Neuroendokrine Neoplasien der Lunge

Zusammenfassung

Neuroendokrine Neoplasien der Lunge leiten sich von diffus im Körper verteilten enterochromaffinen Zellen her. Die Inzidenz der neuroendokrinen Neoplasien der Lunge ist in den letzten Jahrzehnten aufgrund der zur Verfügung stehenden Diagnostik deutlich angestiegen, sie machen etwa 1 – 2 % aller Lungentumoren und ca. 20 – 30 % aller neuroendokrinen Neoplasien aus. Die aktuelle WHO-Klassifikation ist aus dem Jahre 2004 und unterteilt typische Karzinoide (TC), atypische Karzinoide (AC), großzellige Lungenkarzinome (LCNEC) und kleinzellige Lungenkarzinome (SCLC). Die wichtigsten neuroendokrinen Biomarker sind Chromogranin A, CD56 und Synaptophysin. TC haben eine geringe Mitoserate von < 2 Mitosen/2 mm² (10 HPFs), die Mitoserate der AC liegt bei 2 – 10 Mitosen/2 mm² (10 HPFs). Die Ki-67-Färbungen sind zur Abgrenzung typischer bzw. atypischer Karzinoide von den hochmalignen LCNEC bzw. SCLC hilfreich. Klinisch fallen die Patienten zumeist mit Husten, Hämoptysen oder einer bronchialen Obstruktion auf. Das Auftreten eines Karzinoid- bzw. Cushing-Syndroms sowie eine tumorassoziierte paraneoplastische Akromegalie sind selten. Die chirurgische Resektion mit radikaler Lymphknotendissektion ist die Therapie der ersten Wahl zur Erreichung eines langfristigen Überlebens. Bei fehlender Operabilität bzw. Operationsfähigkeit des Patienten stellt die endoskopische Abtragung bei endobronchialem Tumorwachstum eine gute Alternative dar. Die Peptid-Rezeptor-Radionuklid-Therapie (PRRNT) ist eine vielversprechende Behandlungsmöglichkeit für Patienten mit metastasierten oder inoperablen neuroendokrinen Neoplasien der Lunge. Gezielte Therapien mit Angiogenese-Inhibitoren, Tyrosinkinase-Inhibitoren und mTOR-Inhibitoren werden in Studien auf ihre Effektivität und Wirksamkeit untersucht. Vielversprechende Daten liegen für die Therapie mit Everolimus bereits vor. TC metastasieren seltener als AC, die 5-Jahres-Überlebensrate von Patienten mit TC liegt bei über 90 %. Patienten mit AC haben hingegen eine 5-Jahres-Überlebensrate zwischen 35 % und 87 % und die hoch-malignen LCNEC und SCLC eine 5-Jahres-Überlebensrate zwischen 15 % und 57 % bzw. von unter < 5 %.

Die steigende Zahl der therapeutischen Möglichkeiten und diagnostische Verfahren erfordert ein multidisziplinäres Vorgehen und eine Entscheidungsfindung in multidisziplinären Tumorkonferenzen, um eine „maßgeschneiderte“ Therapie zu gewährleisten, weshalb Patienten mit einer neuroendokrinen Neoplasie der Lunge in spezialisierten Zentren behandelt werden sollten.

Abstract

The pulmonary neuroendocrine neoplasms originate from the enterochromaffin cells which are diffusely distributed in the body. The incidence of these tumors has increased significantly in recent decades due to the available diagnostics. They make up about 1 – 2 % of all lung tumors and 20 – 30 % of all neuroendocrine neoplasms. The current WHO classification from 2004 divides them into typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCLC). The major neuroendocrine biomarkers are chromogranin A, synaptophysin and CD56. TC have a low mitotic rate of < 2 mitoses/2 mm² (10 HPF), whereas the mitotic rate of the AC is 2 – 10 mitoses/2 mm² (10 HPF). The Ki-67 staining is helpful to distinguish typical and atypical carcinoids from the highly malignant LCNEC and SCLC. Clinically, the patient presents usually with cough, hemoptysis or bronchial obstruction. The occurrence of a carcinoid or Cushing’s syndrome and a tumor-associated acromegaly are rare. Surgical resection with radical lymph node dissection is the treatment of choice for achieving long-term survival. Endoscopic resection of the endobronchial tumor growth is a good alternative for inoperable endobronchially localized tumors. Peptide receptor radionuclide therapy (PRRT) is a promising treatment option for patients with metastatic or unresectable pulmonary neuroendocrine tumors. New targeted therapies using angiogenesis inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors are being tested for their effectiveness in many previous studies. Typical carcinoid tumors metastasize less frequently than AC, the 5-year survival rate of patients with TC being over 90 %. Patients with AC have a 5-year survival rate between 35 % and 87 %. The highly malignant LCNEC and SCLC, on the other hand, have a 5-year survival rate between 15 % and 57 %, and < 5 % respectively.

The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach and decision-making in multidisciplinary tumor conferences to ensure a personalized treatment approach. Therefore patients with a neuroendocrine neoplasm of the lung should be treated in specialized centers.

• Literatur

• 1 Waxman J. Molecular Endocrinology of Cancer. Volume 1, Part 2, Cambridge University Press; 1996: 318
• 2 Williams ED, Sandler M. The classification of carcinoid tumors. Lancet 1963; 1: 238-239
• 3 Travis WD, Linnoila RI, Tsokos MG et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma: an ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991; 15: 529-553
• 4 Borges M, Linnoila RI, van de Velde HJ et al. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 1997; 386: 852-855
• 5 Ito T, Nogawa H, Udaka N et al. Development of pulmonary neuroendocrine cells of fetal hamster in explant culture. Lab Invest 1997; 77: 449-457
• 6 Montuenga LM, Guembe L, Burrell MA et al. The diffuse endocrine system: from embryogenesis to carcinogenesis. Prog Histochem Cytochem 2003; 38: 155-272
• 7 Cutz E, Speirs V, Yeger H et al. Cell biology of pulmonary neuroepithelial bodies – validation of an in vitro model. I. Effects of hypoxia and Ca2+ ionophore on serotonin content and exocytosis of dense core vesicles. Anat Rec 1993; 236: 41-52
• 8 Fu XW, Wang D, Nurse CA et al. NADPH oxidase is an O2 sensor in airway chemoreceptors: evidence from K+ current modulation in wild-type and oxidase-deficient mice. Proc Natl Acad Sci U S A 2000; 97: 4374-4379
• 9 Sorokin SP, Ebina M, Hoyt Jr RF. Development of PGP 9.5- and calcitonin gene-related peptide-like immunoreactivity in organ cultured fetal rat lungs. Anat Rec 1993; 236: 213-225
• 10 Hoyt Jr RF, Sorokin SP, McDowell EM et al. Neuroepithelial bodies and growth of the airway epithelium in developing hamster lung. Anat Rec 1993; 236: 15-22
• 11 Emanuel RL, Torday JS, Mu Q et al. Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation. Am J Physiol 1999; 277: L1003-1017
• 12 Pan J, Copland I, Post M et al. Mechanical stretch induced serotonin release from pulmonary neuroendocrine cells: implications for lung development. Am J Physiol Lung Cell Mol Physiol 2006; 290: L185-193
• 13 Fu XW, Nurse CA, Wong V et al. Hypoxia-induced secretion of serotonin from intact pulmonary neuroepithelial bodies in neonatal rabbit. J Physiol 2002; 539: 503-510
• 14 Helset E, Kjaeve J, Bjertnaes L et al. Acute alveolar hypoxia increases endothelin-1 release but decreases release of calcitonin gene-related peptide in isolated perfused rat lungs. Scand J Clin Lab Invest 1995; 55: 369-376
• 15 Palmer JB, Cuss FM, Mulderry PK et al. Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle. Br J Pharmacol 1987; 91: 95-101
• 16 Quaedvlieg PF, Visser O, Lamers CB et al. Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. Ann Oncol 2001; 12: 1295
• 17 Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: 934
• 18 Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors. Cancer 2001; 92: 2204
• 19 Hauso O, Gustafsson BI, Kidd M et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 2008; 113: 2655
• 20 Naalsund A, Rostad H, Strom EH et al. Carcinoid lung tumors incidence, treatment and outcomes: a population-based study. Eur J Cardiothorac Surg 2011; 39: 565-569
• 21 Fink G, Krelbaum T, Yellin A et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001; 119: 1647
• 22 Gatta G, Ciccolallo L, Kunkler I et al. Survival from rare cancer in adults: a population-based study. Lancet Oncol 2006; 7: 132
• 23 Skuladottir H, Hirsch FR, Hansen HH et al. Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. Lung Cancer 2002; 37: 127-135
• 24 Yao JC, Hassan M, Phan A et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26: 3063
• 25 US National Cancer Institute. Surveillance Epidemiology and End Results (SEER) data base, 1973–2004. http://seer.cancer.gov/2007
• 26 Takei H, Asamura H, Maeshima A et al. Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-7 cases. J Thorac Cardiovasc Surg 2002; 124: 285-292
• 27 Veronesi G, Morandi U, Alloisio M et al. Large cell neuroendocrine carcinoma of the lung: a retrospective analysis of 144 surgical cases. Lung Cancer 2006; 53: 111-115
• 28 Beasley MB, Thunnissen FBJM, Brambilla E et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000; 31: 1255-1265
• 29 Erasmus JJ, McAdams HP, Patz Jr EF et al. Evaluation of primary pulmonary carcinoid tumors using FDG PET. AJR Am J Roentgenol 1998; 170: 1369-1373
• 30 Kayser K, Kayser C, Rahn W et al. Carcinoid tumors of the lung: emorr- and ligandohistochemistry, analysis of integrated optical density, syntactic structure analysis, clinical data, and prognosis of patients treated surgically. J Surg Oncol 1996; 63: 99-106
• 31 Oliveira AM, Tazelaar HD, Wentzlaff KA et al. Familial pulmonary carcinoid tumors. Cancer 2001; 91: 2104
• 32 Padberg B et al. Multiple endocrine neoplasia type 1 (MEN1) revisited. Virchows Arch 1995; 426: 541-548
• 33 Sachithanandan N, Harle RA, Burgess JR. Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer 2005; 103: 509-515
• 34 Walch AK, Zitzelsberger HF, Aubele MM et al. Typical and atypical carcinoid tumors of the lung are characterized by 11q deletions as detected by comparative genomic hybridization. Am J Pathol 1998; 153: 1089-1098
• 35 Debelenko LV, Swalwell JI, Kelley MJ et al. MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. Genes Chromosomes Cancer 2000; 28: 58-65
• 36 Debelenko LV, Brambilla E, Agarwal SK et al. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 1997; 6: 2285-2290
• 37 Brandi ML, Gagel RF, Angeli A et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86: 5658-5671
• 38 Gustafsson BI, Kidd M, Chan A et al. Bronchopulmonary neuroendocrine tumors. Cancer 2008; 113: 5-21
• 39 Travis WD, Brambilla E, Muller-Hermlink HK et al. World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004: 196-198
• 40 Aubry MC, Thomas Jr CF, Jett JR et al. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: Analysis of 28 patients. Chest 2007; 131: 1635-1643
• 41 D’Agati VD, Perzin KH. Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node. Report of a case and review of the literature. Cancer 1985; 55: 2472-2476
• 42 Hausman DH, Weimann RB. Pulmonary tumorlet with hilar lymph node metastasis. Report of a case. Cancer 1967; 20: 1515-1519
• 43 Travis WD. Advances in neuroendocrine lung tumors. Annals of Oncology 2010; 21 (Suppl. 07) vii65-vii71
• 44 Pelosi G, Rodriguez J, Viale G et al. Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol 2005; 29: 179-187
• 45 Sturm N, Rossi G, Lantuejoul S et al. 34betaE12 expression along the whole spectrum of neuroendocrine proliferations of the lung, from neuroendocrine cell hyperplasia to small cell carcinoma. Histopathology 2003; 42: 156-166
• 46 Folpe AL, Gown AM, Lamps LW et al. Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. Mod Pathol 1999; 12: 5-8
• 47 Sturm N, Rossi G, Lantuejoul S et al. Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol 2002; 33: 175-182
• 48 Roggli VL, Vollmer RT, Greenberg SD et al. Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases. Hum Pathol 1985; 16: 569-579
• 49 Travis WD, Gal AA, Colby TV et al. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 1998; 29: 272-279
• 50 Kema IP, de Vries EG, Slooff MJ et al. Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors. Clin Chem 1994; 40: 86-95
• 51 Feldman JM. Serotonin metabolism in patients with carcinoid tumors: incidence of 5-hydroxytryptophan-secreting tumors. Gastroenterology 1978; 75: 1109-1114
• 52 Castiello RJ, Lynch PJ. Pellagra and the carcinoid syndrome. Arch Dermatol 1972; 105: 574-577
• 53 Fischer S, Kruger M, McRae K et al. Giant bronchial carcinoid tumors: a multidisciplinary approach. Ann Thorac Surg 2001; 71: 386
• 54 Karmy-Jones R, Vallieres E. Carcinoid crisis after biopsy of a bronchial carcinoid. Ann Thorac Surg 1993; 56: 1403
• 55 Anderson AS, Krauss D, Lang R. Cardiovascular complications of malignant carcinoid disease. Am Heart J 1997; 134: 693-702
• 56 Kvols LK. Therapeutic considerations emorrh malignant carcinoid syndrome. Acta Oncologica 1989; 28: 433-438
• 57 Vincent JM, Trainer PJ, Reznek RH et al. The radiological investigation of occult ectopic ACTH-dependent Cushing’s syndrome. Clin Radiol 1993; 48: 11
• 58 Aniszewski JP, Young Jr WF, Thompson GB et al. Cushing syndrome due to ectopic adrenocortictropic hormone secretion. World J Surg 2001; 255: 934-940
• 59 Deb SJ, Nichols FC, Allen MS et al. Pulmonary carcinoid tumors with Cushing’s syndrome: an aggressive variant or not?. Ann Thorac Surg 2005; 79: 1132
• 60 Scanagatta P, Montresor E, Pergher S et al. Cushing’s syndrome induced by bronchopulmonary carcinoid tumours: a review of 98 cases and our experience of two cases. Chir Ital 2004; 56: 63
• 61 Shrager JB, Wright CD, Wain JC et al. Bronchopulmonary carcinoid tumors associated with Cushing’s 12emorrha: amore aggressive variant of typical carcinoid. Jthorac Cardiovasc Surg 1997; 14: 367
• 62 Pass HI, Doppmann JL, Niemann L et al. Management 12emorr ectopic ACTH syndrome due to thoracic carcinoids. Ann Thorac Surg 1990; 50: 52
• 63 Faglia G, Arosio M, Bazzoni N. Ectopic acromegaly. Endocrinol Metab Clin North Am 1992; 21: 575-595
• 64 Scheithauer BW, Carpenter PC, Bloch B et al. Ectopic secretion of a growth hormone-releasing factor. Report of a case of acromegaly with bronchial carcinoid tumor. Am J Med 1984; 76: 605
• 65 Garcia-Luna PP, Leal-Cerro A, Montero C et al. A rare cause of acromegaly: ectopic production of growth hormone-releasing factor by a bronchial carcinoid tumor. Surg Neurol 1987; 27: 563
• 66 Athanassiadi K, Exarchos D, Tsagarakis S et al. Acromegaly caused by ectopic growth hormone-releasing hormone secretion by a carcinoid bronchial tumor: a rare entity. J Thorac Cardiovasc Surg 2004; 128: 631
• 67 Bhansali A, Rana SS, Bhattacharya S et al. Acromegaly: a rare manifestation of bronchial carcinoid. Asian Cardiovasc Thorac Ann 2002; 10: 273
• 68 Reuters VS, Dias EMR, Pupo MRSR et al. Acromegaly secondary to ectopic growth hormone-releasing hormone-secreting bronchial carcinoid cured after pneumectomy. Endocrinologist 2003; 13: 376-379
• 69 Bolanowski M, Schopol J, Marcianak M et al. Acromegaly due to GHRH-secreting large bronchial carcinoid. Complete recovery following tumor surgery. Exp Clin Endocrinol Diabets 2002; 110: 188-192
• 70 Krassoswski J, Zgliczynski W, Jeske W et al. Comment on long-acting lanreotide inducing clinical and biochemical remission of acromegaliy caused by disseminated GHRH secreting carcinoid. J Clin Endocrinol Metab 1999; 84: 1761-1762
• 71 Gustafsson BI, Tommeras K, Nordrum I et al. Long-term serotonin administration induces heart valve disease in rats. Circulation 2005; 111: 1517-1522
• 72 Musunuru S, Carpenter JE, Sippel RS et al. A mouse model of carcinoid syndrome and heart disease. J Surg Res 2005; 126: 102-105
• 73 Greminger P, Hess OM, Muller AE et al. Bronchial neuroendocrine (carcinoid) tumor causing unilateral left-sided carcinoid heart disease. Klin Wochenschr 1991; 69: 128-133
• 74 Westberg G, Wangberg B, Ahlman H et al. Prediction of prognosis by Echocardiography in patients with midgut carcinoid syndrome. Br J Surg 2001; 88: 865-872
• 75 Oberg K. Neuroendocrine gastrointestinal tumors-a condensed overview of diagnosis and treatment. Ann Oncol 1999; 10 (Suppl. 02) S3-S8
• 76 Gustafsson BI, Hauso O, Drozdov I et al. Carcinoid heart disease. Int J Cardiol 2008; Oct 13; 192 (Suppl. 03) 318-324
• 77 Pieroni M et al. Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function. Eur Heart J 2007; 28: 1117-1127
• 78 Nobels FR, Kwekkeboom DJ, Coopmans W et al. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. J Clin Endocrinol Metab 1997; 82: 2622-2628
• 79 Sciarra A, Monti S, Gentile V et al. Chromogranin A expression in familial versus sporadic prostate cancer. Urology 2005; 66: 1010-1014
• 80 Bieglmayer C et al. Chromogranin A: Ein universeller Marker neuroendokriner Tumoren. Austrian Journal of Clinical Endocinology and Metabolism 2010; 3: 8-14
• 81 Kema IP, Schellings AM, Meiborg G et al. Influence of aserotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem 1992; 38: 1730-1736
• 82 Kema IP, de Vries EG, Schellings AM et al. Improved Diagnosis of Carcinoid Tumors by Measurement of Platelet Serotonin. Clin Chem 1992; 38: 534-540
• 83 Bajetta E, Ferrari L, Martinetti A et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 1999; 86: 858-865
• 84 Cunningham RT, Johnston CF, Irvine GB et al. Serum neuron-specific enolase levels in patients with neuroendocrine and carcinoids tumours. Clin Chem Acta 1992; 212: 123-131
• 85 Rosado de Christenson ML, Abbott GF, Kirejczyk WM et al. Thoracic carcinoids: radiologicpathologic correlation. RadioGraphics 1999; 19: 707-736
• 86 Gould PM, Bonner JA, Sawyer TE et al. Bronchial carcinoid tumors: importance of prognostic factors that influence patterns of recurrence and overall survival. Radiology 1998; 208: 181-185
• 87 Magid D, Siegelman SS, Eggleston JC et al. Pulmonary carcinoid tumors: CT assessment. J Comput Assist Tomogr 1989; 13: 244
• 88 Zwiebel BR, Austin JH, Grimes MM. Bronchial carcinoid tumors: assessment with CT of location and intratumoral calcification in 31 patients. Radiology 1991; 179: 483-486
• 89 Takamochi K, Yokose T, Yoshida J et al. Calcification in large cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol 2003; 33: 10-13
• 90 Chong S, Lee KS, Chung MJ et al. Neuroendocrine tumors of the lung: Clinical, Pathologic, and Imaging Findings. RadioGraphics 2006; 26: 41-45
• 91 Sutedja G, Golding RP, Postmus PE. High resolution computed tomography in patients referred for intraluminal bronchoscopic therapy with curative intent. Eur Respir J 1996; 9: 1020-1023
• 92 Douek PC, Simoni L, Revel D et al. Diagnosis of bronchila carcinoid tumor by ultrafast contrast-enhanced MR imaging. AJR Am J Roentgenol 1994; 163: 563
• 93 Aron M, Kapila K, Verma K. Carcinoid tumors 15emorr lung: a diagnostik challenge in bronchial washings. Diagn Cytopath 2004; 30: 62
• 94 Nguyen GK. Cytopathology of pulmonary carcinoid tumors in sputum and bronchial brushings. Acta Cytol 1995; 39: 1152
• 95 Todd TR, Cooper JD, Weissberg D et al. Bronchial carcinoid tumors: twenty years’ experience. Thorac Cardiovasc Surg 1980; 79: 532-535
• 96 Fink G, Krelbaum T, Yellin A et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001; 119: 1647-1651
• 97 Kurimoto N, Murayama M, Yoshioka S et al. Assessment of usefulness of endobronchial ultrasonography in determination of depth of tracheobronchial tumor invasion. Chest 1999; 115: 1500-1506
• 98 Becker H. Endobronchialer Ultraschall. Eine neue Perspektive in der Bronchologie. Ultraschal in Med 1996; 17: 106-112
• 99 Van Boxen TJ, Venmans BJ, van Mourik JC et al. Bronchoscopic treatment of intraluminal typical carcinoid: a pilot study. J Thorac Cardiovasc Surg 1998; 116: 402-406
• 100 Ryan PJ, Fogelmann I. The role of nuclear medicine in orthopaedics. Nuclear Medicine Communications 1994; 15: 341-60
• 101 Focacci C, Lattanzi R, Iadeluca ML et al. Nuclear medicine in primary bone tumors. European Journal of Radiology 1998; 27: 123-31
• 102 Krenning EP, Bakker WH, Breeman WA et al. Localization of endocrine-related tumours with a radioiodinated analogue of somatostatin. Lancet 1989; 1: 242-244
• 103 Reubi JC, Schar JC, Waser B et al. Affinity profiles for human somatostatin receptor subtypes SST1. SST5 of somatostatin tracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000; 27: 273-282
• 104 Hoefnagel CA, den Hartog Jager FC, Taal BG et al. The role of I-131-MIBG in the diagnosis and therapy of carcinoids. Eur J Nucl Med 1987; 13: 187-191
• 105 Eriksson B, Bergstrom M, Sundin A et al. The role of PET in localization of neuroendocrine and adrenocortical tumors. Ann N Y Acad Sci 2002; 970: 159-169
• 106 Baum RP, Hofmann M. Nuklearmedizinische Diagnostik neuroendokriner Tumoren. Onkologe 2004; 10: 598-610
• 107 Kowalski J, Henze M, Schuhmacher J et al. Evaluation of positron emission tomography imaging using Ga-68 DOTA-D Phe(1)-Tyr(3)-Octreotide in comparison to In-111-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol 2003; 5: 42-48
• 108 Gabriel M, Decristoforo C, Kendler D et al. 68Ga-DOTATyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med 2007; 48: 508-518
• 109 Orlefors H, Sundin A, Garske U et al. Whole-body C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. J Clin Endocrinol Metab 2005; 90: 3392-3400
• 110 Koopmans KP, Neels OC, Kema IP et al. Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography. J Clin Oncol 2008; 26: 1489-95
• 111 Kayani I. A Comparison of 68Ga-DOTATATE and 18F-FDG PET/CT in Pulmonary Neuroendocrine Tumors. J Nucl Med December 2009; 50: 1927-1932
• 112 Filosso PL, Rena O, Donati G et al. Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardiovasc Surg 2002; 123: 303-309
• 113 Cooper WA, Thourani VH, Gal AA et al. The surgical spectrum of pulmonary neuroendocrine neoplasms. Chest 2001; 119: 14-18
• 114 Martini N, Zaman MB, Bains MS et al. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994; 107: 1-6
• 115 Davila DG, Dunn WF, Tazelaar HD et al. Bronchial carcinoid tumors. Mayo Clin Proc 1993; 68: 795-803
• 116 McCaughan BC, Martini N, Bains MS. Bronchial carcinoids. Review of 124 cases. J Thorac Cardiovasc Surg 1985; 89: 8-17
• 117 Iyoda A, Hiroshima K, Nakatani Y et al. Pulmonary large cell neuroendocrine carcinoma: its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg 2007; 84: 702-707
• 118 Cardillo G, Sera F, Di Martino M et al. Bronchial carcinoid tumors: nodal status and long – term survival after resection. Ann Thorac Surg 2004; 77: 1781-1785
• 119 Garcia-Yuste M, Matilla J, Alvarez-Gago T et al. Prognostic factors in neuroendocrine lung tumors: a Spanish multicenter study. Ann Thorac Surg 2000; 70: 258-263
• 120 Schreurs A, Westermann C, van den Bosch J et al. A twenty-five-year follow-up of ninety-three resected typical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1992; 104: 1470-1475
• 121 Marty-Ane C, Costes V, Pujol J et al. Carcinoid tumors of the lung: do atypical features require aggressive management?. Ann Thorac Surg 1995; 59: 78-83
• 122 Bertoletti L, Elleuch R, Kaczmarek D et al. Bronchoscopic cryotherapy treatment of isolated endoluminal typical carcinoid tumor. Chest 2006; 130: 1405-1411
• 123 Luckraz H, Amer K, Thomas L et al. J Thorac Cardiovasc Surg 2006; 132: 113-115
• 124 Cavaliere S, Focoli P, Toninelli C. Curative bronchoscopic laser therapy for surgically resectable tracheobronchial tumors. J Bronchol 2002; 9: 90-95
• 125 Mackley HB, Videtic GM. Primary carcinoid tumors of the lung: a role for radiotherapy. Oncology (Williston Park) 2006; 20: 1537-1543
• 126 Ameer F, Zubairi AB, Fawad MU et al. Bronchial carcinoid presenting with abdominal pain. J Coll Physicians Surg Pak 2005; 15: 498-499
• 127 Chakravarthy A, Abrams RA. Radiation therapy in the management of patients with malignant carcinoid tumors. Cancer 1995; 75: 1386-1390
• 128 Yamazaki S, Sekine I, Matsuno Y et al. Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy. Lung Cancer 2005; 49: 217-223
• 129 Rossi G et al. Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFR-Alpha PDGFRß, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung. J Clin Oncol 2005; Dec 1; 23 (Suppl. 34) 8774-8785
• 130 Fujiwara Y et al. Effect of platinum combined with irinotecan or paclitaxel against large cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol 2007; 37: 482-486
• 131 Granberg D, Eriksson B, Wilander E et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Annals of Oncology 2001; 12: 1383-1391
• 132 Ekeblad S et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007; 13: 2986-2991
• 133 Niho S et al. Combination Chemotherapy with Irinotecan and Cisplatin for Large-Cell Neuroendocrine Carcinoma of the Lung: A Multicenter Phase II Study. J Thorac Oncol 2013; 8: 980-984
• 134 Pyronnet S, Bousquet C, Najib S et al. Antitumor effects of somatostatin. Mol Cell Endocrinol 2008; 286: 230-237
• 135 Woltering EA, Watson JC, Alperin-Lea RC et al. Somatostatin analogs: angiogenesis inhibitors with novel mechanisms of action. Invest New Drugs 1997; 15: 77-86
• 136 Bousquet C, Puente E, Buscail L et al. Antiproliferative effect of somatostatin and analogs. Chemotherapy 2001; 47: 30-39
• 137 Rinke A, Müller HH et al. Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in Patients with metastasic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27: 4656-4663
• 138 Tiensuu Janson EM, Ahlström H, Andersson T et al. Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours. Eur J Cancer 1992; 28: 1647-1650
• 139 Faiss S, Pape UF, Bohmig M et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumorsVthe International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003; 21: 2689-2696
• 140 Arnold R. Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroenterol 1999; May; 94 (Suppl. 05) 1381-1387
• 141 Yao JC, Phan A, Hoff PM et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 2008; 26: 1316-1323
• 142 Pavel ME, Hainsworth JD, Baudin E et al. for the RADIANT-2 Study Group. 25.11.2011 DOI: www.thelancet.com
• 143 Fazio N, Granberg D et al. Everolimus Plus Octreotide Long-Acting Repeatable in Patients With Advanced Lung Neuroendocrine Tumors Analysis of the Phase 3, Randomized, Placebo-Controlled RADIANT-2 Study. Chest 2013; 143: 955-962 doi:
• 144 Kulke MH, Lenz HJ, Meropol NJ et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008; 26: 3403-3410
• 145 Raymond E, Dahan L et al. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med 2011; 364: 1082
• 146 Kwekkeboom DJ et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26: 2124-30 doi:
• 147 Baum RP. Peptidrezeptorvermittelte Radiotherapie (PRRT) neuroendokriner Tumoren Klinische Indikationen und Erfahrung mit 90Yttrium-markierten Somatostatinanaloga. Onkologe 2004; 10: 1098-1110
• 148 Van Essen M, Krenning EP, Bakker WH et al. Peptide receptor radionuclide therapy with 177Lu- octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. Eur J Nucl Med Mol Imaging 2007; 34: 1219-1227
• 149 Van Essen M, Krenning EP, Kooij PP et al. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med 2006; 47: 1599-1606
• 150 Baum RP, Kulkarni HR. THERANOSTICS: From Molecular Imaging Using Ga-68 Labelled Tracers and PET/CT to Personalized Radionuclide Therapy – The Bad Berka Experience. Theranostics 2012; 2: 437-447 [Published online 2012 May 7]
• 151 Thomas Jr CF, Tazelaar HD, Jett JR. Typical and atypical pulmonary carcinoids: outcome in patients presenting with regional lymph node involvement. Chest 2001; 119: 1143-1150
• 152 Travis WD, Rush W, Flieder DB et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998; 22: 934-944
• 153 Merrill RM, Henson DE, Barnes M. Conditional survival among patients with carcinoma of the lung. Chest 1999; 116: 697-703
• 154 Elliott JA, Osterlind K, Hirsch FR et al. Metastatic patterns in small cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients. J Clin Oncol 1987; 5: 246-254