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01-10-2014 | Research Paper

The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm

Authors: D. Kaemmerer, N. Posorski, F. von Eggeling, G. Ernst, D. Hörsch, R. P. Baum, V. Prasad, R. Langer, I. Esposito, G. Klöppel, S. Sehner, T. Knösel, M. Hommann

Published in: Clinical & Experimental Metastasis | Issue 7/2014

Abstract

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.

Ettinger DS, Agulnik M, Cates JM et al (2011) Occult primary. J Natl Compr Cancer Netw 9(12):1358–1395

Pavlidis N, Pentheroudakis G (2010) Cancer of unknown primary site: 20 questions to be answered. Ann Oncol 21(Suppl 7):303–307

Morris GJ, Greco FA, Hainsworth JD et al (2010) Cancer of unknown primary site. Semin Oncol 37(2):71–79PubMedCrossRef

Balaker AE, Abemayor E, Elashoff D et al (2012) Cancer of unknown primary: does treatment modality make a difference? Laryngoscope 122(6):1279–1282PubMedCrossRef

Stoyianni A, Pentheroudakis G, Pavlidis N (2011) Neuroendocrine carcinoma of unknown primary: a systematic review of the literature and a comparative study with other neuroendocrine tumors. Cancer Treat Rev 37(5):358–365PubMedCrossRef

Prasad V, Ambrosini V, Hommann M et al (2010) Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68) Ga-DOTA-NOC receptor PET/CT. Eur J Nucl Med Mol Imaging 37(1):67–77PubMedCrossRef

Melle C, Ernst G, Schimmel B et al (2008) Colon-derived liver metastasis, colorectal carcinoma, and hepatocellular carcinoma can be discriminated by the Ca(2+)-binding proteins S100A6 and S100A11. PLoS ONE 3(12):e3767PubMedCrossRefPubMedCentral

Giordano TJ, Shedden KA, Schwartz DR et al (2001) Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles. Am J Pathol 159(4):1231–1238PubMedCrossRefPubMedCentral

Horlings HM, van Laar RK, Kerst JM et al (2008) Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 26(27):4435–4441PubMedCrossRef

10.

Capurso G, Lattimore S, Crnogorac-Jurcevic T et al (2006) Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr Relat Cancer 13(2):541–558PubMedCrossRef

11.

Posorski N, Kaemmerer D, Ernst G et al (2011) Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases. Clin Exp Metastasis 28(7):637–647PubMedCrossRef

12.

Hainsworth JD, Rubin MS, Spigel DR et al (2013) Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol 31(2):217–223PubMedCrossRef

13.

Melle C, Ernst G, Schimmel B et al (2003) Biomarker discovery and identification in laser microdissected head and neck squamous cell carcinoma with ProteinChip technology, two-dimensional gel electrophoresis, tandem mass spectrometry, and immunohistochemistry. Mol Cell Proteomics 2(7):443–452PubMed

14.

Melle C, Ernst G, Schimmel B et al (2004) A technical triade for proteomic identification and characterization of cancer biomarkers. Cancer Res 64(12):4099–4104PubMedCrossRef

15.

Knosel T, Chen Y, Altendorf-Hofmann A et al (2012) High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event. J Cancer Res Clin Oncol 138(3):397–403PubMedCrossRef

16.

Torsten Hothorn KHaAZ (2006) Unbiased recursive partitioning: a conditional inference framework. J Comput Graph Stat 15(3):651–674CrossRef

17.

R Development Core Team (2010) R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing

18.

Ambrosini V, Campana D, Nanni C et al (2012) Is (6) (8)Ga-DOTA-NOC PET/CT indicated in patients with clinical, biochemical or radiological suspicion of neuroendocrine tumour? Eur J Nucl Med Mol Imaging 39(8):1278–1283PubMedCrossRef

19.

Baum RP, Prasad V, Hommann M et al (2008) Receptor PET/CT imaging of neuroendocrine tumors. Recent Results Cancer Res 170:225–242PubMedCrossRef

20.

Baum RP, Kulkarni HR, Carreras C (2012) Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms. Semin Nucl Med 42(3):190–207PubMedCrossRef

21.

Savelli G, Lucignani G, Seregni E et al (2004) Feasibility of somatostatin receptor scintigraphy in the detection of occult primary gastro-entero-pancreatic (GEP) neuroendocrine tumours. Nucl Med Commun 25(5):445–449PubMedCrossRef

22.

Begum N, Hubold C, Buchmann I et al (2013) Diagnostics and therapy for neuroendocrine neoplasia of an unknown primary–a plea for open exploration. Zentralbl Chir 139(3):284–291PubMedCrossRef

23.

Bridgewater J, van Laar R, Floore A et al (2008) Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer 98(8):1425–1430PubMedCrossRefPubMedCentral

24.

Shedden K, Taylor JM, Enkemann SA et al (2008) Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 14(8):822–827PubMedCrossRefPubMedCentral

25.

Ramaswamy S, Tamayo P, Rifkin R et al (2001) Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci USA 98(26):15149–15154PubMedCrossRefPubMedCentral

26.

Alizadeh AA, Ross DT, Perou CM et al (2001) Towards a novel classification of human malignancies based on gene expression patterns. J Pathol 195(1):41–52PubMedCrossRef

27.

Su AI, Welsh JB, Sapinoso LM et al (2001) Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 61(20):7388–7393PubMed

28.

Musella V, Verderio P, Reid JF et al (2013) Effects of warm ischemic time on gene expression profiling in colorectal cancer tissues and normal mucosa. PLoS ONE 8(1):e53406PubMedCrossRefPubMedCentral

29.

Bubendorf L, Nocito A, Moch H et al (2001) Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol 195(1):72–79PubMedCrossRef

30.

Chan ES, Alexander J, Swanson PE et al (2012) PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms. Am J Surg Pathol 36(5):737–743PubMedCrossRef

31.

Agaimy A, Erlenbach-Wunsch K, Konukiewitz B et al (2013) ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin. Mod Pathol 26(7):995–1003PubMedCrossRef

Title: The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm
Authors: D. Kaemmerer
N. Posorski
F. von Eggeling
G. Ernst
D. Hörsch
R. P. Baum
V. Prasad
R. Langer
I. Esposito
G. Klöppel
S. Sehner
T. Knösel
M. Hommann
Publication date: 01-10-2014
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 7/2014
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-014-9672-3

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