Paraneoplastic syndrome explain refer Robbins
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Paraneoplastic Syndromes
As described in Robbins & Cotran Pathologic Basis of Disease and Robbins & Kumar Basic Pathology
Definition
Symptom complexes that occur in patients with cancer that cannot be explained by:
- Local or distant spread (metastasis) of the tumor
- Elaboration of hormones indigenous (normal) to the tissue of tumor origin
They appear in 10% to 15% of patients with cancer (Robbins Basic) / ~10% (Robbins & Cotran).
Why Are They Clinically Important?
Robbins identifies three key reasons to recognize these syndromes:
- Earliest sign of occult neoplasm - may precede detection of the primary tumor
- Significant clinical illness - can cause serious morbidity or even death
- Mimic metastatic disease - can confound staging and treatment decisions
Classification (Table 7.11 / Table 6.5 - Robbins)
1. Endocrinopathies
(Most common category - due to ectopic hormone production by non-endocrine tumors)
| Clinical Syndrome | Major Tumors | Causal Mechanism |
|---|---|---|
| Cushing Syndrome | Small cell carcinoma of lung, Pancreatic carcinoma, Neural tumors | ACTH or ACTH-like substance |
| SIADH | Small cell carcinoma of lung, Intracranial neoplasms | ADH or atrial natriuretic hormones |
| Hypercalcemia | Squamous cell carcinoma of lung, Breast carcinoma, Renal cell carcinoma, Adult T-cell leukemia/lymphoma | PTHrP, TGF-α, TNF, IL-1 |
| Hypoglycemia | Fibrosarcoma, Ovarian carcinoma | Insulin or insulin-like substance |
| Polycythemia | Renal cell carcinoma, Cerebellar hemangioma, Hepatocellular carcinoma | Erythropoietin |
| Osteomalacia | Phosphaturic mesenchymal tumor | FGF-23 |
2. Nerve and Muscle Syndromes
| Syndrome | Tumors | Mechanism |
|---|---|---|
| Myasthenia | Bronchogenic carcinoma, Thymoma | Immunologic |
| CNS/PNS disorders | Breast carcinoma, Teratoma | Immunologic |
3. Dermatologic Disorders
| Syndrome | Tumors | Mechanism |
|---|---|---|
| Acanthosis nigricans | Gastric carcinoma, Lung carcinoma, Uterine carcinoma | Secretion of EGF or other growth factors; Immunologic |
| Dermatomyositis | Bronchogenic carcinoma, Breast carcinoma | Immunologic |
4. Osseous, Articular, and Soft Tissue Changes
| Syndrome | Tumors | Mechanism |
|---|---|---|
| Hypertrophic osteoarthropathy and clubbing | Bronchogenic carcinoma | Unknown |
5. Vascular and Hematologic Changes
| Syndrome | Tumors | Mechanism |
|---|---|---|
| Venous thrombosis (Trousseau phenomenon) | Pancreatic carcinoma, Bronchogenic carcinoma, Other cancers | Tumor products (mucins) that activate clotting |
| Disseminated intravascular coagulation (DIC) | Acute promyelocytic leukemia, Prostatic carcinoma | Tumor products activating clotting |
| Nonbacterial thrombotic endocarditis | Advanced cancers | Hypercoagulability |
| Red cell aplasia | Thymic neoplasms, Large granular lymphocytic leukemia | Immunologic |
6. Others
- Nephrotic syndrome - Various cancers - Tumor antigens, immune complexes
Details on Key Syndromes (Robbins & Cotran)
Hypercalcemia
"Hypercalcemia is probably the most common paraneoplastic syndrome; in fact, symptomatic hypercalcemia is more often related to cancer than to hyperparathyroidism."
Two mechanisms:
- Osteolytic metastases - bone destruction by tumor cells or osteoclast-activating factors (IL-1, TNF, RANKL)
- Humoral hypercalcemia of malignancy - secretion of PTHrP (parathyroid hormone-related protein) by tumor cells (especially squamous cell carcinoma of the lung). PTHrP binds PTH receptors and causes hypercalcemia in the absence of bone metastases.
Cushing Syndrome
- Most common endocrinopathy (~50% due to small cell lung carcinoma)
- Caused by ectopic ACTH or ACTH-like polypeptides secreted by cancer cells
- Distinguished from pituitary Cushing's by very high ACTH levels and failure to suppress with high-dose dexamethasone
SIADH
- Due to ectopic ADH secretion, mainly by small cell carcinoma of the lung
- Results in hyponatremia, water retention, concentrated urine
Trousseau Phenomenon (Migratory Thrombophlebitis)
- Venous thromboses appearing in multiple sites in a migratory pattern
- Associated with pancreatic and other visceral carcinomas (mucin-secreting adenocarcinomas)
- Tumor mucins activate Factors X and other clotting factors directly
Nonbacterial Thrombotic Endocarditis (NBTE)
- Sterile, platelet-fibrin vegetations on heart valves
- Complication of hypercoagulable state in advanced cancers
- Can lead to systemic emboli
Lambert-Eaton Syndrome (Myasthenic Syndrome)
- A paraneoplastic disorder, strongest association with small cell lung cancer
- Autoimmune: antibodies against voltage-gated calcium channels (VGCC) at the presynaptic neuromuscular junction
- Distinct from myasthenia gravis - proximal muscle weakness, improves with repeated activity (vs. fatiguing in MG)
Most Common Syndromes and Associated Tumors (Summary)
"The most common paraneoplastic syndromes are hypercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis, and the neoplasms most often associated with these and other syndromes are lung and breast cancers." -- Robbins & Kumar Basic Pathology (Table 6.5)
Key Mnemonics
Common paraneoplastic syndromes: Hypercalcemia, Cushing, NBTE (HCN - think "HCN is toxic - so are these!")
Small cell lung cancer is the biggest culprit - causes Cushing (ACTH), SIADH (ADH), and Lambert-Eaton.
Squamous cell carcinoma of lung - causes hypercalcemia via PTHrP.
Sources: Robbins & Cotran Pathologic Basis of Disease (9780443264528), pp. 311-312; Robbins & Kumar Basic Pathology (9780323790185), Table 6.5
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