Endocrine Pathology

, Volume 30, Issue 1, pp 35–42 | Cite as

Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites

  • Madhuchhanda RoyEmail author
  • Darya G. Buehler
  • Ranran Zhang
  • Michael L. Schwalbe
  • Rebecca M. Baus
  • M. Shahriar Salamat
  • Ricardo V. Lloyd
  • Jason N. Rosenbaum


Insulinoma-associated protein 1 (INSM1) and orthopedia homeobox (OTP) are transcription factors that play a critical role in neuroendocrine (NE) and neuroepithelial cell development. INSM1 has been identified in multiple tumors of NE or neuroepithelial origin, whereas OTP expression has been mainly studied in NE tumors of pulmonary origin. Expression of OTP appears to correlate with poorer prognosis in pulmonary carcinoids; however, its expression patterns in other NE/neuroepithelial tumors need further investigation. Here, we assessed the diagnostic utility of INSM1 and OTP in tumors with NE differentiation at relatively uncommon sites including prostate, breast, and tumors of gynecologic origin. Thirty-two formalin-fixed, paraffin-embedded cases were used to construct a tissue microarray. Immunohistochemistry for INSM1 and OTP was performed and scored semi-quantitatively. INSM1 was diffusely expressed in 60% of gynecologic tumors, 71.4% of mammary carcinoma, and 25% of prostate adenocarcinoma with NE differentiation. Diffuse expression of OTP was detected in 50% of prostate adenocarcinoma with NE differentiation and 100% neuroendocrine carcinoma of the ovary. Immunostain for achaete-scute homolog 1, chromogranin, synaptophysin, and CD56 supported the NE and/or neuroepithelial differentiation of the tumors. In summary, INSM1 is expressed in most of the tumors with NE and neuroepithelial differentiation in this study, confirming the diagnostic utility of INSM1 as a novel and sensitive marker of NE/neuroepithelial differentiation. The expression of OTP in some NE tumors outside of lung expands the spectrum of tumors that may express this biomarker and should be considered when working up a NE tumor of unknown primary site.


Insulinoma-associated protein 1 (INSM1) Orthopedia homeobox (OTP) Ovarian carcinoma with neuroendocrine differentiation Breast carcinoma with neuroendocrine differentiation Prostate carcinoma with neuroendocrine differentiation 



The authors thank members of the TRIP Laboratory at UW SMPH.

Funding Information

The study was supported by an award from UW Carbone Cancer Center Neuroendocrine Cancer Research Task Force and the Aly Wolff Memorial Fund for Neuroendocrine Carcinoma Research.


  1. 1.
    Acampora, D., Postiglione M.P., Avantaggiato V., di Bonito M., Simeone A., The role of Otx and Otp genes in brain development. Int J Dev Biol, 2000. 44(6): p. 669–677.PubMedGoogle Scholar
  2. 2.
    Breslin, M.B., Zhu M., Notkins A.L., Lan M.S., Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence. Nucleic Acids Res, 2002. 30(4): p. 1038–1045.CrossRefGoogle Scholar
  3. 3.
    Lan, M.S. and M.B. Breslin, Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation. FASEB J, 2009. 23(7): p. 2024–2033.CrossRefGoogle Scholar
  4. 4.
    Liu, W.D., Wang H.W., Muguira M., Breslin M.B., Lan M.S., INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. Biochem J, 2006. 397(1): p. 169–177.CrossRefGoogle Scholar
  5. 5.
    Jia, S., H. Wildner, and C. Birchmeier, Insm1 controls the differentiation of pulmonary neuroendocrine cells by repressing Hes1. Dev Biol, 2015. 408(1): p. 90–98.CrossRefGoogle Scholar
  6. 6.
    Rosenbaum, J.N., Guo Z., Baus R.M., Werner H., Rehrauer W.M., Lloyd R.V., INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms. Am J Clin Pathol, 2015. 144(4): p. 579–591.CrossRefGoogle Scholar
  7. 7.
    Hanley, K.Z., Dureau Z.J., Cohen C., Shin D.M., Owonikoko T.K., Sica G.L., Orthopedia homeobox is preferentially expressed in typical carcinoids of the lung. Cancer Cytopathol, 2018, 126, 236, 242.CrossRefGoogle Scholar
  8. 8.
    Papaxoinis, G., Nonaka D., O’Brien C., Sanderson B., Krysiak P., Mansoor W., Prognostic Significance of CD44 and Orthopedia Homeobox Protein (OTP) Expression in Pulmonary Carcinoid Tumours. Endocr Pathol, 2017. 28(1): p. 60–70.CrossRefGoogle Scholar
  9. 9.
    Pedersen, N., Pedersen M.W., Lan M.S., Breslin M.B., Poulsen H.S., The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer. Cancer Gene Ther, 2006. 13(4): p. 375–384.CrossRefGoogle Scholar
  10. 10.
    Fujino, K., Motooka Y., Hassan W.A., Ali Abdalla M.O., Sato Y., Kudoh S., Hasegawa K., Niimori-Kita K., Kobayashi H., Kubota I., Wakimoto J., Suzuki M., Ito T., Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer. Am J Pathol, 2015. 185(12): p. 3164–3177.CrossRefGoogle Scholar
  11. 11.
    Terry, S. and H. Beltran, The many faces of neuroendocrine differentiation in prostate cancer progression. Front Oncol, 2014. 4: p. 60.CrossRefGoogle Scholar
  12. 12.
    Fine, S.W., Neuroendocrine tumors of the prostate. Modern Pathology, 2018. 31: p. S122, S132.CrossRefGoogle Scholar
  13. 13.
    Rosen, L.E. and P. Gattuso, Neuroendocrine Tumors of the Breast. Arch Pathol Lab Med, 2017. 141(11): p. 1577–1581.CrossRefGoogle Scholar
  14. 14.
    Park, Y.M., Wu Y., Wei W., Yang W.T., Primary Neuroendocrine Carcinoma of the Breast: Clinical, Imaging, and Histologic Features. American Journal of Roentgenology, 2014. 203(2): p. W221-W230.CrossRefGoogle Scholar
  15. 15.
    Tang, F., Wei B., Tian Z., Gilcrease M.Z., Huo L., Albarracin C.T., Resetkova E., Zhang H., Sahin A., Chen J., Bu H., Abraham S., Wu Y., Invasive mammary carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges. Histopathology, 2011. 59(1): p. 106–115.CrossRefGoogle Scholar
  16. 16.
    Wei, B., Ding T., Xing Y., Wei W., Tian Z., Tang F., Abraham S., Nayeemuddin K., Hunt K., Wu Y., Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer, 2010. 116(19): p. 4463–4473.CrossRefGoogle Scholar
  17. 17.
    Zhu, Y., Li Q., Gao J., He Z., Sun R., Shen G., Zhang H., Xia W., Xu J., Clinical features and treatment response of solid neuroendocrine breast carcinoma to adjuvant chemotherapy and endocrine therapy. Breast J, 2013. 19(4): p. 382–387.CrossRefGoogle Scholar
  18. 18.
    Cloyd, J.M., Yang R.L., Allison K.H., Norton J.A., Hernandez-Boussard T., Wapnir I.L., Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast. Breast Cancer Res Treat, 2014. 148(3): p. 637–644.CrossRefGoogle Scholar
  19. 19.
    Gardner, G.J., D. Reidy-Lagunes, and P.A. Gehrig, Neuroendocrine tumors of the gynecologic tract: A Society of Gynecologic Oncology (SGO) clinical document. Gynecologic Oncology, 2011. 122(1): p. 190–198.CrossRefGoogle Scholar
  20. 20.
    Rouzbahman, M. and B. Clarke, Neuroendocrine tumors of the gynecologic tract: select topics. Semin Diagn Pathol, 2013. 30(3): p. 224–233.CrossRefGoogle Scholar
  21. 21.
    Kuji, S., Watanabe R., Sato Y., Iwata T., Hirashima Y., Takekuma M., Ito I., Abe M., Nagashio R., Omae K., Aoki D., Kameya T., A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases. Gynecologic Oncology, 2017. 144(2): p. 384–390.CrossRefGoogle Scholar
  22. 22.
    Eichhorn, J.H., R.H. Young, and R.E. Scully, Primary ovarian small cell carcinoma of pulmonary type. A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases. Am J Surg Pathol, 1992. 16(10): p. 926–938.CrossRefGoogle Scholar
  23. 23.
    Veras, E., Deavers M.T., Silva E.G., Malpica A., Ovarian nonsmall cell neuroendocrine carcinoma: a clinicopathologic and immunohistochemical study of 11 cases. Am J Surg Pathol, 2007. 31(5): p. 774–782.CrossRefGoogle Scholar
  24. 24.
    Clarke, B.A., Witkowski L., Ton Nu T.N., Shaw P.A., Gilks C.B., Huntsman D., Karnezis A.N., Sebire N., Lamovec J., Roth L.M., Stewart C.J.R., Hasselblatt M., Foulkes W.D., McCluggage W.G., Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics. Histopathology, 2016. 69(5): p. 727–738.CrossRefGoogle Scholar
  25. 25.
    Alwazzan, A.B., Popowich S., Dean E., Robinson C., Lotocki R., Altman A.D., Pure Immature Teratoma of the Ovary in Adults: Thirty-Year Experience of a Single Tertiary Care Center. Int J Gynecol Cancer, 2015. 25(9): p. 1616–1622.CrossRefGoogle Scholar
  26. 26.
    Nonaka, D., G. Papaxoinis, and W. Mansoor, Diagnostic Utility of Orthopedia Homeobox (OTP) in Pulmonary Carcinoid Tumors. Am J Surg Pathol, 2016. 40(6): p. 738–744.CrossRefGoogle Scholar
  27. 27.
    Xue, W., et al., Insulinoma-associated protein 1 is a novel sensitive and specific marker for small cell carcinoma of the prostate. Hum Pathol, 2018.Google Scholar
  28. 28.
    Vora, M., Lacour R.A., Black D.R., Turbat-Herrera E.A., Gu X., Neuroendocrine tumors in the ovary: histogenesis, pathologic differentiation, and clinical presentation. Arch Gynecol Obstet, 2016. 293(3): p. 659–665.CrossRefGoogle Scholar
  29. 29.
    Vance, R.P., Geisinger K.R., Randall M.B., Marshall R.B., Immature neural elements in immature teratomas. An immunohistochemical and ultrastructural study. Am J Clin Pathol, 1988. 90(4): p. 397–411.CrossRefGoogle Scholar
  30. 30.
    La Rosa, S., et al., Achaete-scute homolog 1 as a marker of poorly differentiated neuroendocrine carcinomas of different sites: a validation study using immunohistochemistry and quantitative real-time polymerase chain reaction on 335 cases. Hum Pathol, 2013. 44(7): p. 1391–1399.CrossRefGoogle Scholar
  31. 31.
    Chen, C., M.B. Breslin, and M.S. Lan, Sonic hedgehog signaling pathway promotes INSM1 transcription factor in neuroendocrine lung cancer. Cell Signal, 2018. 46: p. 83–91.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Wisconsin Hospital and ClinicsMadisonUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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