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Review Article: Paraneoplastic Syndrome

As we are all acutely aware, neoplasia is an extremely common problem affecting our companion animal patients. Since it may affect almost any area of the body, it can result in a wide variety of clinical signs. In many patients, signs are directly related to the affected organ and diagnosis can be fairly straight forward. However, the presence of distant secondary effects (otherwise known as ‘paraneoplastic syndromes’) can confuse the clinical picture. On the other hand, many patients will present with non-specific signs such as lethargy and diagnosis can then be extremely challenging, particularly when a primary neoplastic mass lesion is not apparent. In these cases the development of secondary paraneoplastic syndromes may actually be helpful with regards to consolidating the diagnosis of neoplasia. Regardless, since paraneoplastic syndromes often result in clinical signs that are more debilitating than the primary neoplastic lesion itself, it is vital that they are identified and treated in order to maximise quality of life in our cancer patients.

Neoplastic cells often produce and release biologically active substances such as hormones, growth factors and cytokines and occasionally these can cause higher morbidity than the tumour itself. Neoplastic cells may also induce immune-mediated problems such as immunosuppression, autoimmunity, and immune complex production.

Fever is a common finding in patients with neoplasia but, although it can be a true paraeoplastic effect, it is more often a result of immunosuppression and secondary infection. Cancer cachexia is the most common paraneoplasic syndrome but is usually treated as a separate entity since it affects multiple organ systems. There are a wide variety of other paraneoplastic syndromes and these are divided into categories based on the target organ affected:

¨ Haematologic disorders

¨ Endocrinopathies

¨ Gastrointestinal manifestations

¨ Renal manifestations

¨ Cutaneous syndromes

¨ Neuromuscular disorders

Cancer anorexia-cachexia syndrome

fig.1 - Gastrostomy PEG-tube feeding to maintain enteral nutrition in a cat

Cytokines released by neoplastic cells can result in anorexia and nausea. In addition, they cause alterations in carbohydrate, fat and protein metabolism which, in contrast to simple starvation, predisposes to profound muscle protein losses as well as reductions in body fat deposits. A loss of greater than ten percent body weight negatively influences survival, predisposes to secondary infections and delays wound healing. The objectives of nutritional support should therefore be to minimise these effects and to enhance immune function. Diets rich in polyunsaturated omega-3 fatty acids have proven benefits resulting in increased mean survival times and disease free intervals. It is also important to try and maintain enteral feeding for as long as possible since this is associated with better outcomes. Early intervention using assisted feeding methods such as naso-oesophageal (fig. 1) and gastric tube feeding is advocated to pre-empt severe cachexia.

Haematologic Syndromes

Fig. 2—Petechiation of the mucous membranes as a result of thrombocytopenia

Haematologic syndromes can be induced in patients with primary bone marrow tumours as a result of ‘crowding-out’ of normal bone marrow precursors by the neoplastic cell mass. Alternatively, the local bone marrow environment can be altered, discouraging the growth and differentiation of normal cell lines. Patients with non-bone marrow neoplasia can also develop haematologic syndromes for a variety of reasons. These include direct bone marrow effects of hormones or growth factors released from tumour cells and autoimmune destruction of haematopoetic cells as a result of cross-reacting antibodies. These syndromes commonly result in one or more of the following:

  1. Anaemia (anaemia of chronic disease, immune-mediated haemolysis, blood loss, microangiopathic haemolysis)
  2. Erythrocytosis (erythopoetin release from renal tumours)
  3. Leukocytosis (usually mature neutrophilia due to release of G-CSF)
  4. Thrombocytopenia (very common with myeloproliferative neoplasms, see fig. 2)
  5. Thrombocytosis (common in humans but rare in dogs and cats)
  6. Platelet hyperaggregability
  7. Pancytopenia (oestrogen release from Sertoli cell tumours)
  8. Coagulation disorders (disseminated intravascular coagulation most common)
  9. Hyperproteinaemia(immunoglobulin release: usually light chains/“Bence Jones proteins” with multiple myeloma or IgM/“Waldenstrom’s macroglobulinaemia” with chronic lymphocytic leukaemia)


Endocrine Manifestations

Hypercalaemia is induced by the excessive release of parathyroid hormone (PTH) from primary tumours of the parathyroid glands. A related substance known as PTH-rP (parathyroid hormone-related peptide) can be released from non-parathyroid tumours resulting in similar effects. This is most commonly seen in T-cell lymphoma, anal sac adenocarcinoma, and multiple myeloma. The presence of significant hypercalcaemia invariably results in lethargy, polydipsia and polyuria and is a negative prognostic indicator. The potential for soft tissue calcification resulting in secondary organ dysfunction is an additional concern if the phosphate levels are concurrently elevated (high calcium x phosphorus product).

Hypoglycaemia is most commonly associated with insulinoma but can also be seen with hepatoma, hepatocellular carcinoma, leiomyosarcoma, and haemangiosarcoma.  It is induced by the excessive release of insulin, insulin-like growth factor (IGF) or somatomedin from neoplastic cells. This results in weakness, reduced mentation and ultimately coma and should be treated promptly with glucose +/- glucagons and prednisolone as required.

Hyponatraemia is an uncommon finding but can be induced by inappropriate vasopressin secretion.

Gastrointestinal Manifestations

Fig. 3—Microscopic appearance of severe duodenal ulceration (x40 magnification)

Gastroduodenal ulceration (fig. 3) is associated with histamine release from mast cell tumours and with excessive gastrin production from gastrinomas.

Renal Manifestations

Some tumours induce the formation of immune complex disease (circulating antigen-antibody complexes) which causes particular problems at capillary beds and can induce glomerulonephritis.  Hypercalcaemic nephropathy is a potentia complication when hypercalcaemia is combined with concurrent high phosphate levels (high calcium x phosphate product) and can result in renal failure.

Cutaneous Manifestations

Hepatocutaneous syndrome or superficial necrolytic dermatitis is an uncommon skin disease which is associated with a variety of systemic metabolic diseases, including neoplasia. The exact pathogenesis is unclear but it is usually found in conjunction with marked vacuolar liver pathology and aberrant amino acid balance and glucagon metabolites are thought to play a key role. 

Nodular dermatofibrosis is associated with renal cystoadenocarcinoma and uterine tumours in the German Shepherd Dog where it is inherited via an autosomal dominant trait.

Neuromuscular Manifestations

Fig. 4—tetraparesis in a Schnauzer with lower motor neurone deficits in all four limbs as a result of peripheral neuropathy

Acquired myasthenia gravis is seen in fifty percent of dogs with thymoma as a result of auto-antibodies that are generated against acetylcholine receptors thus blocking neuromuscular transmission. This results in acute fulminant disease (rapid onset tetraparesis and dyspnoea), chronic generalised disease (gradually progressive generalised muscle weakness) or focal disease (varying degrees of facial, pharyngeal, laryngeal and oesophageal dysfunction). In all forms, mega-oesophagus is a common finding and there is a significant risk of aspiration pneumonia which can be life threatening.

Peripheral neuropathies (fig. 4) can be seen in association with lymphoma and multiple myeloma, as well as various carcinomas and sarcomas. The cause is likely to be a result of cross reacting auto antigens that are shared between the tumour cells and peripheral nerves.

Hypertrophic osteopathy (progressive periosteal hyperostosis of distal extremities a.k.a. ‘Marie’s disease’ in man) can be triggered by space occupying lesions in the either the thorax or abdomen. It is thought to result from irritation of the vagus and intercostals nerves.