Virchows Archiv

, 459:399 | Cite as

Specific expression of ZO-1 and N-cadherin in rosette structures of various tumors: possible recapitulation of neural tube formation in embryogenesis and utility as a potentially novel immunohistochemical marker of rosette formation in pulmonary neuroendocrine tumors

  • Kaishi Satomi
  • Yukio Morishita
  • Shingo Sakashita
  • Yuzuru Kondou
  • Shuichiroh Furuya
  • Yuko Minami
  • Masayuki Noguchi
Original Article


Neuroendocrine tumors can develop in various organs. All of these tumors are designated on the basis of their morphologic characteristics evident by light microscopy, and by immunohistochemistry for antigens such as synaptophysin, chromogranin-A, and CD56/NCAM. In the present study, we attempted to demonstrate the localization of Zonula occludens-1 (ZO-1) and N-cadherin in rosette structures of neuroendocrine tumors using immunohistochemistry and to clarify their specific distribution in rosettes in human pulmonary neuroendocrine tumors in comparison with various types of adenocarcinoma. Among 40 neuroendocrine tumors of the lung examined, 18 cases (45%) and 22 cases (55%) were positive for ZO-1 and N-cadherin, respectively. In addition, we divided the cases into two types: 16 cases of Flexner-type tumor and 24 cases of Homer–Wright-type tumor. We then determined the Rosette Index (RoI; the percentage fraction of rosette structures positive for ZO-1 or N-cadherin among the total number of rosette structures). The Flexner-type neuroendocrine tumors showed significantly higher levels of RoI in ZO-1 than the Homer–Wright-type neuroendocrine tumors (median; 38.8% vs 0%, p < 0.001). On the other hand, N-cadherin and ZO-1 were hardly detected in tubular adenocarcinomas in various organs, and their immunoreactivities differed significantly between adenocarcinoma and pulmonary neuroendocrine tumor (ZO-1, mean 0.23% vs 18%, p < 0.0001; N-cadherin, mean 0% vs 33%, p < 0.0001). In conclusion, expression of ZO-1 and N-cadherin may reflect the mechanisms leading to rosette formation in neuroendocrine tumors, which possibly recapitulate neural tube formation in embryogenesis and could represent a specific immunohistochemical marker for neuroendocrine carcinoma of the lung.


ZO-1 N-cadherin Neuroendocrine carcinoma Endocrine carcinoma Carcinoid Lung 


Conflict of interest statement

We declare that we have no conflicts of interest.


  1. 1.
    Colby TV KM, Travis WD. Large cell neuroendocrine carcinoma:, In: Colby TV KM, Travis WD, editors (1995) Tumors of the lower respiratory tract. Armed Forces Institute of Pathology:248–257Google Scholar
  2. 2.
    Travis WD BE, Müller-Hermelink HK, Harris CC editor (2004) Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. World Health Organization Classification of Tumours 10Google Scholar
  3. 3.
    Arrigoni MG, Woolner LB, Bernatz PE (1972) Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 64(3):413–421PubMedGoogle Scholar
  4. 4.
    Carretta A, Ceresoli GL, Arrigoni G, Canneto B, Reni M, Cigala C, Zannini P (2000) Diagnostic and therapeutic management of neuroendocrine lung tumors: a clinical study of 44 cases. Lung Cancer 29(3):217–225PubMedCrossRefGoogle Scholar
  5. 5.
    Garcia-Yuste M, Matilla JM, Alvarez-Gago T, Duque JL, Heras F, Cerezal LJ, Ramos G (2000) Prognostic factors in neuroendocrine lung tumors: a Spanish Multicenter Study. Spanish Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR). Ann Thorac Surg 70(1):258–263PubMedCrossRefGoogle Scholar
  6. 6.
    Gould VE, Linnoila RI, Memoli VA, Warren WH (1983) Neuroendocrine cells and neuroendocrine neoplasms of the lung. Pathol Annu 18(Pt 1):287–330PubMedGoogle Scholar
  7. 7.
    Jiang SX, Kameya T, Shoji M, Dobashi Y, Shinada J, Yoshimura H (1998) Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases. Am J Surg Pathol 22(5):526–537PubMedCrossRefGoogle Scholar
  8. 8.
    Naranjo Gomez JM, Gomez Roman JJ Behaviour and survival of high-grade neuroendocrine carcinomas of the lung. Respir Med 104 (12):1929–1936Google Scholar
  9. 9.
    Peng WX, Sano T, Oyama T, Kawashima O, Nakajima T (2005) Large cell neuroendocrine carcinoma of the lung: a comparison with large cell carcinoma with neuroendocrine morphology and small cell carcinoma. Lung Cancer 47(2):225–233PubMedCrossRefGoogle Scholar
  10. 10.
    Takei H, Asamura H, Maeshima A, Suzuki K, Kondo H, Niki T, Yamada T, Tsuchiya R, Matsuno Y (2002) Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases. J Thorac Cardiovasc Surg 124(2):285–292PubMedCrossRefGoogle Scholar
  11. 11.
    Warren WH, Faber LP, Gould VE (1989) Neuroendocrine neoplasms of the lung. A clinicopathologic update. J Thorac Cardiovasc Surg 98(3):321–332PubMedGoogle Scholar
  12. 12.
    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):819–825PubMedGoogle Scholar
  13. 13.
    Warren WH, Memoli VA, Gould VE (1988) Well differentiated and small cell neuroendocrine carcinomas of the lung. Two related but distinct clinicopathologic entities. Virchows Arch B Cell Pathol Incl Mol Pathol 55(5):299–310PubMedGoogle Scholar
  14. 14.
    Kloppel G (2007) Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 21(1):15–31PubMedCrossRefGoogle Scholar
  15. 15.
    Wippold FJ 2nd, Perry A (2006) Neuropathology for the neuroradiologist: rosettes and pseudorosettes. AJNR Am J Neuroradiol 27(3):488–492PubMedGoogle Scholar
  16. 16.
    Koch P, Opitz T, Steinbeck JA, Ladewig J, Brustle O (2009) A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci U S A 106(9):3225–3230PubMedCrossRefGoogle Scholar
  17. 17.
    Elkabetz Y, Panagiotakos G, Al Shamy G, Socci ND, Tabar V, Studer L (2008) Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev 22(2):152–165PubMedCrossRefGoogle Scholar
  18. 18.
    Aaku-Saraste E, Hellwig A, Huttner WB (1996) Loss of occludin and functional tight junctions, but not ZO-1, during neural tube closure–remodeling of the neuroepithelium prior to neurogenesis. Dev Biol 180(2):664–679PubMedCrossRefGoogle Scholar
  19. 19.
    Nishimura T, Takeichi M (2008) Shroom3-mediated recruitment of Rho kinases to the apical cell junctions regulates epithelial and neuroepithelial planar remodeling. Development 135(8):1493–1502PubMedCrossRefGoogle Scholar
  20. 20.
    Hatta K, Takeichi M (1986) Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development. Nature 320(6061):447–449PubMedCrossRefGoogle Scholar
  21. 21.
    Hatta K, Takagi S, Fujisawa H, Takeichi M (1987) Spatial and temporal expression pattern of N-cadherin cell adhesion molecules correlated with morphogenetic processes of chicken embryos. Dev Biol 120(1):215–227PubMedCrossRefGoogle Scholar
  22. 22.
    Zynger DL, Dimov ND, Ho LC, Laskin WB, Yeldandi AV (2008) Differential expression of neural-cadherin in pulmonary epithelial tumours. Histopathology 52(3):348–354PubMedCrossRefGoogle Scholar
  23. 23.
    Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA (1986) Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103(3):755–766PubMedCrossRefGoogle Scholar
  24. 24.
    Itoh M, Nagafuchi A, Yonemura S, Kitani-Yasuda T, Tsukita S, Tsukita S (1993) The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy. J Cell Biol 121(3):491–502PubMedCrossRefGoogle Scholar
  25. 25.
    Tsukita S, Yamazaki Y, Katsuno T, Tamura A, Tsukita S (2008) Tight junction-based epithelial microenvironment and cell proliferation. Oncogene 27(55):6930–6938PubMedCrossRefGoogle Scholar
  26. 26.
    Katsuno T, Umeda K, Matsui T, Hata M, Tamura A, Itoh M, Takeuchi K, Fujimori T, Nabeshima Y, Noda T, Tsukita S, Tsukita S (2008) Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol Biol Cell 19(6):2465–2475PubMedCrossRefGoogle Scholar
  27. 27.
    Palatinus JA, O'Quinn MP, Barker RJ, Harris BS, Jourdan J, Gourdie RG ZO-1 determines adherens and gap junction localization at intercalated disks. Am J Physiol Heart Circ Physiol 300 (2):H583-594Google Scholar
  28. 28.
    Smalley KS, Brafford P, Haass NK, Brandner JM, Brown E, Herlyn M (2005) Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion. Am J Pathol 166(5):1541–1554PubMedCrossRefGoogle Scholar
  29. 29.
    Wang Y, Zhou J, Zeng F, Huang Y, Zhou S, Liu X [Expression and clinical significance of ZO-1 in patients with non-small cell lung cancer]. Zhongguo Fei Ai Za Zhi 14 (2):146–150Google Scholar
  30. 30.
    Ohtani S, Terashima M, Satoh J, Soeta N, Saze Z, Kashimura S, Ohsuka F, Hoshino Y, Kogure M, Gotoh M (2009) Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival. Gastric Cancer 12(1):43–51PubMedCrossRefGoogle Scholar
  31. 31.
    Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, Yokose T, Jiang SX, Inoue T, Nakagawa K, Tajima K, Nagai K (2006) Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 24(1):70–76PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Kaishi Satomi
    • 1
  • Yukio Morishita
    • 1
  • Shingo Sakashita
    • 1
  • Yuzuru Kondou
    • 2
  • Shuichiroh Furuya
    • 2
  • Yuko Minami
    • 1
  • Masayuki Noguchi
    • 1
  1. 1.Department of Diagnostic Pathology, Graduate School of Comprehensive Human SciencesUniversity of TsukubaTsukuba-shiJapan
  2. 2.Department of PathologyTsukuba University HospitalTsukuba-shiJapan

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