Paraneoplastic syndromes are clinical signs caused by certain tumours, which are unrelated to the size or location of the primary tumour or its metastases. These signs can be the first indication of the presence of a tumour and may facilitate its diagnosis (e.g., hypercalcaemia may lead to the diagnosis of malignant lymphoma) or may be used as an indication of the effectiveness of the treatment. Sometimes the paraneoplastic syndrome is even more life-threatening than the tumour itself, as in the case of hypoglycemia caused by an insulinoma.
Some good examples of paraneoplastic syndromes are those caused by hormonal products of endocrine tumours, such as Cushing's disease due to tumours of the pituitary or adrenal, hyperthyroidism due to thyroid tumours, and hypoglycemia due to a β-cell tumour of the pancreas. However, these will not be included in the short abstract below.
Tumour-associated hypercalcemia is the most common form of hypercalcemia. Different mechanisms may be involved:
1. Humoral hypercalcemia malignancy: The tumour produces humoral factors which have an effect on the bones, kidneys, and gastrointestinal tract. An important example of this is the PTH-related peptide (PTH-rP). PTH-rP resembles PTH, shares several characteristics of PTH, but differs immunologically. PTH-rP is present in low concentrations in several normal, especially epithelial, tissues, but it is produced in large amounts by some malignant lymphomas and anal sac carcinomas. In anal sac carcinomas there is a linear correlation between PTH-rP and hypercalcemia. In malignant lymphomas in the dog this correlation is less obvious, suggesting a second hormonal factor. In dogs, hypercalcemia is especially seen in cases of T-cell lymphoma. In the Netherlands the boxer is predisposed to lymphoma-associated hypercalcemia. According to published reports, up to 30% of the canine malignant lymphomas cause hypercalcemia, but the frequency is much lower in the cat.
2. Metastases of solid tumours to bone. Bone destruction by metastases may cause hypercalcemia, especially bone metastases of mammary carcinomas. In the dog and cat, however, this type of hypercalcemia is less frequent.
3. Hematological malignancies, excluding malignant lymphoma. In these cases the hypercalcemia is caused by osteoclast activating factors such as IL-1, TNF, and lymphokines, produced by the tumour cells. One of the most common types of hematological tumours producing such osteoclast-activating factors is the plasma cell tumour.
Mast cell tumours frequently cause paraneoplastic syndromes in the dog. Most symptoms are related to the release of mast cell granules substances such as histamine, heparin, and proteolytic enzymes. Histamine binds to H1-and H2-recptors present in several tissues in the body. Binding to H2-recptors in the gastric mucosa results in an increased production of gastric acid, increased mucosal vascularisation, and edema of the mucosa, resulting in ulceration, bleeding, and gastric pain. In other tissues the spontaneous release of mast cell granule constituents can result in edema, erythema, bleeding, and pruritis. Massive histamine release after (cryo)surgery may cause life-threatening cardiopulmonic effects via hypotension, arrhythmias (both H1-and H2-receptors), and bronchospasm (H1-receptor binding).
Tumour-associated heparin release may also result in prolonged bleeding time.
Cancer may influence carbohydrate, protein, and fat metabolism, resulting in a syndrome known as cancer cachexia. Anorexia can worsen the problem. Cancer cachexia decreases the quality of life, the response to treatment, and survival time.
Recently, it has been demonstrated that carbohydrate metabolism in cancer patients is changed, resulting in a net energy gain by the tumour and a net energy loss by the patient. Glucose is the most important source of energy for tumour cells. In normal tissues one molecule of glucose is oxidized via the Krebs cycle to CO2 and water, resulting in 32 molecules of ATP. However, the tumour glycolates glucose to lactate anaerobically with a net energy gain of only 2 molecules of ATP. To fulfill the great energy need of the tumor, the body converts the lactate to glucose again via the Cori cycle. This process costs 4 molecules of ATP and 2 molecules of GTP for every molecule of glucose synthesized. The end result is negative energy balance for the body, but positive energy balance for the tumour.
In addition, a relative insulin resistance has been found in cancer patients. This can be explained by a defect in the insulin receptor or an abnormality in the signal transmission after binding of the insulin to the insulin receptor. The result is glucose intolerance which is present before other symptoms of cancer cachexia are found. Studies in dogs with malignant lymphoma have shown that the insulin resistance is most likely a post-receptor defect. In addition, a glucose tolerance test in these dogs resulted in a significant increase in plasma lactate and plasma insulin levels both before and during the test. The abnormality did not revert to normal when these animals received chemotherapy and were in complete clinically remission. A conclusion which can be drawn from these studies is that cancer patients should not receive Ringer's lactate infusions, as this will increase plasma lactate, further increasing the negative energy balance. Plasma lactate levels can also be increased by infusions of glucose. Furthermore, carbohydrate-rich diets can promote cancer cachexia.
Protein breakdown exceeds protein synthesis in cancer cachexia, resulting in a negative nitrogen balance. The protein loss may influence wound healing, the immune system, and gastrointestinal functions. In addition, plasma levels of amino acids used for gluconeogenesis (arginine, glutamine, glycine, cystine, and valine) have been found to be decreased in dogs with cancer. This necessitates a diet containing proteins having a high biological value, although proteins should not be given in excess, as the tumour might use this as an energy source.
Dogs with cancer have significantly lower plasma levels of high-density lipoproteins. In contrast, free fatty acids, total triglycerides, and very-low-density lipoproteins are increased significantly. All of this is consistent with decreased lipogenesis and increased lipolysis, which is seen in human patients with cancer cachexia. Insulin resistance may aggravate this situation. Diet restrictions can influence the clinical signs caused by the abnormal metabolism of fat. Tumor cells can use carbohydrates and proteins as energy sources, but most cannot use fat. Consequently, diets high in fat are potentially beneficial for patients with cancer cachexia. In addition, some triglycerides and fatty acids have been shown to decrease cancer cachexia experimentally and even to have anti-cancer characteristics. For example, diets rich in fish oil, which has a high content of omega-3 polyunsaturated fatty acids, increase body weight and have anti-tumour effects. In contrast, the omega-6 fatty acids increase oncogenesis.
There are several causes for anaemia in cancer patients.
1. Anaemia of chronic disorders. This type of anaemia is caused by a shortened erythrocyte life-span and is characterized by a mild, normocytic-normochromic, nonregenerative anaemia. The erythrocyte life-span is shortened from 120 days to 60-90 days. The exact cause of this anaemia is not known. Damage to the erythrocyte by abnormal vascular structures, inflammation, or immune complexes may result in increased phagocytosis in the reticuloendothelial system. Abnormal iron metabolism may also contribute to the anaemia.
2. Anaemia caused by myelophthisis. Bone marrow infiltration by tumour cells may suppress the normal bone marrow cells. This is called myelophthisis and is usually only seen in a late stage of the neoplastic disease.
3. Immune-mediated hemolytic anaemia. Immune-mediated hemolytic anaemia is usually associated in the dog and cat with haematopoietic tumours.
4. Microangiopathic hemolytic anaemia. This type of anaemia is usually associated with microvascular tumours. Fragmentation of erythrocytes can occur. Both abnormal erythrocytes, resulting in anaemia, and fragmented platelets are the result of intravascular damage by fibrin threads formed in the course of DIC, or by abnormal vascular structures with fibrin deposits, or by proliferation of the intima in the pulmonary vessels after tumour embolism. Hemangiosarcoma is the most frequent tumour in the dog associated with this type of anaemia.
Polycythemia is a rare paraneoplastic syndrome in the dog and the cat. Usually primary or secondary tumours of the kidney are responsible for the polycythemia. Possible mechanisms are ectopic erythropoietin production by the tumour or increased erythropoietin production by the kidney itself, due to kidney hypoxia caused by compression by the tumour.
The clinical signs are caused by the hyperviscosity and the dilatation and decreased perfusion of small blood vessels, resulting in tissue hypoxia, bleedings, and thrombosis.
Estrogen intoxication may result in pancytopenia due to bone marrow depression. Apart from iatrogenic causes, Sertoli cell tumours of the testicle and granulosa-cell tumours of the ovary can produce estrogens which cause bone marrow depression. Estrogen-induced pancytopenia is only seen in dogs and ferrets.
Thrombocytopenia is one of the most common haemostatic abnormalities in cancer patients, being reported to occur in almost 40% of dogs with cancer. Possible causes for the thrombocytopenia are:
1. A shortened platelet life-span due to binding to abnormal endothelium in blood vessels of the tumour or due to accelerated removal from the circulation because of tumour-stimulated microaggregation or because of coating of the platelets by tumour proteins.
2. An immune-mediated thrombocytopenia, caused by anti-platelet antibody production by the tumour, cross-reactivity between tumour antigens and platelet antigens, and binding of antibody-antigen complexes to the platelets.
A platelet count lower than 75,000/ul can give rise to clinical signs.
Aggressive malignancies in a late stage often result in clinical manifestations of coagulation disorders. Apart from thrombocytopenia, disseminated intravascular coagulation (DIC) is the most frequent abnormality and it is most likely due to a complex of factors. Coagulation-activating substances can be produced by tumour cells. Hemangiosarcoma, for example, can release tissue thromboplastin into the circulation. In addition, the tumour can cause increased platelet aggregation. Tumour necrosis factor (TNF), produced by inflammation-activated macrophages, can change the endothelium of blood vessels, leading to an increased tendency to intravascular coagulation.
The DIC-induced depletion of coagulation factors and the inhibitory properties of fibrinogen degradation products may cause hemorrhagic diathesis. DIC is often associated with hemangiosarcomas, thyroid carcinomas, and mammary gland carcinomas, especially the anaplastic carcinomas.
Plasma viscosity can be increased by both cellular and soluble components. It is often seen in patients with polycythaemia and in those with an increased serum protein concentration, as occurs in multiple myeloma and other diseases with paraproteinaemia.
Patients with plasma hyperviscosity due to an increased protein concentration, especially if raised by IgM and IgA, have an increased bleeding tendency. This is caused by an abnormal platelet function due to binding of proteins to the platelets membrane. In addition, paraproteins can bind coagulation factors or inhibit their function.
The hyperviscosity syndrome also influences the cardiovascular system, the kidney, and the central nervous system. The increased plasma protein concentration results in an increase in plasma osmolality, which causes hypervolemia. This increases the perfusion pressure and therefore the cardiac work load. Because the hyperviscosity also decreases myocardial perfusion, myocardial hypoxia develops and rapidly leads to heart failure.
Severe CNS depression, manifested by dementia, ataxia, and coma, can be seen in patients with hyperviscosity syndrome. This is caused by the cerebral hypoxia induced by the decreased cerebro-vascular perfusion.
Bence-Jones proteinuria predisposes to renal failure through damage to renal tubules, secondary to metabolic degradation of light-chain monomers in the renal tubular cells. An additional cause for renal failure is renal hypoxia as a result of serum hyperviscosity.
Hyperviscosity syndrome is also associated with eye abnormalities. Both the increased vascular volume and bleeding tendencies may lead to ocular changes, including distended and tortuous retinal vessels, cysts of the pars plana, papilledema, and retinal haemorrhage and detachment. These changes can result in the sudden onset of blindness.
Hypertrophic osteoarthropathy is characterized by a very painful, non-edematous, warm, periosteal swelling of the bones of the legs. Radiographic changes are characteristic: periosteal new bone formation occurs as either irregular nodules perpendicular to the cortex or smoother parallel deposits, starting distally in the metacarpals or metatarsals and spreading proximally. It is often associated with processes in the thoracic cavity, especially the peripheral parts of the lungs. However, processes in the abdomen, especially the kidneys, the urinary bladder, and the pelvic cavity, can also be seen in combination with hypertrophic osteoarthropathy.
The exact cause of the osteoarthropathy is still unknown. It has been suggested that humeral vasoactive substances or neural stimulation may cause increased blood perfusion in the extremities, leading to the proliferation of periosteum and connective tissue. Removal of the tumour usually leads to a rapid disappearance of the paraneoplastic syndrome.