Paraneoplastic syndromes

Definition

Paraneoplastic syndromes are manifestations that occur at sites distant from a tumor or its metastases. They do not result from local tumor growth but from substances produced by the tumor (hormones, cytokines) or from antibodies against tumor antigens that cross-react with healthy tissue. Any organ system may be affected. Paraneoplastic syndromes may precede the diagnosis of cancer.

Occurrence & epidemiology

Up to 20 % of patients with cancer develop a paraneoplastic syndrome, which often goes unrecognized. Lung cancer is the most common underlying tumor, especially small cell lung cancer; other typical tumors are kidney, liver, breast, ovarian, stomach, and pancreatic cancer, neuroendocrine tumors, leukemias, and lymphomas.

Aetiopathogenesis

• Ectopic hormone production: ACTH (Cushing syndrome, mainly in small cell lung cancer), vasopressin (hyponatremia), parathyroid hormone-related peptide PTHrP (hypercalcemia, e.g., in squamous cell lung cancer, head and neck, and bladder cancer), erythropoietin (erythrocytosis in kidney and hepatocellular carcinoma), IGF-like growth factors (hypoglycemia), calcitonin.
• Autoimmune mechanisms: antibodies against tumor antigens react with nerve tissue or other cells, e.g., anti-Hu, anti-Yo, anti-Ri; in Lambert-Eaton syndrome, IgG antibodies impair presynaptic acetylcholine release.
• Cytokines and mediators of tumor cell death (e.g., tumor necrosis factor-alpha) cause general symptoms.

Clinical features

• General: fever, night sweats, anorexia, cachexia.
• Skin: pruritus (most common skin symptom, e.g., in leukemias, Hodgkin lymphoma, myeloproliferative neoplasms), flushing, acanthosis nigricans (gastrointestinal tumors), Leser-Trélat sign (sudden appearance of numerous seborrheic keratoses), dermatomyositis.
• Endocrine: Cushing syndrome, hyponatremia, hypercalcemia (polyuria, dehydration, constipation, muscle weakness), hypoglycemia.
• Hematologic: erythrocytosis, thrombocytosis, eosinophilia, leukemoid reaction, pure red cell aplasia, disseminated intravascular coagulation, immune thrombocytopenia and Coombs-positive hemolytic anemia in lymphoid neoplasms.
• Neurologic: distal sensorimotor polyneuropathy (most common neurologic form), subacute sensory neuropathy, Lambert-Eaton syndrome (proximal muscle weakness, dry mouth, ptosis, reduced reflexes), subacute cerebellar degeneration, opsoclonus-myoclonus, limbic encephalitis.
• Kidney: membranous glomerulonephritis.
• Rheumatologic: polyarthritis, hypertrophic osteoarthropathy with painful joint swelling and digital clubbing, dermatomyositis and polymyositis (more frequent in people over 50).

Diagnosis

• Tumor search in a typical syndrome without a known tumor, focused on the commonly underlying tumors (especially lung carcinoma).
• Laboratory tests: electrolytes (sodium, calcium, potassium), glucose, cortisol and ACTH, blood count, coagulation, PTHrP depending on the syndrome.
• Onconeural antibodies in serum or cerebrospinal fluid, e.g., anti-Hu (sensory neuropathy, limbic encephalitis, lung carcinoma), anti-Yo (cerebellar degeneration, especially in women with breast or ovarian cancer), anti-Ri (opsoclonus).
• Lambert-Eaton syndrome: increase in the amplitude of the compound muscle action potential of more than 200 % with repetitive nerve stimulation at more than 10 Hz.
• Cerebrospinal fluid: occasionally mild lymphocytic pleocytosis.
• MRI: cerebellar atrophy in cerebellar degeneration; contrast enhancement and edema in limbic encephalitis; exclusion of epidural metastasis in myelopathy.

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Further reading (open access)

1. MSD Manual Professional: Paraneoplastic Syndromes

Cross-references