Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment
2010; Elsevier BV; Volume: 85; Issue: 9 Linguagem: Inglês
10.4065/mcp.2010.0099
ISSN1942-5546
AutoresLorraine Pelosof, David E. Gerber,
Tópico(s)Peripheral Neuropathies and Disorders
ResumoRecent medical advances have improved the understanding, diagnosis, and treatment of paraneoplastic syndromes. These disorders arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. In some instances, the timely diagnosis of these conditions may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Because paraneoplastic syndromes often cause considerable morbidity, effective treatment can improve patient quality of life, enhance the delivery of cancer therapy, and prolong survival. Treatments include addressing the underlying malignancy, immunosuppression (for neurologic, dermatologic, and rheumatologic paraneoplastic syndromes), and correction of electrolyte and hormonal derangements (for endocrine paraneoplastic syndromes). This review focuses on the diagnosis and treatment of paraneoplastic syndromes, with emphasis on those most frequently encountered clinically. Initial literature searches for this review were conducted using PubMed and the keyword paraneoplastic in conjunction with keywords such as malignancy, SIADH, and limbic encephalitis, depending on the particular topic. Date limitations typically were not used, but preference was given to recent articles when possible. Recent medical advances have improved the understanding, diagnosis, and treatment of paraneoplastic syndromes. These disorders arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. In some instances, the timely diagnosis of these conditions may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Because paraneoplastic syndromes often cause considerable morbidity, effective treatment can improve patient quality of life, enhance the delivery of cancer therapy, and prolong survival. Treatments include addressing the underlying malignancy, immunosuppression (for neurologic, dermatologic, and rheumatologic paraneoplastic syndromes), and correction of electrolyte and hormonal derangements (for endocrine paraneoplastic syndromes). This review focuses on the diagnosis and treatment of paraneoplastic syndromes, with emphasis on those most frequently encountered clinically. Initial literature searches for this review were conducted using PubMed and the keyword paraneoplastic in conjunction with keywords such as malignancy, SIADH, and limbic encephalitis, depending on the particular topic. Date limitations typically were not used, but preference was given to recent articles when possible. acetylcholine receptor antineuronal nuclear antibody atrial natriuretic peptide collapsin response mediator protein fibroblast growth factor receptor 1 factor interacting with PAP 1–like 1 granulocyte colony-stimulating factor granulocyte-macrophage CSF insulin-like growth factor Janus kinase 2 metabotropic glutamate receptor-subtype 1 N-methyl-D-aspartate Purkinje cell cytoplasmic autoantibody platelet-derived growth factor receptor voltage-gated calcium channel voltage-gated potassium channel More than 100 years ago, it was recognized that certain cancers cause various symptoms not attributable to direct tumor invasion or compression.1Oppenheim H Über Hirnsymptome bei Carcinomatose ohne nachweisbare Veränderungen im Gehirn.Charité-Annalen (Berlin). 1888; : 335-344Google Scholar Labeled paraneoplastic syndromes in the 1940s,2Guichard A Vignon G La Polyradiculonéurite cancéreuse métastatique.J Med Lyon. 1949; 30: 197-207PubMed Google Scholar these conditions remained poorly understood until recently. Currently, the best described paraneoplastic syndromes are attributed to tumor secretion of functional peptides and hormones (as in the case of endocrine paraneoplastic syndromes) or immune cross-reactivity between tumor and normal host tissues (as in the case of neurologic paraneoplastic syndromes). During the past several years, medical advances have not only improved the understanding of paraneoplastic syndrome pathogenesis but have also enhanced the diagnosis and treatment of these disorders. Effective diagnosis and treatment of paraneoplastic syndromes may substantially affect overall clinical outcomes. In some instances, paraneoplastic syndromes are manifest before a cancer diagnosis. Thus, their timely recognition may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Such a scenario occurs most commonly with neurologic paraneoplastic disorders. Although considerable clinical overlap with nonparaneoplastic disorders has long confounded the diagnosis of these conditions, numerous serologic and radiographic studies are currently available to aid in this process. It is estimated that paraneoplastic syndromes affect up to 8% of patients with cancer.3Baijens LW Manni JJ Paraneoplastic syndromes in patients with primary malignancies of the head and neck: four cases and a review of the literature.Eur Arch Otorhinolaryngol. 2006; 263: 32-36Crossref PubMed Scopus (10) Google Scholar As patients with cancer live longer, and as diagnostic methods improve, this prevalence will likely increase. Yet, given the rarity of individual paraneoplastic syndromes, there are few prospective clinical trials to guide management. However, paraneoplastic syndromes frequently represent subtypes of conditions that also occur outside of a cancer association. This review incorporates clinical experience from case series of specific paraneoplastic disorders, as well as larger studies of clinically similar, nonparaneoplastic conditions, to provide an overview of the diagnosis and treatment of the most commonly encountered paraneoplastic syndromes. The paraneoplastic endocrine syndromes generally result from tumor production of hormones or peptides that lead to metabolic derangements. Thus, successful treatment of the underlying tumor often improves these conditions. Clinicians may also employ a number of medical therapies directed against the causative biologic process. Typically, paraneoplastic endocrine syndromes are detected in patients after a cancer diagnosis. The development of these disorders does not necessarily correlate with cancer stage or prognosis.4Spinazze S Schrijvers D Metabolic emergencies.Crit Rev Oncol Hematol. 2006; 58: 79-89Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The clinical features, associated malignancies, diagnostic studies, and treatment options of paraneoplastic endocrine syndromes are listed in Table 1.4Spinazze S Schrijvers D Metabolic emergencies.Crit Rev Oncol Hematol. 2006; 58: 79-89Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 7Lee CR Watkins ML Patterson JH et al.Vasopressin: a new target for the treatment of heart failure.Am Heart J. 2003; 146: 9-18Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 8Lumachi F Brunello A Roma A Basso U Medical treatment of malignancy-associated hypercalcemia.Curr Med Chem. 2008; 15: 415-421Crossref PubMed Scopus (25) Google Scholar, 9Stewart AF Hypercalcemia associated with cancer.N Engl J Med. 2005; 352: 373-379Crossref PubMed Scopus (40) Google Scholar, 10Barbosa SL Rodien P Leboulleux S et al.Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature.Thyroid. 2005; 15: 618-623Crossref PubMed Scopus (17) Google Scholar, 11Morandi U Casali C Rossi G Bronchial typical carcinoid tumors.Semin Thorac Cardiovasc Surg. 2006; 18: 191-198Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 12Teves DA Clinical approach of Cushing syndrome resulting from ACTH-producing metastatic neuroendocrine tumor.Endocrinologist. 2005; 15: 401-404Crossref Scopus (3) Google Scholar, 13Nimalasena S Freeman A Harland S Paraneoplastic Cushing's syndrome in prostate cancer: a difficult management problem.BJU Int. 2008; 101: 424-427Crossref PubMed Scopus (9) Google Scholar, 14Nieman LK Medical therapy of Cushing's disease.Pituitary. 2002; 5: 77-82Crossref PubMed Scopus (95) Google Scholar, 15Nayar MK Lombard MG Furlong NJ McNulty SJ Hardy KJ Vora J Diagnosis and management of nonislet cell tumor hypoglycemia: case series and review of the literature.Endocrinologist. 2006; 16: 227-230Crossref Scopus (4) Google Scholar, 16Teale JD Marks V Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH).Clin Endocrinol (Oxf). 1998; 49: 491-498Crossref PubMed Scopus (31) Google Scholar, 17Hoff AO Vassilopoulou-Sellin R The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia.Cancer. 1998; 82: 1585-1592Crossref PubMed Scopus (36) Google Scholar, 18Kacprowicz RF Lloyd JD Electrolyte complications of malignancy.Emerg Med Clin North Am. 2009; 27: 257-269Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 19Gullo D Sciacca L Parrinello G Tomaselli L Vigneri R Treatment of hemangiopericytoma-induced hypoglycemia with growth hormone and corticosteroids.J Clin Endocrinol Metab. 1999; 84: 1758-1759Crossref PubMed Google Scholar, 20Vezzosi D Bennet A Courbon F Caron P Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism.Clin Endocrinol (Oxf). 2008; 68: 904-911Crossref PubMed Scopus (15) Google ScholarTABLE 1Paraneoplastic Endocrine Syndromesa,ACTH = adrenocorticotropic hormone; GI = gastrointestinal; HTLV = human T-lymphotropic virus; IM = intramuscular; IV = intravenous; LAR = long-acting release; PTH = parathyroid hormone; PTHrP = PTH-related protein; SC = subcutaneous; SIADH = syndrome of inappropriate antidiuretic hormone secretion. See Glossary at end of article for expansion of additional abbreviations.bSI conversion factors: To convert calcium values to mmol/L, multiply by 0.25; to convert cortisol values to nmol/L, multiply by 27.588; to convert C-peptide values to nmol/L, multiply by 0.331; to convert insulin values to pmol/L, multiply by 6.945; to convert osmolality values to mmol/kg, multiply by 1; to convert PTH values to ng/L, multiply by 1; and to convert sodium values to mmol/L, multiply by 1.SyndromeClinical presentationLaboratory findingsAssociated cancersTreatment optionscIn addition to treating the underlying malignancy.ReferencesSIADHGait disturbances, falls. headache, nausea, fatigue, muscle cramps, anorexia, confusion, lethargy, seizures, respiratory depression, coma Hyponatremia: mild, sodium 130-134 mEq/L; moderate, sodium, 125-129 mEq/L; severe, sodium 100 mOsm/kg in the context of euvolemic hyponatremia)Small cell lung cancer, mesothelioma, bladder, ureteral, endometrial, prostate, oropharyngeal, thymoma, lymphoma, Ewing sarcoma, brain, GI, breast, adrenal Restrict fluids (usually <1000 mL/d) and encourage adequate salt and protein intakeDemeclocycline, 300-600 mg orally twice dailyConivaptan, 20-40 mg/d IVTolvaptan, ∼ 10-60 mg/d orallyHypertonie (3%) saline at <1-2mL/kg/h5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar, 6Ellison DH Berl T The syndrome of inappropriate antidiuresis.N Engl J Med. 2007; 356: 2064-2072Crossref PubMed Scopus (253) Google Scholar, 7Lee CR Watkins ML Patterson JH et al.Vasopressin: a new target for the treatment of heart failure.Am Heart J. 2003; 146: 9-18Abstract Full Text Full Text PDF PubMed Scopus (119) Google ScholarHyper-calcemiaAltered mental status, weakness, ataxia, lethargy, hypertonia, renal failure, nausea/vomiting, hypertension, bradycardia Hypercalcemia: mild, calcium 10.5-11.9 mg/dL; moderate, calcium 12.0-13.9 mg/dL; severe, calcium ≥14.0 mg/dLLow to normal (<20 pg/mL) PTH levelElevated PTHrP levelBreast, multiple myeloma, renal cell, squamous cell cancers (especially lung), lymphoma (including HTLV-associated lymphoma), ovarian, endometrial Normal saline, 200-500 mL/hFurosemide, 20-40 mg IV (use with caution and only after adequate fluid resuscitation)Pamidronate, 60-90 mg IVZoledronate, 4 mg IVPrednisone, 40-100 mg/d orally (for lymphoma, myeloma)Calcitonin, 4-8 IU/kg SC or IM every 12 hMithramycin, 25 μg/kg IV (often requires multiple doses)Gallium nitrate, 100-200 mg/m2/d IV continuous infusion tor 5 dHemodialysis4Spinazze S Schrijvers D Metabolic emergencies.Crit Rev Oncol Hematol. 2006; 58: 79-89Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 8Lumachi F Brunello A Roma A Basso U Medical treatment of malignancy-associated hypercalcemia.Curr Med Chem. 2008; 15: 415-421Crossref PubMed Scopus (25) Google Scholar, 9Stewart AF Hypercalcemia associated with cancer.N Engl J Med. 2005; 352: 373-379Crossref PubMed Scopus (40) Google ScholarCushing syndromeMuscle weakness, peripheral edema, hypertension, weight gain, centripetal fat distributionHypokalemia (usually 29.0 μg/dL), normal to elevated midnight serum ACTH(>100ng/L) not suppressed with dexamethasoneSmall cell lung cancer, bronchial carcinoid (neuroendocrine lung tumors account for ∼50%-60% of cases of paraneoplastic Cushing syndrome), thymoma, medullary thyroid cancer, GI, pancreatic, adrenal, ovarian Ketoconazole, 600-1200 mg/d orallyOctreotide, 600-1500 μg/d SC or octreotide LAR, 20-30 mg IM monthlyAminoglutethimide, 0.5-2 g/d orallyMetyrapone, ∼1.0 g/d orallyMitotane, 0.5-8 g/d orallyEtomidate, 0.3 mg/kg/h IVMifepristone, 10-20 mg/kg/d orallyAdrenalectomy10Barbosa SL Rodien P Leboulleux S et al.Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature.Thyroid. 2005; 15: 618-623Crossref PubMed Scopus (17) Google Scholar, 11Morandi U Casali C Rossi G Bronchial typical carcinoid tumors.Semin Thorac Cardiovasc Surg. 2006; 18: 191-198Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 12Teves DA Clinical approach of Cushing syndrome resulting from ACTH-producing metastatic neuroendocrine tumor.Endocrinologist. 2005; 15: 401-404Crossref Scopus (3) Google Scholar, 13Nimalasena S Freeman A Harland S Paraneoplastic Cushing's syndrome in prostate cancer: a difficult management problem.BJU Int. 2008; 101: 424-427Crossref PubMed Scopus (9) Google Scholar, 14Nieman LK Medical therapy of Cushing's disease.Pituitary. 2002; 5: 77-82Crossref PubMed Scopus (95) Google ScholarHypoglycemiaSweating, anxiety, tremors, palpitations, hunger, weakness, seizures, confusion, coma For non–islet cell tumor hypoglycemia: low glucose, low insulin (often <1.44-3.60 μIU/mL), low C-peptide (often 10:1)For insulinomas: low glucose, elevated insulin, elevated C-peptide, normal IGF-2:IGF-1 ratioMesothelioma, sarcomas, lung, GI Glucose (oral and/or parenteral)Dexamethasone, 4 mg 2 or 3 times dailyPrednisone, 10-15 mg/dDiazoxide, 3-8 mg/kg/d orally divided in 2 or 3 dosesGlucagon infusion, 0.06-0.3 mg/h IVOctreotide, ∼50-1500 μg/d SC or octreotide LAR, 20-30 mg IM monthly (often with corticosteroids)Human growth hormone, 2 U/d SC (often with corticosteroids)4Spinazze S Schrijvers D Metabolic emergencies.Crit Rev Oncol Hematol. 2006; 58: 79-89Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 15Nayar MK Lombard MG Furlong NJ McNulty SJ Hardy KJ Vora J Diagnosis and management of nonislet cell tumor hypoglycemia: case series and review of the literature.Endocrinologist. 2006; 16: 227-230Crossref Scopus (4) Google Scholar, 16Teale JD Marks V Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH).Clin Endocrinol (Oxf). 1998; 49: 491-498Crossref PubMed Scopus (31) Google Scholar, 17Hoff AO Vassilopoulou-Sellin R The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia.Cancer. 1998; 82: 1585-1592Crossref PubMed Scopus (36) Google Scholar, 18Kacprowicz RF Lloyd JD Electrolyte complications of malignancy.Emerg Med Clin North Am. 2009; 27: 257-269Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 19Gullo D Sciacca L Parrinello G Tomaselli L Vigneri R Treatment of hemangiopericytoma-induced hypoglycemia with growth hormone and corticosteroids.J Clin Endocrinol Metab. 1999; 84: 1758-1759Crossref PubMed Google Scholar, 20Vezzosi D Bennet A Courbon F Caron P Short- and long-term somatostatin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism.Clin Endocrinol (Oxf). 2008; 68: 904-911Crossref PubMed Scopus (15) Google Scholara ACTH = adrenocorticotropic hormone; GI = gastrointestinal; HTLV = human T-lymphotropic virus; IM = intramuscular; IV = intravenous; LAR = long-acting release; PTH = parathyroid hormone; PTHrP = PTH-related protein; SC = subcutaneous; SIADH = syndrome of inappropriate antidiuretic hormone secretion. See Glossary at end of article for expansion of additional abbreviations.b SI conversion factors: To convert calcium values to mmol/L, multiply by 0.25; to convert cortisol values to nmol/L, multiply by 27.588; to convert C-peptide values to nmol/L, multiply by 0.331; to convert insulin values to pmol/L, multiply by 6.945; to convert osmolality values to mmol/kg, multiply by 1; to convert PTH values to ng/L, multiply by 1; and to convert sodium values to mmol/L, multiply by 1.c In addition to treating the underlying malignancy. Open table in a new tab The syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is characterized by hypo-osmotic, euvolemic hyponatremia, affects 1% to 2% of all patients with cancer. Small cell lung cancer accounts for most of these cases, with approximately 10% to 45% of all patients with small cell lung cancer developing SIADH.5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar Paraneoplastic SIADH arises from tumor cell production of antidiuretic hormone (ADH, also known as arginine vasopressin or vasopressin) and atrial natriuretic peptide. Antidiuretic hormone leads to increased free-water reabsorption; atrial natriuretic peptide has natriuretic and antidiuretic properties.5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar Accurate assessment of volume status is a critical step in the diagnosis of SIADH because it affects the interpretation of laboratory data and directs therapy. In contrast to the hypovolemic hyponatremia caused by gastrointestinal losses, excessive diuresis, adrenal insufficiency, salt-wasting nephropathy, and cerebral salt wasting—all of which may be encountered in cancer patients—SIADH causes euvolemic hyponatremia.5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar Both clinical and laboratory parameters may aid in the determination of volume status. A euvolemic state is supported by the absence of orthostatic vital sign changes or edema, normal central venous pressure, a serum uric acid concentration less than 4 mg/dL (to convert to μmol/L, multiply by 59.485), and a blood urea nitrogen level less than 10 mg/dL (to convert to mmol/L, multiply by 0.357). In the setting of euvolemic hyponatremia, a urinary sodium level greater than 40 mmol/L or a urine osmolality greater than 100 mOsm/kg of water (to convert to mmol/kg, multiply by 1) suggests the diagnosis of SIADH.6Ellison DH Berl T The syndrome of inappropriate antidiuresis.N Engl J Med. 2007; 356: 2064-2072Crossref PubMed Scopus (253) Google Scholar By contrast, hyponatremia and elevated urinary sodium or osmolality occurring in a volume-depleted individual represent the appropriate secretion of ADH and respond to volume repletion. The symptoms of SIADH depend on the degree and rapidity of onset of hyponatremia. Mild symptoms include headache, weakness, and memory difficulties. Serum sodium levels less than 125 mEq/L (to convert to mmol/L, multiply by 1), particularly if developing within 48 hours, can be marked by altered mental status, seizures, coma, respiratory collapse, and death.6Ellison DH Berl T The syndrome of inappropriate antidiuresis.N Engl J Med. 2007; 356: 2064-2072Crossref PubMed Scopus (253) Google Scholar When hyponatremia develops during a longer time frame, neurologic complications may not occur.5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar The time course of hyponatremia also affects the treatment of SIADH. In the setting of symptomatic hyponatremia developing within 48 hours, the serum sodium level may be raised 1 to 2 mmol/L per hour and usually no more than 8 to 10 mmol/L during the first 24 hours of treatment.6Ellison DH Berl T The syndrome of inappropriate antidiuresis.N Engl J Med. 2007; 356: 2064-2072Crossref PubMed Scopus (253) Google Scholar With chronic hyponatremia, the brain generates endogenous osmoles to minimize intracellular swelling. Rapid correction leads to water egress, brain dehydration, and central pontine and extrapontine myelinolysis, a condition characterized by lethargy, dysarthria, spastic quadriparesis, and pseudobulbar palsy—all of which can be permanent.5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar, 6Ellison DH Berl T The syndrome of inappropriate antidiuresis.N Engl J Med. 2007; 356: 2064-2072Crossref PubMed Scopus (253) Google Scholar Thus, a correction goal of 0.5 to 1.0 mmol/L per hour is generally recommended for these patients.6Ellison DH Berl T The syndrome of inappropriate antidiuresis.N Engl J Med. 2007; 356: 2064-2072Crossref PubMed Scopus (253) Google Scholar The optimal therapy for paraneoplastic SIADH is treatment of the underlying tumor, which, if successful, can normalize the sodium level in a matter of weeks.5Raftopoulos H Diagnosis and management of hyponatremia in cancer patients.Support Care Cancer. 2007; 15: 1341-1347Crossref PubMed Scopus (26) Google Scholar In the short term, fluid restriction (usually 14 mg
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