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LUNG CANCER
PARANEOPLASTIC SYNDROMES ASSOCIATED WITH BRONCHOGENIC CARCINOMA Robert B. Gerber, MD, Peter Mazzone, MD, MPH, and Alejandro C. Arroliga, MD
The presenting symptoms of lung cancer usually are caused by the physical effects of the primary tumor or its metastases (e.g., compression, obstruction, local invasion of normal tissue). A constellation of symptoms and signs at a site distant to the primary tumor, unrelated to local effects or metastases, is termed a paraneoplastic syndrome. The mechanisms by which these syndromes occur are not understood fully. The cancer can produce its distant effects in several ways, such as the ectopic production of peptide proteins (hormones) or through immunologic mechanisms (as in the paraneoplastic neurologic syndromes). Paraneoplastic syndromes can serve as the first sign of disease because they frequently occur before the appearance of the primary tumor, or they can be a clinician’s first indication of tumor recurrence.48 They can produce constitutional symptoms or affect virtually every organ system in the body. Their prognostic implications are varied.14 This article focuses on the features of the most common or well-studied paraneoplastic endocrine and neurologic syndromes. The following are paraneoplastic syndromes associated with bronchogenic carcinoma: Endocrine Ectopic Cushing’s syndrome Syndrome of inappropriate antidiuretic hormone (SIADH) Hypercalcemia Atrial natriuretic peptide Transforming growth factor  Interleukin-1a
Granulocyte colony stimulating factor Tumor necrosis factor (cachexia syndrome) Human chorionic gonadotropin Growth hormone–releasing hormone Hematologic Anemia Polycythemia Granulocytosis Eosinophilia Disseminated intravascular coagulation Migratory thrombophlebitis Renal Nephrotic syndrome Glomerulonephritis Cutaneous Hypertrophic pulmonary osteoarthropathy Sign of Leser-Tre´lat Acanthosis nigricans Dermatomyositis Peripheral vasculitis Pseudoscleroderma Neurologic Subacute cerebellar degeneration Encephalomyelitis Limbic Brain stem Opsoclonus-myoclonus Sensory neuropathy Motor neuropathy Chronic sensorimotor neuropathy Autonomic dysfunction Cancer-associated retinopathy Optic neuritis
From the Division of Pulmonary, Critical Care and Occupational Medicine, Saint Louis University, St. Louis, Missouri (RBG); Department of Pulmonary and Critical Care Medicine (PM, ACA). The Cleveland Clinic Foundation, Cleveland, Ohio (PM, ACA)
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Dementia Lambert-Eaton myasthenic syndrome (LEMS) Myasthenia gravis Subacute necrotizing myelopathy Polymyositis-dermatomyositis Intestinal pseudo-obstruction (Ogilvie’s syndrome) PARANEOPLASTIC ENDOCRINE SYNDROMES (PARAENDOCRINE SYNDROMES) The ectopic production of hormones by a malignancy can cause effects on many different organ systems. Three of the most common paraendocrine syndromes seen in bronchogenic carcinoma are ectopic Cushing’s syndrome, SIADH, and humoral hypercalcemia of malignancy. Other substances produced by bronchogenic carcinoma include atrial natriuretic peptide, transforming growth factor B, interleukin-1a, granulocyte colony stimulating factor, tumor necrosis factor, and human chorionic gonadotropin. Ectopic Cushing’s Syndrome Twenty percent to 30% of Cushing’s syndrome cases are caused by the ectopic production of adrenocorticotropic hormone (ACTH) Lung cancer is the cause of this ectopic production approximately 50% of the time. Small cell carcinoma accounts for most cases, but carcinoid tumors and non–small cell carcinomas also have been responsible.25, 27, 70 Although up to 50% of patients with lung carcinoma may have elevated levels of ACTH by assay, case series report a prevalence of clinically significant disease of only 2% to 10% of individuals with small cell carcinoma15, 16, 52 and 0.4% to 2% of patients with lung cancer overall. In contrast to the female predominance of Cushing’s disease, ectopic Cushing’s syndrome occurs with equal frequency in men and women.19 Normal human lung produces small amounts of the parent compound proopiomelanocortin (POMC).69 Proopiomelanocortin is cleaved to proACTH, ACTH, -lipotropin, N-terminal peptide of POMC, and -endorphin. 56 Although the exact cause of ectopic Cushing’s Syndrome is not known yet, it is believed that the increase in POMC levels seen in the setting of malignancy is the result of overexpression of the gene responsible for its production.56 The clinical manifestations of ectopic Cushing’s syndrome are less prominent than with Cushing’s disease because of the shorter time period that the individual is exposed to excessive ACTH because the underlying cancer is aggressive in nature. Clinical manifestations occur in at least 57% of individuals who are defined as having ectopic Cushing’s syndrome, but the classic symptoms are often absent and the entire syndrome rarely is observed.12, 15, 16 Peripheral edema, proximal myopathy, and
moon facies most commonly are reported,52 with weight loss being more common than weight gain. Biochemical abnormalities also differ. Hypokalemia and alkalosis are seen in nearly all cases, and hyperglycemia is present in most.12, 15, 16, 52, 70 The diagnosis of ectopic Cushing’s syndrome is made by finding an elevated 24-hour urinary free cortisol level, an elevated plasma cortisol level, and an elevated plasma ACTH that do not decrease after administering a high-dose dexamethasone suppression test (2 mg every 6 hours for a total of 8 dosages).9 Imaging studies (e.g., CT scanning, MR imaging, somatostatin receptor scintigraphy) then are used to attempt to locate the source of ectopic production if not previously known. Inferior petrosal vein sampling, with or without corticotropia releasing hormone (CRH) or metyrapone stimulation, is occasionally necessary to assist in the diagnosis. The primary therapy of ectopic Cushing’s syndrome secondary to lung cancer is treatment of the underlying tumor. If patients experience significant clinical effects from the hypercortisolism, cortisol production blockers (steroid synthesis inhibitors), such as aminoglutethimide, mitotane, metyropone, and ketoconazole,11, 12, 15, 70 or suppressors of ACTH production, such as the somatostatin analogue octreotide,62 have shown some efficacy. Bilateral adrenalectomy may be an effective therapy for the patient with refractory disease.12 The presence of clinically apparent ectopic Cushing’s syndrome (but not simply elevated ACTH levels) in the setting of small cell carcinoma has been associated with a reduction in responsiveness to chemotherapy, an increase in the rate of chemotherapy-related toxicity, an increase in the rate of severe opportunistic infection after the initiation of treatment, and decreased survival.12, 15, 16, 52 The Syndrome of Inappropriate Antidiuretic Hormone Hyponatremia is a frequent finding in patients with lung cancer. It is more commonly a sign of small cell carcinoma, where it usually is caused by the ectopic secretion of arginine vasopressin and is termed the syndrome of inappropriate antidiuretic hormone (SIADH). Approximately 7% to 11% of individuals with small cell lung cancer develop SIADH.24, 31 Atrial natriuretic peptide also is produced ectopically in some patients.22, 34, 53 The contribution of this ectopic production to hyponatremia is unclear. Clinical features include mental status changes, confusion, lethargy, and seizures. Hyponatremia rarely causes symptoms unless the serum sodium falls below 125 mmol/L. Symptoms are related to the rate of sodium decline more than the absolute value. Up to 50% of small cell lung carcinomas have elevated levels of ADH, but fewer than 10% have clinically apparent disease. Although the hyponatremia is usually severe, only few patients are symptomatic at the time of diagnosis.24, 31 The lack
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of symptoms at diagnosis is likely is related to the prolonged period of time during tumor growth, in which the syndrome develops (i.e., slow rate of sodium decline). The syndrome of inappropriate antidiuretic hormone production is diagnosed by finding an inappropriately increased urinary sodium and osmolarity in the setting of serum hyponatremia and reduced serum osmolarity. The ADH level is elevated. Other causes of SIADH (e.g., medications) and hyponatremia (e.g., renal, adrenal, thyroid dysfunction) should be considered. Therapy should begin with treatment of the underlying tumor. Chemotherapy for small cell carcinoma leads to resolution of SIADH in most cases. As the tumor progresses, dilutional hyponatremia recurs in up to 70% of cases.24, 31 Additional management of the hyponatremia may be necessary while awaiting a response to chemotherapy or when the tumor is resistant to therapy. This management involves fluid restriction and medications, such as demeclocycline, lithium carbonate, and phenytoin. These agents act by interfering with the effect of ADH at the collecting duct. Demeclocycline is the drug of choice because of the side effects of the other agents.55 In severe, symptomatic hyponatremia, hypertonic saline and furosemide administration may be necessary. Rapid correction of hyponatremia should be avoided because it may lead to central pontine myelinolysis. The prognosis of patients with small cell carcinoma and SIADH is similar to those without SIADH.24, 31 Humoral Hypercalcemia of Malignancy Up to 40% of patients with cancer have hypercalcemia at some point in their clinical course, making hypercalcemia the most common paraneoplastic syndrome. At presentation, approximately 1% of patients with non–small cell lung cancer have severe hypercalcemia, and another 1% have moderate hypercalcemia.63 Humoral hypercalcemia of malignancy is caused by the production of parathyroid hormone-related protein (PTHrP) by the tumor. This protein has homology with parathyroid hormone and similar functional activity, but they are structurally different. It most commonly is associated with squamous cell carcinoma of the lung and has been purified from a lung cancer cell line.7, 39 Other mechanisms of hypercalcemia associated with malignancy include direct bony metastases, hormonally mediated local activation of osteoclasts by cancers that have invaded bone, and rare production of steroid hormones (e.g., 1,25-dihydroxyvitamin D) by tumors. Clinical features of hypercalcemia include fatigue, lethargy, mental status change, weakness, abdominal pain, constipation, nausea, vomiting, anorexia, and polyuria. Electrocardiographic abnormalities occur, including prolongation of the PR interval, widening of the QRS interval, and shortening of the QT intervals, followed by bradycardia and finally heart block.
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Finding an elevated calcium level in an individual with squamous cell carcinoma of the lung should lead the clinician to consider the diagnosis of humoral hypercalcemia of malignancy. Patients with humoral hypercalcemia have elevated levels of PTHrP by assay. This elevation is not detected by conventional assays for parathyroid hormone. Other causes of hypercalcemia should be ruled out, including primary hyperparathyroidism; medications, such as thiazides and lithium; hyperthyroidism; sarcoidosis; and osseous metastases. Treatment of humoral hypercalcemia starts with the treatment of the primary tumor. Treatment of the hypercalcemia is recommended, regardless of symptoms, if the serum calcium level is above 3.5 mmol/L (14 mg/dL) (the upper limit of normal varies among laboratories but is generally about 2.6 mmol/L [10.5 mg/dL]).8 Therapies include vigorous intravenous hydration with normal saline and the administration of diuretics once the intravascular volume has been repleted. Loop diuretics are the diuretics of choice because they promote calciuresis. Loop diuretics allow further saline administration while avoiding volume overload. Currently, perhaps the most commonly used (and believed to be the most effective) therapy is the bisphosphonates, particularly pamidronate. These agents function by inhibiting osteoclastic bone resorption. Gallium nitrate is another effective therapy.68 Gallium also functions through the inhibition of osteoclastic bone resorption. It can worsen renal function by the formation of renal tubular plugs and is contraindicated in the presence of severe renal impairment. Close monitoring of renal function and the avoidance of other nephrotoxins are recommended in patients receiving the drug.3, 29, 61 Other treatment options include the use of calcitonin and plicamycin. Humoral hypercalcemia of malignancy develops in patients with advanced, aggressive cancer and is associated with an increased frequency of metastases and increased mortality.63 As such, the clinician must consider the appropriateness of reversing the hypercalcemia with any of the previously mentioned treatments in the context of the overall prognosis of the underlying disease. PARANEOPLASTIC NEUROLOGIC SYNDROMES Paraneoplastic syndromes can affect any part of the nervous system, from the CNS to the neuromuscular junction and muscles. Paraneoplastic neurologic syndromes often develop before the tumor is evident, and their course may be independent of the clinical course of the tumor or its therapy. The mechanisms by which paraneoplastic neurologic syndromes occur have not been elucidated fully. The tumor and the nervous system seem to have common antigens. An immune response directed at the tumor may cross-react with anti-
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Table 1. ANTIBODIES ASSOCIATED WITH PARANEOPLASTIC NEUROLOGIC SYNDROMES IN SMALL CELL CARCINOMA Syndrome Paraneoplastic encephalomyelitis and sensory neuropathy Paraneoplastic Cerebellar Degeneration Cancer-Associated Retinopathy Opsoclonus-Myoclonus Lambert-Eaton Myasthenic Syndrome
Antibodies Involved Anti-Hu (ANNA-1) Anti-amphiphysin Anti-CV2 Anti-Hu Anti-CAR None in most Anti–voltage-gated calcium channel antibodies
gens in the nervous system, which results in an autoimmune disease with manifestations varying depending on the location of the cross-reacting antigens. It is unclear if the antigens expressed by the cancer are identical to the antigens expressed by the nervous system or if they are mutated.47 Removal of the antibodies formed by this immune response, by plasma exchange or immunosuppression, may not affect the neurologic disorder. There are several theories for the lack of improvement seen. These disorders develop quickly; by the time the antibodies are removed, the damage may be irreparable. The antibodies can be produced directly in the CNS and the periphery and are not removed by plasma exchange. Antibodies might be only markers of inflammation, not causative agents of disease (Table 1). Paraneoplastic Encephalomyelitis and the Anti-Hu Antibody Syndrome Encephalomyelitis can involve several areas of the nervous system, including the limbic region, the brain stem, cerebellum, spinal cord, dorsal root ganglion, and the autonomic nervous system. Presenting symptoms vary, depending on the region involved. Paraneoplastic Limbic Encephalitis Paraneoplastic limbic encephalitis (PLE) is a rare disorder, with fewer than 200 cases reported in the English medical literature. More than 50% of the time, it is caused by lung cancer, most being small cell carcinomas.23 Paraneoplastic limbic encephalitis is characterized by mood and behavior changes, memory problems progressing to dementia, and occasionally seizures. The course is subacute, with progression over weeks to months. 5, 23, 43 These symptoms can occur before the appearance of the primary tumor. Computed tomographic scans of the head are usually normal, whereas MR imaging often reveals increased T2 signal in the limbic system.23 Fluorode oxyglucose PET scan has been reported to show hypermetabolism in the medial temporal lobe.42 The cerebrospinal fluid (CSF) is
characterized by a mononuculear pleocytosis, elevated protein level, increased IgG synthesis and oligoclonal bands, although it can be normal.5, 23, 43 An electroencephalogram (EEG) is frequently abnormal, demonstrating generalized slowing, a temporal epileptic focus, or periodic lateralized epileptiform discharges. 5, 23, 43 Pathology, if obtained, reveals lymphocytic interstitial infiltrates, microglial proliferation, gliosis, and neuronal degeneration.5, 23, 43 In the setting of small cell carcinoma, approximately 50% to 80% of patients with PLE have high titers of anti-Hu antibodies in their serum (also known as type I antineuronal nuclear antibodies [ANNA-1]).1, 23 Compared with patients with PLE who do not have anti-Hu antibodies, those patients with anti-Hu antibodies are more likely to develop diffuse disease (i.e., encephalomyelitis), are less likely to respond to therapy, and are more likely to die of the neurologic syndrome rather than direct effects of the cancer.1, 13 Paraneoplastic Cerebellar Degeneration Paraneoplastic cerebellar degeneration (PCD) also occurs in patients with small cell carcinoma. Typical presenting features include ataxia, nystagmus, dysarthria, and diplopia, with or without extracerebellar signs of diffuse encephalomyelitis. Symptoms progress over weeks or months until they limit the patient’s ability to ambulate. Frequently, the symptoms occur before the diagnosis of cancer. Lambert-Eaton myasthenic syndrome may occur concomitantly. Less than one half of patients with PCD have abnormal neuroradiology studies. Periventricular white matter changes and abnormal T2 signal on MR imaging have been noted. The CSF is often inflammatory. Pathology reveals inflammatory infiltrates, perivascular lymphocytic cuffing, and loss of Purkinje cells. Treatment of the tumor or immune modulating therapy does not alter the course of PCD. Those with PCD and small cell carcinoma have a shorter survival than those without PCD.36 Approximately 44% of patients with PCD have high titers of anti-Hu antibodies. Individuals with anti-Hu antibodies are more likely to be women, have extracerebellar manifestations (e.g., encephalomyelopathy or sensory neuropathy), have severe disability, and have localized or undetected tumor at the time of death. Progression of neurologic disease is the cause of death in most patients with PCD who have positive anti-Hu antibodies and in few who are anti-Hu–negative.36 Opsoclonus-Myoclonus Opsoclonus-myoclonus (OM) can be idiopathic or paraneoplastic. It is believed to represent a distinct paraneoplastic syndrome, most commonly associated with small cell carcinoma. Predominant clinical features include involuntary rapid conjugate eye movements, myoclonus, truncal ataxia, dysarthria, and encephalopathy. Symptoms often
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precede the tumor diagnosis and are progressive.6 Neuroimaging may show areas of increased T2 signal on MR imaging, and the CSF shows a mild pleocytosis, elevated protein, and occasionally oligoclonal bands. The EEG may be normal or may show mild to severe diffuse background slowing.2 In general, there are no immune markers that identify paraneoplastic OM in small cell carcinoma, although anti-Hu and anti-amphiphysin antibodies have been reported to occur.6 Those patients with anti-Hu antibodies may have a variant of the anti-Hu syndrome. Pathology may reveal mild patchy or diffuse perivascular lymphocytic infiltrates and mild Purkinje cell loss.2 Treatment of the small cell carcinoma frequently leads to partial or complete neurologic recovery. Treatment with corticosteroids, intravenous immunoglobulins, and plasmapheresis has not proved beneficial. Paraneoplastic OM can have a severe clinical course, and if the tumor cannot be treated ultimately may be the cause of death.2, 6 The Anti-Hu Antibody Syndrome Patients with small cell cancer with high-titer anti-Hu antibodies present in their serum and CSF often develop diffuse neurologic symptoms. An anti-Hu syndrome (also called the encephalomyelitis and subacute sensory neuropathy syndrome) may occur, with presenting symptoms of a sensory neuropathy or a manifestation of encephalomyelitis. Whatever the presentation, the disorder often progresses to a diffuse encephalomyelopathy with sensory and autonomic deficits. These symptoms typically precede the diagnosis of small cell carcinoma.32, 67 Although the pathogenesis remains to be defined completely, an antigen-driven oligoclonal cytotoxic T-cell response may play a role.66 One large case series describing patients with the antiHu syndrome found that multifocal involvement was present in 73% of patients—with a sensory neuropathy in 74%, motor neuron dysfunction in 20%, limbic encephalopathy in 20%, cerebellar symptoms in 15%, brain stem encephalophathy in 14%, and autonomic dysfunction in 10%. The syndrome led to a search for the tumor in 60% of the patients.13 Chest CT scanning has a greater chance of detecting a previously unknown tumor than chest xray (CXR) does.10 Fluorode oxyglucose (FDG)-PET scanning also has been used with some success.4 Complete response of the tumor to therapy favors stabilization of the paraneoplastic manifestations. Immune modulating therapies do not improve the symptoms.23, 28 Death frequently occurs from the progression of neurologic dysfunction. The associated tumors seem to be more indolent than those without paraneoplastic responses.28, 67 The most sensitive and specific method of measuring the presence of antibodies is immunoblot of recombinant proteins, such as HuD, HuC, or Hel-N1. A titer is considered positive when the immunoreactivity is present at serum dilutions above 1:10,000 (this varies with the type of antigen
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used).54, 67 At least 88% of individuals with anti-Hu antibodies in their serum have cancer, with more than 80% of these being small cell carcinoma.32 Lower titer anti-Hu antibodies have been detected in 16% of patients with small cell carcinoma who do not have a paraneoplastic neurologic disorder. The presence of these antibodies is associated with limited stage disease, a complete response to therapy, and longer survival.21 Other antibodies have been found in patients with small cell carcinoma with or without the previously mentioned syndrome, including anti-amphiphysin and anti-CV2 antibodies.17, 26, 49 Cancer-associated Retinopathy Cancer-associated retinopathy (CAR) is a rare phenomenon, most commonly associated with small cell carcinoma of the lung. Clinical features include rapid vision loss, night blindness, color loss, and central or ring scotomas. Loss of visual acuity can be asymmetric. Vitreous cells, disc pallor, and arteriole narrowing are noted on examination.59 The triad of ring scotomata, photosensitivity, and decreased retinal arteriole caliber suggests the presence of CAR. Electroretinograms reveal flat or greatly reduced amplitudes. Findings on fluorescein angiography include leakage from retinal vessels, mottling of retinal pigment epithelium, and a window defect through altered retinal pigment epithelium or along the retinal vessels themselves.35 Cancer-associated retinopathy is not uncommonly the first sign of an undiagnosed cancer. Cancer-associated retinopathy is caused by autoantibodies directed against retinal proteins, including the CAR antigen, recoverin, a photoreceptor-specific 23-kd protein.41, 58 An autoimmune mechanism is suspected, with common antigens being shared between the cancer tissue and retina. Unlike in other paraneoplastic neurologic syndromes, immune modulating therapy with steroids has been modestly effective in some cases.41, 59 Treatment of the primary tumor has little effect on the progression of CAR. The prognosis is not good; most cases progress toward blindness over many months. Lambert-Eaton Myasthenic Syndrome One of the most well-studied neurologic paraneoplastic syndromes is LEMS. From 40% to 60% of individuals with LEMS have lung cancer, most being small cell carcinomas.44, 60 This syndrome is the most common of the neurologic paraneoplastic syndromes, with a prevalence of close to 3% in small cell carcinoma. 18, 51 Lambert-Eaton myasthenic syndrome is characterized clinically by proximal muscle weakness affecting the lower extremities (pelvic girdle and thigh) more than the upper extremities, fatigue, and depressed deep tendon reflexes. Autonomic features, such as dry
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mouth and ptosis, are common.44 A transient increase in strength as exercise occurs, a lack of ocular involvement, and the failure to improve with the administration of anticholinesterases are features that help to differentiate LEMS from myasthenia gravis. The syndrome often develops before the diagnosis of the cancer, which is usually evident within 2 years of symptom onset.44 Electromyography reveals a decreased baseline muscle action potential with an increase in action potential with repeated stimulation. Increased T2 signal in various regions may be noted on MR imaging.20 The pathogenesis of LEMS involves the production of IgG antibodies against P/Q-type voltagegated calcium channels.30 The autoantibodies are believed to be triggered by similar channels in the cancer cells.38, 65 These calcium channels are responsible for the influx of calcium into the neuron, which is required for the release of acetylcholine. As a result, these antibodies prevent the release of neurotransmitters, causing depletion of neurotransmitters at the neuromuscular junction. As a test, the detection of these autoantibodies is sensitive for the detection of LEMS but may be found in individuals with small cell carcinoma without LEMS.40, 46 In a given patient, an inverse relationship may be seen between the antibody titer and disease severity.40 The main therapy of LEMS is to treat the underlying tumor. The syndrome usually improves as the tumor responds to treatment. Additional therapies of benefit include 3,4-diaminopyridine, which promotes the release of acetylcholine from presynaptic terminals; immunosuppresive agents, such prednisone and azathioprine; and plasma exchange and intravenous immunoglobulins.37, 50, 57, 60 The prognosis of patients with small cell carcinoma with LEMS has been reported to be better than those without.33 The autoimmune response growth. SUMMARY Paraneoplastic syndromes associated with lung cancer are diverse in their presentation, pathophysiology, and implications. They can be seen as a diagnostic and therapeutic challenge or as an opportunity to detect an otherwise asymptomatic malignancy. Unraveling the mechanisms that produce these syndromes will lead to insight into tumor biology that will be translated into novel approaches for early detection and therapy. References 1. Alanowitch S, Graus F, Uchuya M: Limbic encephalitis and small cell lung cancer: Clinical and immunological features. Brain 120:928–928, 1997 2. Anderson NE, Budde-Steffen C, Rosenblum MK, et al: Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: A distinct paraneoplastic syndrome. Medicine 67:100–109, 1988
3. Anonymous: Gallium for hypercalcemia of malignancy. The Medical Letter 33:41–42, 1991 4. Antoine JC, Cinotti L, Tilikete C, et al: [18F]Fluorodeoxyglucose positron emission tomography in the diagnosis of cancer in patients with paraneoplastic neurological syndrome and anti-Hu antibodies. Ann Neurol 48:105–108, 2000 5. Bakheit AMO, Kennedy PGE, Behan PO: Paraneoplastic limbic encephalitis: Clinicopathological correlations. J Neurol Neurosurg Psychiatry 53:1084– 1088, 1990 6. Bataller L, Graus F, Saiz A: Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 124:437–443, 2001 7. Benson RC, Riggs BL, Pickard BM, et al: Immunoreactive forms of circulating parathyroid hormone in primary and ectopic hyperparathyroidism. J Clin Invest 54:175–181, 1974 8. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 326:196–203, 1992 9. Boscaro M, Barzon L, Fallo F, et al: Cushing’s syndrome. Lancet 357:83–91, 2001 10. Chartrand-Lefebvre C, Howarth N, Grenier P, et al: Association of small cell lung cancer and the antiHu paraneoplastic syndrome: Radiographic and CT findings. AJR Am J Roentgenol 170:1513–1517, 1998 11. Coll R, Horner I, Kraiem Z, et al: Successful metyrapone therapy of the ectopic ACTH syndrome. Arch Intern Med 121:549–553, 1968 12. Collichio FA, Woolf PD, Brower M: Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion. Cancer 73:1361– 1367, 1994 13. Dalmau J, Graus F, Rosenblum MK, et al: Anti-Hu– associated paraneoplastic encephalomyelitis/sensory neuronopathy: A clinical study of 71 patients. Medicine 71:59–72, 1992 14. de la Monte SM, Hutchins GM, Moore GW: Paraneoplastic syndromes and constitutional symptoms in prediction of metastatic behavior of small cell carcinoma of the lung. Am J Med 77:851–857, 1984 15. Delisle L, Boyer MJ, Warr D, et al: Ectopic corticotropin syndrome and small cell carcinoma of the lung: Clinical features, outcome, and complications. Arch Intern Med 153:746–752, 1993 16. Dimopoulos MA, Fernandez JF, Samaan NA, et al: Paraneoplastic Cushing’s syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer. Cancer 69:66–71, 1992 17. Dropcho EJ: Antiamphiphysin antibodies with small cell lung carcinoma and paraneoplastic encephalomyelitis. Ann Neurol 39:659–667, 1996 18. Elrington GM, Murray NMF, Spiro SG, et al: Neurological paraneoplastic syndromes in patients with small cell lung cancer: A prospective survey of 150 patients. J Neurol Neurosurg Psychiatry 54:764–767, 1991 19. Findling JW, Tyrrell JB: Occult ectopic secretion of corticotropin. Arch Intern Med 146:929–933, 1986 20. Glantz MJ, Biran H, Myers ME, et al: The radiographic diagnosis and treatment of paraneoplastic central nervous system disease. Cancer 73:168–175, 1994 21. Graus F, Dalmau J, Rene R, et al: Anti-Hu antibodies in patients with small cell lung cancer: Association with complete response to therapy and improved survival. J Clin Oncol 15:2866–2872, 1997 22. Gross AJ, Steinberg SM, Garrett Reilly JG, et al: Atrial natriuretic factor and arginine vasopressin produc-
PARANEOPLASTIC SYNDROMES ASSOCIATED WITH BRONCHOGENIC CARCINOMA
23.
24.
25.
26. 27. 28.
29. 30.
31.
32.
33.
34. 35. 36.
37.
38.
39.
40. 41.
tion in tumor cell lines from patients with lung cancer and their relationship to serum sodium. Cancer Res 53:67–74, 1993 Gultekin SH, Rosenfeld MR, Voltz R, et al: Paraneoplastic limbic encephalitis: Neurological symptoms, immunological findings, and tumor association in 50 patients. Brain 123:1481–1494, 2000 Hainsworth JD, Workman R, Greco FA: Management of the syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. Cancer 51: 161–165, 1983 Imura H, Matsukura S, Yamamoto H, et al: Studies on ectopic ACTH-producing tumors: Clinical and biochemic features of 30 cases. Cancer 35 (part 2): 1430–1437, 1975 Inuzuka T: Autoantibodies in paraneoplastic neurological syndrome. Am J Med Sci 319:217–226, 2000 Jex RK, van Heerden JA, Carpenter PC, et al: Ectopic ACTH syndrome: Diagnostic and therapeutic aspects. Am J Surg 149:276–282, 1985 Keime-Guibert F, Graus F, Broet P, et al: Clinical outcome of patients with anti-Hu–associated encephalomyelitis after treatment of the tumor. Neurology 53:1719–1723, 1999 Kinirons MT: Newer agents for the treatment of malignant hypercalcemia. Am J Med Sci 305:403–406, 1993 Lennon VA, Kryzer TJ, Griesmann GE, et al: Calcium channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 332:1467–1474, 1995 List AF, Hainsworth JD, Davis BW, et al: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small cell lung cancer. J Clin Oncol 4:1191–1198, 1986 Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 50:652–657, 1998 Maddison P, Newsom-Davis J, Mills KR, et al: Favourable prognosis in Lambert-Eaton myasthenic syndrome and small cell lung carcinoma. Lancet 353: 117–118, 1999 Marchioli CC, Graziano SL: Paraneoplastic syndromes associated with small cell lung cancer. Chest Surg Clin N Am 7:65–80, 1997 Masaoka N, Emoto Y, Sasaoka A, et al: Fluorescein angiographic findings in a case of cancer-associated retinopathy. Retina 19:462–464, 1999 Mason WP, Graus F, Lang B, et al: Small cell lung cancer, paraneoplastic cerebellar degeneration, and the Lambert-Eaton myasthenic syndrome. Brain 120: 1279–1300, 1997 McEvoy KM, Windebanck AJ, Daube JR, et al: 3,4diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 321:1567–1571, 1989 Morris CS, Esiri MM, Marx A, et al: Immunocytochemical characteristics of small cell lung carcinoma associated with the Lambert-Eaton myasthenic syndrome. Am J Pathol 140:839–845, 1992 Moseley JM, Kubota M, Diefenbach-Jagger H, et al: Parathyroid hormone–related protein purified from a human lung cancer cell line. Proc Natl Acad Sci USA 84:5048–5052, 1987 Motomura M, Lang B, Johnston I, et al: J Neurol Sci 147:35–42, 1997 Murphy MA, Thirkill CE, Hart WM: Paraneoplastic retinopathy: A novel autoantibody reaction associ-
42.
43. 44. 45. 46.
47. 48. 49.
50. 51. 52.
53.
54.
55. 56. 57.
58.
59.
60.
263
ated with small cell lung carcinoma. J Neuroophthalmol 17:77–83, 1997 Na DL, Hahm DS, Park JM, et al: Hypermetabolism of the medial temporal lobe in limbic encephalitis on 18FDG-PET scan: A case report. Eur Neurol 45: 187–189, 2001 Newman NJ, Bell IR, McKee AC: Paraneoplastic limbic encephalitis: Neuropsychiatric presentation. Biol Psychiatry 27:529–542, 1990 O’Neill JH, Murray NM, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome: A review of 50 cases. Brain 111:577–596, 1988 Patel AM, Davila DG, Peters SG: Paraneoplastic syndromes associated with lung cancer. Mayo Clin Proc 68:278–287, 1993 Pelucchi A, Ciceri E, Clementi F, et al: Calcium channel autoantibodies in myasthenic syndrome and small cell lung cancer. Am Rev Respir Dis 147:1229– 1232, 1993 Posner JB, Dalmau J: Paraneoplastic syndromes. Curr Opin Immunol 9:723–729, 1997 Richardson GE: Paraneoplastic syndromes in lung cancer. In Johnson BE, Johnson DH (eds): Lung Cancer. Wiley-Liss, 1995, pp 281–301 Saiz A, Dalmau J, Butler MH, et al: Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma. J Neurol Neurosurg Psychiatry 66:214– 217, 1999 Sanders DB, Massey JM, Sanders LL, et al: A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 54:603–607, 2000. Seneviratne U, de Silva R: Lambert-Eaton myasthenic syndrome. Postgrad Med J 75:516–520, 1999 Shepherd FA, Laskey J, Evans WK, et al: Cushing’s syndrome associated with ectopic corticotropin production and small cell lung cancer. J Clin Oncol 10: 21–27, 1992 Shimizu K, Nakano S, Nakano Y, et al: Ectopic atrial natriuretic peptide production in small cell lung cancer with the syndrome of inappropriate antidiuretic hormone secretion. Cancer 68:2284–2288, 1991 Sillevis-Smitt P, Manley G, Moll JWB, et al: Pitfalls in the diagnosis of autoantibodies associated with paraneoplastic neurologic disease. Neurology 46: 1739–1741, 1996 Sordillo P, Matarese RA, Novich RK, et al: Specific modalities of therapy for inappropriate antidiuretic hormone secretion. Clin Nephrol 15:107–110, 1981 Stewart PM, Gibson S, Crosby SR, et al: ACTH precursors characterize the ectopic ACTH syndrome. Clin Endocrinol (Oxf) 40:199–204, 1994 Takano H, Tanaka M, Koike R, et al: Effect of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome with small cell lung cancer: Correlation with the titer of antivoltage-gated calcium channel antibody. Muscle Nerve 17:1073–1075, 1994 Thirkill CE, Fitzgerald P, Sergott RC, et al: Cancerassociated retinopathy (CAR syndrome) with antibodies reacting with retinal, optic nerve, and cancer cells. N Engl J Med 321:1589–1594, 1989 Thirkill CE, Keltner JL, Tyler NK, et al: Antibody reactions with retina and cancer-associated antigens in 10 patients with cancer-associated retinopathy. Arch Ophthalmol 111:931–937, 1993 Tim RW, Massey JM, Sanders DB: Lambert-Eaton myasthenic syndrome: Electrodiagnostic findings and response to treatment. Neurology 54:2176–2178, 2000
264
GERBER et al
61. Todd PA, Fitton A: Gallium nitrate: A review of its pharmacological properties and therapeutic potential in cancer-related hypercalcemia. Drugs 42:261–273, 1991 62. Van den Bruel A, Bex M, Van Dorpe J, et al: Occult ectopic ACTH secretion due to recurrent lung carcinoid: Long-term control of hypercortisolism by continuous subcutaneous infusion of octreotide. Clin Endocrinol 49:541–546, 1998 63. Vassilopoulou-Sellin R, Newman BM, Taylor SH, et al: Incidence of hypercalcemia in patients with malignancy referred to a comprehensive cancer center. Cancer 71:1309–1312, 1993 64. Vaughn CB, Pearson S, Chapman J, et al: The treatment of ACTH paraneoplastic syndrome with aminoglutethimide. J NaH Med Assoc: 71:21–23, 1979 65. Viglione MP, O’Shaughnessy TJ, Kim YI: Inhibition of calcium currents and exocytosis by Lambert-Eaton syndrome antibodies in human lung cancer cells. J Physiol 488:303–317, 1995
66. Voltz R, Dalmau J, Posner JB, et al: T-cell receptor analysis in anti-Hu–associated paraneoplastic encephalomyelitis. Neurology 51:1146–1150, 1998 67. Voltz RD, Posner JB, Dalmau J, et al: Paraneoplastic encephalomyelitis: An update of the effects of the anti-Hu immune response on the nervous system and tumor. J Neurol Neurosurg Psychiatry: 63:133– 136, 1997 68. Warrell RP, Murphy WK, Schulman P, et al: A randomized, double-blind study of gallium nitrate compared with etidronate for acute control of cancerrelated hypercalcemia. J Clin Oncol 9:1467–1475, 1991 69. White A, Clark AJ, Stewart MF: The synthesis of ACTH and related peptides by tumours. Baillieres Clin Endocrinol Metab 4:1–27, 1990 70. Winquist EW, Laskey J, Crump M, et al: Ketoconazole in the management of paraneoplastic Cushing’s syndrome secondary to ectopic adrenocorticotropin production. J Clin Oncol 13:157–164, 1995 Address reprint requests to Alejandro Arroliga, MD Section of Critical Care Medicine Department of Pulmonary and Critical Care Medicine Cleveland Clinic Foundation 9500 Euclid Ave Department G62 Cleveland, OH 44195 e-mail:
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