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Paraneoplastic Syndromes


Robert Peter Gale

, MD, PhD, Imperial College London

Last full review/revision Jul 2018| Content last modified Jul 2018
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Paraneoplastic syndromes are symptoms that occur at sites distant from a tumor or its metastasis.

Although the pathogenesis remains unclear, these symptoms may be secondary to substances secreted by the tumor or may be a result of antibodies directed against tumors that cross-react with other tissue. Symptoms may occur in any organ or physiologic system. Up to 20% of cancer patients experience paraneoplastic syndromes, but often these syndromes are unrecognized.

The most common cancers associated with paraneoplastic syndromes include

Successful treatment is best achieved by controlling the underlying cancer, but some symptoms can be controlled with specific drugs (eg, cyproheptadine or somatostatin analogs for carcinoid syndrome, bisphosphonates and corticosteroids for hypercalcemia).

General paraneoplastic symptoms

Patients with cancer often experience fever, night sweats, anorexia, and cachexia. These symptoms may arise from release of cytokines involved in the inflammatory or immune response or from mediators involved in tumor cell death, such as tumor necrosis factor-alpha. Alterations in liver function and steroidogenesis may also contribute.

Cutaneous paraneoplastic syndromes

Patients may experience many skin symptoms.

Itching is the most common cutaneous symptom experienced by patients with cancer (eg, leukemia, lymphomas) and may result from hypereosinophilia.

Flushing may also occur and is likely related to tumor-generated circulating vasoactive substances (eg, prostaglandins).

Pigmented skin lesions, or keratoses, may appear, including acanthosis nigricans (GI cancer), generalized dermic melanosis (lymphoma, melanoma, hepatocellular carcinoma), Bowen disease (lung, GI, GU cancer), and large multiple seborrheic keratoses, ie, Leser-Trélat signs (lymphoma, GI cancer).

Herpes zoster may result from reactivation of latent virus in patients with immune system depression or dysfunction.

Endocrine paraneoplastic syndromes

The endocrine system is often affected by paraneoplastic syndromes.

Cushing syndrome (cortisol excess, leading to hyperglycemia, hypokalemia, hypertension, central obesity, moon facies) may result from ectopic production of ACTH or ACTH-like molecules, most often with small cell cancer of the lung.

Abnormalities in water and electrolyte balance, including hyponatremia, may result from production of vasopressin and parathyroid hormone–like hormones from small cell and non–small cell lung cancer.

Hypoglycemia may result from production of insulin-like growth factors or insulin production by pancreatic islet cell tumors, hemangiopericytomas, or large retroperitoneal tumors.

Refractory hyperglycemia may be due to glucagon-producing pancreatic tumors.

Hypertension may result from abnormal epinephrine and norepinephrine secretion (pheochromocytomas) or from cortisol excess (ACTH-secreting tumors).

Other ectopically produced hormones include parathyroid hormone-related peptide (PTHRP—from squamous cell lung cancer, head and neck cancer, bladder cancer), calcitonin (from breast cancer, small cell lung cancer, and medullary thyroid carcinoma), and thyroid-stimulating hormone (from gestational choriocarcinoma). PTHRP causes hypercalcemia and its associated symptoms (polyuria, dehydration, constipation, muscle weakness); calcitonin causes a fall in the serum calcium level, leading to muscle twitching and cardiac arrhythmias.

GI paraneoplastic syndromes

Watery diarrhea with subsequent dehydration and electrolyte imbalances may result from tumor-related secretion of prostaglandins or vasoactive intestinal peptide. Implicated tumors include pancreatic islet cell tumors (gastrinoma) and others.

Carcinoid tumors produce serotonin degradation products that lead to flushing, diarrhea, and breathing difficulty. Protein-losing enteropathies may result from tumor mass inflammation, particularly with lymphomas.

Hematologic paraneoplastic syndromes

Patients with cancer may develop pure RBC aplasia, anemia of chronic disease, leukocytosis (leukemoid reaction), thrombocytosis, eosinophilia, basophilia, and disseminated intravascular coagulation. In addition, immune thrombocytopenia and a Coombs-positive hemolytic anemia can complicate the course of lymphoid cancers and Hodgkin lymphoma. Erythrocytosis may occur in various cancers, especially renal cancers and hepatomas, due to ectopic production of erythropoietin or erythropoietin-like substances, and monoclonal gammopathies may sometimes be present.

Demonstrated mechanisms of hematologic abnormalities include tumor-generated substances that mimic or block normal endocrine signals for hematologic cell line development and generation of antibodies that cross-react with receptors or cell lines.

Neurologic paraneoplastic syndromes

Several types of peripheral neuropathy are among the neurologic paraneoplastic syndromes. Cerebellar syndromes and other central neurologic paraneoplastic syndromes also occur.

Peripheral neuropathy is the most common neurologic paraneoplastic syndrome. It is usually a distal sensorimotor polyneuropathy that causes mild motor weakness, sensory loss, and absent distal reflexes.

Subacute sensory neuropathy is a more specific but rare peripheral neuropathy. Dorsal root ganglia degeneration and progressive sensory loss with ataxia but little motor weakness develop; the disorder may be disabling. Anti-Hu, an autoantibody, is found in the serum of some patients with lung cancer. There is no treatment.

Guillain-Barré syndrome, another ascending peripheral neuropathy, is a rare finding in the general population and probably more common in patients with Hodgkin lymphoma.

Eaton-Lambert syndrome is an immune-mediated, myasthenia-like syndrome with weakness usually affecting the limbs and sparing ocular and bulbar muscles. It is presynaptic, resulting from impaired release of acetylcholine from nerve terminals. An IgG antibody is involved. The syndrome can precede, occur with, or develop after the diagnosis of cancer. It occurs most commonly in men with intrathoracic tumors (70% have small or oat cell lung carcinoma). Symptoms and signs include fatigability, weakness, pain in proximal limb muscles, peripheral paresthesias, dry mouth, erectile dysfunction, and ptosis. Deep tendon reflexes are reduced or lost. The diagnosis is confirmed by finding an incremental response to repetitive nerve stimulation: Amplitude of the compound muscle action potential increases > 200% at rates > 10 Hz. Treatment is first directed at the underlying cancer and sometimes induces remission. Guanidine (initially 125 mg po qid, gradually increased to a maximum of 35 mg/kg), which facilitates acetylcholine release, often lessens symptoms, but may depress bone marrow and liver function. Corticosteroids and plasma exchange benefit some patients.

Subacute cerebellar degeneration causes progressive bilateral leg and arm ataxia, dysarthria, and sometimes vertigo and diplopia. Neurologic signs may include dementia with or without brain stem signs, ophthalmoplegia, nystagmus, and extensor plantar signs, with prominent dysarthria and arm involvement. Cerebellar degeneration usually progresses over weeks to months, often causing profound disability. Cerebellar degeneration may precede the discovery of the cancer by weeks to years. Anti-Yo, a circulating autoantibody, is found in the serum or CSF of some patients, especially women with breast or ovarian cancer. MRI or CT may show cerebellar atrophy, especially late in the disease. Characteristic pathologic changes include widespread loss of Purkinje cells and lymphocytic cuffing of deep blood vessels. CSF occasionally has mild lymphocytic pleocytosis. Treatment is nonspecific, but some improvement may follow successful cancer therapy.

Opsoclonus (spontaneous chaotic eye movements) is a rare cerebellar syndrome that may accompany childhood neuroblastoma. It is associated with cerebellar ataxia and myoclonus of the trunk and extremities. Anti-Ri, a circulating autoantibody, may be present. The syndrome often responds to corticosteroids and treatment of the cancer.

Subacute motor neuronopathy is a rare disorder causing painless lower motor neuron weakness of upper and lower extremities, usually in patients with Hodgkin lymphoma or other lymphomas. Anterior horn cells degenerate. Spontaneous improvement usually occurs.

Subacute necrotizing myelopathy is a rare syndrome in which rapid ascending sensory and motor loss occurs in gray and white matter of the spinal cord, leading to paraplegia. MRI helps rule out epidural compression from metastatic tumor—a much more common cause of rapidly progressive spinal cord dysfunction in patients with cancer. MRI may show necrosis in the spinal cord.

Encephalitis may occur as a paraneoplastic syndrome, taking several different forms, depending on the area of the brain involved. Global encephalitis has been proposed to explain the encephalopathy that occurs most commonly in small cell lung cancer. Limbic encephalitis is characterized by anxiety and depression, leading to memory loss, agitation, confusion, hallucinations, and behavioral abnormalities. Anti-Hu antibodies, directed against RNA binding proteins, may be present in the serum and spinal fluid. MRI may disclose areas of increased contrast uptake and edema.

Renal paraneoplastic syndrome

Membranous glomerulonephritis may occur in patients with colon cancer, ovarian cancer, and lymphoma as a result of circulating immune complexes.

Rheumatologic paraneoplastic syndromes

Rheumatologic disorders mediated by autoimmune reactions can also be a manifestation of paraneoplastic syndromes.

Arthropathies (rheumatic polyarthritis, polymyalgia) or systemic sclerosis may develop in patients with hematologic cancers or with cancers of the colon, pancreas, or prostate. Systemic sclerosis or SLE may also develop in patients with lung and gynecologic cancers.

Hypertrophic osteoarthropathy is prominent with certain lung cancers and manifests as painful swelling of the joints (knees, ankles, wrists, elbows, metacarpophalangeal joints) with effusion and sometimes fingertip clubbing.

Secondary amyloidosis may occur with myeloma, lymphomas, or renal cell carcinomas.

Dermatomyositis and, to a lesser degree, polymyositis are thought to be more common in patients with cancer, especially in those > 50 yr. Typically, proximal muscle weakness is progressive with pathologically demonstrable muscle inflammation and necrosis. A dusky, erythematous butterfly rash with a heliotrope hue may develop on the cheeks with periorbital edema. Corticosteroids may be helpful.

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