A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases


Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7/CK20+/CDX2+/PAX8. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1–50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol. 2003;27:281–92.

  2. 2.

    Stewart CJ, Ardakani NM, Doherty DA, Young RH. An evaluation of the morphologic features of low-grade mucinous neoplasms of the appendix metastatic in the ovary, and comparison with primary ovarian mucinous tumors. Int J Gynecol Pathol. 2014;33:1–10.

  3. 3.

    Vang R, Gown AM, Wu LS, Barry TS, Wheeler DT, Yemelyanova A, et al. Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7. Mod Pathol. 2006;19:1421–8.

  4. 4.

    McCluggage WG. Immunohistochemistry in the distinction between primary and metastatic ovarian mucinous neoplasms. J Clin Pathol. 2012;65:596–600.

  5. 5.

    Ates Ozdemir D, Usubutun A. PAX2, PAX8 and CDX2 expression in metastatic mucinous, primary ovarian mucinous and seromucinous tumors and review of the literature. Pathol Oncol Res. 2016;22:593–9.

  6. 6.

    Moh M, Krings G, Ates D, Aysal A, Kim GE, Rabban JT. SATB2 expression distinguishes ovarian metastases of colorectal and appendiceal origin from primary ovarian tumors of mucinous or endometrioid type. Am J Surg Pathol. 2016;40:419–32.

  7. 7.

    Strickland S, Parra-Herran C. Immunohistochemical characterization of appendiceal mucinous neoplasms and the value of special AT-rich sequence-binding protein 2 in their distinction from primary ovarian mucinous tumours. Histopathology. 2016;68:977–87.

  8. 8.

    Dobreva G, Chahrour M, Dautzenberg M, Chirivella L, Kanzler B, Farinas I, et al. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell. 2006;125:971–86.

  9. 9.

    Magnusson K, de Wit M, Brennan DJ, Johnson LB, McGee SF, Lundberg E, et al. SATB2 in combination with cytokeratin 20 identifies over 95% of all colorectal carcinomas. Am J Surg Pathol. 2011;35:937–48.

  10. 10.

    Ozcan A, Shen SS, Hamilton C, Anjana K, Coffey D, Krishnan B, et al. PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. Mod Pathol. 2011;24:751–64.

  11. 11.

    Tabrizi AD, Kalloger SE, Kobel M, Cipollone J, Roskelley CD, Mehl E. Primary ovarian mucinous carcinoma of intestinal type: significance of pattern of invasion and immunohistochemical expression profile in a series of 31 cases. Int J Gynecol Pathol. 2010;29:99–107.

  12. 12.

    Groisman GM, Meir A, Sabo E. The value of Cdx2 immunostaining in differentiating primary ovarian carcinomas from colonic carcinomas metastatic to the ovaries. Int J Gynecol Pathol. 2004;23:52–7.

  13. 13.

    Zaino RJ, Brady MF, Lele SM, Michael H, Greer B, Bookman MA. Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal: a Gynecologic Oncology Group study. Cancer. 2011;117:554–62.

  14. 14.

    Rambau PF, Vierkant RA, Intermaggio MP, Kelemen LE, Goodman MT, Herpel E, et al. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study. J Pathol Clin Res. 2018;4:250–61.

  15. 15.

    Ovarian Tumor Tissue Analysis C, Goode EL, Block MS, Kalli KR, Vierkant RA, Chen W, et al. Dose-Response Association of CD8+Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncol. 2017;3:e173290.

  16. 16.

    Kobel M, Madore J, Ramus SJ, Clarke BA, Pharoah PD, Deen S, et al. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. 2014;111:2297–307.

  17. 17.

    Sieh W, Kobel M, Longacre TA, Bowtell DD, deFazio A, Goodman MT, et al. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol. 2013;14:853–62.

  18. 18.

    Gui X, Meng Z, McConnell YJ, Liu S, Falck VG, Mack LA, et al. Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours. J Clin Pathol. 2017;70:40–50.

  19. 19.

    Kobel M, Rahimi K, Rambau PF, Naugler C, Le Page C, Meunier L, et al. An immunohistochemical algorithm for ovarian carcinoma typing. Int J Gynecol Pathol. 2016;35:430–41.

  20. 20.

    Kelemen LE, Kobel M. Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma. Lancet Oncol. 2011;12:1071–80.

  21. 21.

    Landau MS, Kuan SF, Chiosea S, Pai RK. BRAF-mutated microsatellite stable colorectal carcinoma: an aggressive adenocarcinoma with reduced CDX2 and increased cytokeratin 7 immunohistochemical expression. Hum Pathol. 2014;45:1704–12.

  22. 22.

    Yang C, Sun L, Zhang L, Zhou L, Zhao M, Peng Y, et al. Diagnostic utility of SATB2 in metastatic Krukenberg tumors of the ovary: an immunohistochemical study of 70 cases with comparison to CDX2, CK7, CK20, chromogranin, and synaptophysin. Am J Surg Pathol. 2018;42:160–71.

  23. 23.

    Ma C, Lowenthal BM, Pai RK. SATB2 is superior to CDX2 in distinguishing signet ring cell carcinoma of the upper gastrointestinal tract and lower gastrointestinal tract. Am J Surg Pathol. 2018;42:1715–22.

  24. 24.

    Tacha D, Zhou D, Cheng L. Expression of PAX8 in normal and neoplastic tissues: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol. 2011;19:293–9.

  25. 25.

    Black JD, Roque DM, Pasternak MC, Buza N, Rutherford TJ, Schwartz PE, et al. A series of malignant ovarian cancers arising from within a mature cystic teratoma: a single institution experience. Int J Gyneacol Cancer. 2015;25:792–7.

  26. 26.

    Peres LC, Cushing-Haugen KL, Kobel M, Harris HR, Berchuck A, Rossing MA, et al. Invasive epithelial ovarian cancer survival by histotype and disease stage. J Natl Cancer Inst. 2018;111:60–8.

  27. 27.

    Le Page C, Kobel M, Meunier L, Provencher DM, Mes-Masson AM, Rahimi K. A COEUR cohort study of SATB2 expression and its prognostic value in ovarian endometrioid carcinoma. J Pathol Clin Res. 2019. https://doi.org/10.1002/cjp2.131.

  28. 28.

    Wang L, Rambau PF, Kelemen LE, Anglesio MS, Leung S, Talhouk A, et al. Nuclear beta-catenin and CDX2 expression in ovarian endometrioid carcinoma identify patients with favourable outcome. Histopathology. 2019;74:452–62.

  29. 29.

    Rambau P, Kelemen LE, Steed H, Quan ML, Ghatage P, Kobel M. Association of hormone receptor expression with survival in ovarian endometrioid carcinoma: biological validation and clinical implications. Int J Mol Sci. 2017;18:515.

  30. 30.

    Sangoi AR, Kshirsagar M, Horvai AE, Roma AA. SATB2 expression is sensitive but not specific for osteosarcomatous components of gynecologic tract carcinosarcomas: a clinicopathologic study of 60 cases. Int J Gynecol Pathol. 2017;36:140–5.

  31. 31.

    Eberhard J, Gaber A, Wangefjord S, Nodin B, Uhlén M, Ericson Lindquist K, et al. A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer. 2012;106:931.

  32. 32.

    Song GA, Deng G, Bell I, Kakar S, Sleisenger MH, Kim YS. Mucinous carcinomas of the colorectum have distinct molecular genetic characteristics. Int J Oncol. 2005;26:745–50.

  33. 33.

    Crobach S, Ruano D, van Eijk R, Schrumpf M, Fleuren G, van Wezel T, et al. Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations. J Pathol Clin Res. 2016;2:166–74.

  34. 34.

    Nishikawa G, Sekine S, Ogawa R, Matsubara A, Mori T, Taniguchi H, et al. Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms. Br J Cancer. 2013;108:951–8.

  35. 35.

    Meagher NS, Schuster K, Voss A, Budden T, Pang CNI, deFazio A, et al. Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials. Gynecol Oncol. 2018;150:527–33.

  36. 36.

    Ryland GL, Hunter SM, Doyle MA, Caramia F, Li J, Rowley SM, et al. Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. Genome Med. 2015;7:87.

Download references


This study is supported by research funds from Cancer Research Society of Canada (19319). NSM is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network, a translational cancer research center program funded by the Cancer Institute NSW. The Gynaecological Oncology Biobank at Westmead was funded by Cancer Institute NSW (12/RIG/1–17 and 15/RIG/1–16) and the National Health and Medical Research Council of Australia (ID310670, ID628903). FM is funded by University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award. The HOPE study is funded by: US National Cancer Institute (K07-CA80668, P50-CA159981, R01CA095023), US Army Medical Research and Materiel Command (DAMD17–02–1–0669) and NIH/National Center for Research Resources/General Clinical Research Center (MO1- RR000056). KS is funded by the Swedish Cancer foundation. The Generations Study thank Breast Cancer Now, the Institute of Cancer Research and Ovarian Cancer Action for support and funding. The ICR acknowledge NHS funding to the NIHR Biomedical Research Centre. Tissue samples for GER were provided by the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the ethics committee of the University of Heidelberg. The Health Science Alliance (HSA) Biobank acknowledges the UNSW Biorepository, UNSW Sydney, Australia. We thank Shuhong Liu, Young Ou, and Deon Richards for immunohistochemical stains, and Thomas Kryton, BFA, digital imaging specialist for Alberta Public Lab for creating the figures. We especially thank all the study participants, health care staff and data providers internationally who have made this research possible.

Author information

Correspondence to Martin Köbel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplemental material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark