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Paraneoplastic syndromes

PRESENTED BY:DR. HITESH GOURJ.R. PULMONARY MEDICINEDEFINATION

Paraneoplastic syndromes refer to the disorders that accompany benign or malignant tumors but are not directly related to mass effects or invasion by the primary tumor or its metastases.Although, almost every type of malignancy has the potential to produce hormones or cytokines or to induce immunologic responses , tumors of neuroendocrine origin, such as small cell lung carcinoma and carcinoids are common causes of paraneoplastic syndromes.So, atypical clinical manifestations in a patient with cancer should prompt consideration of a paraneoplastic syndrome. PARANEOPLASTIC SYNDROMESETIOLOGY:Ectopic hormones refers to hormone production from an atypical tissue source.Several molecular mechanisms has been suggested to cause ectopic hormone production, but this process remains incompletely understood. Genetic rearrangements can explain aberrant hormone expression e.g., translocation of the parathyroid hormone (PTH) gene resulted in high levels of PTH expression in an ovarian carcinoma, because the genetic rearrangement brings the PTH gene under the control of ovary-specific regulatory elements

ectopic expression is typically characterized by abnormal regulation of hormone production (e.g., defective feedback control)that can lead to substantial morbidity and can complicate the cancer treatment planParaneoplastic sundromes associated with bronchogenic carcinoma

Endocrine:Cushing's syndromeSIADH HypercalcemiaCarcinoid syndromeHyperglycemia/hypoglycemiaGynecomastiaGalactorrheaGrowth hormone excessCalcitonin secretionThyroid-stimulating hormone

Neurological

Lambert-Eaton myasthenic syndromePeripheral neuropathyEncephalopathyMyelopathyCerebellar degenerationPsychosisDementiaCancer related retinopathyOpsoclonus and myoclonus MUSCULOSKELETALClubbingHypertrophic osteoarthropathyPolymyositisOsteomalaciaMyopathy

CutaneousDermatomyositisAcanthosis nigricansPruritusErythema multiformeHyperpigmentationUrticariaSclerodermaVascular/hematologicThrombophlebitisArterial thrombosisGranulocytosis Nonbacterial thrombotic endocarditisThrombocytosisPolycythemiaHemolytic anemiaRed cell aplasiaDysproteinemiaLeukemoid reactionEosinophiliaThrombocytopenic purpura

Miscellaneous

CachexiaFatigueHyperuricemiaNephrotic syndrome

Ectopic Corticotropin Syndrome

Ectopic production of corticotropin or corticotropin-releasing hormone with associated Cushing's syndrome has been identified in patients who have SCLC, carcinoid tumor (lung, thymus, or pancreas), and neurocrest tumors such as pheochromocytoma, neuroblastoma, and medullary carcinoma of the thyroid.

SCLC accounts for 75% of cases, although only 1% to 2% of patients with SCLC develop Cushing's syndrome. Cushing's syndrome is seldom caused by NSCLCClassic features of Cushing's syndrome include truncal obesity, striae, rounded (moon) facies, dorsocervical fat pad (buffalo hump), myopathy and weakness, osteoporosis, diabetes mellitus, hypertension, and personality changes.

Because of rapid growth of SCLC ,patients are more likely to present with edema, hypertension, and muscular weakness than with the classic features of Cushing's syndrome.

Hypokalemic alkalosis and hyperglycemia are usually present.

Patients with SCLC and Cushing's syndrome have shortened survival compared to those without the syndrome, perhaps because of frequent opportunistic infections.

The best screen for Cushing's syndrome is the 24-hour urine free cortisol measurement.

Elevation of cortisol production, lack of suppression with high-dose dexamethasone, and plasma corticotropin levels greater than 200 pg/mL (40 pmol/L) are highly suggestive of ectopic corticotropin as the cause of Cushing's syndrome in the absence of a pituitary adenoma. The plasma level of corticotropinis elevated in many, but not in all patients.Treatment:

Adrenal enzyme inhibitors such as metyrapone, aminoglutethimide, and ketoconazole, given alone or in combination. Ketoconazole given orally at a dosage of 400 to 1200 mg/day or metyrapone 250 to 750 mg three times per day control hypercortisolism within a few days to weeks,

Dose adjustments are based on achieving normal urinary free cortisol levels or morning plasma cortisols of 7 to 11 g/mL.

Symptomatic hypoadrenalism may result from treatment.

When Cushing's syndrome arises from SCLC, it is advisable to proceed with appropriate chemotherapy and carefully watch for superimposed infections.

Cushing's syndrome related to a bronchial carcinoid or thymic carcinoid is best treated by surgical resection of the tumor.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

SIADH production defined as low serum and a dilute plasma osmolality along with a higher or inappropriate urine osmolality in the presence of continous urinary sodium excreation.

10% of patients with SCLC exhibit SIADH,.SCLC accounts for approximately 75% of cases of SIADH. Antidiuretic hormone (vasopressin) is secreted in the anterior hypothalamus and exerts its action on the renal collecting ducts by enhancing the flow of water from the lumen into the medullary interstitium, thereby concentrating the urine.

The criteria for the diagnosis of SIADH include (1) hyponatremia associated with serum hypoosmolality (200 mOsm/kg) relative to serum osmolality; (3) elevated urine sodium (>20 mEq/L); (4) clinical euvolemia without edema; and (5) normal renal, adrenal, and thyroid function.

The serum uric acid is usually low, and the urine osmolalitytoserum osmolality ratio is frequently greater than 2.

The severity of symptoms is related to the degree of hyponatremia and the rapidity of the fall in serum sodium.

Symptoms of hyponatremia include anorexia, nausea, and vomiting. With a rapid onset of hyponatremia, symptoms caused by cerebral edema may include irritability, restlessness, personality changes, confusion, coma, seizures, and respiratory arrest.Treatment:

In minimally symptomatic or asymptomatic patients, fluid restriction of 500 to 1000 mL/24 hr is the initial treatment of choice.

Conivaptan is an intravenous vasopressin receptor antagonist that has been shown to be useful in correcting hyponatremia but its use is limited to the hospital.

If further treatment is needed, oral demeclocycline (9001200 mg/day) is given. It induces a nephrogenic diabetes insipidus and blocks the action of antidiuretic hormone on the renal tubule, thereby increasing water excretion.

The onset of action varies from a few hours to a few weeks, so this drug is not recommended for acute emergency treatment.

Demeclocycline has potential kidney toxicity.

In patients who have more severe or life-threatening symptoms (serum sodium