What paraneoplastic syndromes are associated with lung cancer?

Paraneoplastic Syndromes Associated with Lung Cancer

Lung cancer, particularly small cell lung cancer (SCLC), is associated with numerous paraneoplastic syndromes that can be broadly categorized into endocrine/hormonal syndromes and neurologic/immunologic syndromes, with early recognition being critical as these syndromes cause significant morbidity and mortality that may limit effective cancer treatment. 1

Endocrine and Metabolic Syndromes

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

• SIADH is the most common endocrine paraneoplastic syndrome in SCLC, occurring more frequently than Cushing syndrome 1
• SIADH is observed in approximately 10-45% of SCLC cases but only 1% of non-small cell lung cancer (NSCLC) cases 2
• Caused by ectopic production of vasopressin (ADH) by SCLC cells, resulting in hyponatremia of malignancy 1
• Clinical features include hyponatremia (serum sodium <134 mEq/L), hypoosmolality, inappropriately high urine osmolality (>500 mosm/kg), and elevated urinary sodium (>20 mEq/L) 3
• Hyponatremia typically improves after successful treatment of the underlying SCLC 1, 3

Ectopic Cushing Syndrome

• Caused by ectopic production of adrenocorticotropic hormone (ACTH), with bronchial carcinoid and SCLC being the most commonly associated lung cancers 1
• Clinically apparent in 1.6% to 4.5% of SCLC cases, though biochemical abnormalities suggestive of ectopic Cushing syndrome may be found in 30% to 50% of SCLC patients 1
• Ectopic Cushing syndrome is associated with poor prognosis in SCLC 1
• Clinical features include moon facies, acne, purple striae, proximal muscle weakness, peripheral edema, hypertension, and metabolic alkalosis with hypokalemia 1
• Skin hyperpigmentation is usually more prominent with ectopic ACTH compared to other causes of Cushing syndrome 1
• Weight loss occurs in about 10% of Cushing syndrome cases associated with SCLC, despite weight gain being more typical 1

Hypercalcemia

• Hypercalcemia can occur secondary to excessive parathyroid hormone (PTH) secretion or PTH-related peptide production 4
• More commonly associated with squamous cell carcinoma of the lung 1

Neurologic and Immunologic Syndromes

Lambert-Eaton Myasthenic Syndrome (LEMS)

• Patients present with proximal leg weakness caused by antibodies directed against voltage-gated calcium channels 1
• One of the most common neurologic paraneoplastic syndromes associated with SCLC 1

Paraneoplastic Encephalomyelitis and Sensory Neuropathy

• Caused by production of anti-Hu antibody that cross-reacts with both small cell carcinoma antigens and human neuronal RNA-binding proteins, resulting in multiple neurologic deficits 1
• Paraneoplastic encephalomyelitis may precede the diagnosis of the tumor 1
• If neurologic paraneoplastic syndrome is suspected, obtaining a comprehensive paraneoplastic antibody panel should be considered 1

Other Paraneoplastic Syndromes

Dermatologic Manifestations

• Hypertrophic pulmonary osteoarthropathy can occur with NSCLC 5
• Hyperkeratosis of palms and soles and erythema annulare centrifugum have been reported 5

Multiple Concurrent Syndromes

• Patients can present with multiple paraneoplastic syndromes simultaneously, including both SIADH and Cushing syndrome in the same patient 6, 4
• Cases with simultaneous ADH and ACTH production have been reported, though historically associated with extremely poor prognosis 6

Clinical Management Considerations

Early Recognition

• Early recognition and intervention can limit the associated morbidity and mortality, facilitating more effective cancer treatment 1
• Paraneoplastic syndromes are associated with significant morbidity and mortality that may limit effective cancer treatment if undiagnosed 1

Treatment Approach

• Treatment of the underlying malignancy is the most important intervention for paraneoplastic syndromes 3, 2
• For SIADH: primary treatment includes fluid restriction (1 L/day), demeclocycline, or vasopressin receptor inhibitors (conivaptan, tolvaptan) for refractory cases 1, 3
• Cancer treatment and supportive care (cisplatin, opiates) may also cause or worsen hyponatremia 1

Prognostic Implications

• Ectopic hormone production has been associated with extensive-stage disease and poorer outcomes 7
• Antibody-mediated paraneoplastic syndromes are prognostic factors associated with more favorable outcomes 7
• Both types have the potential for improvement with cancer treatment 7