Paraneoplastic manifestations of cancer, probably under-recognised in equine clinical practice, are often observed before the underlying primary disease is identified. This review provides a summary of paraneoplastic phenomena that have been reported in horses. The inclusion of paraneoplastic explanations in the differential diagnosis of common and challenging clinical problems should lead to earlier diagnosis and greater chance for successful therapeutic outcomes. In some cases, alterations in the clinical severity of paraneoplastic signs can be used as indicators of disease progression or response to treatment.
Paraneoplastic syndromes are defined as diseases or clinical signs arising as a consequence of the presence of cancer in the body, but not resulting from the physical presence of cancer. Paraneoplastic phenomena are mediated by tumour-derived circulating factors (typically hormones or cytokines), depletion of normal substances causing a paraneoplastic manifestation, or by an immune response directed against the cancer (Durham et al. 2009). In many instances, a satisfactory pathophysiological explanation for an observed paraneoplastic phenomenon is lacking. In those situations where the pathophysiological process has been investigated, polypeptide molecules have most commonly been implicated as mediators of the disease.
In many cases, the clinical recognition of paraneoplastic signs precedes recognition and identification of the underlying cancer. Clinical signs resulting from paraneoplastic phenomena are often distinct from those associated with disease of the tissue in which the primary cancer developed. Paraneoplastic phenomena may be clinically more detrimental to the patient than the primary cancer and may be sufficiently severe to prevent effective treatment of the underlying cancer. Paraneoplastic manifestations usually resolve following successful treatment of the underlying cancer and reappearance of those signs may suggest that recrudescence of the primary cancer is occurring.
Although there is a diverse range of syndromes described in human medicine, paraneoplastic syndromes are probably under-recognised in veterinary medicine. Increased awareness of the manifold clinical manifestations of paraneoplastic phenomena in horses will surely lead to earlier diagnosis of the primary cancer and thus improved treatment outcomes.
Clinical manifestations of an increased plasma ionised calcium concentration will result in signs related to the gastrointestinal, neuromuscular, cardiovascular and renal systems. Anorexia and constipation are associated with decreased contractility of the gastrointestinal smooth muscle. Decreased neuromuscular excitability results in generalised weakness, and behavioural changes including depression, stupor, coma, seizures and muscle twitching can also occur. Myocardial excitabilityis increased with decreased ventricular systole, resulting in weakness and syncope. Polyuria and polydipsia are a result of decreased renal concentrating ability, and high ionised calcium is toxic to the renal tubules (either directly or due to ischaemia induced by vasoconstriction), resulting in acute renal failure (Ogilvie 1998).
The most common mechanism of paraneoplastic hypercalcaemia in human and animal cancer patients is tumour production of parathyroid related protein (PTHrp), which leads to bone resorption and elevated blood calcium levels. Other reported mediators of hypercalcaemia include tumour-derived prostaglandins, osteoclast-activating factors, or extensive bone lysis resulting from metastasis (Ogilvie 1998; Taylor et al. 2009). Multiple myeloma and ameloblastoma producing PTHrp have been reported in horses (Rosol et al. 1994; Barton et al. 2004). Non-neoplastic causes of hypercalcaemia in the horse include chronic renal failure, hypervitaminosis D, plant toxicosis (Cestrum diurnum) and primary hyperparathyroidism.
Hypertrophic osteopathy (Marie's disease)
Hypertrophic osteopathy (HO, Marie's disease), also known as hypertrophic osteoarthropathy, represents one of the more commonly reported paraneoplastic phenomena in the equine species. This debilitating condition is characterised by the development of symmetrical proliferation of connective tissue and subperiosteal bone along the diaphyses and metaphyses of appendicular bones resulting in limb swelling of all 4 limbs (Mair et al. 1996) (Fig 2). Periosteal proliferation may interrupt circulation within the limbs, resulting in the development of oedema at distal sites.
Limb swelling is characterised as being painful in approximately 25% of cases. Less frequently, HO may affect the mandible, maxilla and nasal bones. In addition to symmetrical distal limb swelling, affected horses usually also exhibit lameness, reluctance to move, synovial effusions, stiffness and reduced joint flexibility. Unlike the condition in human patients, periosteal new bone formation rarely involves the articular surfaces in affected horses (Fig 3). Depending on the primary condition, affected horses may also develop ventral subcutaneous oedema, lethargy, fever, increased respiratory rate and effort, and cough (Mair et al. 1996). Radiographically, new bone proliferation is often characterised by a palisade-like appearance, perpendicular to the cortex.
Most cases of HO develop as a secondary manifestation of another disease, most commonly cancer and usually cancer within the thoracic cavity. However, when compared with man and dogs, equine cases of HO are much less commonly associated with cancer and most reported cases have been associated with inflammatory conditions of the chest, especially granulomatous inflammatory disease (Mair et al. 1996). It should be noted that intrathoracic neoplasia is comparatively uncommon in the equine species (Davis and Rush 2011).
Intrathoracic neoplastic conditions that have been reported to provoke HO in horses have included squamous cell carcinoma, granular cell myoblastoma and metastatic pulmonary tumours (Leach and Pool 1992; Godber et al. 1993). Hypertrophic osteopathy has also been reported as a complication of certain non-neoplastic conditions such as an intrathoracic abscess or granuloma, pulmonary infarction, tuberculosis, pneumonia, pleuritis, fibrosing mediastinal lymphadenitis and rib fracture with pleural adhesion formation (Messer et al. 1983; Chaffin et al. 1990; Mair et al. 1996). Examples of cases of extra-thoracic tumours in which HO developed in horses have included pituitary adenoma and ovarian neoplasia (McLennan and Kelly 1977; Sweeney et al. 1989; Heinola et al. 2001). In one case, HO developed in parallel with pregnancy and regressed after foaling (Lavoie et al. 1992). In human medicine, the development of HO without identification of an underlying primary condition is referred to as pachydermoperiostosis (Nahar et al. 2007).
A satisfactory explanation for the development of HO is presently lacking. Endothelial cell activation and vascular hyperplasia are prominent features. Distal limb swelling develops as a result of oedema and excessive collagen deposition. At the tubular bone level, there is vascular hyperplasia with proliferation of the periosteal layers. Endocrinopathic, hypoxic, arteriovenous shunt-mediated and neurological mechanisms have all been suggested as plausible explanations. Any hypothesis attempting to explain the pathophysiology of HO should explain how such diverse illnesses as lung cancer, cyanotic heart disease and inflammatory bowel disease (among many others) can produce the unique histological alterations that characterise HO.
Recent work suggests that overproduction of vascular endothelial growth factor (VEGF) may be involved in the pathogenesis of HO and may explain how diverse hypoxic or neoplastic pathologies induce HO (Martinez-Lavin et al. 2008). A variety of malignant tumours produce VEGF, promoting and supporting their uncontrolled growth. Plasma levels of VEGF are increased in human patients with primary HO and HO associated with lung cancer (Silveira et al. 2000; Atkinson and Fox 2004). Immunohistochemistry studies of HO-affected human patients have shown increased VEGF deposition in the connective tissue stroma of clubbed digits (Olan et al. 2004). Nevertheless, it is clear that more studies are needed to elucidate the pathogenesis of HO. Untested for treatment of HO in horses, bisphosphonates are currently being investigated for the treatment of HO in human patients (Martinez-Lavin et al. 2008).
Hypoglycaemia associated with noninsulin-secreting tumours in horses and in other species has been attributed to the production of insulin-like growth factor-II (ILGF-II) or an abnormal, large molecular weight form of ILGF-II known as ‘big ILGF-II’ (Sakamoto et al. 1994). Although ‘big’ ILGF-II possesses approximately 6% of the activity of insulin, it circulates in concentrations 1000 times that of insulin and enhances removal of glucose from the circulation by skeletal muscle (Sakamoto et al. 1994). The effects of tumour-derived insulin-like molecular signals are particularly relevant in the face of concomitant anorexia. Confirmation that hypoglycaemia may be attributable to tumour-derived ILGF-II would require either demonstrating elevated serum ILGF-II concentrations or employing ILGF-II immunohistochemistry to representative tumour tissue samples. Insulinoma is clearly rare in the equine species and should be ruled out upon consideration of the circulating plasma insulin concentrations in suspected cases (Ross et al. 1983).
Both hypercupraemia and increased levels of serum ceruloplasmin have been reported in human cancer patients (Yenisey et al. 1996; Vaidya and Kamalakar 1998). Elevated circulating blood copper concentrations were identified in one horse affected with renal adenocarcinoma and prompted the suggestion that hypercupraemia might be an under-recognised paraneoplastic manifestation in horses (Owen et al. 1986). However, the clinical evaluation of circulating copper and ceruloplasmin concentrations is rarely undertaken in equine practice.
Circulating copper and ceruloplasmin levels may help with determination of both the prognosis and early diagnosis of cancer (Yenisey et al. 1996). For example, the identification of copper deposits on Descemet's membrane, the surface of the iris, and lens capsule is instrumental in early diagnosis of multiple myeloma (Hawkins et al. 2001). Corneal copper deposition may also be associated with systemic malignancies such as chronic lymphocytic leukaemia (Aldave et al. 2006). Strategies for the pharmacological control of paraneoplastic hypercupraemia are being investigated for purposes of cancer treatment (Goodman et al. 2005; Khan and Merajver 2009).
Tumour lysis syndrome
Tumour lysis syndrome (TLS) is a well-recognised oncological emergency in human medicine, characterised by severe metabolic derangements (Davidson et al. 2004; Locatelli and Rossi 2005). Although most commonly reported in patients with lymphoproliferative malignancies who are treated using radiation, chemotherapy or corticosteroids, TLS sometimes develops in the absence of treatment (Davidson et al. 2004; Locatelli and Rossi 2005). Identified risk factors for TLS include a large tumour burden, neoplasms with either high growth fraction or high sensitivity to chemotherapy, increased serum lactate dehydrogenase (LD) activity and pre-existing renal impairment (Locatelli and Rossi 2005). TLS frequently is associated with acute renal failure (ARF) and pre-existing impairment of renal function is regarded as an important risk factor for TLS in susceptible individuals (Davidson et al. 2004).
In horses, hyperkalaemia, hyperphosphataemia and hypocalcaemia are more commonly associated with acute renal failure. Therefore, TLS should be carefully considered in those equine patients presenting with signs of both renal failure and cancer. Excess uric acid, hypoxanthine and calcium phosphate resulting from TLS are toxic to renal epithelial cells and contribute to worsening renal failure (Davidson et al. 2004; Locatelli and Rossi 2005). Pre-existing volume depletion or renal dysfunction may further aggravate the metabolic derangements of TLS.
Although it has been reported rarely in horses, TLS was suspected in one horse affected with mesothelioma in which characteristic metabolic perturbations (hyperkalaemia, hyperphosphataemia, hypocalcaemia), acute renal failure, extensive tumour burden with a high-grade histopathological classification, and marked increase in serum LD activity were identified (LaCarrubba et al. 2006). In that case, hyperkalaemia and hyperphosphataemia may have been attributable to the effects of both TLS (increased release of potassium and phosphate) and ARF (excretory failure). Hyperphosphataemia in the face of TLS is partly explained by the fact that malignant tumour cells may contain up to 4 times more phosphate than normal cells (Flombaum 2000). Although not commonly reported in veterinary species, TLS has been reported in dogs and cats with lymphoma (Laing and Carter 1988; Calia et al. 1996).
Cachexia is one of the most debilitating and life-threatening aspects of cancer. It is associated with weight loss, anorexia and inflammation, and is one of the most frequently reported paraneoplastic syndromes in human medicine; it is also an indicator of poor prognosis (Bennani-Baiti and Walsh 2009). The exact mechanisms by which cachexia occur are largely unknown; however, it is recognised by major metabolic alterations. Resting energy expenditure is increased and energy intake is decreased due to inappetence. It is thought that cancer-associated inflammation causes anorexia, impaired muscle protein synthesis, and the stimulation of muscle breakdown. Inflammatory mediators can cause anorexia via up-regulation of pituitary pro-opiomelanocortin expression, which is a precursor for adrenocorticotropin, melanocyte stimulating hormone, lipotropin and beta-endorphin (‘melanocortins’).
Clinically, cancer cachexia is recognised as severe weight loss, specifically wasting of muscle and fat, often in the face of seemingly adequate nutrition. Muscle weakness and fatigue are commonly present and negatively impact the quality of life. Elevated resting energy expenditure is present, and there is a profound tumour utilisation of glucose through anaerobic glycolysis (increased lactate production) causing a net energy gain by the tumour. The body subsequently expends energy converting lactate to glucose and gluconeogenesis is stimulated, causing a net energy loss by the host. Protein degradation is enhanced as amino acids are transferred to the tumour and a negative nitrogen balance occurs. End results of cachexia are impaired wound healing, muscle wasting and fat mobilisation.
It is likely that cancer cachexia has been under-recognised and under-reported in horses affected with cancer. However, the presence of cancer cachexia is a negative prognostic indicator, and treatment involves extensive supportive care and directed therapy towards the underlying cause (Durham et al. 2009). Although recognised in veterinary medicine, research is needed to facilitate better optimisation of nutrition for horses affected with cancer cachexia. Although there are currently no available drugs for antagonism of the peripheral melanocortin actions believed to be very important in the pathogenesis of cancer cachexia, there is considerable current interest in the development of pharmacological agents for this purpose.
Fever and hyperfibrinogenaemia
Paraneoplastic fever results from the excessive release of cytokines, specifically interleukin-1 (IL-1), IL-6, TNFα, and interferons. Hyperfibrinogenaemia results from the action of elevated IL-6 levels acting on the liver (acute phase protein response). Although the incidences of paraneoplastic fever and hyperfibrinogenaemia are unknown in veterinary medicine, approximately one-third of human patients presenting with fever of unknown origin are diagnosed with cancer. More common causes of fever include infection, inflammation, autoimmune disease and drug interactions. In horses, alimentary lymphoma may be complicated by intestinal epithelial ulceration, infection and abscess development (Fig 4). In these cases, early clinical signs of septic peritonitis, fever and hyperfibrinogenaemia may mask the presence of an underlying neoplastic condition. If the primary tumour can be successfully treated, signs of paraneoplastic fever and hyperfibrinogenaemia can be resolved (Ogilvie 1998).
Multiple causes of thrombocytopenia are present in the cancer patient, including increased platelet consumption, sequestration of platelets in the spleen, sequestration within blood-filled sinuses, or decreased production due to bone marrow infiltration. The incidence of thrombocytopenia in horses diagnosed with lymphoma has been reported at 35% and, in most cases, was coupled with myelophthisis (Meyer et al. 2006).
Haemangiosarcoma has also been associated with thrombocytopenia in the horse. In middle-aged horses, haemangiosarcoma often presents with multiple organ involvement, particularly the respiratory and musculoskeletal systems (Southwood et al. 2000). However, Johns et al. (2005) reported that cutaneous masses, leg swelling and joint effusion were the more common presenting complaints in a case series describing haemangiosarcoma in 11 horses of less than 3 years of age. Although reported in both studies, thrombocytopenia was more common in older horses with disseminated forms of the disease (Southwood et al. 2000; Johns et al. 2005). Most likely, haemangiosarcoma-associated thrombocytopenia results from increased platelet consumption. As a malignant tumour of the vascular endothelium, haemangiosarcoma can lead to dyshaemostasis due to irregular vasculature, such as blind ended and tortuous vessels, incomplete endothelial lining, exposed subendothelial collagen, and platelet-tumour aggregates (Thamm and Helfand 2000).
Absolute erythrocytosis is defined as an increase in total circulating red blood cell mass, and can be primary or secondary. Primary erythrocytosis is a disease of the bone marrow, with erythropoiesis occurring regardless of erythropoietin stimulation. Secondary erythrocytosis is stimulated erythropoiesis due to chronic hypoxia (appropriate) or inappropriate excessive production of erythropoietin. Paraneoplastic erythrocytosis is a form of secondary erythrocytosis due to tumour production of erythropoietin or tumour prostaglandin production enhancing the effect of erythropoietin (Roby et al. 1990; Lennox et al. 2000).
One tumour type associated with erythrocytosis in horses is hepatoblastoma. Two horses affected with hepatoblastoma and erythrocytosis were young (age 10 months and 2.5 years) and presented with clinical signs of inappetence, weight loss, and mucous membrane congestion (marked reddening). Supportive care including phlebotomy and i.v. fluid therapy was initiated but the prognosis for this condition is poor and both horses were subjected to euthanasia. Diagnosis in both cases was made on post mortem examination and histopathological examination of the liver masses (Lennox et al. 2000; Axon et al. 2008). Additionally, erythrocytosis was reported in one mare diagnosed with metastatic carcinoma (Cook et al. 1995) and in a yearling filly affected with hepatocellular carcinoma (Roby et al. 1990).
One of the authors (P.J.J.) has observed both clinical improvement and significant reversal of erythrocytosis following treatment with hydroxyurea for the management of paraneoplastic erythrocytosis. In one case of suspected myosarcoma in which the plasma erythropoietin concentration (8 mu/ml, reference range <6 mu/ml) and packed cell volume (PCV) (64%) were elevated at the outset of treatment (Fig 5), the PCV decreased to 51% after 10 days of palliative treatment with hydroxyurea (15 mg/kg bwt, per os q. 12 h) and clinical signs of erythrocytosis improved (M. Mogni, personal communication).
Multiple myeloma, or plasma cell myeloma, is a tumour type of the plasma cells. Plasma cells are normally responsible for production of the M component of immunoglobulins. The M component can consist of the entire immunoglobulin, free light chains, light chain fragments or partial immunoglobulins. Multiple myeloma consists of a malignant plasma cell line that produces a monoclonal immunoglobulin product, and therefore results in monoclonal gammopathy, usually immunoglobulins of the IgG isotype (Ogilvie 1998; Pusterla et al. 2004).
Multiple myeloma is rare but has been reported in horses. Clinical signs in 2 horses were vague and included weight loss, pale mucous membranes, limb oedema and pneumonia. Hypoalbuminaemia and hypergammaglobulinaemia were found in both cases in addition to proteinuria. Electrophoresis of plasma and urine revealed monoclonal gammopathies. Although IgG is the most common paraprotein produced by malignant plasma cells, these 2 horses both had elevations in plasma IgA concentrations (Pusterla et al. 2004). Elevated circulating IgG concentrations were identified in an additional 4 horses diagnosed with multiple myeloma (Edwards et al. 1993).
Oral cavity amyloidosis in human patients, usually affecting the tongue (macroglossia), has been associated with (mostly) multiple myeloma, idiopathic monoclonal gammopathy and non-Hodgkin lymphoma (van der Waal et al. 2002). Oral cavity amyloidosis is therefore regarded as a paraneoplastic manifestation of plasma cell dyscrasias, especially multiple myeloma. Similarly, secondary amyloidosis of the conjunctiva and the mucosa of nasal and paranasal sinuses have been reported in human patients affected with renal carcinoma (Ibrahim and Iheonunekwu 2009).
Systemic light chain (AL) amyloidosis has been reported in equine patients affected with multiple myeloma (Kim et al. 2005), localised plasmacytoma (Linke et al. 1991), lymphoma (Gliatto et al. 1995) and adrenocortical adenoma (van Andel et al. 1988). Nasal cavity and cutaneous amyloidosis represent 2 of the most commonly reported locations for reactive amyloidosis in horses (Figs 6 and 7). It is recommended that diagnostic testing for further evidence of malignancy is warranted in patients with unexplained reactive amyloidosis. However, it may be difficult to identify the primary cancer responsible for secondary amyloidosis.
Dermatological paraneoplastic syndromes
Oral blisters in addition to lethargy and anorexia occurred in a 6-year-old gelding. Histologically, the oral lesions were consistent with bullous pemphigoid, definitively diagnosed with immunoprecipitation. A cervical haemangiosarcoma was excised from this horse, and resolution of bullae and other clinical signs coincided with excision of the mass (Williams et al. 1995). Other dermatological paraneoplastic syndromes in the horse include pruritus and alopecia associated with lymphoma (Finley et al. 1998) and granulomatous dermatitis associated with a granulosa cell tumour (Abbott et al. 2004). Treatment of cutaneous manifestations of cancer is directed to the primary cause.
Recognition of the surprisingly diverse array of paraneoplastic manifestations of cancer should increase veterinary diagnosticians' awareness for a neoplastic aetiology when faced with these clinical problems. Although many of these clinical presentations result from more common, non-neoplastic aetiologies, some of the problems (e.g. amyloidosis) can be quite implicative for cancer. This article serves to summarise what has been reported in the veterinary medical literature regarding paraneoplastic syndrome in horses, to date. It is likely that, as reported in the human medical literature, other hitherto unrecognised paraneoplastic complications of cancer will probably be reported in horses in the future. Examples of other paraneoplastic signs that have not been reported for horses include various paraneoplastic neurological disorders, myasthaenia, chronic pruritus, Cushing's syndrome, osteomalacia, the syndrome of inappropriate anti-diuretic hormone, carcinoid syndrome and glomerulonephritis. The reader is directed to other reviews of paraneoplastic syndromes (such as McAllister and Weinberg 2010) for further information pertaining to this interesting, complex and diagnostically challenging clinical problem.
Authors' declaration of interests
No conflicts of interest have been declared.
Howard Wilson and Don Connor were instrumental in preparation of the figures. Thanks to Drs Nat Messer and Maurizio Mogni for providing some of the photographs.