Paraneoplastic Syndromes

Cancer Cachexia and Anorexia

An important systemic effect of cancer in animals is profound malnutrition and wasting. The weight loss and metabolic alterations observed in cancer patients despite adequate nutritional intake are termed cancer cachexia, whereas alterations observed as the result of poor nutritional intake are termed cancer anorexia. The clinical outcome of either cancer cachexia and/or anorexia is a progressive wasting (Figure 5-1). The weight loss endured by these patients is more than a simple cosmetic abnormality as human patients with cancer cachexia can have significantly reduced survival times, and many patients are unable to undergo appropriate therapy because of their poor clinical status.

Cancer cachexia occurs frequently in human oncology, with estimated incidences from 40% to approximately 90% of hospitalized patients.^2,3 Importantly, cancer cachexia accounts for approximately 20% of cancer deaths.^4,5 The incidence of cancer cachexia in veterinary oncology patients is presently unknown, although this author believes that an estimated incidence of cancer cachexia in dogs is realistically 10% or less. For example, only 4% of dogs presenting to an academic oncology center were found to have cachexia, although referral bias likely results in some reporting artifact.⁶ The metabolic alterations associated with this PNS usually occur before weight loss is detected in both human and veterinary cancer patients.^3,7-11 These metabolic alterations may last for some time after the patient is tumor free making it difficult for the clinician to reverse the weight loss.^8,10 A plasmid-DNA–mediated approach utilizing growth hormone–releasing hormone (GHRH) in dogs appears to increase insulin-like growth factor-1 (IGF-1) levels (a measure of GHRH activity) and may represent a mechanism for attenuating cancer cachexia.^12-15

In the clinical evaluation of a veterinary patient for the possibility of cancer cachexia/anorexia, a detailed history and physical examination are crucial. The prognostic importance of the presence of cancer cachexia in human cancer patients cannot be overstated because many studies show that this PNS is the only or one of very few independent multivariate negative prognostic factors for a variety of malignancies.^2,3 A more detailed discussion of this syndrome is found in Chapter 15, Section B.

Protein-Losing Enteropathy

Protein-losing enteropathy (PLE) is a syndrome whereby excessive serum proteins are lost into the gastrointestinal (GI) tract, leading to hypoproteinemia.¹⁶ The hypoproteinemia seen in cancer patients can be due to impaired synthesis and/or increased loss into the GI tract or urine (see Renal Manifestations of Cancer later in this chapter). Once the loss of proteins becomes greater than the body’s ability to synthesize them, serum protein levels begin to decrease. The half-life of many serum proteins is long, and patients with hypoproteinemia caused by PLE or some other cancer-related protein loss may represent long-standing protein loss.^2,16 PLE is thought to result from an increase in mucosal serum protein permeability because of mucosal erosion, ulceration, or lymphatic obstruction.

The diagnosis of PLE is made by noting hypoproteinemia on serum chemistry evaluation with subsequent exclusion of severe malnutrition and liver disease. Confirmation of the diagnosis is made in humans with PLE by alpha-1-antitrypsin detection,¹⁷ but this methodology has not been validated in veterinary medicine.¹⁸ In addition, nuclear scintigraphy appears to be a reliable methodology for the diagnosis of PLE.¹⁹ The incidence of PLE as a PNS is unknown in veterinary medicine but is likely to be rare. The treatment for PLE consists of treating the primary malignancy; however, those patients with a lymphangiectasia-related PLE may also be treated with medium-chain triglycerides that do not undergo transport by intestinal lymphatics.

Gastroduodenal Ulceration

The most common cause of PNS-associated gastroduodenal ulceration is mast cell tumor (MCT). The excess histamine seen in MCTs stimulates gastric H₂ receptors, leading to increased gastric acid secretion. Clinical manifestations of mucosal damage and/or ulceration with gastric vessel thrombosis occur in association with gastric hyperacidity. Plasma histamine concentrations are elevated in approximately 75% of dogs with macroscopic MCT, although only 30% have GI signs.^20,21 Abnormally elevated plasma histamine concentrations have also been found to be a negative prognostic factor in dogs with MCT.²¹ Symptomatic therapies such as proton-pump inhibitors, H₂ blockers, misoprostol, sucralfate, and rehydration may be helpful in combating PNS-associated gastroduodenal ulceration. MCTs are covered in greater detail in Chapter 20.

An additional cause of PNS-associated gastroduodenal ulceration is gastrinoma (gastrin-secreting non–islet cell pancreatic tumor). Although these tumors are relatively rare, they have been reported in both dogs and cats.^22-26 Gastrinomas can be associated with vomiting, lethargy, anorexia, blood loss, and abdominal pain. Many of these features are also seen in humans with gastrinoma-related Zollinger-Ellison syndrome. Gastrinomas are covered in greater detail in Chapter 25.

Hypercalcemia

The most common cause of hypercalcemia in the dog is cancer. A variety of tumors have been associated with hypercalcemia of malignancy (HM), and neoplasia is diagnosed in approximately two-thirds of dogs^27,28 and one-third of cats with hypercalcemia.²⁹ Lymphoma is the most common cause of HM (10% to 35% occurrence). Other tumor types associated with HM in dogs and cats include anal sac apocrine gland adenocarcinoma (≥25%), thyroid carcinoma, multiple myeloma (20%), bone tumors, thymoma, squamous cell carcinoma, mammary gland carcinoma/adenocarcinoma, melanoma, primary lung tumors, chronic lymphocytic leukemia, renal angiomyxoma, and parathyroid gland tumors.^30-40 The causes of HM are varied and include ectopic production of parathormone (PTH) or PTH-related peptide (PTH-rp) by the tumor, extensive and usually multifocal lytic bone metastases, primary hyperparathyroidism, tumor-associated prostaglandins (PGE_1/2), interleukin-1-β (IL-1β, previously known as osteoclast-activating factor [OAF]), transforming growth factor-β (TGF-β), and receptor activator of nuclear factor kappa-B ligand (RANKL).^2,34,41-46 Interestingly, TGF-β1 regulates the mRNA stability of PTH-rp.⁴⁷ The HM seen in lymphoma and anal sac apocrine gland adenocarcinoma is commonly caused by tumor-associated PTH-rp.^48,49 PTH-rp is a 16-kDa protein with significant sequence identity to PTH, suggesting it may act and function like PTH. In addition to HM, other hypercalcemia differential diagnoses include “lab error” (lipemia and hemolysis), acute renal failure, hypervitaminosis D, hypoadrenocorticism, and granulomatous disease.

In addition to ensuring the hypercalcemia is not due to lipemia or hemolysis, it is important to interpret the calcium value in relation to the level of serum albumin if ionized calcium determination is not available. Two commonly utilized correction formulas that controversially attempt to account for the level of serum albumin follow:

or

Similarly, an increase in the free ionized fraction of calcium can occur with acidosis. Acidotic HM patients may have an increase in clinical signs of hypercalcemia when compared to nonacidotic HM patients.

The primary clinical manifestations of HM are due to renal function impairment. Severe HM (calcium > 18 mg/dL) should be considered a medical emergency. An inability to concentrate urine is the initial manifestation of hypercalcemia and is due to decreased responsiveness to antidiuretic hormone (ADH) at the distal tubule; the calcium then decreases renal blood flow and glomerular filtration rate (GFR) as the result of severe vasoconstriction. Calcium salt deposition in the renal parenchyma may also contribute to renal azotemia, although this is uncommon. The urinary epithelium may then undergo degeneration, and in severe cases, necrosis results in exposure of the basement membrane of the renal tubule. The situation worsens as the patient becomes polyuric and polydipsic, resulting in progressive dehydration. In addition to effects on the renal system, severe HM may cause constipation, hypertension, twitching, weakness, shaking, depression, vomiting, bradycardia, stupor, and possibly coma and/or death.

When HM is diagnosed, appropriate steps for identification of the underlying neoplasm cause are necessary, and if azotemia accompanies HM, appropriate therapy to support renal function should be instituted quickly. The diagnostic evaluation of HM should begin with procedures used in the staging of lymphoma (as outlined in Chapter 32, Sections A and B) in addition to a rectal palpation and examination for anal sac apocrine gland adenocarcinoma. If these diagnostics do not confirm the specific cause of the HM, then the aforementioned hypercalcemia differential diagnoses should be considered and appropriately pursued. Dogs and cats with HM will typically have low PTH and high PTH-rp concentrations; however, the cause of the HM can usually be delineated with appropriate diagnostics before the return of PTH/PTH-rp assay results and such tests may not be routinely needed. Since HM is a potential medical emergency, the primary goal is elucidation of the underlying cause in order to institute the appropriate therapy for the specific tumor. Symptomatic therapy must be judiciously utilized while searching for the underlying cause of the HM. The premature administration of symptomatic therapy that includes the use of corticosteroids prior to the confirmation of the cause of the HM can have serious consequences. If lymphoma is the underlying cause of the HM, the use of corticosteroids may interfere with the ability to confirm a diagnosis, necessitating either additional diagnostics and/or waiting to determine if the lymphoma reappears after glucocorticoid withdrawal. In addition, glucocorticoids may induce resistance to other chemotherapy agents with a decrease in the ability to induce a complete remission, as well as a decrease in the length of survival.⁵⁰ Therefore the use of corticosteroids in cases of undiagnosed hypercalcemia is strongly discouraged.

Symptomatic therapies that promote external loss of calcium, increase renal excretion of calcium, and inhibit bone reabsorption may be utilized in HM patients. The severity of clinical signs and associated hypercalcemia determine the preferred therapy (Box 5-2). The use of 0.9% NaCl intravenously (IV) is recommended for management of existing dehydration and to expand the extracellular fluid volume, increase GFR, increase calciuresis and natriuresis, and decrease calcium reabsorption by the kidneys. Once rehydrated, the loop diuretic furosemide with continued normosaline diuresis can be utilized to potently inhibit calcium reabsorption in the ascending loop of Henle. If the cause of the HM is determined, corticosteroids can be extremely effective as adjunct therapy for HM by their inhibition of PGE, OAF (IL-1β), vitamin D, and intestinal calcium absorption. Corticosteroids can also be cytotoxic to lymphoma cells, the most common cause of HM. The most common therapies utilized in the treatment of HM are outlined in Box 5-2. In rare cases that are unresponsive to these symptomatic therapies and treatment of the underlying cause, other treatments such as calcitonin, bisphosphonates, or gallium nitrate may be utilized.⁵¹ Bisphosphonates have become the standard of therapy for human nonhumoral HM because of their potent inhibition of bone resorption without affecting tubular calcium reabsorption.⁵² The use of bisphosphonates in dogs and cats appears to be a promising treatment for hypercalcemia but requires additional study.^53,54 In the future, treatment options for refractory HM may include osteoprotegerins, more potent bisphosphonates, anti-PTH-rp antibodies, noncalcemic calcitriol analogs, distal tubule calcium reabsorption inhibitors, RANKL antagonists, and new bone resorption inhibitors.^52,55

Hypoglycemia

The most common cause of cancer-induced hypoglycemia (<65 to 70 mg/dL serum glucose) in the dog is insulinoma (beta-islet cell tumor), and the reader is directed to Chapter 25 for a discussion of insulinomas.⁵⁶ Nonislet cell tumors can also serve as sources of ectopic hormone production with resultant hypoglycemia in dogs and humans. Nonislet cell tumors with PNS hypoglycemia have been most commonly associated with hepatocellular carcinomas; however, lymphoma, hemangiosarcoma, oral melanoma, hepatoma, plasma cell tumor, multiple myeloma, smooth muscle tumors (leiomyoma and leiomyosarcoma), mammary tumors, renal tumors, and salivary gland tumors have also been reported.^57-62 The hypoglycemia of extrapancreatic tumors has interestingly been associated with low insulin levels, whereas pancreatic beta-islet cell tumors (insulinomas) induce hypoglycemia by excessive circulating insulin levels. Nonislet cell tumors may induce hypoglycemia by increased tumor utilization of glucose, decreased hepatic glycogenolysis or gluconeogenesis, or the secretion of insulin or IGF-1 and IGF-2. Additional mechanisms include upregulation of insulin receptors, increased insulin binding by M proteins in myeloma, and increased production of somatomedins.^2,63 The differential diagnoses of hypoglycemia include insulinoma, nonislet cell tumor hyperinsulinism, nonislet cell tumor, hypoadrenocorticism, starvation, sepsis, liver dysfunction, and laboratory error (lack of timely serum separation). Tumors associated with extrapancreatic hypoglycemia are often extremely large and therefore radiographs/ultrasound of the abdomen and/or thorax may be helpful. Exploratory laparotomy may be necessary if a space-occupying mass is not identified. Provocative testing via glucagon or glucose tolerance testing may be useful in cases when the diagnosis is uncertain. The reader is directed to Chapter 25 for an extensive discussion of the clinical consequences, diagnosis, and therapy of tumor-induced hypoglycemia.

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Syndrome of inappropriate secretion of ADH (SIADH) is a PNS widely recognized in lung, head, neck, and many other tumors in humans^1,2; however, it continues to be essentially unrecognized in veterinary oncology. SIADH has been reported in dogs associated with heartworm disease, congenital hydrocephalus, and granulomatous amebic meningoencephalitis.^64-66 In addition to PNS-associated SIADH, chemotherapy agents and other drugs (vincristine, cyclophosphamide, cisplatin, thiazides, morphine, and chlorpropamide), pulmonary and/or central nervous system (CNS) infections, and a variety of other conditions can cause SIADH.^67,68 The initial finding in SIADH patients is hyponatremia. In addition to hyponatremia, serum hypo-osmolarity, hypernatriuresis, urine hyperosmolarity, and euvolemia with normal renal, thyroid, and adrenal function is noted.^2,67 Although most human SIADH patients are asymptomatic, clinical signs can develop due to hyponatremia that result in CNS signs such as fatigue, anorexia, confusion and potentially seizures. The treatment of choice for PNS-associated SIADH is removal of the underlying cause. In addition, water restriction, demeclocycline (ADH antagonist), and hypertonic sodium chloride may be useful in SIADH cases.⁶⁹

Ectopic Adrenocorticotropic Hormone Syndrome

The ectopic production of adrenocorticotropic hormone (ACTH) or ACTH-like substances is the second most common PNS reported in humans.² This PNS is associated with small cell lung tumors, pancreatic tumors, and a wide variety of other human tumors.^2,67 In the dog, this PNS is reported to occur in primary lung tumors and a single case of an abdominal neuroendocrine tumor.^70,71 The predominant active molecules in this PNS are ACTH, ACTH precursors, endorphins, enkephalins, and melanocyte-stimulating hormone (MSH).^2,67 All result in excessive production of steroids from the adrenal glands resulting in clinical signs similar to those seen in hyperadrenocorticism (Cushing’s disease). Invariably, tumors that cause this PNS are dexamethasone insuppressible. The diagnosis of this PNS is made by the concomitant presentation of Cushing’s-like signs with an abnormal dexamethasone suppression test and a localizable tumor. The treatment of choice is removal of the underlying cause by surgical extirpation of the tumor. When necessary, the medical therapy for this PNS centers on inhibiting cortisol production by mitotane or ketoconazole. The use of selegiline (Anipryl) in the management of this PNS in dogs has not been evaluated to date in veterinary medicine.

Hypocalcemia/Hyperglycemia

Paraneoplastic hypocalcemia and hyperglycemia are extremely rare. Tumors associated with lytic bone metastases and tumors that secrete calcitonin (medullary carcinoma of the thyroid) are the most common causes of human PNS hypocalcemia.² A variety of nonthyroid cancers such as breast cancer, GI cancer, carcinoids, and lung cancer in humans have been reported to secrete calcitonin.⁷² Most cases of PNS hypocalcemia are asymptomatic, although human patients may have neuromuscular irritability and/or tetany. A gingival vascular hamartoma in a 4-month-old kitten has been reported to be associated with PNS hyperglycemia, and the hyperglycemia resolved within 24 hours on removal of the tumor.⁷³ Treatment of choice for either PNS is eradication of the primary tumor whenever possible, calcium infusion in severe hypocalcemia cases, and diabetes-like support for severe hyperglycemia cases.

Hypergammaglobulinemia

Monoclonal gammopathies can be common in animals and people with cancer and they are termed M-component disorders.^1,2,74-76 The hypergammaglobulinemia seen as a PNS is due to the excessive production of proteins from a monoclonal line of immunoglobulin (Ig)-producing plasma cells or lymphocytes. When production of these Igs, partial Igs, heavy chains, and/or light chains becomes extreme, clinical signs of hyperviscosity (ataxia, depression, dementia, cardiac disease and/or failure, seizures, and coma), tissue hypoxia, bleeding (poor platelet aggregation, platelet coating with Igs, and release of platelet factor III), and/or ocular disorders (e.g., papilledema, retinal hemorrhage, detachment) may occur. These proteins may be identified by performing a protein electrophoresis on the serum and/or urine.⁷⁶ Similarly, light chain production may be detected in the urine as Bence-Jones proteins. In addition to the hypergammaglobulinemia PNS seen in plasma cell tumors (multiple myeloma and extramedullary plasmacytoma), lymphomas, lymphocytic leukemias, and primary macroglobulinemia can also cause this PNS.^75,76 Further discussion of plasma cell tumors, myeloma and lymphoma/leukemia can be found in Chapter 32.

Anemia

Anemia is one of the most common PNSs seen in veterinary and human oncology. Approximately 20% to 25% of human cancer patients have PNS anemia, and although the exact incidence of PNS anemia in veterinary oncology is unknown, it is thought to be a significant problem.⁷⁷ There are numerous possible causes for PNS anemia in veterinary oncology patients, and the vast majority are due to either anemia of chronic disease (ACD), immune-mediated hemolytic anemia (IMHA), blood loss anemia, or microangiopathic hemolytic anemia (MAHA).

ACD is extremely common in veterinary and human oncology patients with disseminated and/or metastatic tumors. This anemia is due to disordered iron storage and metabolism, shortened red blood cell (RBC) lifespan, and occasionally decreased bone marrow response.⁷⁷ The anemia seen in ACD is normocytic/normochromic, and evaluation of the bone marrow does not suggest significant problems with cellularity. Treatment of choice is removal of the tumor.

IMHA can be triggered by tumors in animals and humans. Immune mechanisms then result in the premature destruction of RBCs.⁷⁸ The diagnosis of PNS IMHA is typically established by a Coombs’ slide agglutination test, and many patients will have concurrent spherocytosis and a regenerative anemia. The treatment of choice is removal of the tumor; however, if this is not immediately possible, the use of immunosuppressive dosages of prednisone (1 to 2 mg/kg daily to two times a day by mouth [BID PO]) may be indicated if a diagnosis has been established. Similar to non-PNS IMHA, the use of additional agents such as azathioprine (1 to 2 mg/kg daily for 4 to 7 days, then 0.5 to 1 mg/kg every 48 hrs PO), cyclosporine, cyclophosphamide, and others may be necessary for complicated IMHA cases.^78-81

Blood loss anemia can be a sequela to many types of cancer. Due to decreased hemoglobin content, the RBCs in blood loss anemia are microcytic/hypochromic. In addition, decreased serum iron, increased total iron-binding capacity, and poikilocytosis may also be noted.^82,83 The blood loss may be readily apparent in some patients (e.g., bleeding splenic tumor or bleeding superficial tumor), whereas others may not have a readily identifiable source for the loss (e.g., GI tumors). The treatment of choice is removal of the tumor, although severe anemia may necessitate blood transfusions. The use of oral and/or injectable iron may be a useful adjunct therapy.

MAHA is a secondary phenomenon to hemolysis and is typically due to fibrin deposition and/or endothelial damage.⁷⁷ The most common causes of MAHA are PNS disseminated intravascular coagulation (DIC) and RBC shearing as the result of hemangiosarcoma.^77,80 Schistocytosis and hemolysis are common indicators of ongoing MAHA. While any tumor can cause DIC and subsequent MAHA, hemangiosarcoma is most common.⁸⁴ The treatment of choice is removal of the tumor; however, additional ancillary treatments such as aggressive supportive therapy and transfusions may be useful.

Chemotherapy-induced anemia can be quite common in people because of more aggressive chemotherapy protocols²; however, this is rarely seen in veterinary patients.^77,82,83 The degree of anemia seen in veterinary cancer patients undergoing chemotherapy is generally mild, with typical packed cell volumes hovering in the 28% to 32% range for dogs and 24% to 28% range for cats. This anemia rarely necessitates therapy and resolves on discontinuation of the chemotherapy protocol.

A relatively uncommon cause of PNS-associated anemia is myelophthisis (bone marrow invasion/crowding out), and it is most commonly caused by leukemias.² Another uncommon cause of PNS-associated anemia is bone marrow hypoplasia resulting from hyperestrogenism. Sertoli cell tumors in the male dog and granulosa cell tumors of the female dog are commonly associated with hyperestrogenism, and anemia is a common presenting feature.^85-87

Erythrocytosis

Erythrocytosis is a relatively uncommon PNS. Tumors that have been associated with PNS erythrocytosis include renal tumors (primary and secondary), lymphoma (including renal origin), lung or liver tumors, cecal leiomyosarcoma, nasal fibrosarcoma, and transmissible venereal tumor (TVT).^62,88-93 The erythrocytosis seen in cancer patients can be due directly to overproduction of erythropoietin, indirect excess erythropoietin from renal hypoxia, or increased production of hypoxia-inducible factors such as HIF-1.⁹⁴ Interestingly, some tumor suppressor genes (TSG) are important proteosomal regulators of HIF-1, which may explain some of the vascular diseases seen in human patients with certain TSG mutations.⁹⁵ Other differential diagnoses for polycythemia include arteriovenous shunts, severe dehydration, hyperadrenocorticism, polycythemia vera (primary polycythemia), and a variety of cardiac and/or pulmonary diseases.

It is important to differentiate primary and secondary causes of erythrocytosis. Polycythemia vera is a myeloproliferative disorder resulting in clonal proliferation of RBCs with splenomegaly and possibly pancytosis most commonly associated with acquired recurrent mutation in JAK2.^1,2,96 Secondary polycythemia results from decreased arterial oxygen saturation. PNS erythrocytosis is best treated by removal of the erythropoietin-producing tumor whenever possible; phlebotomy can be a useful temporary adjunct therapy. Unfortunately, the volumes typically needed for a therapeutic phlebotomy in PNS erythrocytosis cases necessitates administration of fluids and potentially readministration of plasma. The use of hydroxyurea (40 to 50 mg/kg divided BID PO)⁹¹ as a chemotherapeutic agent for polycythemia vera has been previously recommended; however, this author has noted limited benefit with use of this agent.

Neutrophilic Leukocytosis

Increases in the number of circulating neutrophils have occasionally been associated with a variety of tumors in humans and dogs. Unfortunately, a leukemoid reaction of this nature can be difficult to distinguish from a true leukemia without extensive diagnostics. Neutrophilic leukocytosis has been reported in dogs with lymphoma, renal carcinoma, primary lung tumor, rectal polyp, and metastatic fibrosarcoma.^97-100 The exact mechanism of PNS leukemoid reactions is unknown; however, the production of a colony-stimulating factor such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) is considered likely. Reports have documented tumor-produced G-CSF and GM-CSF in dogs with primary lung tumor and renal transitional cell carcinoma, whereas tumor-produced G-CSF has been documented in a cat with dermal adenocarcinoma and suspected in a cat with pulmonary squamous cell carcinoma.^101-103 This PNS is generally of minimal clinical significance, and normalization of the PNS is possible following removal of the inciting tumor.

Thrombocytopenia

Thrombocytopenia in human and veterinary cancer patients is typically secondary to chemotherapy administration; however, the incidence of thrombocytopenia in tumor-bearing dogs prior to chemotherapy administration has been reported to be as high as 36%.⁸⁰ Dogs with lymphoproliferative tumors have been reported to have thrombocytopenia in 58% of cases.¹⁰⁴ Dogs with Sertoli cell tumors (or occasionally seminomas) that excessively produce estrogen are also prone to thrombocytopenia.^85,87 Twenty percent of the cases of thrombocytopenia in cats have been reported to be due to cancer, most commonly associated with lymphoma.¹⁰⁵

Numerous mechanisms for PNS thrombocytopenia are possible and include platelet destruction, sequestration, or consumption and/or decreased platelet production. The most common tumors associated with PNS thrombocytopenia are vascular tumors of the spleen and tumors infiltrating the marrow, such as lymphoma or leukemias.¹⁰⁶ Immune-mediated thrombocytopenia (ITP) is an additional significant cause of thrombocytopenia.¹⁰⁷ The treatment of PNS-associated thrombocytopenia is removal of the inciting tumor; however, adjunctive therapies such as intravenous fluids, plasma, and heparin may be beneficial. For those cases secondary to ITP, the use of immunosuppressive drugs such as corticosteroids (≥2 mg/kg PO daily) and azathioprine (2 mg/kg PO daily then 0.5 to 1 mg/kg PO every other day) may be necessary.

Coagulopathies and Disseminated Intravascular Coagulation

Alterations in hemostasis can be common in human and veterinary cancer patients. PNS coagulopathies are most commonly associated with tumors that cause thrombocytopenia, thrombocytosis, DIC, platelet dysfunction, changes in platelet aggregation, or hyperheparinemia (due to MCT).^108,109 Trousseau’s syndrome is a carcinoma-associated human coagulopathy that appears to be related to excess production of hypoxia factors leading to angiogenesis and a procoagulant state.¹¹⁰ PNS-associated DIC has been reported to be the cause of consumptive thrombocytopenia in almost 40% of DIC cases,⁸⁰ suggesting this PNS may be an important clinical syndrome based on the potentially devastating morbidity and mortality associated with DIC. The diagnosis of DIC is made when the patient has thrombocytopenia, prolongation of activated partial thromboplastin time (aPTT), elevated fibrin degradation products (FDP), and hypofibrinogenemia.^80,111,112 A reduction in serum antithrombin III levels appears to be one of the most reliable and prognostic measurements for the presence of DIC.^104,113,114

The incidence of DIC in dogs with malignant tumors is approximately 10%.¹¹⁵ A variety of tumors have been associated with DIC; hemangiosarcoma is the most common in dogs. Other associated tumors include inflammatory mammary gland tumors, thyroid carcinomas, primary lung tumors, and intraabdominal carcinomas.^113,115-117 DIC has not been evaluated as a prognostic factor in veterinary cancer patients to date; however, the presence and severity of DIC in human cancer patients is a significant negative prognostic factor. Although not specifically related to DIC, the hyperheparinemia associated with MCTs can be associated with prolonged bleeding times and poor hemostasis during and after biopsy or surgery.²⁰

Miscellaneous

Thrombocytosis is a common PNS in humans with lymphomas and leukemias, although it is rarely noted in veterinary oncology. Myeloproliferative disorders appear to be the most common cause of PNS thrombocytosis in dogs and cats.^118-120 Important differential diagnoses include causes of primary thrombocytosis such as inflammatory processes, some hemolytic anemias, posthemorrhage, iron deficiency, and postsplenectomy.

PNS eosinophilia is rarely reported in veterinary medicine. Dogs with mammary tumors, leiomyosarcoma, T-cell lymphosarcoma (LSA), or fibrosarcoma and cats with a variety of tumors (lymphoma, sarcomas, MCT, and bladder tumors) have been reported to have tumor-associated eosinophilia.^121-125 In addition, eosinophilic effusions have been documented in dogs and cats with cancer and nonneoplastic conditions.¹²⁶ The cause of eosinophilia in these cases is poorly understood; however, the production of eosinophilic substances such as GM-CSF, various interleukins (e.g., IL-5, -13, and -17), and eotaxins are likely. PNS eosinophilia should be distinguished from eosinophilic leukemia and hypereosinophilia syndrome. The treatment for PNS eosinophilia is removal of the inciting tumor; PNS-associated eosinophilia is typically of little clinical significance.

Although lymphocytosis can be noted with various lymphocytic neoplasms and reactive nonneoplastic conditions, it is rarely noted as a PNS. T-cell lymphocytosis has been recently reported as a PNS in association with thymoma in a dog.¹²⁷

Platelets may play a role in cancer progression and metastasis attributable to platelet aggregation–mediated augmentation of tumor cell extravasation, survival, and angiogenesis. Platelet aggregation was investigated in a study of 59 dogs with cancer.¹⁰⁹ When compared to control dogs, the platelets of dogs with cancer exhibited significantly higher maximum aggregation, higher adenosine triphosphate (ATP) secretion, and shorter delays in the aggregation response. In addition to aiding the metastatic process, platelet hyperaggregation may also lead to thromboembolism.¹²⁸

Alopecia

Pancreatic carcinoma has been reported in cats as the cause of a progressive, nonscarring PNS alopecia.^132-135 The alopecia is acute, bilaterally symmetric (ventrum and limbs), and ventrally glistening. The hair easily epilates from nonalopecic areas and histologically exhibits severe follicular and adnexal atrophy with absence of stratum corneum in many areas, including the foot pads. Clinical signs include anorexia, weight loss, lethargy, and difficulty walking and/or standing, which is most likely due to the aforementioned foot pad histologic changes. In two reports, a similar presentation was noted in cats with bile duct carcinoma.^134,136 The cause of this PNS is presently unknown.

Cutaneous Flushing

When the skin episodically turns various shades of red because of changes in cutaneous blood vessel vasodilation, it is termed cutaneous flushing. Intermittent or paroxysmal cutaneous flushing can be associated with pheochromocytoma (see Chapter 25).^2,137,138 This PNS has also been reported in a dog with primary lung tumor and concomitant intrathoracic MCT.¹³⁹ Dogs that undergo MCT degranulation may also have cutaneous flushing. Important nonneoplastic diagnoses to rule out for this PNS include drug reactions, demodicosis, and systemic lupus erythematosus. In addition to pheochromocytoma, humans may experience cutaneous flushing caused by Zollinger-Ellison syndrome, carcinoids, leukemias, renal cell carcinoma, and many other conditions.^2,140

Nodular Dermatofibrosis

Nodular dermatofibrosis (ND) is a well-recognized PNS of multiple, slowly growing cutaneous nodules in dogs with bilateral renal cysts or cystadenocarcinomas (Figure 5-2).^141-144 The nodules are composed of dense but well-differentiated collagen tissue (collagenous nevi) and are found predominately on the limbs, although the head and trunk may be affected in advanced cases. ND appears to be inherited in an autosomal dominant fashion and is most commonly seen in middle-aged German shepherd dogs.^141-143,145 The ND-associated mutation was mapped to exon 7 of the Birt-Hogg-Dube (BHD) locus on canine chromosome 5, which is the same locus for a phenotypically similar human disease.¹⁴⁶ Intact females with ND are also at increased risk for the development of uterine leiomyomas, and the BHD mutation appears to be homozygous lethal.^143,146,147 The pathogenesis of ND is unknown; however, the BHD mutation in humans leads to a novel protein called folliculin, which may be related to the mTOR pathway.^148,149 Currently, there is no effective therapy for the underlying tumor; however, palliative therapy via surgical removal of nodules may be utilized in cases in which the nodules are ulcerated, cosmetically displeasing, or interfering with function.

Necrolytic Migratory Erythema/Superficial Necrolytic Dermatitis

Superficial necrolytic dermatitis (SND) is a rare PNS in humans and dogs characterized by circinate and gyrate areas of erosive blistering and erythema as the result of glucagonomas (glucagon-secreting pancreatic alpha-cell tumors).^2,150-153 Marked fissuring, ulceration, and crusting of foot pads have also been noted in dogs. Nonneoplastic differential diagnoses for SND include hepatic disease and diabetes mellitus. Necrolytic migratory erythema, metabolic epidermal necrosis, diabetic dermatopathy, and hepatocutaneous syndrome are terms that have been previously used to describe SND. This PNS resolves in people after surgical extirpation of the glucagonoma, although the prognosis may be poor in dogs due to multiple postoperative complications.¹⁵⁴ Octreotide (2 to 3 µg/kg BID) has been reported to successfully treat paraneoplastic SND.¹⁵⁵ Although not specifically related to hepatocutaneous syndrome, a dog with sarcomatoid renal cell carcinoma and paraneoplastic hepatopathy with similarities to Stauffer’s syndrome in humans has been reported.^152,156

Miscellaneous Syndromes

The number of recognized cutaneous PNSs in humans easily reaches into the dozens; however, the specificity of which we are able to delineate similar PNS in veterinary oncology is limited.¹³⁰ Ischemic necrosis of the digits and/or feet is a common human PNS associated with lymphoma, adenocarcinoma, and occasionally other malignancies.¹⁵⁷ Symmetric cutaneous necrosis of the hind feet has been reported in a cat with multicentric follicular lymphoma.¹⁵⁸ Interestingly, the necrosis was not associated with a neoplastic infiltrate and thrombotic/vasculitic causes were not seen histologically, suggesting it was of paraneoplastic origin.

Malassezia-associated dermatitis was first reported in a cat with paraneoplastic alopecia from a metastatic exocrine pancreatic carcinoma.¹⁵⁹ A study of over 500 feline skin biopsies found fifteen (2.7%) of the submissions contained Malassezia organisms. Ten of the 15 cats also had neoplasia, suggesting that Malassezia yeast in feline skin biopsies should prompt a clinical workup for neoplasia.¹⁶⁰

Pemphigus vulgaris (PV) is a dermatopathy characterized by intraepidermal bullae and erosions of the skin and oral mucosa.^161,162 In humans, paraneoplastic PV (PPV) can be associated with lymphoma, Kaposi’s sarcoma, and various carcinomas.² PPV has been reported in association with mediastinal lymphoma and splenic sarcoma in dogs.^163,164 Canine paraneoplastic pemphigus may be an excellent comparative model to human pemphigus PNS.¹⁶⁵ Recent reports suggest that paraneoplastic pemphigus is due to circulating IgG autoantibodies against desmoglein 3 across species.^161,166,167

Erythema multiforme has been associated with thymoma in a dog.¹⁶⁸ The erythema multiforme resolved after thymectomy, suggesting it was paraneoplastic in origin and may be similar to feline thymoma-associated exfoliative dermatitis.^169,170 The variety noted in miscellaneous reports should serve as a reminder that there are likely many other uncharacterized cutaneous PNSs in veterinary oncology.

Myasthenia Gravis

Myasthenia gravis (MG) is an acquired or congenital disorder of the neuromuscular junction that results from a failure of synaptic transmission. Antibodies to nicotinic acetylcholine receptors (nACHRs) can be documented in dogs with MG and are useful in the diagnosis and follow-up.^183,190 In a similar fashion, Lambert-Eaton syndrome in humans occurs as the result of calcium-channel autoantibody formation from predominately lung tumors, which then result in an MG-like syndrome caused by poor calcium influx from the presynaptic neuromuscular junction.^191,192

The most common cause of acquired MG in the dog is thymoma, although it has also been reported in association with osteosarcoma, lymphoma, and bile duct carcinoma.^184,193-199 The clinical signs revolve around intermittent mild-to-severe muscular weakness, exercise intolerance, dysphagia, and megaesophagus (and possible secondary aspiration pneumonia). Rapid clinical improvement and decreases in nACHR antibodies have been noted after surgical extirpation of thymoma.^194,200 The use of immunosuppressive doses of prednisone (>2 mg/kg PO daily) may be a useful adjunct in the treatment of paraneoplastic MG.¹⁹⁵

Peripheral Neuropathy

Peripheral nerve lesions that are the result of cancer are a relatively common event in humans and animals. When nerve fibers were analyzed from dogs with a wide variety of malignancies, a significant percentage of abnormal findings such as demyelination, myelin globulation, and axonal degeneration were noted in some specific malignancies.¹⁸⁵ Tumors associated with large numbers of peripheral nerve changes included primary lung tumors, insulinoma, MCT, thyroid adenocarcinoma, melanoma, and mammary tumors.¹⁸⁵ In contrast, clinically apparent PNS of the peripheral nerves in veterinary medicine is rare. Tumors associated with PNS peripheral neuropathy in dogs and cats include primary lung tumor, leiomyosarcoma, undifferentiated sarcoma, hemangiosarcoma, mammary tumor, multiple myeloma, lymphoma, and insulinoma.^{185-187,201-203} A multisystemic PNS in humans caused by plasma cell dyscrasia or tumor is termed POEMS syndrome for polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. The treatment for paraneoplastic peripheral neuropathy is removal of the inciting tumor.

Diencephalic Syndrome and Miscellaneous Neuromuscular Syndromes

Diencephalic syndrome is a PNS seen in infants with rostral hypothalamic tumors that undergo extreme emaciation despite normal to increased caloric intake.² All cases occur in association with a tumor in the diencephalic region that secretes excess growth hormone. Only one case has been reported in the veterinary literature to date (affecting a 3-year-old Doberman pinscher).¹⁸⁸ Similar to human cases of diencephalic syndrome, this dog had extreme emaciation despite increased caloric intake with a growth-hormone producing astrocytoma in the diencephalic region. The cause for the lack of acromegalic and accelerated growth signs in this case is unknown.

Hypertrophic Osteopathy

Hypertrophic osteopathy (HO) is a syndrome characterized by periosteal proliferation of new bone along the shafts of long bones in response to malignant and nonmalignant diseases (Figure 5-3). HO has been present in the medical literature for over 25 centuries—Hippocrates described “Hippocratic fingers” (digital clubbing seen in humans with HO). As a PNS, HO is reported most commonly with primary lung tumors^2,204; however, in clinical veterinary practice, HO secondary to pulmonary metastatic disease (especially osteosarcoma) is common. It has also been reported with urinary bladder rhabdomyosarcoma, esophageal tumors, malignant Sertoli cell tumor, renal TCC, and nephroblastoma and in cats with renal adenoma, papillary carcinoma, and adrenocortical carcinoma.^102,205-213 Nonmalignant conditions such as heartworms, heart disease, focal lung atelectasis, pregnancy, abscesses, granulomas, foreign bodies, and pneumonia have also been associated with HO.

The clinical signs of dogs or cats afflicted with HO typically include a history of shifting-leg lameness and/or reluctance to move with all four limbs affected. The limbs are typically warm to the touch and swollen with occasional cases having involvement of the ribs and/or pelvis. The diagnosis of HO is made by radiography of the affected bones (starts distally and moves proximally) and finding the unique 90-degree periosteal reaction seen in Figure 5-3. The search for the inciting tumor begins with radiographs of the thorax, and if negative, radiographs and/or ultrasound of the abdomen with blood work and urinalysis should be pursued.

The etiology of HO is still unknown; however, based on measurable increase in blood flow to extremities and resultant connective tissue and periosteal proliferation, it has been well accepted that HO likely develops in part as a result of afferent neurologic stimulation.²¹⁴ This is further supported by the resolution of HO after vagotomy; however, this therapy is not routinely used in veterinary patients.²¹⁵ Recent work suggests that excess production of GHRH and/or vascular endothelial growth factor (VEGF) by the tumor may also contribute to HO.^12,216 The treatment for HO is removal of the inciting tumor when possible, and reports have been published documenting resolution of HO in dogs treated for their primary tumor.^217,218 Prednisone (1 to 2 mg/kg PO daily) or nonsteroidal antiinflammatory drugs (NSAIDs) may be a useful adjunct therapy for HO when the inciting tumor cannot be removed (i.e., diffuse metastasis). Other treatments for HO such as intercostal nerve resection, unilateral vagotomy, bilateral cervical vagotomy, analgesics, and subperiosteal rib resection have been suggested; however, these therapies have not been evaluated extensively in veterinary patients.^204,219 The use of bisphosphonates has become more common for human patients with HO²²⁰ and likely represents an exciting new therapeutic modality in veterinary medicine for a variety of indications.^53,54 Furthermore, the use of agents such as toceranib phosphate (Palladia),²²¹ in light of its antiangiogenic mechanisms of action, may warrant investigation for patients with resistant HO.

Fever

Although the most common causes of fever are infection, inflammation, autoimmune disease, or drug/blood product reactions, cancer can cause fever as a PNS and should remain an important differential diagnosis. Paraneoplastic fever can accompany a wide variety of tumors in human and veterinary patients. The incidence of fever as a PNS in veterinary medicine is unknown; however, in human patients presenting with fever of unknown origin, cancer is the cause in over one-third of the cases, with the most commonly diagnosed cancers being lymphoma, hepatoma, and renal cell carcinoma.² Approximately 10% of human cancer patients develop noninfectious/inflammation-related fever at some point during the course of their disease.²²² The pathogenesis of PNS fever is predominately due to excess production of cytokines (IL-1, IL-6, TNF-α, and interferons) and febrile-promoting prostaglandins.^1,222,223

The most important point in managing fever in veterinary patients with cancer is the evaluation for the presence of concurrent infection. Cancer patients with neutropenia and fever represent a medical emergency. Cancer patients with fever in the absence of neutropenia are not generally medical emergencies but should still be worked up to determine the presence or absence of an infectious and/or inflammatory nidus. If one is not found, then PNS fever is more likely the cause. If the fever is severe and threatens quality of life, the use of an NSAID such as indomethacin or naproxen is commonly utilized in humans with PNS fever. The best therapy for PNS fever is removal of the inciting tumor; however, if this cannot be accomplished, NSAIDs may be useful.

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