Paraneoplastic syndromes in dogs and cats

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Paraneoplastic syndromes (PNS) are a consequence of neoplasia at a site distant from the primary tumor. They have many etiologies, including release of hormones, cytokines, or other inflammatory markers from the primary tumor, the immune system’s reaction to a primary tumor, and depletion of normal substances in the body by a tumor. Understanding common PNS, their effects, and how to treat them can help veterinarians more quickly recognize neoplasia and improve the quality of life of patients living with neoplasia. Kaitlyn Curran, DVM, MS, DACVIM (Oncology), assistant professor of oncology at Oregon State University, Carlson College of Veterinary Medicine in Corvallis, discussed common PNS seen in veterinary medicine, during a session at the 2024 American Veterinary Medical Association (AVMA) Convention in Austin, Texas.¹

Why we care about paraneoplastic syndromes

“Sometimes, paraneoplastic syndromes can help us in coming to a diagnosis,” Curran said. She noted that some patients present initially with clinical signs associated with a PNS that may prompt veterinarians to search for a primary tumor. “I definitely think [paraneoplastic syndromes] might be…why the patient is coming in to you urgently or emergently,” Curran stated.

Additionally, PNS can parallel the course of neoplasia. Monitoring laboratory parameters or clinical signs associated with the PNS can help in monitoring patient response to treatment. The PNS may resolve with treatment of the primary disease and recur when remission ends, or the disease has metastasized elsewhere in the body. “They can become this hallmark or biomarker for that individual patient,” Curran said. In some cases, the PNS may be the first indication of recurrent disease.

Finally, the PNS may cause higher morbidity than the primary tumor. Curran shared that in some cases, “the paraneoplastic syndrome associated with the tumor [has] more of a quality-of-life impact than the cancer itself. Managing that becomes an important focus” for individual patients and clients. This can be important for client communication around the expected course of disease, quality-of-life decisions, and prognosis.

Hematologic abnormalities

There are 2 hematologic abnormalities that can be classified as PNS: anemia and thrombocytopenia. Both abnormalities can be caused by multiple mechanisms.

The most common mechanisms of disease include amenia of chronic disease and immune-mediated hemolytic anemia. Anemia of chronic disease is generally a mild, normocytic, normochromic nonregenerative anemia caused by defects in iron storage and metabolism, shortened lifespan of red blood cells, and/or decreased bone marrow response. Immune-mediated hemolytic anemia is often more severe. It may be regenerative, depending on the timing of the diagnosis. Patients may also have hyperbilirubinemia, spherocytosis, saline agglutination, and may or may not be Coombs’ positive.

Less common causes of anemia include blood loss and microangiopathic hemolytic anemia. Blood loss is often a microcytic, hypochromic, regenerative anemia. It may be readily apparent, such as with hemoabdomen from a hemangiosarcoma, or harder to identify such as a bleeding gastrointestinal tumor. Microangiopathic hemolytic anemia occurs due to endothelial damage and/or fibrin deposition leading to secondary hemolysis and schistocytes. It is often associated with hemangiosarcoma.

Thrombocytopenia can also vary in underlying mechanism and severity. Secondary immune-mediated destruction (IMTP) results in severely low platelets counts. In lymphoproliferative neoplasia, platelet production can be decreased. Additionally, platelets can be consumed more quickly or sequestered with vascular tumors, especially in the spleen.

Treatment of these hematologic PNS is aimed at controlling the primary disease through either removal or treatment. In cases with a secondary immune-mediated destruction of red blood cells and/or platelets, immunosuppressive therapy is also required.

Hypercalcemia of malignancy

“Cancer is the most common cause of hypercalcemia in dogs,” Curran said. It can occur in many types of neoplasia, but top causes include lymphoma, anal sac apocrine gland adenocarcinoma, multiple myeloma, thymomas, and thyroid carcinomas.

“It isn’t uncommon for these patients to present for their hypercalcemia,” Curran said. Clinical signs can include polyuria and polydipsia, vomiting, anorexia, lethargy, weakness, depression, and bradycardia. In severe cases, patients can become comatose and die.

When hypercalcemia is present, Curran stated, “I’m really focusing in on the physical exam. There’s a lot to be gained.” She reminded veterinarians to thoroughly assess the head and neck, including retropulsion of the eyes, oral examination, and palpation of the ventral cervical neck. Additionally, peripheral lymph nodes, mammary glands, and a rectal examination, including expression of the anal glands, should be carefully evaluated.

Numerous mechanisms have been identified for paraneoplastic hypercalcemia. The most common is production of parathormone (PTH) or PTH-related peptide by the tumor. These substances are often measured in the diagnostic workup of hypercalcemia, along with an ionized calcium level. Through this testing, “we’re likely to pick up a lot of situations of hypercalcemia of malignancy, but it is important to remember that we will not pick up all of them,” said Curran.

Treatment focuses on eliminating the inciting tumor, but additional treatment may be needed depending on the severity of hypercalcemia. Treatment of hypercalcemia starts with rehydration with normal saline. Additional treatments may include furosemide in appropriately hydrated patients, prednisone, bisphosphonates and calcitonin. “Prednisone is quite effective, but I only want to recommend that after we’ve identified the root cause of our hypercalcemia,” Curran cautioned.

Hypertrophic osteopathy

“Hypertrophic osteopathy (HO) is a syndrome distinguished by painful periosteal proliferation of new bone and soft tissue swelling along the diaphysis of long bones associated with malignant and non-malignant diseases,” Curran said. Although it is less common than other PNS, it is still important to remember.

Common neoplastic causes include pulmonary metastasis—especially because of osteosarcoma—and other thoracic and abdominal tumors, including primary pulmonary, renal, and bladder tumors.

Patients may present with warm, swollen limbs, shifting leg lameness, and/or reluctance to move. Radiographs show classic periosteal proliferative changes along the long bones that often occur bilaterally. The ribs and pelvic bones may also be involved, which may make pain more difficult to localize. Curran shared findings of a retrospective study that found 1/3 of dogs present with a cough and 2/3 present with ocular signs such as episcleral injection and discharge.²

Treatment is aimed at treating the primary tumor when possible. However, as these patients often have widespread metastatic disease, symptomatic treatment with oral analgesics, bisphosphonates, and palliative radiation may be the only options.

Hypoglycemia

Hypoglycemia is a blood glucose level less than 60-70 mg/dL. This PNS is a hallmark of insulinomas in dogs, though nonpancreatic tumors can also cause hypoglycemia.

When diagnosing tumors causing this PNS, Curran noted that veterinarians must distinguish between insulin-producing tumors such as insulinomas and beta-islet cell tumors, and noninsulin producing tumors such as leiomyosarcoma and leiomyoma. For insulin-producing tumors, a low blood glucose reading paired with a high insulin level is diagnostic. Abdominal imaging is the next step, though sometimes these tumors are too small to identify with imaging. An exploratory laparotomy may be needed. Non-insulin producing tumors are less common, but are often big, bulky tumors that can be located with imaging.

Treatment depends on the inciting tumor. Managing blood glucose both acutely and chronically is essential. This may include small, frequent feedings, and/or low-dose prednisone to stimulate glucose production.

Fever and anorexia

Additional PNS that may be seen in practice include fever and anorexia. Both are nonspecific clinical signs that can be due to both neoplastic and non-neoplastic causes but are not pathognomonic for any one type of neoplasia. Many of the mechanisms overlap and are related to excess production of cytokines and prostaglandins.

Some fevers may be cyclical, and cancer should always be a differential diagnosis for a fever of unknown origin. Additionally, fevers may come from a tumor that has become secondarily infected. Anorexia is decreased nutritional intake, which may be a true paraneoplastic syndrome or a side-effect of cancer treatment.

Take home points

Paraneoplastic syndromes may be an early indicator of neoplasia. Veterinarians should be aware of common presentations of PNS and have neoplasia on the differential diagnosis list. Treatment for most PNS is a combination of treating the primary tumor as well as controlling clinical signs related to the PNS. In some cases, a PNS may cause more significant impacts to a patient’s quality of life than the primary tumor, and they should be discussed with clients.

References

1. Curran KM. What you need to know about paraneoplastic syndromes in dogs and cats. Presented at AVMA Convention: Austin, Texas. June 21, 2024.
2. Withers SS, Johnson EG, Culp WTN, Rodriguez CO, Skorupski KA, Rebhun RB. Paraneoplastic hypertrophic osteopathy in 30 dogs. Vet Comp Oncol. 2015;13(3):157–165. doi:10.1111/vco.12026