Brooke Fowler, DVM, MS, DACVIM
Paraneoplastic syndromes are often the first manifestations of cancer. They can show up in the most unusual places and in the most unusual ways. Often, these syndromes are generalized and do not lend themselves to specific diagnoses e.g. anorexia, diarrhea, weight loss. However, often cancer can manifest with very specific clinical representations that may help client discussions as well as diagnostic pursuits.
The most common cause of hypercalcemia is cancer. Patients often present with complaints of polyuria/polydipsia. Hypercalcemia of malignancy is diagnosed in in 2/3 of dogs and 1/3 of cats with hypercalcemia. While lymphoma is, by far, the most common cause of hypercalcemia other tumors such as anal sac apocrine gland denocarcinoma, thyroid carcinoma, multiple myeloma, bone tumors, thymoma, squamous cell carcinoma, mammary gland carcinomas, melanoma, primary lung tumors, leukemia and parathyroid gland tumors have also been reported. The most commonly known mechanism of hypercalcemia is driven by parathyroid related protein which mimics physiologic parathyroid hormone driving the calcium high without appropriate feedback mechanisms. Other factors involved in driving calcium to be elevated include PGE, IL-1-B, TGF-B, RANKL and osteoclast activating factor. Other differentials include acute renal failure, hypervitaminosis D, granulomatous disease, osteolysis, parathyroid adenomas, and a few others. Treatment of this syndrome is often accomplished by dealing with the inciting cause or the primary tumor. Ancillary therapies include steroid therapy, loop diuretics (furosemide), salmon calcitonin, or use of a bisphosphonate to inhibit osteoclastic activity.
Hypoglycemia is another paraneoplastic syndrome seen most commonly in dogs. The most common cause of hypoglycemia is an insulinoma. Other tumors associated with hypoglycemia most commonly include hepatocellular carcinomas, but tumors such as lymphoma, hemangiosarcoma, oral melanoma, hepatoma, plasma cell tumors, leiomyosarcomas, multiple myeloma, salivary carcinoma, mammary carcinoma, and renal tumors. The mechanism of hypoglycemia is overproduction of insulin for insulinomas. The insulin to glucose ratio can be measured to verify that glucose feedback mechanisms are being ignored. Imaging for these tumors can be challenging since a number of modalities have limited sensitivity in detection of these tumors. Tumors other than insulinoma can drive glucose levels low by secretion of other factors including IGF-1, IGF-2, upregulation of insulin receptors, somatomedin production, binding of insulin by M proteins, and additional upregulation of insulin receptors.
Alopecia is a common clinical finding in small animal patients in general. One unusual cause of alopecia in cats is pancreatic carcinoma. This tumor can cause progressive, nonscarring alopecia. The alopecia is usually acute, bilaterally symmetrical, and the skin is glabrous. The hair epilates easily. Often these changes are noted in the foot pads as well. Clinical signs associated with the pancreatic carcinoma including anorexia, weight loss, weakness are usually present. Difficulty standing is also a common complaint, likely due to the pain associated with the footpad changes.
Cutaneous flushing is a syndrome noted as the skin turns shades of red due to changes in blood vessels. Cutaneous flushing can be seen with pheochromocytomas and has been noted in primary lung tumors, and mast cell tumors.
Myasthenia Gravis is a disease process whereby the body attacks acetylcholine receptors. Patients often present with histories of progressive weakness, exercise intolerance, and polyphagia. Radiographs of the chest may reveal megaesophagus and as a sequelae, pneumonia. The most common cause of MG is thymoma. Rapid resolution is often noted after removal of the tumor. Prednisone can be used as adjunctive care until the tumor can be removed.
Hypertrophic Osteopathy is a syndrome of periosteal proliferation along the long bones. HO is reported commonly with primary lung tumors, but can be associated with any intrathoracic mass. We often note this disease with pulmonary metastatic disease. The suggested mechanism is vagal nerve stimulation. However other endogenous pathways such as VEGF and GHRH may be part of the pathology as well. Clinical signs include leg-shifting lameness and the classic osteoproliferative disease on radiographs. The disease often starts distally and works its way proximally. Treatment often involves pain management, and in severe cases with motivated clientele intercostal nerve resection, unilateral or bilateral vagotomy, and rib resection may be warranted.
There are many other paraneoplastic syndromes that can accompany neoplasia. These are some of the more specific syndromes that should focus your diagnostic repertoire towards finding neoplasia. Some other syndromes not mentioned here include DIC (disseminated intravascular coagulopathy), erythrocytosis, anemia, fever, thrombocytopenia, neutrophilic leukocytosis, excessive ADH secretion, hyperglobulinemia, and a few others. General work-up include bloodwork and imaging of the thorax and abdomen. These can be some of the most interesting and intriguing cases to work-up, however they can also be some of the most challenging when the suspicion for neoplasia is high and a primary tumor can’t be found.
1) Recognizing paraneoplastic syndromes can guide your diagnostic decisions
2) If hypercalcemia is present consider lymphoma as your primary differential
3) Alopecia may be more than just dermatologic disease
4) Long bone pain may warrant chest radiographs
5) Aquired myasthenia gravis and megaesophagus may be curable by removal of a tumor