Paraneoplastic Syndromes

What makes a syndrome paraneoplastic

Definition. A paraneoplastic syndrome is a set of signs or symptoms that cannot be explained by local invasion, metastasis, or hormones native to the tissue of origin. Insulin from an insulinoma or hypercalcemia from lytic bone metastases therefore does not qualify, whereas ACTH from a lung carcinoma does.

Two mechanisms. Most syndromes arise either from ectopic production of hormones and cytokines (PTHrP, ACTH, ADH, erythropoietin, IGF-2) or from an immune response against a tumor antigen that cross-reacts with normal tissue, which underlies most neurologic syndromes. Small cell lung carcinoma, a neuroendocrine tumor, is the single most frequent culprit.

The syndrome can precede the tumor by months. A new diagnosis of Lambert-Eaton syndrome, anti-Hu neuronopathy, malignant acanthosis nigricans, or adult dermatomyositis should trigger a search for cancer, and a syndrome can also mimic metastatic disease.

Endocrine syndromes

PTHrP-mediated hypercalcemia. Hypercalcemia is among the most common paraneoplastic syndromes. Squamous cell carcinomas (lung, head and neck, esophagus), renal cell carcinoma, and breast cancer secrete PTH-related peptide, which activates PTH receptors in bone (resorption) and kidney (calcium reabsorption, phosphaturia). Labs show high calcium, low phosphate, suppressed PTH, and low-normal calcitriol.

Calcitriol-mediated hypercalcemia. Hodgkin and non-Hodgkin lymphomas express 1α-hydroxylase activity and convert 25-OH vitamin D to calcitriol, the same mechanism seen in sarcoid granulomas. Intestinal calcium absorption rises, PTH is suppressed, PTHrP is not elevated, and glucocorticoids reduce calcitriol production and correct the hypercalcemia.

Ectopic ACTH. Small cell lung carcinoma, bronchial carcinoid, medullary thyroid carcinoma, and pancreatic neuroendocrine tumors can secrete ACTH. Hypercortisolism develops rapidly, often without the classic body habitus, and features hypokalemic metabolic alkalosis, hypertension, weakness, and hyperpigmentation from POMC-derived peptides. Massive cortisol overwhelms renal 11β-HSD2 and acts on mineralocorticoid receptors, which explains the profound hypokalemia. ACTH is very high, and cortisol does not suppress with high-dose dexamethasone, whereas pituitary Cushing disease usually does.

SIADH. Small cell lung carcinoma can secrete ADH (or ANP), causing euvolemic hypotonic hyponatremia with inappropriately concentrated urine (osmolality above 100 mOsm/kg), high urine sodium, and low BUN and uric acid. Severe or rapid falls in sodium produce confusion and seizures. Management is fluid restriction, hypertonic saline for severe symptoms, and vaptans; chronic hyponatremia is corrected slowly to avoid osmotic demyelination.

Erythropoietin. Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine leiomyoma, and pheochromocytoma can produce EPO, causing secondary polycythemia with high serum EPO and normal oxygen saturation, the reverse of polycythemia vera, where EPO is low. Von Hippel-Lindau disease links three of them: loss of VHL stabilizes HIF, which activates EPO and VEGF genes.

IGF-2 hypoglycemia. Large mesenchymal tumors (solitary fibrous tumor, sarcomas), mesothelioma, and hepatocellular carcinoma can release incompletely processed big IGF-2, which activates insulin receptors and causes fasting hypoglycemia with low insulin, low C-peptide, and low IGF-1. An insulinoma, by contrast, raises both insulin and C-peptide.

Neurologic syndromes

Onconeural immunity. Tumors that express neuronal proteins provoke antibodies and cytotoxic T cells that also attack the nervous system, often before the cancer is found. Antibodies against intracellular antigens (Hu, Yo) mark T cell-mediated neuronal destruction that responds poorly to treatment. Antibodies against surface channels and receptors (P/Q calcium channel, acetylcholine receptor, NMDA receptor) are directly pathogenic and often improve with tumor removal and immunotherapy.

Lambert-Eaton myasthenic syndrome. Antibodies to presynaptic P/Q-type voltage-gated calcium channels reduce acetylcholine release. Patients have proximal leg weakness that briefly improves with repeated effort, depressed reflexes, and autonomic symptoms (dry mouth, constipation, impotence). About half have small cell lung carcinoma. High-frequency repetitive nerve stimulation shows an incremental response. Amifampridine, a potassium channel blocker that prolongs presynaptic depolarization, improves strength.

Myasthenia gravis and thymoma. Antibodies to postsynaptic nicotinic acetylcholine receptors (less often MuSK) cause fatigable ptosis, diplopia, and proximal weakness that worsens with use. About 10–15% of patients with myasthenia have a thymoma, and roughly a third of thymoma patients develop myasthenia, so every new diagnosis gets chest imaging. Thymoma can also cause pure red cell aplasia and hypogammaglobulinemia (Good syndrome).

Anti-Hu (ANNA-1). Linked to small cell lung carcinoma. T cells destroy dorsal root ganglion neurons, producing a subacute sensory neuronopathy: asymmetric numbness and pain, sensory ataxia with pseudoathetosis, and areflexia with preserved strength. Encephalomyelitis, limbic encephalitis, and autonomic failure with GI dysmotility may accompany it.

Paraneoplastic cerebellar degeneration. Loss of Purkinje cells causes subacute, severe ataxia, dysarthria, and nystagmus. Anti-Yo (PCA-1) antibodies point to ovarian or breast cancer in a woman; anti-Tr (DNER) antibodies point to Hodgkin lymphoma.

Anti-NMDA receptor encephalitis. Antibodies against the GluN1 subunit affect mostly young women. After a viral-like prodrome come psychosis, agitation, memory loss, seizures, orofacial dyskinesias, reduced consciousness, hypoventilation, and autonomic instability. An ovarian teratoma, which contains neural tissue, is found in a substantial fraction; tumor removal plus immunotherapy leads to recovery in most. Anti-Ma2 encephalitis, by comparison, accompanies testicular germ cell tumors in young men.

Opsoclonus-myoclonus-ataxia. Chaotic multidirectional saccades, myoclonic jerks, ataxia, and irritability in a toddler signal neuroblastoma. These tumors usually have favorable biology, but neurodevelopmental sequelae are common. In adults the syndrome accompanies small cell lung and breast cancer, the latter with anti-Ri (ANNA-2) antibodies.

Skin and musculoskeletal syndromes

Malignant acanthosis nigricans. Abrupt, extensive, velvety hyperpigmented plaques of the axillae and neck, often with mucosal involvement or tripe palms, in a thin older adult signal an intra-abdominal adenocarcinoma, most often gastric; tumor-derived TGF-α is implicated. The ordinary form is far more common and reflects insulin resistance. The sign of Leser-Trélat, a sudden eruption of many seborrheic keratoses, has the same association.

Dermatomyositis. Heliotrope rash, Gottron papules, and proximal weakness with elevated CK in an adult carry a markedly increased cancer risk, highest in the first few years: ovarian (the strongest association), lung, gastrointestinal (gastric, pancreatic, colorectal), breast, and nasopharyngeal carcinomas and lymphoma. Anti-TIF1-γ and anti-NXP2 antibodies raise the likelihood further, so new adult cases get age-appropriate and targeted cancer screening.

Hypertrophic osteoarthropathy. Digital clubbing plus painful periosteal new bone along the distal long bones (tibia, radius, ulna) and arthritis, most often from lung cancer, especially adenocarcinoma, and pleural tumors. A proposed mechanism is that megakaryocyte and platelet clumps bypass the pulmonary capillary filter, lodge in fingertip vessels, and release PDGF and VEGF. It can regress after tumor resection.

Hematologic and renal syndromes

Trousseau syndrome. Mucin-producing adenocarcinomas (pancreas classically, also lung and stomach) release tissue factor and mucins that activate coagulation. The results are migratory superficial thrombophlebitis, DVT, and nonbacterial thrombotic (marantic) endocarditis: small, sterile fibrin-platelet vegetations along mitral or aortic closure lines that do not destroy the valve but embolize to the brain and viscera. Cancer-associated clots often recur on warfarin, so LMWH or a DOAC (apixaban, rivaroxaban, edoxaban) is preferred for cancer-associated VTE, and heparin remains the choice for Trousseau migratory thrombophlebitis and marantic endocarditis. DIC is another cancer-associated coagulopathy, classically with acute promyelocytic leukemia.

Glomerular disease. Solid tumors (lung, GI, breast, prostate, kidney) cause membranous nephropathy, with subepithelial IgG and C3 deposits and a spike-and-dome basement membrane on silver stain; an older patient with membranous nephropathy who is negative for anti-PLA2R antibodies deserves a search for cancer. Hodgkin lymphoma instead causes minimal change disease: normal light microscopy with podocyte foot-process effacement on electron microscopy, probably from T-cell cytokines, which remits with lymphoma therapy.

Classic tumor pairings: squamous cell lung with PTHrP; small cell lung with ACTH, ADH, Lambert-Eaton, and anti-Hu; thymoma with myasthenia gravis; ovarian teratoma with anti-NMDA receptor encephalitis; pancreatic adenocarcinoma with Trousseau syndrome; Hodgkin lymphoma with calcitriol, anti-Tr, and minimal change disease.