004).

II. Syndromes most often described include gastroduodenal ulceration, localized cutaneous reactions, and systemic reactions.

III. These syndromes occur most often in dogs.


I. Dogs with mast cell tumors (MCT) typically have in -creased circulating concentrations of histamine (Fox et al., 1990).

II. Massive release of histamine from mast cell tumors may occur during surgical removal, trauma, or chemotherapy.

III. Gastroduodenal ulceration may occur.A. Histamine (H) interacts with H2 receptors in the

parietal cells of the stomach and stimulates secretion of gastric acid.

B. Increased acidity in the stomach may result in ulcer-ation of the stomach, duodenum, and esophagus.

C. Histamine may also damage vascular endothelium, possibly causing ischemic necrosis of the GI mucosa.

IV. Release of histamine and other substances from mast cell granules may result in local recruitment of infl ammatory cells and other cutaneous changes.

V. Marked release of histamine may also result in hypotensive shock that typically occurs with manipulation and treat-ment of large neoplasms, multiple tumors, and advanced stages of mast cell cancer.

Clinical Signs

I. Systemic signsA. Anorexia, inappetenceB. EmesisC. Abdominal painD. Hematochezia, melenaE. Shock

II. Localized skin changesA. Poor wound healingB. Erythema, hemorrhageC. PruritusD. SwellingE. Ulceration

Diagnosis

I. Clinical signs and physical examination fi ndings may be suggestive.

II. Cutaneous MCT is often diagnosed by cytological exami-nation of fi ne-needle aspirates.

III. Histological evaluation is necessary for proper grading of the tumor.

IV. Noncutaneous MCT often requires histopathology and other diagnostic tests.

V. Assays for plasma histamine are not usually necessary or widely available.


I. Other causes of GI bleeding, abdominal pain, anorexia II. Other cutaneous tumors: histiocytoma, plasmacytoma, etc. III. Other causes of circulatory shock and hypotension

Treatment

I. The primary goal is treatment and/or elimination of the tumor.

II. Pretreatment with H1 and H2 receptor blockers may be necessary to minimize the negative effects of massive hista-mine release during surgical removal.A. H1 receptor blockers: diphenhydramine 1 mg/kg IMB. H2 receptor blockers

1. Ranitidine 0.5 to 2 mg/kg PO, SC, IV BID to TID2. Cimetidine 4 to 6 mg/kg PO, SC, IV TID to QID3. Dogs: famotidine 0.1 to 1 mg/kg PO, IV SID to BID4. Cats: nizatidine 2 to 5 mg/kg SID PO or 1 to 3 mg/kg

SC, IM, IV TID III. Proton pump inhibitors such as omeprazole or lansoprazole

may be given to dogs at 1 to 2 mg/kg PO SID (maximum 20 mg/day) for cases of severe gastric ulceration (Hall, 2000).

IV. Sucralfate 0.5 to 1 g PO BID to QID may also be used in dogs for gastric ulcers, but must be administered 30 to 60 minutes after H2 blockers to minimize interference with their absorption.

V. Prednisone 1 to 2 mg/kg PO SID to BID is used to mini-mize edema and infl ammation at the site of the tumor, and possibly to inhibit tumor growth and granule formation (Bergman, 2002; Rogers, 1996).

VI. Palliative radiation therapy may be useful if complete removal of the tumor is not possible.


I. Monitor regularly for impaired wound healing after re-moval of MCTs.

II. Monitor for continued histamine-related problems, such as gastroduodenal ulceration, delayed wound healing, etc.

ZOLLINGER-ELLISON SYNDROME

Defi nition and Causes I. Zollinger-Ellison syndrome is gastroduodenal ulceration

associated with increased gastrin blood concentrations. II. Excessive secretion of gastrin occurs from gastrin-secreting

pancreatic tumors (gastrinomas). III. Gastrin increases the secretion of acid in the stomach.

Clinical Signs

I. Anorexia, weight loss II. Vomiting

Ch073-X3949.indd 729 8/8/07 11:13:04 AM


III. Abdominal pain IV. Depression, lethargy V. Hematochezia, hematemesis, melena

Diagnosis

I. Suspicious clinical signs and physical fi ndings II. Determination of basal blood gastrin concentrations

A. Increased in dogs and cats with gastrin-secreting tumors (normal = 3.65 ng/L in dogs, <18 pg/mL in cats [Garcia-Sancho et al., 2005; Goldstein et al., 1998]).

B. Not entirely specifi c for gastrinoma, as basal gastrin may be increased with renal failure, chronic gastritis, liver disease, small intestinal resection, and during therapy with H2 receptor blockers

C. Stimulation tests possibly necessary for confi rmation of the diagnosis1. These tests require additional investigation in dogs

and cats.2. Secretin and calcium stimulation tests induce in-

creases in gastrin with gastrinomas but not in nor-mal animals.

D. Assays for gastrin not widely available III. Other tests to diagnose the neoplasm: diagnostic imaging,

serum biochemical analyses, biopsy, histopathology


I. Other nonneoplastic causes of GI bleeding, abdominal pain, anorexia

II. Other neoplastic causes of gastroduodenal ulceration, such as mast cell tumors

Treatment and Monitoring

I. The primary goal is treatment and/or elimination of the tumor.

II. Correct any electrolyte, acid-base, and fl uid disorders. III. Start H2 receptor blockers.

A. Ranitidine 0. to 2 mg/kg PO, SC, IV BID to TIDB. Cimetidine 4 to 6 mg/kg PO, SC, IV TID to QIDC. Dogs: famotidine 0.1 to 1 mg/kg PO, IV SID to BIDD. Cats: nizatidine 2 to 5 mg/kg SID PO or 1 to 3 mg/kg

SC, IM, IV TID IV. Sucralfate 0.5 to 1g PO BID to QID may be used in dogs

to promote healing of gastric ulcers, but must be admin-istered 30 to 60 minutes after H2 blockers to minimize interference with their absorption.

V. Proton pump inhibitors such as omeprazole or lansopra-zole may be given in dogs at 1 to 2 mg/kg PO SID for severe gastric ulceration (Hall, 2000).

VI. Prognosis in dogs and cats is grave owing to a high inci-dence of metastasis.

CANCER-ASSOCIATED CACHEXIA

Defi nition I. It is general physical wasting and malnutrition associated

with cancer (Ogilvie, 2000). II. Cachexia may be defi ned as >20% weight loss; however,

weight loss of 10% should be thoroughly investigated (Greco, 2000).


I. Cancer-associated cachexia is a derangement of lipid, protein, and carbohydrate metabolism in animals with cancer (Morrison, 2002; Ogilvie, 2000).

II. The chemical mediators have not been entirely defi ned; however, changes in cytokines and hormones such as interferon, TNF, interleukin-1, IL-6, insulin, and growth hormone may be involved.

III. There is a net loss of energy in the body. IV. Tumor cells have a high rate of glucose consumption.

A. Consumption occurs at the expense of the animal.B. Less glucose is available for healthy cells.C. Increased lactic acid concentrations occur from glyco-

lysis in tumor cells.D. Lactic acid is converted to glucose by the animal’s non-

neoplastic tissues at a net loss of energy.E. Some animals may have concurrent insulin resistance

that results in less glucose entering nonneoplastic cells. V. Circulating concentrations of amino acids used for gluco-

neogenesis are also decreased.A. Protein catabolism is greater than protein synthesis.B. Indicators of severe protein catabolism include the

following:1. Muscle wasting2. Decreased albumin concentrations3. Impaired healing of wounds4. Secondary infections from compromised immune

function VI. Derangements in fat metabolism also occur.

A. Body fat is decreased owing to lipolysis, as the body tries to oxidize lipids for energy.

B. Cancer cells do not utilize lipids as well as noncancerous cells.

Clinical Signs

I. Anorexia II. Decreased body weight III. Muscle wasting IV. Weakness, fatigue

Diagnosis

I. Suspicious clinical signs, especially in the absence of mal-nutrition, malabsorption, cardiac disease

II. Tests to diagnose neoplasia: diagnostic imaging, labora -tory testing (CBC, serum biochemical analyses), biopsy, histopathology, etc.


I. Malnutrition II. Anorexia of nonneoplastic cause: dental disease, CNS

disease, intoxication (e.g., aspirin, ethylene glycol, rodenticides)

III. Gastrointestinal malabsorption IV. Severe parasitism V. Chronic diarrhea, vomiting, or both VI. Heart disease VII. Diabetes mellitus, hyperthyroidism VIII. Protein-losing nephropathy

Ch073-X3949.indd 730 8/8/07 11:13:04 AM


Treatment

I. The primary goal is treatment or elimination of the tumor.

II. The secondary goal is to increase intake of nutrients. III. Institute measures to increase appetite.

A. Warm, aromatic foodsB. Diazepam 0.05 to 0.15 mg/kg IV SID to QOD in cats

(Bergman, 2002)C. Cyproheptadine 1 to 2 mg PO SID to BID in cats

(Bergman, 2002) IV. Nutritional supplementation includes the following

(Ogilvie, 2000):A. Diets with highly bioavailable protein, modest

amounts of simple carbohydrates, and n-3 fatty acids (Hill’s n/d; Hill’s Pet Nutrition, Inc., Topeka, Kan.)

B. Increased fi ber content V. Increase frequency of feeding or consider enteral feeding. VI. Provide parenteral nutrition if necessary. VII. Avoid lactate and glucose-containing fl uids during fl uid

therapy.


I. Monitor body weight on a weekly basis. II. Repeat CBC every 2 weeks and serum biochemical profi les

monthly to monitor general health and evaluate for opportunistic infections and anemia.

III. Document food intake at home and while hospitalized. IV. Prognosis is poor.

CANCER-ASSOCIATED FEVER

Defi nition and Causes I. Fever is an increase in body temperature above the

expected normal temperature for that species. II. Endogenous or exogenous pyrogens act on the thermo-

regulatory center in the anterior hypothalamus to elevate the body temperature (Miller, 2000).

III. Excessive heat production or inadequate heat loss occur to meet the new temperature “set-point.”

IV. Fever develops from the presence of cancer in the body. V. Fever of unknown origin (FUO) is a term typically used

for fever that persists for a period ≥2 to 3 weeks and for which a cause has not been identifi ed.A. With transient, self-limiting causes, fever usually re-

solves within 2 weeks.B. There are numerous causes of FUO, including cancer.

VI. Fever must be differentiated from other causes of hyper-thermia, such as excessively high ambient temperatures (i.e., heat stroke), vigorous exercise on a hot day, excessive exercise, and injury to the thermoregulatory center.

Pathophysiology

I. Neoplasms produce cytokines and other chemical mediators that act on the thermoregulatory center to result in fever.

II. Specifi c immune-mediated reactions to the tumor or gen-eralized infl ammatory reactions to tumor necrosis may also elicit release of cytokines and chemical mediators.

Clinical Signs

I. Increased body temperature II. Clinical signs associated with the neoplastic process III. Weight loss or cachexia IV. Anorexia and dehydration V. Lethargy

Diagnosis

I. Rule out other causes of fever. II. Diagnostic imaging, laboratory testing, biopsy, fl uid anal-

yses (e.g., joints, cerebrospinal fl uid, abdominal fl uid, urine), and histopathologic analysis help to diagnose neoplastic disease and to rule out other causes of fever.


I. Immune-mediated diseases (e.g., immune-mediated poly-arthritis), noninfectious infl ammatory diseases

II. Infections: bacterial, fungal, viral, parasitic III. Tissue injury: trauma, infarction, ischemia IV. Drugs: tetracycline (cats), levamisole (cats), bleomycin,

colchicine, halothane, succinylcholine

Treatment

I. Primary treatment is directed at eliminating or controlling the neoplastic process.

II. If the fever exceeds 41° C (106° F), cool the animal.A. Bathe with cool water.B. Excessively cold water may interfere with release of

heat because of vasoconstriction of the cutaneous vas-culature.

C. Consider cool water enemas or cool water gastric lavage.

III. Nonsteroidal antiinfl ammatory drugs may be given as antipyretics if fever persists. A. Dogs: aspirin 5 to 10 mg/kg PO SID to BIDB. Cats: aspirin 3 to 6 mg/kg PO every 2 to 3 days


I. Measure and document the body temperature SID to QID (Bergman, 2002).

II. Monitor response to antitumor therapy and for recurrence and metastasis of the tumor.

HYPERGLOBULINEMIA

Defi nition I. Increased concentration of immunoglobulins in the blood

from excessive production by neoplastic cells II. Generally arises from a monoclonal (sometime biclonal)

synthesis of immunoglobulin (Ig) M, IgG, or IgA

Causes

I. Multiple myeloma II. Extramedullary plasmacytoma III. Lymphoma IV. Lymphocytic leukemia

Ch073-X3949.indd 731 8/8/07 11:13:04 AM


Pathophysiology

I. Neoplastic lymphocytes produce excessive amounts of immunoglobulins, such as IgA, IgG, IgM, or light chains.

II. Markedly increased protein concentrations result in in-creased resistance to the fl ow of blood or hyperviscosity.

III. Increased serum viscosity may result in hyperviscosity syndrome (HVS).A. In dogs HVS has been associated most often with eleva-

tions of IgM because of its larger size compared with IgG and IgA.

B. Slow blood fl ow and distention of small blood vessels (e.g., retinal vessels) occur.

C. Delivery of oxygen and nutrients to tissues is inade-quate.1. Hypoxic injury to tissues results.2. Organs most commonly affected are the central

nervous system, eyes, and kidneys (Morrison, 2002).3. Cardiac disease may occur secondary to hypoxic

injury and excessive cardiac workload.4. Renal disease may be complicated by amyloidosis

and light chain proteinuria (Bence-Jones protein-uria).

IV. Immunoglobulins produced by the neoplastic cells may interfere with coagulation and result in increased bleeding.A. Inhibition of platelet functionB. Interference with clotting factors

Clinical Signs

I. Some clinical signs are directly related to the physical presence of the neoplasm.

II. Neurological abnormalities develop secondary to hyper-viscosityA. Lethargy and weaknessB. SeizuresC. Dementia, depressionD. AtaxiaE. Anorexia and weight loss: common in cats with multi-

ple myeloma III. Abnormal bleeding also occurs with hyperviscosity.

A. EpistaxisB. Mucosal hemorrhagesC. Petechiae, ecchymosesD. Excessive bleeding at sites of venipuncture or injec-

tions IV. Ocular abnormalities include hyphema, retinal hemor-

rhage, retinal detachment, and tortuosity and distention of retinal vessels.

V. Polyuria/polydipsia may develop from impaired renal func-tion secondary to glomerular amyloidosis, decreased renal perfusion, or Bence-Jones proteinuria.

Diagnosis

I. Confi rm and characterize the hyperglobulinemia.A. Increased total protein and globulin levels on serum

biochemistry profi leB. Serum protein electrophoreses

1. Electrophoresis: monoclonal spike, sometimes bi-clonal spikes

2. Immunoelectrophoresis: exact immunoglobulin identifi ed

II. Search for an underlying cause.A. CBC, blood smear evaluation, and fi ne-needle aspirates

of lesions, bone marrow, and lymph nodes1. Marked leukocytosis and neoplastic lymphocytes

with leukemia2. Neoplastic plasma cells in lymph nodes, bone marrow,

or masses3. Cytopenias from bone marrow infi ltration4. Infl ammatory leukograms with opportunistic infec-

tionsB. Serum biochemistry analyses

1. Evidence of renal insuffi ciency (azotemia with in-appropriately concentrated urine) may be detected.

2. Hypercalcemia may occur with some neoplasms.C. Urinalysis

1. Bence Jones test: detects light chains in the urine2. Immunoelectrophoresis: identifi es immunoglobu -

lin light chainsD. Other tests to consider

1. Diagnostic imaging2. Fluid analyses3. Histopathology4. Coagulation assays5. Ophthalmologic examination


I. Infection with Ehrlichia spp. may cause monoclonal pro-tein spikes on electrophoresis assays (See Chapter 115).

II. Other causes of hyperviscosity include primary or second-ary polycythemia (see Chapter 64).

Treatment

I. Direct treatment at the elimination or control of the primary neoplasm.

II. Phlebotomy and administration of isotonic fl uids may be necessary in severe cases.

III. Plasmapheresis is helpful for severe cases but is a compli-cated procedure.

IV. Antimicrobials may be needed to prevent or treat second-ary infections from immunosuppression.


I. Monitor for response to chemotherapy. II. Osteolytic lesions of multiple myeloma may take months

to partially resolve. III. Decreased serum immunoglobulin and urinary light chain

concentration may occur within 3 to 8 weeks, if chemo-therapy is successful.

IV. Evaluate CBCs and coagulation parameters every 2 to 4 weeks to monitor for improvement.

V. The prognosis for dogs with multiple myeloma uncompli-cated by hypercalcemia, Bence-Jones proteinuria, and marked bone lysis is generally good.

VI. The prognosis for cats with multiple myeloma is typically poor because of a limited response to chemotherapy.

Ch073-X3949.indd 732 8/8/07 11:13:05 AM


OTHER PARANEOPLASTIC SYNDROMES

See Table 73-1.

Continued

TABLE 73-1

Other Paraneoplastic Syndromes

CLASS OF DISORDER SPECIFIC DISORDER CAUSES CLINICAL SIGNS

Cutaneous paraneoplastic Superfi cial necrolytic Glucagonoma (dogs) Well-demarcated erythematous erosions diseases (Adapted dermatitis Pancreatic carcinoma (cat) and alopecia involving haired skin and from Turek, 2003; Rule out hepatopathy pressure points, mucocutaneous Angarano and Brewer, junctions, perineum, feet, muzzle 1993) Hyperkeratosis of the footpad Nodular dermatofi brosis Cystadenoma or carcinoma Multiple masses and papules in the dermis of the kidney and subcutaneous tissues Females develop leiomyomas Extremities preferentially affected of the uterus Predilection for German shepherd dogs Paraneoplastic pemphigus Thymic lymphoma Erosions in the oral and nasal mucosa, Splenic sarcoma mucocutaneous junctions, and haired

skin In haired skin lesions may begin as vesicobullous lesions Feminization in male dogs Sertoli cell tumor Gynecomastia, bilateral symmetrical alopecia, pendulous prepuce, linear

preputial dermatosis Possible enlarged testicles Possible cryptorchid testicle Feline thymoma-associated Thymoma Erythema and scaling progressing to exfoliative dermatitis alopecia Ulcers and crusts may occur Sebaceous debris in ear canals, nail bed, and between digits Nonpruritic Feline paraneoplastic Pancreatic and biliary Progressive, bilaterally symmetrical alopecia carcinoma alopecia Nonpruritic Footpads may be erythematous, dry, fi ssured, and crusted Concurrent clinical signs of illness (inappetence, vomiting, weight loss) Necrosis of skin Lymphoma, possibly others Necrotic skin on the extremities May be symmetricalHematological, Anemia Multiple tumors Weakness, pallor, decreased hematocrit coagulation Anemia may arise secondary to blood loss, bone marrow infi ltration by neoplastic

cells, chemotherapy, iron or vitamin defi ciency, and hemolysis

Thrombocytopenia or Multiple tumors Petechiae, hemorrhages decreased platelet coagulopathies counts, increased coagulation times Polycythemia Renal neoplasms, hepatic Increased hematocrit, lethargy, depression, neoplasms, nasal anorexia, polyuria, polydipsia, vomiting, fi brosarcoma weakness

Ch073-X3949.indd 733 8/8/07 11:13:05 AM


BibliographyAngarano DW, Brewer WG: Comparative dermatology. Clin Dermatol

11:15,1993Ashley PR, Bowman LA: Symmetric cutaneous necrosis of the hind feet

and multicentric follicular lymphoma in a cat. J Am Vet Med Assoc 214:211, 1999

Battaglia L, Petterino C, Zapulli V et al: Hypoglycaemia as a para-neoplastic syndrome associated with renal adenocarcinoma in a dog. Vet Res Commun 29:671, 2005

Bergman PJ: Paraneoplastic syndromes. p. 735. In Morgan RV, Bright RM, Swartout MS (eds): Handbook of Small Animal Practice. 4th Ed. WB Saunders, Philadelphia, 2003

Bertazzolo W, Comazzi S, Roccabianca P et al: Hypercalcemia asso-ciated with a retroperitoneal apocrine gland adenocarcinoma in a dog. J Small Anim Pract 44:221, 2003

Bienzle D, Silverstein DC, Chaffi n K: Multiple myeloma in cats: variable presentation with different immunoglobulin isotypes in two cats. Vet Pathol 37:364, 2000

Braund KG: Endogenous metabolic disorders. In Braund KG (ed): Clinical Neurology in Small Animals—Localization, Diagnosis and Treatment. Chapter published online by International Veterinary Information Service (www.ivis.org), Ithaca, NY, 2003. Available at www.ivis.org/special_books/Braund/braund21/IVIS.pdf. Accessed May 7, 2007

Braund KG: Remote effects of cancer on the nervous system. Semin Vet Med Surg (Small Anim) 5:262, 1990

Capen CC: Tumors of the endocrine system. p. 607. In Meuten DJ (ed): Tumors in Domestic Animals. 4th Ed. Iowa State Press, Ames, 2002

Cohen M, Post GS, Wright JC: Gastrointestinal leiomyosarcoma in 14 dogs. J Vet Intern Med 17:107, 2003

Cohen M, Post GS: Nephrogenic diabetes insipidus in a dog with intestinal leiomyosarcoma. J Am Vet Med Assoc 215:1818, 1999.

Cullen JM, Page R, Misdrop W: An overview of cancer pathogenesis, diagnosis and management. p. 3. In Meuten DJ (ed): Tumors in Domestic Animals. 4th Ed. Iowa State Press, Ames, 2002

Dyer Inzana K: Paraneoplastic neuromuscular disorders. Vet Clin North Am Small Anim Pract 34:1453, 2004

Eubig PA, Brady MS, Gwaltney-Brant SM et al: Acute renal failure in dogs after the ingestion of grapes or raisins: a retrospective evalua-tion of 43 dogs (1992-2002). J Vet Intern Med 19:663, 2005

Feldman EC. Hyperadrenocorticism. p. 1460. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Foley P, Shaw D, Runyon C et al: Serum parathyroid hormone-related protein concentration in a dog with a thymoma and persistent hypercalcemia. Can Vet J 41:867, 2000

Fox LE, Rosenthal RC, Twedt DC et al: Plasma histamine and gastrin concentrations in 17 dogs with mast cell tumors. J Vet Intern Med 4:242, 1990

Garcia-Sancho M, Rodriguez-Franco F, Sainz A et al: Serum gastrin in canine chronic lymphocytic-plasmacytic enteritis. Can Vet J 46:630, 2005

TABLE 73-1

Other Paraneoplastic Syndromes—cont’d

CLASS OF DISORDER SPECIFIC DISORDER CAUSES CLINICAL SIGNS

Rule out polycythemia vera, and dehydration Leukocytosis Multiple tumors Increased white blood cell counts (nonleukemic)Neurological (Adapted Myasthenia gravis Thymoma, other mediastinal Muscle weakness, exercise intolerance, from Dyer, 2004; tumors diffi culty holding up the head, and Braund, 1990) closing mouth or eyelids Dysphagia, regurgitation Megaesophagus Polyneuropathies Multiple tumors No clinical signs or weakness, paresis, ataxiaUrinary, endocrine Nephrogenic diabetes Intestinal leiomyosarcoma Increased water consumption insipidus (Cohen and Inability to concentrate urine despite Post, 1999) adequate antidiuretic hormone

concentrations Polyuria, polydipsia Inappropriate secretion Lymphoma, carcinoma, No clinical signs of ADH (Bergman, meningeal sarcoma Hyponatremia, anorexia, increased body 2002; Ogilvie, 2000) Rule out other nonneoplastic weight (water retention), vomiting, causes (e.g., vincristine, weakness, seizures, coma barbiturates)Musculoskeletal Hypertrophic osteopathy Primary or secondary Thickened, painful, possibly deformed (see Chapter 81) pulmonary tumors are the extremities most frequent cause in dogs Extremities may be warm to the touch Other neoplastic and nonneoplastic conditions of the thorax and abdomen

Ch073-X3949.indd 734 8/8/07 11:13:05 AM


Gerritsen RJ, Testke E, Kraus JS et al: Multi-agent chemotherapy for mast cell tumors in the dog. Vet Q 20:28, 1998

Goldstein RE, Marks SL, Kass PH et al: Gastrin concentrations in plasma of cats with chronic renal failure. J Am Vet Med Assoc 231:826, 1998

Gorman NT: Clinical management of tumors in geriatric dogs and cats: systemic effects of tumors and paraneoplastic syndromes. Vet Rec 126:395, 1990

Greco DS: Cachexia. p. 72. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Hall JA: Diseases of the stomach. p. 1154. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Hasler AH, Giger U: Polycythemia: p. 203. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Inzana KD: Paraneoplastic neuromuscular disorders. Vet Clin North Am Small Anim Pract 34:1453, 2004

Kirby R, Rudloff E: Fluid and electrolyte therapy. p. 325. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Kraegel SA, Madewell BR: Tumors of the skin. p. 523. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Kumar V, Abbas AK, Fausto N: Neoplasia. p. 269. In Pathologic Basis of Disease. 7th Ed. Elsevier Saunders, Philadelphia, 2005

McClain HM, Barsanti JA, Bartges JW: Hypercalcemia and calcium oxalate urolithiasis in cats: a report of fi ve cases. J Am Anim Hosp Assoc 35:297, 1999

Mello JR: Calcinosis—calcinogenic plants. Toxicology 41:1, 2003Miller JB: Hyperthermia and hypothermia. p. 6. In Ettinger SJ, Feldman

EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Misdrop W: Mast cells and canine mast cell tumors. A review. Vet Q 26:156, 2004

Morrison WB: Paraneoplastic syndromes and the tumors that cause them. p. 730. In Morrison WB (ed): Cancer in Dogs and Cats. Medical and Surgical Management. 2nd Ed. Teton New Media, Jackson, Wyo, 2002

Nelson RW: Insulin-secreting islet cell neoplasia. p. 1429. In Ettinger

SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Ogilvie GK: Paraneoplastic syndromes. p. 498. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Padgett SL, Tillson DM, Henry CJ et al: Gingival vascular hamartoma with associated paraneoplastic hyperglycemia in a kitten. J Am Vet Med Assoc 210:914, 1997

Rogers KS: Mast cell tumors. Dilemmas of diagnosis and treatment. Vet Clin North Am Small Anim Pract 26:87, 1996

Rossmeisl JH, Forrester SD, Robertson JL et al: Chronic vomiting asso-ciated with a gastric carcinoid in a cat. J Am Hosp Assoc 38:61, 2002

Roth AR, Basello GM: Approach to the adult animal with fever of unknown origin. Am Fam Physician 68:2223, 2003

Scott-Moncrieff JCR, Guptill-Yoran L: Hypothyroidism. p. 1419. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Sellers RS, Capen CC, Rosol TJ: Messenger RNA stability of parathyroid hormone-related protein regulated by transforming growth factor-b1. Mol Cell Endocrinol 188:37, 2002

Stockham SL, Scott MA: Calcium, phosphorus, magnesium, and their regulatory hormones. p. 401. In Fundamentals of Veterinary Clinical Pathology. Iowa State Press, Ames, 2002a

Stockham SL, Scott MA: Glucose and related regulatory hormones. p. 487. In Fundamentals of Veterinary Clinical Pathology. Iowa State Press, Ames, 2002b

Stockham SL Scott MA: Proteins. p. 251. In Fundamentals of Veterinary Clinical Pathology. Iowa State Press, Ames, 2002c

Teske E: Paraneoplastic syndromes. Proc World Small Anim Vet Assn. Available at http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2004&PID=8712&O=Generic, 2004. Accessed March 5, 2006

Turek MM: Cutaneous paraneoplastic syndromes in dogs and cats: a review of the literature. Vet Dermatol 14:279, 2003

Vail DM: Hematopoietic tumors. p. 507. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Zerbe CA, Washabau RJ: Gastrointestinal endocrine disease. p. 1500. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. 5th Ed. WB Saunders, Philadelphia, 2000

Ch073-X3949.indd 735 8/8/07 11:13:05 AM

handbook of small animal practice || paraneoplastic diseases

Documents