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Virchows Archiv
Published in: Virchows Archiv 3/2012

01-03-2012 | Original Article

Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach

Authors: Tina Zahel, Sabine Krysa, Esther Herpel, Albrecht Stenzinger, Benjamin Goeppert, Peter Schirmacher, Hans Hoffmann, Philipp A. Schnabel, Arne Warth

Published in: Virchows Archiv | Issue 3/2012

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Abstract

Pulmonary carcinoids (PC) are separated into typical (TC) and atypical carcinoids (ATC). However, the biological behavior cannot be reliably predicted, and in small biopsies differential diagnosis can be challenging. To provide a basis for a grading approach, we analyzed mitoses and the proliferative index (PI; Ki-67) of 200 PC specimens (TC: n = 114; ATC: n = 86). To define suitable diagnostic and to screen for putative therapeutic markers, CD56, CD57, CD99, CD117, TTF-1, synaptophysin, chromogranin A, CK 18, KL-1, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her-2/neu), somatostatin receptor subtype 2A (SSTR2A), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC-1) expression was analyzed. A combination of synaptophysin and cytokeratins is the most sensitive marker panel for PC with unclear histomorphology. Predictive phenotyping revealed that SSTR2A is expressed in >80% of all PC and may be used both, as a diagnostic marker for imaging approaches and as a predictive marker for octreotide-based therapies. We introduced a grading system distinguishing between PC with low and highly aggressive biological behavior similar to the grading system for gastrointestinal neuroendocrine tumors. The system is superior to the classical separation into TC and ATC. This study indicates that PI in addition to mitotic count may improve prediction of the biological behavior of PC and should be validated in prospective studies.
Literature
1.
2.
Travis WD (ed) (2004) WHO classification of tumours: pathology and genetics of tumours of the lung, pleura, thymus and heart, 1st edn. IARC, Lyon
3.
4.
Warth A, Herpel E, Krysa S, Hoffmann H, Schnabel PA, Schirmacher P, Mechtersheimer G, Blaker H (2009) Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of metastatic potential. Exp Mol Med 41(5):349–353. doi:10.​3858/​emm.​2009.​41.​5.​039 PubMedCrossRef
5.
Ducrocq X, Thomas P, Massard G, Barsotti P, Giudicelli R, Fuentes P, Wihlm JM (1998) Operative risk and prognostic factors of typical bronchial carcinoid tumors. Ann Thorac Surg 65(5):1410–1414. doi:S000349759800083​6 PubMedCrossRef
6.
Warren WH, Gould VE, Faber LP, Kittle CF, Memoli VA (1985) Neuroendocrine neoplasms of the bronchopulmonary tract. A classification of the spectrum of carcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg 89(6):819–825PubMed
7.
Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M, Kramer MR (2001) Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 119(6):1647–1651PubMedCrossRef
8.
9.
Hage R, de la Riviere AB, Seldenrijk CA, van den Bosch JM (2003) Update in pulmonary carcinoid tumors: a review article. Ann Surg Oncol 10(6):697–704PubMedCrossRef
10.
Warth A, Krysa S, Zahel T, Hoffmann H, Schirmacher P, Schnabel PA, Herpel E (2010) S100 protein positive sustentacular cells in pulmonary carcinoids and thoracic paragangliomas: differential diagnostic and prognostic evaluation. Pathologe 31(5):379–384. doi:10.​1007/​s00292-010-1293-2 PubMedCrossRef
11.
12.
Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449(4):395–401. doi:10.​1007/​s00428-006-0250-1 PubMedCrossRef
13.
Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA, Koss MN (1998) Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22(8):934–944PubMedCrossRef
14.
Skuladottir H, Hirsch FR, Hansen HH, Olsen JH (2002) Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. Lung Cancer 37(2):127–135PubMedCrossRef
15.
Klimstra DS, Modlin IR, Adsay NV, Chetty R, Deshpande V, Gonen M, Jensen RT, Kidd M, Kulke MH, Lloyd RV, Moran C, Moss SF, Oberg K, O’Toole D, Rindi G, Robert ME, Suster S, Tang LH, Tzen CY, Washington MK, Wiedenmann B, Yao J (2010) Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 34(3):300–313. doi:10.​1097/​PAS.​0b013e3181ce1447​ PubMedCrossRef
16.
Oliveira AM, Tazelaar HD, Myers JL, Erickson LA, Lloyd RV (2001) Thyroid transcription factor-1 distinguishes metastatic pulmonary from well-differentiated neuroendocrine tumors of other sites. Am J Surg Pathol 25(6):815–819PubMedCrossRef
17.
Folpe AL, Gown AM, Lamps LW, Garcia R, Dail DH, Zarbo RJ, Schmidt RA (1999) Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors. Mod Pathol 12(1):5–8PubMed
18.
Sturm N, Rossi G, Lantuejoul S, Papotti M, Frachon S, Claraz C, Brichon PY, Brambilla C, Brambilla E (2002) Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids. Hum Pathol 33(2):175–182PubMedCrossRef
19.
Du EZ, Goldstraw P, Zacharias J, Tiffet O, Craig PJ, Nicholson AG, Weidner N, Yi ES (2004) TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location. Hum Pathol 35(7):825–831PubMedCrossRef
20.
La Rosa S, Chiaravalli AM, Placidi C, Papanikolaou N, Cerati M, Capella C (2010) TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies. Virchows Arch 457(4):497–507. doi:10.​1007/​s00428-010-0954-0 PubMedCrossRef
21.
Rindi G, Kloppel G, Couvelard A, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2007) TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 451(4):757–762. doi:10.​1007/​s00428-007-0452-1 PubMedCrossRef
22.
Mengel M, von Wasielewski R, Wiese B, Rudiger T, Muller-Hermelink HK, Kreipe H (2002) Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. J Pathol 198(3):292–299. doi:10.​1002/​path.​1218 PubMedCrossRef
23.
24.
Dhall D (2009) Interobserver variability in assessing Ki67 proliferative index in gastrointestinal well-differentiated neuroendocrine neoplasms. Mod Pathol 22:116A
25.
26.
Righi L, Volante M, Tavaglione V, Bille A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M (2010) Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol 21(3):548–555. doi:10.​1093/​annonc/​mdp334 PubMedCrossRef
27.
Volante M, Brizzi MP, Faggiano A, La Rosa S, Rapa I, Ferrero A, Mansueto G, Righi L, Garancini S, Capella C, De Rosa G, Dogliotti L, Colao A, Papotti M (2007) Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol 20(11):1172–1182. doi:10.​1038/​modpathol.​3800954 PubMedCrossRef
28.
Rusch VW, Klimstra DS, Venkatraman ES (1996) Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg 62(3):798–809, discussion 809-710PubMedCrossRef
29.
30.
Ceppi P, Volante M, Ferrero A, Righi L, Rapa I, Rosas R, Berruti A, Dogliotti L, Scagliotti GV, Papotti M (2008) Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. Clin Cancer Res 14(4):1059–1064. doi:10.​1158/​1078-0432.​CCR-07-1513 PubMedCrossRef
31.
Oberg K, Norheim I, Theodorsson E (1991) Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide. Acta Oncol 30(4):503–507PubMedCrossRef
32.
33.
Nilsson O, Kolby L, Wangberg B, Wigander A, Billig H, William-Olsson L, Fjalling M, Forssell-Aronsson E, Ahlman H (1998) Comparative studies on the expression of somatostatin receptor subtypes, outcome of octreotide scintigraphy and response to octreotide treatment in patients with carcinoid tumours. Br J Cancer 77(4):632–637PubMedCrossRef
34.
Haug AR, Auernhammer CJ, Wangler B, Schmidt GP, Uebleis C, Goke B, Cumming P, Bartenstein P, Tiling R, Hacker M (2010) 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J Nucl Med 51(9):1349–1356. doi:10.​2967/​jnumed.​110.​075002 PubMedCrossRef
35.
Bajetta E, Catena L, Procopio G, De Dosso S, Bichisao E, Ferrari L, Martinetti A, Platania M, Verzoni E, Formisano B, Bajetta R (2007) Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother Pharmacol 59(5):637–642. doi:10.​1007/​s00280-006-0306-6 PubMedCrossRef
36.
37.
38.
Righi L, Papotti MG, Ceppi P, Bille A, Bacillo E, Molinaro L, Ruffini E, Scagliotti GV, Selvaggi G (2010) Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. J Clin Oncol 28(9):1534–1539. doi:10.​1200/​JCO.​2009.​25.​9275 PubMedCrossRef
Metadata
Title
Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach
Authors
Tina Zahel
Sabine Krysa
Esther Herpel
Albrecht Stenzinger
Benjamin Goeppert
Peter Schirmacher
Hans Hoffmann
Philipp A. Schnabel
Arne Warth
Publication date
01-03-2012
Publisher
Springer-Verlag
Published in
Virchows Archiv / Issue 3/2012
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-012-1194-2

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