When Neoplasia is Just the Beginning: Early Signs of Paraneoplastic Syndromes
Kathi L. Smith, RVT, LVT
Paraneoplastic syndromes are defined as syndromes caused by a malignant neoplasm, resulting in alterations in bodily structure and/or function, but not from the presence of tumor cells in the affected areas. These syndromes are unrelated to the tissue of origin by size, location, metastases and physiological activity. They are initiated by the production and release of hormones from endocrine tumors into circulation as well as secretory proteins from non-endocrine tumors. The relevance of recognizing and understanding these syndromes is that they may be the initial or only sign of malignancy. They can be utilized to quantify and monitor response to therapy, aid in evaluation of tumor recurrence or disease progression. Their presence results in higher rates of morbidity than the primary malignancy. Oncology technicians must familiarize themselves with these syndromes in order to educate their clients, and improve disease control.
Hypercalcemia of Malignancy
The potential causes of hypercalcemia of malignancy include the direct resorption of bone by tumor cells, and tumor-induced production of osteoclast-activation factors (OAFs). These OAFs include interleukins, tumor necrosis factor (TNF), lymphotoxins, colony stimulating factors and Interferon-γ. Other causes include the tumor-induced production of 1,25-dihydroxyvitamin D, prostaglandin-induced osteolysis and the tumor-induced production of parathyroid hormone-related protein (PTHrP).
Patients with hypercalcemia of malignancy may present with anorexia or weight loss, vomiting, constipation, generalized muscle weakness, polyuria/polydipsia, dehydration, bradycardia, lethargy or depression. In more advanced cases stupor, coma or seizure activity may occur. Subsequent alterations in renal function cause the most common clinical signs.
Diagnosis is via blood chemistry profiles that demonstrate increased Ca++ levels, decreased phosphorus levels, normal creatinine and BUN; urinalysis that results in a decreased specific gravity; decreased serum PTH levels, increased serum PTHrP levels, and increased ionized Ca++.
The most common neoplasms associated with hypercalcemia of malignancy include lymphoma (10-40% of dogs with mediastinal T cell lymphoma and usually present with PU/PD), anal sac apocrine gland adenocarcinoma (up to 90% are hypercalcemic), multiple myeloma, nasal adenocarcinoma, thymoma and mammary adenocarcinoma.
Treatment for hypercalcemia of malignancy is based on the degree of hypercalcemia and the severity of clinical signs. Treatment of mild hypercalcemia and mild clinic signs includes controlling hydration with 0.9% saline (increases calcium excretion), monitoring the serum calcium, phosphorus and creatinine, and avoiding nephrotoxic drugs. Treatment of patients with moderate hypercalcemia and moderate clinical signs should include saline diuresis at 1-2 x maintenance, evaluation of urine output to exceed 2 ml/kg/hr, with the addition of 20-30 mEq KCl/L of 0.9% saline to prevent potassium depletion, monitoring of electrolytes and monitoring for overhydration and congestive heart failure. Furosemide can help prevent calcium resorption in the kidney. Prednisone inhibits osteoclast-activating factors, prostaglandins, vitamin D, and calcium absorption across the intestinal tract. Prednisone is also cytotoxic to lymphoma cells but should not be used unless all diagnostic samples have been obtained. Those patients that have severe hypercalcemia and severe clinical signs constitutes an emergent situation: use all the treatments for a patient with moderate hypercalcemia along with the addition of increased saline diuresis (> 132 ml/kg/day), monitoring for vomiting, diarrhea, dehydration and the need for potassium supplementation. The addition of bone resorption inhibitors such as calcitonin is indicated. Bisphosphonates such as etidronate, clodronate or pamidronate impede osteoclast activity and also induce osteoclast apoptosis. Mithramycin which is a chemotherapeutic agent has also been shown to be useful in quickly decreasing calcium levels.
Hypoglycemia results from a pancreatic (beta cell) tumor that increases the production of insulin, resulting in a decrease in blood glucose levels. It may also result from an extra-pancreatic (beta cell) tumor. This type of tumor is usually associated with low to normal insulin levels that increase the production of a secondary insulin-like substance. This causes increased utilization of glucose by the tumor and the failure of gluconeogenesis and/or glycogenolysis by the liver.
Clinical signs associated with hypoglycemia include ataxia, lethargy, weakness (polyneuropathy), nervousness or collapse, hunger or anorexia, focal neurological abnormalities, seizures and/or coma (BG < 40-50 mg/dl). Tachycardia, vomiting and/or restlessness may occur due to compensatory adrenergic effects.
Diagnostics for suspected hypoglycemia include complete blood count, biochemical profile, urinalysis, insulin levels (>20µU/ml with a BG <50 mg/dl--normal insulin level= 5-20µU/ml with a BG of 70-100 mg/dl) and search for the primary tumor. Radiographs and abdominal ultrasound to rule out metastatic sites is prudent. Exploratory surgery and biopsy will provide a more definitive diagnosis.
Pancreatic tumors associated with hypoglycemia are insulinomas (BG 30-50 mg/dl). Extra-pancreatic tumors include hepatoma/hepatocellular carcinoma, mammary carcinoma, salivary gland adenocarcinoma, pulmonary carcinoma, leiomyoma/ leiomyosarcoma, oral melanoma, multiple myeloma, and lymphoma.
Treatment for the seizuring hypoglycemic patient includes IV fluid therapy with fluids containing dextrose. Other therapies include using constant rate infusion with glucagon USP as it increases gluconeogenesis (initial dose 5-10 ng/kg/min). Careful monitoring of serial blood glucose levels is necessary. Octreotide acetate is a synthetic long acting analog of somatostatin. It inhibits the synthesis and secretion of insulin (in both normal and neoplastic beta cells), glucagon, secretin, gastrin and motilin. Diazoxide is a vasodilator related to thiazide diuretics that inhibits pancreatic insulin secretion.
Treatment options for hypoglycemia in the non-seizuring patient include IV fluids containing dextrose and prednisone to induce hepatic gluconeogenesis and decrease peripheral utilization of glucose, diazoxide to elevate BG levels by inhibiting pancreatic insulin secretion, octreotide acetate, and streptozotocin, a nitrosurea chemotherapeutic agent that selectively destroys pancreatic beta cells. After the patient has been medically stabilized, a partial pancreatectomy may be indicated. Surgery is not usually curative due to the high metastatic rate but the combination of surgery and medical management can generally lead to longer survival times (215-680 days). Patients with insulinomas may also benefit from dietary therapy. The feeding of 3-6 small meals daily that are high in fat, complex carbohydrates and fiber helps to delay gastric emptying, slows intestinal glucose absorption, minimizes the increase in the portal blood glucose concentration and stimulates pancreatic insulin secretions.
Cancer cachexia is a complex paraneoplastic syndrome that results in dramatic alterations in lipid, carbohydrate and protein metabolism. It results in net energy loss despite adequate intake of calories by the patient. Clinical signs associated with cachexia include anorexia, nausea, weight loss (>30% weight loss may be fatal), anemia, and muscle weakness. Cancer cachexia can occur before weight loss is even noted. In the early phase of the condition, lethargy and exercise intolerance can be noted. As patient cachexia progresses, muscle wasting and loss of body condition are evident. Treatment includes providing the patient with highly bioavailable quality foods. Diets should include moderate amounts of highly bioavailable proteins, moderate amounts of complex carbohydrates, moderate amounts of fats (n-3polyunsaturated fatty acids), and minimal amounts of rapidly absorbed simple carbohydrates. Food can be made more palatable by warming to body temperature prior to feeding, choosing aromatic foods can enhance voluntary intake, and hand feeding small amounts more frequently may all increase the patients desire to eat. Appetite stimulants such as mirtazapine have shown to be beneficial in the anorexic patient. If none of these suggestions is successful, then assisted feeding with the use of nasogastric, gastrostomy or jejunostomy tubes is warranted.
Fever of Malignancy
Fever of malignancy is the result of overproduction of cytokines in tumor cells. These proteins are released by the immune system and include interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor α, (TNF alpha), interferon, and the production of prostaglandins within the hypothalamus which controls thermoregulation.
Clinical signs on presentation include elevated body temperature (103°F>), depression ("hang dog look"), anorexia, lethargy, and weight loss. Infrequently, vomiting and diarrhea may also be noted.
Diagnosis is based on a through patient history, physical examination for possible enlarged lymph node(s) or spleen, complete blood count, chemistry profile (hypercalcemia), and documentation of persistent fever (temp q 4-8 hrs). Neoplasm-specific testing (FNA/cytology and bone marrow evaluation), urinalysis/urine culture (UTI), blood culture (sepsis), thoracic/abdominal radiographs (organomegaly), echocardiogram (rule out bacterial endocarditis), and MRI/CT/myelogram (CNS involvement).
Tumors commonly associated with fever of malignancy include lymphoma, hepatic adenoma/carcinoma, renal carcinoma, mast cell tumor, leukemias, myeloproliferative disorders, and intracranial tumors.
Fever is usually resolved when the underlying malignancy is addressed. However, treatment with IV fluids and NSAIDS (Metacam®) may benefit a febrile patient.
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