Gastrointestinal Paraneoplastic Syndromes in Small Animals

Cancer anorexia (poor nutritional intake as a consequence of neoplasia) and cancer cachexia (weight loss and metabolic alterations in cancer patients despite adequate nutritional intake) are common and debilitating paraneoplastic syndromes.

Even in the presence of an adequate BCS, muscle wasting can still be present and is clinically relevant finding.

Approximately 45–55% of cats with lymphoma or other (solid/nonhematopoietic) tumors have a body condition score (BCS) of ≤ 5/9 at diagnosis. Muscle wasting is present in 93% of cats, including in 72% of cats with an "adequate" BCS (≥ 5) (1).

Only approximately 4% of dogs are classified as emaciated (BCS ≤ 3/9) at diagnosis. Muscle wasting is present in approximately 35% of dogs with cancer, with moderate to severe muscle wasting present in approximately 15%. In addition, approximately 14% of dogs lose 5–10% of their body weight, and 23% of dogs lose > 10% of their body weight, in the 12 months before cancer diagnosis (2).

Substantial loss of body weight prior to diagnosis is a negative prognostic indicator, particularly in cats.

Cancer Cachexia

Cancer cachexia is characterized by severe metabolic derangement and profound muscle wasting despite adequate nutrient intake. Diagnostic criteria for cancer cachexia in dogs and cats with cancer are not well defined.

Glycolysis and pyruvate production (energy-costly processes that contribute to increases in resting energy requirements and other metabolic changes in cancer patients) are critical to neoplastic cell proliferation. However, alterations in resting energy and consumption are not uniform across the spectrum of malignancies. Documented examples include the following (5, 6):

• alterations in glucose metabolism, increased protein turnover, and urinary protein loss in dogs with osteosarcoma

• alterations in carbohydrate metabolism suggesting insulin resistance in dogs with lymphoma

• mild alterations in lipid metabolism in dogs with lymphoma

Tumor necrosis factor alpha (TNF-alpha), IL-1, and IL-6 have been implicated in driving cancer cachexia by promoting insulin resistance, extensive lipolysis, and proteolysis of tissue stores (3, 4). Excessive cytokine stimulation induces anorexia, increases energy metabolism, and accelerates muscle wasting, producing an inexorable cycle of decline.

Cats commonly exhibit cancer cachexia (ie, weight loss despite adequate nutritional intake), with characteristic excessive lean muscle wasting (see cachexia image). True cachexia is uncommon in dogs with nonhematopoietic cancer.

Cachexia, cat

Image

Courtesy of Dr. Brooke Britton.

Most cachectic cats have diagnoses of GI lymphoma or oral squamous cell carcinoma. Low BCS and low body weight are also negative prognostic indicators in cats—across tumor types—portending a less durable response to treatment and lower overall survival times (1).

Mast cell tumors (MCTs) are the most common cause of paraneoplastic GI ulceration; they are secondary to tumor-associated hyperhistaminemia. Histamine release can be spontaneous, triggered by tumor manipulation, or it can result from degranulation induced by chemotherapy or radiation.

By binding to gastric parietal cell H₂ receptors, histamine stimulates gastric acid secretion and exerts direct effects on the gastric mucosa, causing increased vascular permeability and mucosal blood flow, in addition to protein exudation (7). Plasma histamine concentrations are typically elevated in dogs with macroscopic MCTs, but these higher concentrations do not predict clinical signs of ulceration; therefore, some of these patients might have subclinical ulceration.

Cutaneous MCTs in cats are more likely to behave benignly, as compared with MCTs in dogs, in which a wider spectrum of biological behavior is noted. However, cats are more likely to have visceral involvement of MCTs (eg, spleen, liver, GI tract).

In cats, degranulation of cutaneous MCTs that causes stomach upset and GI ulceration is rare in the author’s experience. Therefore, cats in GI distress with minimal cutaneous disease burden should be thoroughly staged using abdominal ultrasonography, buffy coat examination, and cytological evaluation of liver and splenic aspirates to look for evidence of visceral or systemic disease.

Gastrinomas, gastrin-secreting neuroendocrine pancreatic tumors, are a rare additional cause of paraneoplastic gastroduodenal ulceration in both dogs and cats. These tumors are rare in dogs and exceptionally rare in cats.

Gastrinomas almost always arise from the pancreatic islet D cells; rarely, they have been reported to arise within the duodenum. Diagnosis is supported via visualization of a mass (with or without metastatic disease) on abdominal ultrasonography, endoscopy (in the case of duodenal disease), or advanced imaging (CT or MRI); however, a definitive primary tumor is not always apparent.

Elevated basal serum gastrin concentrations or concentrations after gastrin provocative testing or somatostatin receptor scintigraphy can also be used to support a diagnosis of gastrinoma. Measurement of serum gastrin concentrations is nonspecific, however, and should not be used as the sole diagnostic criterion. Exploratory surgery might ultimately be required for definitive diagnosis.

"Zollinger-Ellison syndrome" refers to the triad of a non–beta-cell neuroendocrine tumor, hypergastrinemia, and GI ulceration (8). Gastrinomas are highly metastatic, with appreciable extrapancreatic involvement in approximately 85% of dogs and cats at diagnosis (8).

Treatment with gastroprotectants (H₂ receptor antagonists, proton pump inhibitors, sucralfate, or misoprostol) is warranted in dogs and cats as a preventive measure against ulceration, or to treat known or suspected paraneoplastic GI ulceration. Commonly used drugs and their dosages are detailed below.

H₁ receptor antagonists (as needed, can be continued long-term if gross disease is present):

• Diphenhydramine: in dogs and cats, 2–4 mg/kg, PO, every 12 hours

• Chlorpheniramine: in dogs, 0.22–0.5 mg/kg, PO, every 12 hours; in cats, 2–4 mg/cat, PO, every 12 hours

• Cyproheptadine: in dogs, 0.2–2 mg/kg, PO, every 12 hours; in cats, 1–4 mg/cat (0.35–1 mg/kg), PO, every 12–24 hours

• Cetirizine: in dogs, 1–4 mg/kg, PO, every 24 hours; in cats, 5 mg/cat, PO, every 24 hours

H₂ receptor antagonists:

• Famotidine: in dogs and cats, 0.5–1 mg/kg, PO, every 12–24 hours. Note: Tachyphylaxis can occur with chronic administration of famotidine (> 10 days).

• Cimetidine: in dogs and cats, 5–10 mg/kg, PO, every 6–8 hours. Note: Because cimetidine is a hepatic microsomal enzyme inhibitor, evaluation for drug interactions is advised.

Proton pump inhibitors:

• Omeprazole: in dogs and cats, 0.5–1 mg/kg, PO, every 12–24 hours, or IV, every 24 hours. Note: Proton pump inhibitors should be tapered after prolonged use (> 3–4 weeks).

Gastroprotectants:

• Sucralfate: for dogs ≤ 15 kg and cats, 250–500 mg/animal, PO, dissolved in water, every 6–12 hours; for dogs > 15 kg, 1,000 mg/dog, PO, dissolved in water, every 6–12 hours. Note: Sucralfate can decrease the bioavailability of other oral drugs when coadministered.

• Misoprostol: in dogs and cats, 2–5 mcg/kg, PO, every 8–12 hours

• Bailey DB. Paraneoplastic syndromes. In: Vail DM, Thamm DH, Lipták JM, eds. Withrow & MacEwen's Small Animal Clinical Oncology. 6th ed. Elsevier; 2020:98-100.

• London CA, Thamm DH. Mast cell tumors. In: Vail DM, Thamm DH, Lipták JM, eds. Withrow & MacEwen's Small Animal Clinical Oncology. 6th ed. Elsevier; 2020:382-403.

• Lunn KF, Boston SE. Tumors of the endocrine system. In: Vail DM, Thamm DH, Lipták JM, eds. Withrow & MacEwen's Small Animal Clinical Oncology. 6th ed. Elsevier; 2020:565-596.

• Ledur GR, Trindade-Gerardi AB, Pavarini SP, et al. Presence of gastrointestinal paraneoplastic syndrome at diagnosis in dogs with cutaneous mast cell tumors and its influence on disease-free interval and survival. Top Companion Anim Med. 2023;56-57:100808.

• Hughes SM. Canine gastrinoma: a case study and literature review of therapeutic options. N Z Vet J. 2006;54(5):242-247. doi:10.1080/00480169.2006.36705

• Also see pet owner content regarding peripheral nerve disorders in dogs and cats.

1. Baez JL, Michel KE, Sorenmo K, Shofer FS. A prospective investigation of the prevalence and prognostic significance of weight loss and changes in body condition in feline cancer patients. J Feline Med Surg. 2007;9(5):411-417. doi:10.1016/j.jfms.2007.02.005

2. Michel KE, Sorenmo K, Shofer FS. Evaluation of body condition and weight loss in dogs presented to a veterinary oncology service. J Vet Intern Med. 2004;18(5):692-695. doi:10.1111/j.1939-1676.2004.tb02607.x

3. Freeman LM. Cachexia and sarcopenia: emerging syndromes of importance in dogs and cats. J Vet Int Med. 2012;26(1):3-17. doi:10.1111/j.1939-1676.2011.00838.x

4. August DA, Beier MA, Davis CH. Nutrition support. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Devita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 12th ed. Wolters Kluwer; 2023:1811-1818.

5. Ogilvie GK, Walter LM, Salman MD, et al. Resting energy expenditure in dogs with nonhematopoietic malignancies before and after excision of tumors. Am J Vet Res. 1996;57(10):1463-1467.

6. Vail DM, Ogilvie GK, Wheeler SL, Fettman MJ, Johnston SD, Hegstad RL. Alterations in carbohydrate metabolism in canine lymphoma. J Vet Int Med. 1990;4(1):8-11. doi:10.1111/j.1939-1676.1990.tb00868.x

7. Fox LE, Rosenthal RC, Twedt DC, Dubielzig RR, MacEwen EG, Grauer GF. Plasma histamine and gastrin concentrations in 17 dogs with mast cell tumors. J Vet Intern Med. 1990;4(5):242-246. doi:10.1111/j.1939-1676.1990.tb03116.x

8. Simpson KW, Dykes NL. Diagnosis and treatment of gastrinoma. Semin Vet Med Surg Small Anim. 1997;124):274-281. doi:10.1016/s1096-2867(97)80022-9