But I Thought My Pet Had Cancer: Long Term Manifestations of Paraneoplastic Syndromes
Kathi L. Smith, RVT, LVT
Paraneoplastic syndromes are defined as syndromes caused by a malignant neoplasm, resulting in alterations in bodily structure and/or function, but not from the presence of tumor cells in the affected areas. These syndromes are unrelated to the tissue of origin by size, location, metastases and physiological activity. They are initiated by the production and release of hormones from endocrine tumors into circulation as well as secretory proteins from non-endocrine tumors. The relevance of recognizing and understanding these syndromes is that they may be the initial or only sign of malignancy. They can be utilized to quantify and monitor response to therapy, aid in evaluation of tumor recurrence or disease progression. Their presence results in higher rates of morbidity than the primary malignancy. Oncology technicians must familiarize themselves with these syndromes in order to educate their clients, and improve disease control
Hypertrophic osteopathy (HO) is a bone disease that is usually secondary to disease in the lungs. It is thought that HO develops as a result of afferent neurologic stimulation. This stimulation in turn, causes a rapid increase in peripheral blood flow to distal extremities resulting in both connective tissue and periosteal proliferation. HO is most often associated with primary pulmonary neoplasia and metastatic pulmonary neoplasia. However, it has also been associated with non-neoplastic conditions such as heartworm disease, pneumonia, abscesses/granulomas, focal lung atelectasis, and congenital/acquired heart disease.
Clinical signs usually start with a gradual onset of lameness and reluctance to move. The distal portions of all four limbs are usually involved. Patients present with shifting leg lameness and the limbs are warm to the touch, painful on deep digital palpation, swollen but not edematous, and the skin is taut over the metacarpal/metatarsal regions.
Diagnosis is made by thoracic radiographs (indicating primary or metastatic lesions) and appendicular radiographs demonstrating changes in bone appearance. These abnormalities in appearance include changes in bilateral symmetry, periosteal proliferation, and scalloped or lacey irregularities of the bone cortices.
Tumors associated with hypertrophic osteopathy include pulmonary adenocarcinoma, bronchoalveolar carcinoma, squamous cell carcinoma, esophageal sarcoma, nephroblastoma, and urinary bladder neoplasms.
Resection of the primary tumor is the treatment of choice for HO. Other options include lung lobectomy, intercostal nerve resection and subperiosteal rib resection. Unilateral vagotomy and bilateral cervical vagotomy have also been suggested. Prednisone or non-steroidal anti-inflammatory agents may be helpful in reducing inflammation and clinical signs. Chemotherapy with cisplatin has been mentioned in the literature, but its efficacy has not been proven.
The more common paraneoplastic syndromes associated with neuropathies include peripheral nerve syndromes and myasthenia gravis. Peripheral nerve syndromes result from nerve fibers that undergo demyelination, remyelination and axonal necrosis. Myasthenia gravis is an immune mediated (acquired or congenital) condition resulting from antibodies to nicotinic acetylcholine receptors, thus preventing electrical impulse transmission.
Clinical signs associated with peripheral nerve syndromes include behavior changes, reduced/absent reflexes, reduced muscle tone, flaccid weakness, paralysis of limb or head muscles, and neuromuscular atrophy. Patients with myasthenia gravis may present with excessive muscular weakness, exercise intolerance and/or regurgitation, megaesophagus, and aspiration pneumonia.
Diagnostics for peripheral nerve syndrome should include complete blood count and serum chemistries, CT/MRI, electrodiagnostics (electromyography) and muscle biopsies. Diagnostics for myasthenia gravis should include complete blood count and serum chemistries, MG antibody titers, thyroid and adrenal screening (rule out hypothyroidism, hypoadrenocorticism ), and thoracic radiographs to rule out thymoma, megaesophagus, and aspiration pneumonia.
Neoplasms associated with peripheral nerve syndromes include bronchogenic carcinoma, mammary adenocarcinoma, malignant melanoma, insulinoma, osteosarcoma, thyroid adenocarcinoma, mast cell tumors, leiomyosarcoma and hemangiosarcoma. Myasthenia gravis is most commonly associated with thymoma but cholangiocellular carcinoma and osteogenic sarcoma have reported.
Treatment involves eliminating the neoplastic condition with surgical removal for thymoma and immunosuppressive drugs (glucocorticoids) for peripheral nerve syndromes.
Gastroduodenal ulceration can occur as the result of increased histamine from the degranulation of mast cells. It usually occurs after physical manipulation of the mast cell tumor. Manipulation causes a release of histamine which stimulates gastric H2 receptors increased gastric acid production. Gastrinomas, which are gastrin-secreting non-islet cell pancreatic tumors, can also cause gastroduodenal ulcers.
Clinical signs include vomiting, anorexia, lethargy, hematemesis, and melena (gastric ulceration). Hematologic abnormalities include local/systemic coagulopathies and vascular damage. These patients may also suffer from hypotensive shock. Patients with gastrinomas will commonly present with lethargy, vomiting, inappetence, anorexia, abdominal pain and blood loss.
Treatment options with proton pump inhibitors (omeprazole); H2 blockers (cimetidine, famotidine), sucralfate and antihistamines (diphenhydramine) will help to reduce gastric acid production. Surgical resection of the gastrinoma may also help alleviate clinical signs.
Hyperviscosity syndrome is caused by the increased secretion of immunoglobulin by a monoclonal line of immunoglobulin producing cells. This produces a monoclonal gammopathy. The abnormal proteins may be macroglobulins, cryoglobulins or myeloma-type proteins. The specific immunoglobulins may be IgM, IgG or IgA class.
Clinical signs include: hematologic forms (epistaxis, excessive bleeding from venipuncture sites, petechiae/ecchymoses), polydipsia; CNS forms (ataxia, dementia, depression, coma), as well as congestive heart failure, retinal hemorrhage/detachment, and renal dysfunction.
Diagnostics include complete blood count, serum chemistries (total protein), urinalysis, serum protein electrophoresis (monoclonal gammopathy, type of immunoglobulins present), Bence Jones urine protein test, APTT/PT/ACT/Platelet count, skeletal radiographs (lytic lesionsmultiple myeloma), thoracic/abdominal radiographs (hepatosplenomegaly), and retinal examination.
Tumor types associated with hyperviscosity syndrome are multiple myeloma, lymphoma and lymphocytic leukemia.
Treatment for multiple myeloma includes melphalan (Alkeran®) and prednisone. Palliative radiation may be beneficial in those patients with lytic bone lesions. Treatment for lymphoma includes single agent doxorubicin (Adriamycin®) and combination agents (COP or CHOP protocols).
Hematologic Forms: Anemia, Thrombocytopenia, Leukocytosis, Erythrocytosis
Anemia can result from chronic disease, bone marrow invasion by tumor cells, blood loss, chemotherapy-induced bone marrow suppression, immune-mediated destruction, and microangiopathic hemolytic anemia.
Anemia from chronic disease can be mild to moderate, usually normochromic/normocytic; red cell life span is shortened, depressed bone marrow production and abnormal iron metabolism. Treatment intervention is usually not necessary.
Bone marrow invasion by tumor cell is common with various leukemias. The malignancy-related cytokine production competes for nutrients and less likely due to physical "crowding out" of red blood cells by the tumor cells. Treat the primary tumor.
Blood loss can be associated with an ulcerated tumors (superficial tumors, bladder carcinoma, mast cell tumor with histamine induced increased gastric acid production) and coagulopathies (hemangiosarcoma, thyroid carcinoma, mammary adenocarcinoma). Treatment includes removal of the primary tumor, blood transfusion if applicable, and supportive therapy.
Chemotherapy induced bone marrow suppression is usually due to chronic administration of chemotherapy and progresses slowly. Treatment usually not necessary, but transfusing emergent patients may be warranted.
Immune-mediated destruction results from immune mechanisms that are activated by tumor cells. Lymphoid tumors are the most common cause. Additional immunosuppressive drugs may need to be included (azathioprine, cyclosporine, danocrine).
Microangiopathic hemolytic anemia is caused by shearing of red blood cells and platelets on fibrin strands within blood vessels and tumor vasculature. It is associated with disseminated intravascular coagulation (DIC). Hemangiosarcoma (splenic), thyroid carcinoma, and inflammatory mammary adenocarcinoma are most commonly associated with this syndrome. These patients may be asymptomatic or present with lethargy, exercise intolerance, or pale mucous membranes. Treat the underlying malignancy. Further treatment may not be necessary unless the patient is symptomatic or if surgery is necessary.
Thrombocytopenia can occur when the platelet numbers are affected by bone marrow infiltration of tumor cells, immune mediated destruction, increased consumption of platelets secondary to DIC, and sequestration in capillary beds. Patients with thrombocytopenia tend to asymptomatic and it is usually discovered on routine complete blood counts. They will commonly be <100,000/µl and clinical bleeding is normally seen at < 30,000/µl. Discontinuation of the drug representing a risk is advised and vincristine therapy (.50 mg/m2) initiated to reverse the thrombocytopenia.
Leukocytosis is a hematologic paraneoplastic syndrome that may be associated with excess secretion of granulocyte colony stimulating factors. Differentiation between a leukemoid response and a true leukemia may be difficult. Neutrophils are the most commonly seen cell type with counts as high as 100,000/µl and greater.
Malignancies associated with paraneoplastic leukocytosis include lymphoma, hemangiosarcoma, fibrosarcoma, renal tubular adenocarcinoma and primary pulmonary adenocarcinoma. Patients may present with lethargy, anorexia, lameness (bone pain from bone marrow proliferation of leukocytes), and +/- vomiting/diarrhea/fever. Leukocyte counts usually return to normal with the surgical removal and/or medical treatment of the primary tumor.
Erythrocytosis as a paraneoplastic syndrome in cancer patients may be the result of several factors. Increased secretion of erythropoietin by the tumor, erythropoietin produced as the result of renal hypoxia or vascular obstruction, renal induced erythropoietin production in response to a tumor-induced factor, or by tumor-induced change in metabolism of erythropoietin.
Erythropoietin production is usually performed by the kidney so most of the tumors associated with this syndrome are renal in nature. They include renal cell carcinoma, renal lymphoma, and renal fibrosarcoma. Those tumors not associated with the kidney include nasal fibrosarcoma, pulmonary and hepatic carcinoma, cecal leiomyosarcoma, and transmissible venereal tumors.
Patients with increased red blood cell counts may present with the following clinical signs: PU/PD, vomiting, diarrhea, anorexia, generalized weakness, erythematous skin and mucous membranes, neurologic signs (depression, seizures), and retinal vessels may be dilated and tortuous.
Treatment involves the elimination and/or treatment of the primary tumor (chemotherapy, radiation therapy).
1. Willard MD, et al. Small Animal Clinical Diagnosis by Laboratory Methods (ed.4). St. Louis, Saunders, 2004, p 298-299.
2. Withrow SJ, et al. Small Animal Clinical Oncology (ed.4). St. Louis, Saunders, 2007, p 77-89.
3. Ogilvie GK, et al. Managing the Canine Cancer Patient. Yardley, VLS, 2006, p 277-284.
4. Morrison WB. Cancer in Dogs and Cats (ed.2). Jackson, TNM, 2002, p 731-743.