The recognition of paraneoplastic syndromes in veterinary patients is important. In humans the prevalence of paraneoplastic syndromes is high. How high the prevalence is in veterinary patients is unknown but it is probably frequent and underestimated.

What are paraneoplastic syndromes and why are they important?

Paraneoplastic syndromes (PNS) result as a consequence of an indirect effect of tumours that produce biologically active substances, either in the form of hormones or their precursors – growth factors, cytokines or interleukins. The immune system may be involved, resulting in autoimmunity, immune complex formation or immunosuppression.

Recognizing paraneoplastic syndromes is important because:

• it may be the first sign of neoplasia, e.g. polyuria/polydipsia (PU/PD), in patients with hypercalcaemia secondary to an anal sac adenocarcinoma; early detection may lead to a better prognosis for the patient

• monitoring a PNS means that the progression, regression or relapse of a tumour can be followed

• the signs of a PNS can sometimes be confused with the direct effects of neoplasia or treatment, e.g. presentations of anaemia in lymphoma

• a PNS in itself may adversely affect prognosis as it may cause other problems, e.g. renal failure in patients with hypercalcaemia

• the presence of a detrimental PNS means that achieving either static disease or a partial response may not be an option for the patient, e.g. a dog with anal sac adenocarcinoma metastatic to the sub-iliac lymph nodes can be kept comfortable with palliative care (chemotherapy or radiotherapy to reduce the size of the lymph nodes, faecal softeners, etc.), providing he is not hypercalcaemic; for the hypercalcaemic patient the inability to attain a complete remission will result in a reduced life span. This is because the persistence of the PNS will not only adversely affect quality of life for the patient, it will also lead to other significant consequences, e.g. renal failure.

The most commonly encountered PNS in veterinary medicine are anaemia, thrombocytopenia and hypercalcaemia (see Table 10.1 and Table 10.2 for some common tumours and their associated PNS).

**Table 10.1** Common tumours and haematological paraneoplastic syndromes
Paraneoplastic syndrome	Tumour
Anaemia	Lymphoma, leukaemia, multiple myeloma, haemangiosarcoma, intestinal carcinoma, etc.
Thrombocytopenia	Lymphoma, leukaemia, multiple myeloma, haemangiosarcoma, etc.
Pancytopenia	Leukaemia, lymphoma, Sertoli cell tumour, granulosa cell tumour
Eosinophilia	Mast cell tumours, lymphoma, sarcomas, bladder carcinoma
Disseminated intravascular coagulation	Haemangiosarcoma, inflammatory carcinoma, thyroid carcinoma, lymphoma, leukaemia, any advanced cancer
Polycythaemia	Renal carcinoma/lymphoma
Leucocytosis	Lymphoma, haemangiosarcoma

**Table 10.2** Tumours and non-haematological paraneoplastic syndromes
Paraneoplastic syndrome	Tumour
Hypercalcaemia	Lymphoma, leukaemia, multiple myeloma, squamous cell carcinoma, anal sac adenocarcinoma, histiocytic disease, metastatic carcinomas
Hypoglycaemia	Insulinoma, leiomyomas/sarcomas, hepatic carcinomas, haemangiosarcomas
Fever	Lymphoma, leukaemia, solid tumours, etc.
Cachexia	Lymphoma, leukaemia, any advanced neoplasm
Hyperviscosity	Multiple myeloma, lymphoma, leukaemia
Neuromuscular	Thymoma, lymphoma, insulinoma, pancreatic carcinoma, prostatic carcinoma, etc.
Hypertrophic osteopathy	Osteosarcoma, metastatic carcinoma
Skin	Mast cell tumours, pheochromocytomas, carcinoids, haemangiosarcoma, renal cystadenocarcinomas
Hyperhistaminaemia	Mast cell tumours
Renal	Lymphoma, multiple myeloma, anal sac adenocarcinoma, any advanced tumour

Anaemia

Anaemia is the most commonly encountered PNS (Fox 1995). In many cases, although present, it is not clinically relevant. When dealing with the anaemic patient it is important to establish the underlying cause and type of anaemia.

Anaemia of chronic disease

This is the most common form of anaemia seen in cancer patients. The mechanisms involved include impaired iron use, suppressed erythroid progenitor cell differentiation, insufficient erythropoietin (EPO) production and decreased survival of erythrocytes. It is characterized as mild/moderate, normocytic, normochromic and non-regenerative, with normal bone marrow cellularity and reduced serum iron. Specific treatment is seldom required but in rare instances EPO may be beneficial.

Haemolytic anaemia

Haemolytic anaemia is most often encountered in association with haemolymphatic tumours (see Chapter 22), but has been reported in association with solid tumours (Ogilvie 2000). The mechanism is due to cross-reacting antibodies against cell-membrane antigens or direct interference with the immune system via suppressor T cells leading to premature destruction of erythrocytes. It can be mild, moderate or severe and is characterized as macrocytic, hypochromic and regenerative.

Any patient presenting with immune-mediated haemolytic anaemia (IMHA) warrants investigation to rule out underlying neoplasia. It can be life-threatening and may require intervention with blood products (packed red blood cells, whole blood or blood substitutes, e.g. oxyglobin; see Chapter 9).

Microangiopathic haemolytic anaemia (MAHA)

This form of anaemia is most commonly seen with haemangiosarcoma (HSA) but can be seen with any microvascular tumour and is due to fragmentation of erythrocytes producing schistocytes. Schistocyte production is the result of intravascular shearing due to the presence of fibrin strands from chronic disseminated intravascular coagulation (DIC) or abnormal tumour vasculature. MAHA can be mild to moderate and may require intervention with blood products.

Blood loss anaemia

Any bleeding tumour can cause blood loss anaemia, e.g. primary gastrointestinal tumours, splenic, renal and hepatic tumours. It is also seen with paraneoplastic gastroduodenal ulceration caused by, for example, gastrinomas and mast cell tumours. The mechanism depends on the underlying tumour. The characteristics of the anaemia depend on chronicity as it can start off regenerative and with, for example, a slowly bleeding intestinal tumour, become non-regenerative, microcytic and hypochromic.

Thrombocytopenia

This is the most common haemostatic problem in dogs with cancer, and is seen in up to 30% of dogs with solid tumours and 50% of dogs with lymphoma (Grindem et al 1994, Madewell et al 1980). In cats, feline leukaemia virus (FeLV) and myeloproliferative diseases are the major neoplasms to result in thrombocytopenia and account for 20% of cases (Jordan et al 1993).

Mechanisms include immune-mediated (idiopathic thrombocytopenic purpura, ITP) due to the formation of anti-platelet antibodies or cross-reactivity of platelet antigens and tumour antigens (lymphoma).

Microangiopathy can cause fragmentation of platelets and chronic DIC will reduce platelet numbers (HSA) due to increased platelet consumption. Spontaneous bleeding is expected with a platelet count of <20 × 10⁹/l, although bleeding can occur at platelet counts of 50 × 10⁹/l following surgery or trauma.

In patients with thrombocytopenia a coagulation profile is indicated, if possible to include D-dimers to assess the presence of fibrin degradation products (FDPs). Treatment depends upon treating the underlying neoplasm.

Pancytopenia

Pancytopenias are associated with leukaemia and, for solid tumours, most often with Sertoli cell tumours and granulosa cell tumours. In the latter instances the mechanism of pancytopenia is oestrogen-induced production of myelopoiesis inhibitory factor by thymic stromal cells, leading to the inhibition of granulocyte/macrophage progenitor cell growth. In many cases the effect can be long term (Teske 1986). Pancytopenias due to leukaemia are the result of ‘crowding out’ of normal cells.

Leucocytosis

Leucocytosis in veterinary patients not associated with infection or leukaemia is rare and when seen does not in itself result in clinical signs. It is usually a mature neutrophilia and has been reported with lymphoma, rectal carcinoma, pulmonary carcinoma and metastatic fibrosarcoma. Production of colony-stimulating factors by the tumour is thought to be responsible for the leucocytosis (Sharkey et al 1996).

Hypereosinophilia

This is rarely seen as a consequence of neoplasia. It has been reported in a cat with T-cell lymphoma (Barrs et al 2002) and bladder carcinoma (Sellon et al 1992), and even more rarely in the dog (Couto 1984). It is most often seen in patients with disseminated mast cell tumours and appears to be a response to the production of interleukin (IL)-2 and IL-5 (Gaschen & Teske 2005).