Pathology & Oncology Research

, Volume 24, Issue 2, pp 277–282 | Cite as

TFF3 Expression as Stratification Marker in Borderline Epithelial Tumors of the Ovary

  • Ahmed El-Balat
  • Iryna Schmeil
  • Thomas Karn
  • Sven Becker
  • Nicole Sänger
  • Uwe Holtrich
  • Ruza Arsenic
Original Article


Borderline tumors (BOT) of the ovary account for 10% to 20% of ovarian neoplasms. Like ovarian cancer, BOT encompass several different histological subtypes (serous, mucinous, endometrioid, clear cell, transitional cell and mixed) with serous (SBOT) and mucinous (MBOT) the most common. Current hypotheses suggest low-grade serous carcinoma may develop in a stepwise fashion from SBOT whereas the majority of high grade serous carcinomas develop rapidly presumably from inclusion cysts or ovarian surface epithelium. The pathogenesis of mucinous ovarian tumors is still puzzling. Molecular markers could help to better define relationships between such entities. Trefoil factor-3 (TFF3) is an estrogen-regulated gene associated with prognosis in different types of cancer. It has also been included in a recent marker panel predicting subtypes of ovarian carcinoma. We analyzed the expression of TFF3 by immunohistochemistry in a cohort of 137 BOT and its association with histopathological features. Overall expression rate of TFF3 was 21.9%. None of the BOT with serous and endometrioid histology displayed strong TFF3 expression. On the other hand, TFF3 was highly expressed in 61.4% of MBOT cases and 33.3% of BOT with mixed histology (P < 0.001) suggesting a potential function of the protein in that subtypes. Associations of TFF3 expression with FIGO stage and micropapillary pattern were significant in the overall cohort but confounded by their correlation with histological subtypes. The highly specific expression of TFF3 in MBOT may help to further clarify potential relationships of tumors with mucinous histology and warrants further studies.


Ovarian cancer Borderline tumors Histological subtypes Prognosis 



We thank Katerina Brinkmann and Samira Adel for expert technical assistance. Furthermore, the authors thank Prof. Dr. M.-L. Hansmann, Senckenberg Institute of Pathology, University of Frankfurt, for providing formalin-fixed, paraffin-embedded tissue samples. This work was supported by grants from the Margarete Bonifer-Stiftung, Bad Soden, the H.W. & J. Hector-Stiftung, Mannheim (grant number: M67), and the BANSS-Stiftung, Biedenkopf.

Compliance with Ethical Standards

Conflict of Interest

The authors have declared no conflicts of interest.

Supplementary material

12253_2017_240_MOESM1_ESM.pdf (189 kb)
Supplementary Fig S1 (PDF 189 kb)


  1. 1.
    Shih IM, Kurman RJ (2005) Molecular pathogenesis of ovarian borderline tumors: new insights and old challenges. Clin Cancer Res 11(20):7273–7279. doi: 10.1158/1078-0432.CCR-05-0755 CrossRefPubMedGoogle Scholar
  2. 2.
    Skirnisdottir I, Garmo H, Wilander E, Holmberg L (2008) Borderline ovarian tumors in Sweden 1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer 123(8):1897–1901. doi: 10.1002/ijc.23724 CrossRefPubMedGoogle Scholar
  3. 3.
    Morice P, Uzan C, Fauvet R, Gouy S, Duvillard P, Darai E (2012) Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol 13(3):e103–e115. doi: 10.1016/S1470-2045(11)70288-1 CrossRefPubMedGoogle Scholar
  4. 4.
    Hart WR (2005) Borderline epithelial tumors of the ovary. Mod Pathol 18(Suppl 2):S33–S50. doi: 10.1038/modpathol.3800307 CrossRefPubMedGoogle Scholar
  5. 5.
    du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, Kommoss F, Schmalfeldt B, Hilpert F, Fehm T, Burges A, Meier W, Hillemanns P, Hanker L, Hasenburg A, Strauss HG, Hellriegel M, Wimberger P, Keyver-Paik MD, Baumann K, Canzler U, Wollschlaeger K, Forner D, Pfisterer J, Schroder W, Munstedt K, Richter B, Kommoss S, Hauptmann S, Arbeitsgmeinschaft Gynakologische Onkologie Study G (2013) Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) study group. Eur J Cancer 49(8):1905–1914. doi: 10.1016/j.ejca.2013.01.035 CrossRefPubMedGoogle Scholar
  6. 6.
    Shih KK, Zhou Q, Huh J, Morgan JC, Iasonos A, Aghajanian C, Chi DS, Barakat RR, Abu-Rustum NR (2011) Risk factors for recurrence of ovarian borderline tumors. Gynecol Oncol 120(3):480–484. doi: 10.1016/j.ygyno.2010.11.016 CrossRefPubMedGoogle Scholar
  7. 7.
    Lenhard MS, Mitterer S, Kumper C, Stieber P, Mayr D, Ditsch N, Friese K, Burges A (2009) Long-term follow-up after ovarian borderline tumor: relapse and survival in a large patient cohort. Eur J Obstet Gynecol Reprod Biol 145(2):189–194. doi: 10.1016/j.ejogrb.2009.04.031 CrossRefPubMedGoogle Scholar
  8. 8.
    Tinelli R, Tinelli A, Tinelli FG, Cicinelli E, Malvasi A (2006) Conservative surgery for borderline ovarian tumors: a review. Gynecol Oncol 100(1):185–191. doi: 10.1016/j.ygyno.2005.09.021 CrossRefPubMedGoogle Scholar
  9. 9.
    Kaern J, Trope CG, Kristensen GB, Abeler VM, Pettersen EO (1993) DNA ploidy; the most important prognostic factor in patients with borderline tumors of the ovary. Int J Gynecol Cancer 3(6):349–358CrossRefPubMedGoogle Scholar
  10. 10.
    Ayhan A, Guvendag Guven ES, Guven S, Kucukali T (2005) Recurrence and prognostic factors in borderline ovarian tumors. Gynecol Oncol 98(3):439–445. doi: 10.1016/j.ygyno.2005.05.033 CrossRefPubMedGoogle Scholar
  11. 11.
    Singer G, Oldt R 3rd, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih Ie M (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95(6):484–486CrossRefPubMedGoogle Scholar
  12. 12.
    Seidman JD, Kurman RJ (1996) Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases. Am J Surg Pathol 20(11):1331–1345CrossRefPubMedGoogle Scholar
  13. 13.
    Chan WY, Cheung KK, Schorge JO, Huang LW, Welch WR, Bell DA, Berkowitz RS, Mok SC (2000) Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers. Am J Pathol 156(2):409–417. doi: 10.1016/S0002-9440(10)64744-X CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR (2005) Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up. Am J Surg Pathol 29(6):707–723CrossRefPubMedGoogle Scholar
  15. 15.
    Ortiz BH, Ailawadi M, Colitti C, Muto MG, Deavers M, Silva EG, Berkowitz RS, Mok SC, Gershenson DM (2001) Second primary or recurrence? Comparative patterns of p53 and K-ras mutations suggest that serous borderline ovarian tumors and subsequent serous carcinomas are unrelated tumors. Cancer Res 61(19):7264–7267PubMedGoogle Scholar
  16. 16.
    Emerson RE, Wang M, Liu F, Lawrence WD, Abdul-Karim FW, Cheng L (2007) Molecular genetic evidence of an independent origin of serous low malignant potential implants and lymph node inclusions. Int J Gynecol Pathol 26(4):387–394. doi: 10.1097/pgp.0b013e3180336287 CrossRefPubMedGoogle Scholar
  17. 17.
    Vang R, Shih Ie M, Kurman RJ (2013) Fallopian tube precursors of ovarian low- and high-grade serous neoplasms. Histopathology 62(1):44–58. doi: 10.1111/his.12046 CrossRefPubMedGoogle Scholar
  18. 18.
    Ates Ozdemir D, Usubutun A (2016) PAX2, PAX8 and CDX2 expression in metastatic mucinous, primary ovarian mucinous and Seromucinous tumors and review of the literature. Pathol Oncol Res 22(3):593–599. doi: 10.1007/s12253-016-0040-2 CrossRefPubMedGoogle Scholar
  19. 19.
    Mok SC, Bell DA, Knapp RC, Fishbaugh PM, Welch WR, Muto MG, Berkowitz RS, Tsao SW (1993) Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res 53(7):1489–1492PubMedGoogle Scholar
  20. 20.
    Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry JP, Scolyer RA, Smith AN, Bali A, Vanden Bergh P, Baron-Hay S, Scott C, Fink D, Hacker NF, Sutherland RL, O'Brien PM (2006) A distinct molecular profile associated with mucinous epithelial ovarian cancer. Br J Cancer 94(6):904–913. doi: 10.1038/sj.bjc.6603003 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lau WH, Pandey V, Kong X, Wang XN, Wu Z, Zhu T, Lobie PE (2015) Trefoil factor-3 (TFF3) stimulates de novo angiogenesis in mammary carcinoma both directly and indirectly via IL-8/CXCR2. PLoS One 10(11):e0141947. doi: 10.1371/journal.pone.0141947 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ahmed ARH, Griffiths AB, Tilby MT, Westley BR, May FEB (2012) TFF3 is a normal breast epithelial protein and is associated with differentiated phenotype in early breast cancer but predisposes to invasion and metastasis in advanced disease. Am J Pathol 180(3):904–916. doi: 10.1016/j.ajpath.2011.11.022 CrossRefPubMedGoogle Scholar
  23. 23.
    Perry JK, Kannan N, Grandison PM, Mitchell MD, Lobie PE (2008) Are trefoil factors oncogenic? Trends Endocrinol Metab 19(2):74–81. doi: 10.1016/j.tem.2007.10.003 CrossRefPubMedGoogle Scholar
  24. 24.
    Mhawech-Fauceglia P, Wang D, Samrao D, Liu S, DuPont NC, Pejovic T (2013) Trefoil factor family 3 (TFF3) expression and its interaction with estrogen receptor (ER) in endometrial adenocarcinoma. Gynecol Oncol 130(1):174–180. doi: 10.1016/j.ygyno.2013.03.030 CrossRefPubMedGoogle Scholar
  25. 25.
    Emami S, Rodrigues S, Rodrigue CM, Le Floch N, Rivat C, Attoub S, Bruyneel E, Gespach C (2004) Trefoil factor family (TFF) peptides and cancer progression. Peptides 25(5):885–898. doi: 10.1016/j.peptides.2003.10.019 CrossRefPubMedGoogle Scholar
  26. 26.
    Pandey V, Wu ZS, Zhang M, Li R, Zhang J, Zhu T, Lobie PE (2014) Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma. Breast Cancer Res 16(5):429. doi: 10.1186/s13058-014-0429-3 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jatoi A, Vierkant RA, Hawthorne KM, Block MS, Ramus SJ, Larson NB, Fridley BL, Goode EL (2016) Clinical and emergent biomarkers and their relationship to the prognosis of ovarian cancer. Oncology 90(2):59–68. doi: 10.1159/000442710 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kalloger SE, Kobel M, Leung S, Mehl E, Gao D, Marcon KM, Chow C, Clarke BA, Huntsman DG, Gilks CB (2011) Calculator for ovarian carcinoma subtype prediction. Mod Pathol 24(4):512–521. doi: 10.1038/modpathol.2010.215 CrossRefPubMedGoogle Scholar
  29. 29.
    LM MS, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCIEWGoCD (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97(16):1180–1184. doi: 10.1093/jnci/dji237 CrossRefGoogle Scholar
  30. 30.
    Kurman RJ, Carcangiu, M.L., Herrington, C.S., Young, R.H (2014) WHO classification of tumours of female reproductive organs. 4th ed. Lyon: International Agency for Research on Cancer, vol 6.Google Scholar
  31. 31.
    Kjellev S (2009) The trefoil factor family - small peptides with multiple functionalities. Cell Mol Life Sci 66(8):1350–1369. doi: 10.1007/s00018-008-8646-5 CrossRefPubMedGoogle Scholar
  32. 32.
    Thim L, Woldike HF, Nielsen PF, Christensen M, Lynch-Devaney K, Podolsky DK (1995) Characterization of human and rat intestinal trefoil factor produced in yeast. Biochemistry 34(14):4757–4764CrossRefPubMedGoogle Scholar
  33. 33.
    Walker G, MacLeod K, Williams AR, Cameron DA, Smyth JF, Langdon SP (2007) Estrogen-regulated gene expression predicts response to endocrine therapy in patients with ovarian cancer. Gynecol Oncol 106(3):461–468. doi: 10.1016/j.ygyno.2007.05.009 CrossRefPubMedGoogle Scholar
  34. 34.
    Kirikoshi H, Katoh M (2002) Expression of TFF1, TFF2 and TFF3 in gastric cancer. Int J Oncol 21(3):655–659PubMedGoogle Scholar
  35. 35.
    Nowak M, Merz C, von Maessenhausen A, Vogel W, Boehm D, Svensson M, Carlsson J, Andren O, Perner S (2015) Role of trefoil factor-3 peptide (TFF3) in prostate cancer progression. Lab invest 95:248a-248aGoogle Scholar
  36. 36.
    Kurman RJ, Shih Ie M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34(3):433–443. doi: 10.1097/PAS.0b013e3181cf3d79 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Seidman JD, Khedmati F (2008) Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neoplasms and their relationship with Walthard cell nests: a study of 120 tumors. Arch Pathol Lab Med 132(11):1753–1760. doi: 10.1043/1543-2165-132.11.1753 PubMedGoogle Scholar
  38. 38.
    Lee KR, Scully RE (2000) Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'. Am J Surg Pathol 24(11):1447–1464CrossRefPubMedGoogle Scholar
  39. 39.
    Morito K, Nakamura J, Kitajima Y, Kai K, Tanaka T, Kubo H, Miyake S, Noshiro H (2015) The value of trefoil factor 3 expression in predicting the longterm outcome and early recurrence of colorectal cancer. Int J Oncol 46(2):563–568. doi: 10.3892/ijo.2014.2755 CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  • Ahmed El-Balat
    • 1
  • Iryna Schmeil
    • 1
  • Thomas Karn
    • 1
  • Sven Becker
    • 1
  • Nicole Sänger
    • 1
  • Uwe Holtrich
    • 1
  • Ruza Arsenic
    • 2
  1. 1.Department of Obstetrics and GynecologyGoethe University FrankfurtFrankfurtGermany
  2. 2.Institute of PathologyCharite University HospitalBerlinGermany

Personalised recommendations