What is a paraneoplastic syndrome? This is a group of incredibly varied neoplasia or cancer-associated changes that can occur in a patient distant to the actual tumor.
In many cases, the paraneoplastic syndrome (PNS) is the first sign of cancer, so being able to recognize it can lead to an early diagnosis (and better outcome).
The PNS will often parallel the underlying cancer. So if the underlying cancer is in remission, the PNS will resolve. If we later see return of the PNS, we will likely find return of the cancer on further investigation as well. PNS can be very helpful in monitoring the remission status of a patient.
In many cases, the PNS can be more life threatening than the underlying cancer itself, so recognizing the PNS and obtaining a timely diagnosis (what cancer is present) is critical.
In this article, I will address the most common PNS that we see in veterinary oncology; there are far too many to cover in one article (this topic usually takes up an entire chapter in an oncology textbook) so this will be a two-part series.
Weight loss and muscle wasting despite adequate nutritional intake is called cancer cachexia; this is due to metabolic changes that occur in cancer patients. Sometimes this is accompanied by cancer anorexia, which is inadequate nutritional intake. This occurs frequently in people with cancer and when present, causes an increased risk of death. It's unclear how commonly this occurs in veterinary patients.
PNS-associated ulceration of the stomach or duodenum is most commonly noted with mast cell tumors (MCT). MCTs carry histamine, which stimulate gastric (stomach) H2 receptors to produce more acid. Increased acid production increases the risk for ulceration in patients with MCT. About 75% of dogs with MCT have elevated histamine levels and 30% have gastrointestinal signs. For patients with MCT (before surgery) or with metastatic disease, it is standard to treat with Benadryl (an anti-histamine) and Prilosec (to decrease acid production by the stomach) to decrease the risk of ulceration.
Signs of gastroduodenal ulceration are varied but could include: dark tarry stool, vomiting, vomiting material that looks like coffee grounds, decreased appetite, anorexia, abdominal pain.
Elevated blood calcium (hypercalcemia) is one of the more notorious paraneoplastic syndromes. The most common cause of hypercalcemia in the dog is cancer, so if this is found on routine blood work, we should be looking for cancer. We call this "hypercalcemia of maligancy".
Typically it's the ionized calcium that we care about, so if a regular blood panel shows an elevated calcium, we then check ionized calcium to see if the calcium elevation is "real". We shouldn't blow off the lab abnormality, we should investigate.
The most common cancers associated with hypercalcemia of malignancy are lymphoma (10-35%), anal sac apocrine gland adenocarcinoma (25%), multiple myeloma (20%), parathyroid tumors, and far less commonly: thyroid carcinoma, thymoma. Other cancers have been reported to cause hypercalcemia, but not in enough frequency to bother mentioning here. Almost any cancer can cause hypercalcemia, but the most likely are those already mentioned.
There are MANY causes of hypercalcemia. The most common include the production of PTH (parathyroid hormone) or PTH-rp (parathyroid related peptide). Hypercalcemia of malignancy caused by lymphoma and anal sac adenocarcinoma is typically related to the production of PTH-rp.
If we have a dog with elevated ionized calcium, our job is to go on a cancer hunt to try and find the tumor. This typically involves an excellent physical exam including a thorough rectal exam, palpation of neck and oral exam, 3-view thoracic radiographs with radiologist review, abdominal ultrasound. If we can't make an easy diagnosis of lymphoma or anal sac adenocarcinoma, we typically have Michigan State run a Hypercalcemia of Malignancy Panel (blood test) to figure out why the ionized calcium is high - is it due to elevated PTH (which would suggest the patient has a parathyroid tumor) or an elevated PTH-rp.
Severe hypercalcemia is a medical emergency and can lead to death. Prior to that, we worry about it causing kidney failure, hypertension, nausea and vomiting, anorexia, depression, and bradycardia (a slow heart rate).
The most common signs of hypercalcemia include nausea, decreased appetite or anorexia and PU/PD (excessive thirst and urination).
There are many treatments for hypercalcemia such as intravenous fluids, bisphosphonates, steroids, etc. Ideally, we would not use steroids (unless medically necessary) prior to having a diagnosis. Treating with steroids can make it very difficult to diagnose certain underlying cancers, such as lymphoma.
Thankfully, if we are able to successfully diagnose and treat underlying cancer, the hypercalcemia will resolve as well.
Low blood glucose (hypoglycemia) is most commonly seen when a patient has a type of cancer called insulinoma. Insulinoma is a cancer of the pancreatic beta islet cells.
Other tumors have been implicated in PNS-associated hypoglycemia, but these cause hypoglycemia far less commonly: hepatocellular carcinoma, lymphoma, hemangiosarcoma, leiomyoma, leiomyosarcoma, mammary tumors, renal (kidney) tumors, salivary tumors.
Insulinomas cause hypoglycemia through excess insulin levels. The other tumors that can produce hypoglycemia are typically associated with low insulin.
To diagnose insulinoma, we usually perform an abdominal ultrasound to identify (and sample) the tumor, but we also send out blood samples to assess the patient's insulin: glucose ratio. This is part of obtaining a definitive diagnosis.
Signs of low glucose can include weakness, lethargy, poor appetite, fainting, losing balance, weakness, seizures.
The incidence of paraneoplastic fever is unknown in veterinary patients, however, cancer is the cause of fever of unknown origin in approximately 1/3 of human cases. If an obvious cause of fever in a veterinary patient is not present, cancer should remain on the list.
As with other PNS, treating underlying cancer will typically resolve the fever. If the fever is elevated enough and is impacting the quality of life (causing lethargy, decreased appetite, etc), NSAIDs (carprofen, meloxicam, etc) can be used in an attempt to resolve the fever.
Next week I'll publish Part 2 of this article. We'll cover additional paraneoplastic syndromes including anemia, hypertrophic osteopathy, myasthenia gravis, and more!
Dr. Lori Cesario
Board Certified Veterinary Oncologist
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