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Top 5 Paraneoplastic Syndromes

Leah Ackerman, DVM, University of Florida

Stacey Fox-Alvarez, DVM, MPH, DACVIM (Oncology), University of Florida

Endocrinology & Metabolic Diseases

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November/December 2021
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Peer Reviewed
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Web-Exclusive

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Paraneoplastic syndromes are physiologic disorders that occur secondary to cancer-associated change in the body. Systemic signs can result from tumor-associated production of biologically active products (eg, antibodies, hormones, cytokines), tumor-driven increases in metabolic rate, or induction of the immune system.1,2 Clinical signs secondary to paraneoplastic condition can often be the first sign of a problem, and early recognition may lead to improved patient outcome.

Following are the 5 most common paraneoplastic syndromes according to the authors.

1

Hypercalcemia of Malignancy

Neoplasia is the leading cause of hypercalcemia in dogs and the third most common cause in cats.3,4 T-cell lymphoma and apocrine gland adenocarcinoma of the anal sac are the most common cancerous causes of hypercalcemia in dogs,3,5 and lymphoma and carcinoma are the most common cancerous causes in cats.6,7 Hypercalcemia, however, is also possible with other tumor types, including multiple myeloma, parathyroid tumors, thymoma, melanoma, primary lung carcinomas, and acute and chronic lymphocytic leukemia.3,5 

Hypercalcemia of malignancy is often caused by tumor production of parathyroid hormone-related protein (PTHrp), which activates osteoclasts, inducing bone resorption and calcium release. Other mechanisms are also possible via cytokine release or through direct release from bone secondary to widespread osteolysis.8 Absence of detectable PTHrp does not therefore rule out hypercalcemia of malignancy.8

Common clinical signs include polyuria/polydipsia, vomiting, inappetence, bradycardia, and weakness.8,9 In cats, anorexia and lethargy are the most common clinical signs, whereas polyuria/polydipsia and GI upset occur less frequently.6 Minimum database should include CBC, serum chemistry profile, and urinalysis. A rectal examination should also be performed in all patients with hypercalcemia. A high total calcium concentration warrants analysis of ionized calcium (iCa), as iCa is a more accurate reflection of physiologically active calcium.10 

Several diagnostic laboratories offer a malignancy panel that includes iCa, PTH, and PTHrp and is helpful in diagnosing hypercalcemia of malignancy and primary hyperparathyroidism.11 Additional screening (eg, thoracic radiography, abdominal ultrasonography, cervical ultrasonography) may be required to identify a primary tumor and/or adequately stage a patient. More advanced diagnostics (eg, bone marrow aspiration, CT scan) can also be considered.

PTHrp and iCa levels (and, consequently, clinical signs) generally improve with successful treatment of the primary tumor.5,10 For critical patients, fluid therapy with 0.9% sodium chloride promotes volume expansion and diuresis, effectively diluting calcium concentrations acutely. Bisphosphonates (eg, zoledronate, pamidronate) induce osteoclast apoptosis, thereby inhibiting release of calcium from bone and temporarily reducing calcium levels in patients with hypercalcemia of malignancy.4,9,12 Loop diuretics are used for their calciuretic effect; however, these should only be used in patients that are well-hydrated and under close medical supervision.9 

After a definitive diagnosis is determined, glucocorticoids are useful in decreasing absorption and promoting excretion of calcium through multiple physiologic mechanisms.9 In patients with steroid-responsive cancers (eg, lymphoma, multiple myeloma), glucocorticoids may impede future staging tests or, when used in advance of chemotherapy, increase resistance to some chemotherapy drugs. In these patients, steroids should be reserved for palliative treatment or withheld until all staging diagnostics have been performed and a chemotherapy plan has been instituted.

2

Hypoglycemia

Insulinoma is the most common neoplastic cause of hypoglycemia in dogs.13 Paraneoplastic hypoglycemia is also observed with hepatocellular carcinoma, leiomyosarcoma, and lymphoma, among other tumors.5,13 Hypoglycemia with malignancy is frequently due to overproduction of insulin or insulin-like growth factors by tumor tissue.5 Patients are clinically normal in the early stages of disease, as is commonly seen with insulinoma. Clinical signs, including weakness, ataxia, disorientation, seizures, and collapse, can develop as the underlying disease progresses and hypoglycemia becomes more severe.13,14

Exogenous insulin overdose, hypoadrenocorticism, hepatic insufficiency, sepsis, and xylitol toxicosis should be ruled out prior to testing for excess insulin secretion.10 Diagnosis for paraneoplastic hypoglycemia requires an inappropriately elevated insulin level, despite pronounced hypoglycemia, with an insulin:glucose ratio >30.5,14 This test is only accurate in patients with glucose concentrations <60 mg/dL at time of venipuncture. CT and ultrasound images may reveal a primary tumor; however, exploratory laparotomy is often required to identify smaller pancreatic masses.5,14 

Surgical removal of the tumor is recommended for insulinoma, hepatocellular carcinoma, and leiomyosarcoma.5 Glucose levels typically normalize postoperatively with complete surgical excision and no overt metastasis.14,15 Postoperative hypoglycemia is a negative prognostic indicator, as incomplete surgical excision or metastatic disease is typically indicated.14 Medical management with glucocorticoids is recommended after tumor removal and as palliative therapy for acute hypoglycemia (ideally after an insulin:glucose ratio has been submitted) in patients with persistent hypoglycemia.14

3

Hypertrophic Osteopathy

Hypertrophic osteopathy is an inflammatory condition that can occur in dogs with underlying intrathoracic disease and is characterized by painful swelling of the distal limbs and periosteal proliferation evident on radiographs.16,17 Patients may demonstrate dyspnea or coughing due to intrathoracic disease or display signs of systemic inflammation (eg, scleral injection, fever, ocular/nasal discharge).16

Hypertrophic osteopathy is most common with primary or metastatic pulmonary neoplasia but may also occur with extrapulmonary neoplasia, with Spirocerca lupi granulomas, and in lung disease of various infectious or inflammatory etiologies.16 

Distal limb and concurrent thoracic radiography are the diagnostics of choice.18 Resolution of underlying intrathoracic disease should result in resolution of clinical signs of hypertrophic osteopathy.16,19,20 Temporary or palliative administration of anti-inflammatory drugs can alleviate lameness, swelling, and distal limb pain but rarely provide long-term relief.17 

Hypertrophic osteopathy is an uncommon paraneoplastic syndrome in cats.21 One case of idiopathic hypertrophic osteopathy in a cat has been reported.22 Feline lung-digit syndrome (ie, acrometastasis), in which pulmonary carcinomas metastasize to the bones of one or multiple digits, may also cause lameness and focal peridigital swelling that affects multiple limbs. Acrometastasis can be distinguished from hypertrophic osteopathy on radiographs and is associated with bone lysis ± periosteal proliferation confined to the second and third phalanges of digits.23

4

Myasthenia Gravis

Myasthenia gravis is an acquired disorder that results from formation of autoantibodies against nicotinic acetylcholine receptors in the neuromuscular junction,24 leading to clinical signs of weakness and skeletal muscle impairment.24,25 Presentations of myasthenia gravis are diverse and range from focal esophageal dysmotility to generalized weakness or acute fulminating disease that causes respiratory paralysis and death.24,26 Paraneoplastic myasthenia gravis occurs predominately in middle-aged to older dogs and cats and should be a differential diagnosis in older patients with these clinical signs.27 

Thymoma (ie, neoplasia of the epithelial component of the thymus) and cranial mediastinal lymphoma (ie, neoplasia of the lymphoid component) are the most common causes of paraneoplastic myasthenia gravis in dogs.24,27,28 Thymoma has been associated with a variety of paraneoplastic syndromes in dogs and cats (including myasthenia gravis, exfoliative dermatitis, erythema multiforme, hypercalcemia, circulating T-cell lymphocytosis, polymyositis, anemia, and myocarditis) and is the leading cause of paraneoplastic myasthenia gravis in cats.5,26 Myasthenia gravis and concurrent megaesophagus have been reported in 40% of dogs with thymoma.27 Exfoliative dermatitis is more common in cats with thymoma. Peripheral lymphocytosis can occur in cats and dogs.29-31 

Diagnostic tests include thoracic radiography or CT to identify a cranial mediastinal mass.27,29 Treatment differs for thymoma and lymphoma; therefore, using diagnostic tests (eg, flow cytometry, PCR for antigen receptor rearrangements [ie, PARR], histopathology) is critical to distinguish between these differentials.32,33 Serum autoantibodies are inconsistently observed in patients with paraneoplastic myasthenia gravis.26,27,34

Surgery is the treatment of choice for thymoma.27,34 Cranial mediastinal lymphoma is treated medically with chemotherapeutics and, often, glucocorticoids.35 Incomplete resolution of myasthenia gravis can occur despite treatment of the underlying disease.26,34 Pyridostigmine can be used when indicated to minimize cholinergic crisis.34 Prokinetics and elevated feeding with smaller, more frequent meals can help mitigate clinical signs.34

5

Hyperestrogenism

Hyperestrogenism (ie, feminization syndrome) can cause a unique array of clinical signs in dogs. Dermatologic changes (eg, bilaterally symmetric alopecia, cutaneous hyperpigmentation, epidermal thinning) are common.36,37 Penile atrophy, gynecomastia (ie, prominent mammary tissue), and galactorrhea (ie, lactation) may be observed.5 Patients may have a history of cryptorchidism; neuter history should be investigated in male patients with these signs.

Sertoli cell tumor is the most common cause of paraneoplastic hyperestrogenism in dogs, and 50% of these dogs have concurrent cryptorchidism.37-39 Irreversible and potentially fatal pancytopenia is uncommon but can be a poor prognostic indicator.36,37 CBC is recommended to identify cytopenias.36,37,40 Abdominal ultrasonography is useful to identify undescended testicles and possible intra-abdominal metastasis and to assess adrenal glands.

Bilateral orchiectomy is the treatment of choice in patients with Sertoli cell tumor.5 Exploratory laparotomy is indicated in dogs with cryptorchidism; resolution of clinical signs typically occurs within 3 months following castration.38,39 Recurrence of clinical signs postoperatively may be an indicator of metastasis.41 

Various diagnostic laboratories offer canine and feline adrenal panels that evaluate steroid sex hormone levels in addition to cortisol and can be useful for evaluating patients with suspected sex hormone overproduction from Sertoli cell tumor or adrenal tumors.42

Conclusion

Clinical signs caused by paraneoplastic syndromes are frequently the first indicator of an underlying neoplastic disease process. Awareness of common paraneoplastic syndromes is critical for early diagnosis and intervention. Clinical signs from paraneoplastic disease can also serve as a marker for disease control or progression and may be a valuable monitoring tool.2

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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