Paraneoplastic syndrome

Overview

Paraneoplastic syndrome is a group of rare disorders that occur in individuals with cancer, but are not caused directly by the tumor itself or its metastases. Instead, these syndromes arise from abnormal immune system responses to a malignancy or from substances (such as hormones or cytokines) secreted by tumor cells. Paraneoplastic syndromes can affect nearly every organ system, including the nervous system, endocrine system, skin, joints, and blood. They often precede the diagnosis of cancer and may serve as early warning signs. Because of their diverse presentations, paraneoplastic syndromes pose a diagnostic challenge but also offer an important opportunity for early cancer detection.

Causes

Paraneoplastic syndromes are typically triggered by the body's immune response to cancer. The immune system mistakenly targets normal tissues, believing them to be associated with tumor antigens. Additionally, tumors can produce hormone-like substances or cytokines that disrupt normal physiological functions. These mechanisms include:

• Autoimmune reactions: Antibodies or immune cells generated in response to tumor antigens attack healthy tissues (e.g., neurons, muscles, skin).

• Ectopic hormone production: Tumor cells may produce hormones or hormone-like substances (e.g., ACTH, PTHrP) that affect body systems.

• Cytokine release: Inflammatory cytokines released by tumors may lead to systemic symptoms such as fever or weight loss.

Paraneoplastic syndromes are most often associated with cancers such as:

• Small cell lung cancer (SCLC)

• Breast cancer

• Ovarian and uterine cancers

• Thymoma

• Lymphomas and leukemias

Symptoms

The symptoms of paraneoplastic syndromes are highly variable and depend on the organ systems involved. They can be grouped into several categories:

1. Neurological Syndromes

• Paraneoplastic cerebellar degeneration: Ataxia, unsteady gait, dysarthria.

• Limbic encephalitis: Memory loss, confusion, seizures, personality changes.

• Lambert-Eaton myasthenic syndrome (LEMS): Muscle weakness, especially in the limbs.

• Peripheral neuropathy: Tingling, numbness, burning sensations in the extremities.

2. Endocrine Syndromes

• SIADH (Syndrome of inappropriate antidiuretic hormone secretion): Hyponatremia, confusion, seizures.

• Cushing’s syndrome: Weight gain, hypertension, hyperglycemia due to ectopic ACTH production.

• Hypercalcemia of malignancy: Weakness, constipation, abdominal pain due to PTHrP secretion.

3. Dermatologic Syndromes

• Acanthosis nigricans: Dark, velvety skin patches in body folds.

• Dermatomyositis: Rash and muscle inflammation.

• Paraneoplastic pemphigus: Painful blisters and erosions on the skin and mucous membranes.

4. Rheumatologic and Hematologic Syndromes

• Hypertrophic osteoarthropathy: Clubbing of fingers, joint pain, periostitis.

• Anemia and thrombocytosis: Common in various cancers due to cytokine release or bone marrow involvement.

• Vasculitis or coagulopathies: Inflammation of blood vessels or abnormal clotting.

Diagnosis

Diagnosing a paraneoplastic syndrome requires careful evaluation to distinguish it from primary autoimmune, infectious, or degenerative diseases. The process typically includes:

• Clinical history and physical examination: Identifying characteristic patterns of symptoms and signs.

• Serologic testing: Detection of paraneoplastic (onconeural) antibodies such as anti-Hu, anti-Yo, anti-Ri, anti-Ma2, and anti-Tr.

• Imaging studies: CT scans, MRI, or PET scans to search for hidden tumors.

• Lumbar puncture: May reveal inflammatory markers or antibodies in cerebrospinal fluid for neurologic syndromes.

• Tissue biopsy: From affected organs or suspicious lesions to confirm cancer diagnosis.

In some cases, the paraneoplastic syndrome may present months before the tumor is detectable, requiring periodic follow-up imaging to monitor for cancer development.

Treatment

Treatment of paraneoplastic syndromes focuses on two goals: addressing the underlying cancer and managing immune-mediated symptoms. Key approaches include:

1. Treating the Underlying Cancer

• Surgical resection: Removal of the tumor, when possible, may halt the progression of the syndrome.

• Chemotherapy and radiation: Target systemic or inoperable cancers.

• Targeted therapy: In cancers with known mutations or hormone production.

2. Immunotherapy and Symptom Control

• Corticosteroids: Reduce inflammation and immune response.

• Intravenous immunoglobulin (IVIG): Used in neurologic and autoimmune presentations.

• Plasmapheresis: Removes circulating autoantibodies from the bloodstream.

• Immunosuppressive drugs: Such as azathioprine or cyclophosphamide in refractory cases.

• Supportive therapy: Physical therapy, speech therapy, hormone replacement, and pain management.

Prognosis

The prognosis of paraneoplastic syndrome varies depending on several factors:

• Type and stage of the associated cancer: Early detection and successful treatment of the tumor can improve outcomes.

• Severity and reversibility of the syndrome: Some neurological syndromes may result in permanent deficits even after cancer treatment.

• Response to immunotherapy: Individuals who respond well to immunosuppressive treatment often experience symptom improvement.

In general, early diagnosis and prompt treatment of both the underlying malignancy and the paraneoplastic manifestations offer the best chance for symptom control and improved quality of life. However, some paraneoplastic syndromes can be progressive and debilitating, even in the context of effective cancer therapy.