What are the main paraneoplastic manifestations of pulmonary (lung) cancer?

Main Paraneoplastic Manifestations of Pulmonary Cancer

Lung cancer, particularly small cell lung cancer (SCLC), causes two major categories of paraneoplastic syndromes: endocrine/hormonal syndromes (most commonly SIADH and ectopic Cushing syndrome) and neurologic/immunologic syndromes (most commonly anti-Hu syndrome and Lambert-Eaton myasthenic syndrome). 1, 2

Endocrine and Metabolic Syndromes

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

• SIADH is the most common endocrine paraneoplastic syndrome in lung cancer, occurring in 10-45% of SCLC cases but only 1% of non-small cell lung cancer (NSCLC) 2
• Caused by ectopic vasopressin (ADH) production by SCLC cells, resulting in hyponatremia of malignancy 2
• Clinical presentation includes hyponatremia, hypoosmolality, inappropriately elevated urine osmolality, and elevated urinary sodium 2
• Hyponatremia typically improves after successful treatment of the underlying SCLC 2

Ectopic Cushing Syndrome

• Caused by ectopic ACTH production, most commonly associated with bronchial carcinoid tumors and SCLC 1, 2
• Clinically apparent in 1.6-4.5% of SCLC cases, though biochemical abnormalities occur in 30-50% of patients 1, 2
• Associated with poor prognosis in SCLC 1, 2
• Clinical features include moon facies, acne, purple striae, proximal muscle weakness, peripheral edema, hypertension, and metabolic alkalosis with hypokalemia 1
• Skin hyperpigmentation is more prominent with ectopic ACTH compared to other causes of Cushing syndrome 1
• Weight loss occurs in approximately 10% of SCLC-associated Cushing syndrome, unlike typical Cushing syndrome 1

Humoral Hypercalcemia of Malignancy

• Most commonly associated with squamous cell carcinoma of the lung 3
• Should be screened for by checking calcium levels as part of initial evaluation 1, 4

Neurologic and Immunologic Syndromes

Anti-Hu Syndrome (Paraneoplastic Encephalomyelitis/Sensory Neuropathy)

• The most common paraneoplastic neurological syndrome in lung cancer, with SCLC accounting for >90% of cases 1, 5, 2
• Anti-Hu antibodies have 82% sensitivity and 99% specificity for diagnosis but are not pathogenic; T-cell-mediated autoimmunity causes the neurologic damage 1, 5
• Clinical manifestations include limbic encephalitis (rapidly progressive short-term memory loss, seizures, psychosis), brainstem encephalitis, cerebellar degeneration (ataxia), opsoclonus-myoclonus, myelopathy, cranial nerve palsy, and sensory neuropathy 1, 5
• Serious complications include epilepsy, status epilepticus, and central respiratory failure 5
• The prevalence of anti-Hu antibodies in SCLC is 22.5%, making it the most relevant paraneoplastic neurological syndrome for lung cancer 1

Lambert-Eaton Myasthenic Syndrome (LEMS)

• One of the most common neurologic paraneoplastic syndromes in SCLC, occurring in 1-1.6% of cases 1, 2
• Caused by antibodies against voltage-gated calcium channels (VGCC) type P/Q, present in >90% of LEMS cases 1
• Presents with proximal leg weakness due to impaired neuromuscular transmission 1, 2
• Anti-VGCC antibodies directly block ion channel function 1

Anti-Yo Syndrome

• More commonly associated with ovarian and breast cancers than SCLC, but can occur with lung cancer 1, 5
• Anti-Yo antibodies are directly pathogenic, causing apoptosis of Purkinje cells 1, 5
• Clinical manifestations primarily include brainstem abnormalities and cerebellar degeneration 1, 5
• The prevalence of anti-Yo antibodies in SCLC is only 0.5% 1

Other Neurologic Syndromes

• Acquired neuromyotonia caused by antibodies against voltage-gated potassium channels 1
• Autoimmune autonomic ganglionopathy causing dysautonomia, orthostatic hypotension, and cardiac arrhythmias 5

Other Paraneoplastic Manifestations

Dermatologic Syndromes

• Dermatomyositis, often diagnosed within 1 year of cancer diagnosis 5
• Hypertrophic pulmonary osteoarthropathy 3, 6
• Hyperkeratosis of palms and soles 6
• Erythema annulare centrifugum 6

Hematologic and Rheumatologic Syndromes

• Various hematologic abnormalities including anemia 1, 4, 3
• Trousseau's syndrome (coagulopathy) 3
• Rheumatologic manifestations 3

Carcinoid Syndrome

• Associated with neuroendocrine tumors, particularly bronchial carcinoids 1, 5
• Managed with somatostatin analogs, serotonin receptor blockers, interferon, and antidiarrheal medications 1

Clinical Significance and Management Principles

Early recognition is critical because paraneoplastic syndromes cause significant morbidity and mortality that may limit effective cancer treatment if undiagnosed 1, 2, 4

• Symptoms often precede the diagnosis of lung cancer, especially neurologic and dermatologic manifestations 3, 7
• Treating the underlying malignancy is the primary and most important intervention, as successful tumor therapy often improves paraneoplastic symptoms 5, 2, 4
• Response to cancer therapy favorably affects the course of paraneoplastic syndromes, and concomitant immunotherapy does not adversely affect malignancy outcomes 5
• For neurologic/immunologic syndromes, first-line immunotherapy includes IV immunoglobulin (IVIg) and high-dose IV methylprednisolone, particularly effective when administered within 1 month of symptom onset 1, 5
• Second-line immunotherapy (rituximab, cyclophosphamide, azathioprine, mycophenolate) should be considered if no improvement after 2-4 weeks 5
• Immunosuppression can transiently stabilize paraneoplastic syndromes but rarely provides long-term improvement, and some neurological deficits may be irreversible due to low CNS regenerative capacity 5
• Paraneoplastic syndrome workup should be performed in parallel with cancer diagnosis and staging to minimize delays in definitive cancer treatment 5, 4