Küçük Hücreli Akciğer Kanserinde İzlenen Paraneoplastik Sendromlar
Özet
Paraneoplastik sendromlar, tümörün doğrudan invazyonu veya metastazı dışındaki mekanizmalarla ortaya çıkan ve akciğer kanserlerinde, özellikle de küçük hücreli akciğer kanserinde (KHAK) sıklıkla gözlenen heterojen bozukluklardır. KHAK, nöroendokrin diferansiyasyona sahip yapısı gereği biyolojik olarak aktif maddeler salgılayarak bu sendromların gelişiminde kritik rol oynar. Bu kapsamda en yaygın görülen endokrin bozukluk, hiponatremi ve övolemi ile karakterize olan Uygunsuz Antidiüretik Hormon Salınımı Sendromu’dur (SIADH). Ayrıca, hipofiz dışı dokulardan kontrolsüz ACTH salınımıyla tetiklenen Ektopik Cushing Sendromu ve malign hiperkalsemi de belirgin endokrin tablolar arasındadır. Nörolojik alanda ise presinaptik kalsiyum kanallarına karşı gelişen onkonöral antikorların yol açtığı Lambert-Eaton Miyastenik Sendromu (LEMS) en sık karşılaşılan klasik tablodur; bunu limbik ensefalit ve serebellar dejenerasyon izler. Dermatolojik ve romatolojik sistemlerde ise proksimal kas güçsüzlüğü ve tipik deri döküntüleriyle seyreden dermatomiyozit ve polimiyozit öne çıkar. Bu sendromlar genellikle tümörün lokal belirtilerinden önce ortaya çıktığı için okkült kanserlerin erken teşhis edilmesine ve tedavi başarısının artırılmasına olanak tanır. Tedavinin temel sütununu altta yatan malignitenin sitotoksik kemoterapi veya cerrahiyle ortadan kaldırılması oluştururken, semptomlara yönelik sıvı kısıtlaması, V2 reseptör antagonistleri veya immünoglobulinler gibi spesifik medikal yaklaşımlar da hastaların yaşam kalitesini ve sağkalımını optimize etmek amacıyla sürece dahil edilir.
Paraneoplastic syndromes are a heterogeneous group of disorders caused by mechanisms other than direct tumor invasion or metastasis, frequently observed in lung cancers, particularly small cell lung cancer (SCLC). Due to its neuroendocrine differentiation, SCLC produces biologically active substances that trigger these remote systemic effects. The most prevalent endocrine manifestation is the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), characterized by hyponatremia and euvolemia. Ectopic Cushing Syndrome, driven by uncontrolled non-pituitary ACTH secretion, and malignant hypercalcemia represent other prominent endocrine conditions. Neurologically, Lambert-Eaton Myasthenic Syndrome (LEMS), caused by onconeural antibodies targeting presynaptic calcium channels, is the most common classical syndrome, followed by limbic encephalitis and cerebellar degeneration. In dermatological and rheumatological spheres, inflammatory myopathies such as dermatomyositis and polymyositis stand out with proximal muscle weakness and distinct cutaneous lesions. Because these symptoms often precede typical respiratory tumor signs, they facilitate the early detection of occult malignancies at potentially curable stages. While the definitive long-term treatment relies entirely on managing the underlying malignancy through chemotherapy or surgical excision, specialized interventions—including fluid restriction, V2 receptor antagonists, corticosteroids, and intravenous immunoglobulins—are essential to alleviate severe symptoms, enhance quality of life, and improve overall patient survival.
Referanslar
Baijens 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(1):32-6.
İnternational Agency for Research on Cancer- Cancer Today [Internet]. 2020.
Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85(9):838-54.
Anwar A, Jafri F, Ashraf S, Jafri MAS, Fanucchi M. Paraneoplastic syndromes in lung cancer and their management. Ann Transl Med. 2019;7(15):359.
Imura H, Matsukura S, Yamamoto H, Hirata Y, Nakai Y. Studies on ectopic ACTH-producing tumors. II. Clinical and biochemical features of 30 cases. Cancer. 1975;35(5):1430-7.
Vanhees SL, Paridaens R, Vansteenkiste JF. Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review. Ann Oncol. 2000;11(8):1061-5.
Tai P, Yu E, Jones K, Sadikov E, Mahmood S, Tonita J. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with limited stage small cell lung cancer. Lung Cancer. 2006;53(2):211-5.
Soomro Z, Youssef M, Yust-Katz S, Jalali A, Patel AJ, Mandel J. Paraneoplastic syndromes in small cell lung cancer. J Thorac Dis. 2020;12(10):6253-63.
List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986;4(8):1191-8.
Hainsworth JD, Workman R, Greco FA. Management of the syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. Cancer. 1983;51(1):161-5.
Lokich JJ. The frequency and clinical biology of the ectopic hormone syndromes of small cell carcinoma. Cancer. 1982;50(10):2111-4.
Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957;23(4):529-42.
Raftopoulos H. Diagnosis and management of hyponatremia in cancer patients. Support Care Cancer. 2007;15(12):1341-7.
Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-72.
Mazzone PJ, Arroliga AC. Endocrine paraneoplastic syndromes in lung cancer. Curr Opin Pulm Med. 2003;9(4):313-20.
Lee CR, Watkins ML, Patterson JH, Gattis W, O'Connor C M, Gheorghiade M, et al. Vasopressin: a new target for the treatment of heart failure. Am Heart J. 2003;146(1):9-18.
De Troyer A. Demeclocycline. Treatment for syndrome of inappropriate antidiuretic hormone secretion. Jama. 1977;237(25):2723-6.
Spiro SG, Gould MK, Colice GL. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):149s-60s.
Yoshimoto K, Yamasaki R, Sakai H, Tezuka U, Takahashi M, Iizuka M, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab. 1989;68(5):976-81.
Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011;18(6):339-46.
Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132-9.
Takai E, Yano T, Iguchi H, Fukuyama Y, Yokoyama H, Asoh H, et al. Tumor-induced hypercalcemia and parathyroid hormone-related protein in lung carcinoma. Cancer. 1996;78(7):1384-7.
Ost DE, Jim Yeung SC, Tanoue LT, Gould MK. Clinical and organizational factors in the initial evaluation of patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e121S-e41S.
Boscaro M, Barzon L, Fallo F, Sonino N. Cushing's syndrome. Lancet. 2001;357(9258):783-91.
Barbosa SL, Rodien P, Leboulleux S, Niccoli-Sire P, Kraimps JL, Caron P, et al. Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature. Thyroid. 2005;15(6):618-23.
Morandi U, Casali C, Rossi G. Bronchial typical carcinoid tumors. Semin Thorac Cardiovasc Surg. 2006;18(3):191-8.
Wajchenberg BL, Mendonca BB, Liberman B, Pereira MA, Carneiro PC, Wakamatsu A, et al. Ectopic adrenocorticotropic hormone syndrome. Endocr Rev. 1994;15(6):752-87.
Shepherd FA, Laskey J, Evans WK, Goss PE, Johansen E, Khamsi F. Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol. 1992;10(1):21-7.
Delisle L, Boyer MJ, Warr D, Killinger D, Payne D, Yeoh JL, et al. Ectopic corticotropin syndrome and small-cell carcinoma of the lung. Clinical features, outcome, and complications. Arch Intern Med. 1993;153(6):746-52.
Teves DA. Clinical Approach of Cushing Syndrome Resulting From ACTH-Producing Metastatic Neuroendocrine Tumor. The Endocrinologist. 2005;15(6):401-4.
Nimalasena S, Freeman A, Harland S. Paraneoplastic Cushing's syndrome in prostate cancer: a difficult management problem. BJU Int. 2008;101(4):424-7.
Nieman LK. Medical therapy of Cushing's disease. Pituitary. 2002;5(2):77-82.
Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-40.
Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini G. Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol. 2010;67(3):330-5.
de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist. 2006;11(3):292-305.
Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis. 2007;2:22.
Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135-40.
García Vicente AM, Delgado-Bolton RC, Amo-Salas M, López-Fidalgo J, Caresia Aróztegui AP, García Garzón JR, et al. (18)F-fluorodeoxyglucose positron emission tomography in the diagnosis of malignancy in patients with paraneoplastic neurological syndrome: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2017;44(9):1575-87.
Antoine JC, Honnorat J, Camdessanché JP, Magistris M, Absi L, Mosnier JF, et al. Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann Neurol. 2001;49(2):214-21.
Ricard D, Rogemond V, Charrier E, Aguera M, Bagnard D, Belin MF, et al. Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3a- sensitive oligodendrocytes. J Neurosci. 2001;21(18):7203-14.
Antoine JC, Absi L, Honnorat J, Boulesteix JM, de Brouker T, Vial C, et al. Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. Arch Neurol. 1999;56(2):172-7.
Keime-Guibert F, Graus F, Fleury A, René R, Honnorat J, Broet P, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry. 2000;68(4):479-82.
Didelot A, Honnorat J. Update on paraneoplastic neurological syndromes. Curr Opin Oncol. 2009;21(6):566-72.
McEvoy KM, Windebank AJ, Daube JR, Low PA. 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med. 1989;321(23):1567-71.
Gandhi L, Johnson BE. Paraneoplastic syndromes associated with small cell lung cancer. J Natl Compr Canc Netw. 2006;4(6):631-8.
Verschuuren JJ, Wirtz PW, Titulaer MJ, Willems LN, van Gerven J. Available treatment options for the management of Lambert-Eaton myasthenic syndrome. Expert Opin Pharmacother. 2006;7(10):1323-36.
Lee WJ, Lee ST, Byun JI, Sunwoo JS, Kim TJ, Lim JA, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016;86(18):1683-91.
Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992;42(10):1931-7.
Posner JB. Neurologic complications of systemic cancer. Dis Mon. 1978;25(2):1-60.
Ohara S, Iijima N, Hayashida K, Oide T, Katai S. Autopsy case of opsoclonus-myoclonus-ataxia and cerebellar cognitive affective syndrome associated with small cell carcinoma of the lung. Mov Disord. 2007;22(9):1320-4.
Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain. 2001;124(Pt 2):437-43.
Hiasa Y, Kunishige M, Mitsui T, Kondo S, Kuriwaka R, Shigekiyo S, et al. Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer. Clin Neurol Neurosurg. 2003;106(1):47-9.
Hassan KA, Kalemkerian GP, Trobe JD. Long-term survival in paraneoplastic opsoclonus-myoclonus syndrome associated with small cell lung cancer. J Neuroophthalmol. 2008;28(1):27-30.
Chalk CH, Windebank AJ, Kimmel DW, McManis PG. The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci. 1992;19(3):346-51.
Keime-Guibert F, Graus F, Broët P, Reñé R, Molinuevo JL, Ascaso C, et al. Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor. Neurology. 1999;53(8):1719-23.
Hirano S, Nakajima Y, Morino E, Fujikura Y, Mochizuki M, Takeda Y, et al. A case of spontaneous regression of small cell lung cancer with progression of paraneoplastic sensory neuropathy. Lung Cancer. 2007;58(2):291-5.
Uchuya M, Graus F, Vega F, Reñé R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry. 1996;60(4):388-92.
Thiers BH, Sahn RE, Callen JP. Cutaneous manifestations of internal malignancy. CA Cancer J Clin. 2009;59(2):73-98.
Koh ET, Seow A, Ong B, Ratnagopal P, Tjia H, Chng HH. Adult onset polymyositis/dermatomyositis: clinical and laboratory features and treatment response in 75 patients. Ann Rheum Dis. 1993;52(12):857-61.
Sigurgeirsson B, Lindelöf B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med. 1992;326(6):363-7.
Fujita J, Tokuda M, Bandoh S, Yang Y, Fukunaga Y, Hojo S, et al. Primary lung cancer associated with polymyositis/dermatomyositis, with a review of the literature. Rheumatol Int. 2001;20(2):81-4.
Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet. 2003;362(9388):971-82.
Mori H, Habe K, Hakamada A, Isoda K, Mizutani H. Relapse of dermatomyositis after 10 years in remission following curative surgical treatment of lung cancer. J Dermatol. 2005;32(4):290-4.
