In endometrial endometrioid adenocarcinoma (EEC), the depth of myometrial invasion (MI) is an important parameter for determining whether additional treatment is warranted. The present study investigated the association between MI patterns, cancer stem cell (CSC) phenotypes, and their clinicopathological significance in EEC. A total of 73 cases of EEC with MI were examined in this study. Haematoxylin and eosin-stained tissue specimens were analysed for MI pattern, which was categorised as infiltrating; expansile; adenomyosis (AM)-like; or microcystic, elongated, and fragmented (MELF)-type. The expression of CSC markers such as cluster of differentiation (CD)44, CD133, and Nanog1, as well as oestrogen receptor (ER) and progesterone receptor (PR) was examined by immunohistochemistry. Clinicopathological features including age, DOI, MI pattern, LVI, lymph node (LN) metastasis, disease progression, and survival outcome were recorded. Most examined cases (45/73) were International Federation of Gynecology and Obstetrics (FIGO) stage I. MI showed infiltrating (49.3%), AM-like (26.3%), MELF (15.1%), and expansile (9.6%) patterns. Tumours with the infiltrating pattern were associated with high FIGO grade (P = 0.002), reduced ER and PR, and CD44 expression (P = 0.014, 0.026, and 0.030, respectively); those with a MELF pattern showed LN metastasis (P < 0.001), lymphovascular invasion (P = 0.011), and reduced ER, CD44, and CD133 expression (P = 0.036, 0.006, and 0.016, respectively). EEC with infiltrating/MELF patterns of MI is associated with worse prognosis. These results suggest that CSC expression profiles are an unfavourable indicator of EEC.
Cancer stem cell marker Epithelial-to-mesenchymal transition Endometrioid carcinoma Myometrial invasion
cluster of differentiation
endometrial endometrioid carcinoma
cancer stem cells
depth of invasion
International Federation of Gynecology and Obstetrics
lymph node involvement.
lower uterine segment.
microcystic, elongated, and fragmented.
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This work was supported by Biomedical Research Institute grant, Kyungpook National University Hospital (2014).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Cole AJ, Quick CM (2013) Patterns of myoinvasion in endometrial adenocarcinoma: recognition and implications. Adv Anat Pathol 20(3):141–147CrossRefGoogle Scholar
Euscher E, Fox P, Bassett R, Al-Ghawi H, Ali-Fehmi R, Barbuto D, Malpica A (2013) The pattern of myometrial invasion as a predictor of lymph node metastasis or extrauterine disease in low-grade endometrial carcinoma. Am J Surg Pathol 37(11):1728–1736CrossRefGoogle Scholar
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Wahl GM (2006) Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66(19):9339–9344CrossRefGoogle Scholar
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648CrossRefGoogle Scholar
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988CrossRefGoogle Scholar
Singh SK, Hawkins C, Clark ID, Squire JA, Bayani J, Hide T, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401CrossRefGoogle Scholar
Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, Shukla S, Neubauer A (2007) Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 21(6):1267–1275CrossRefGoogle Scholar
Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66(15):7445–7452CrossRefGoogle Scholar
Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98(24):1777–1785CrossRefGoogle Scholar
Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Donahoe PK (2006) Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A 103(30):11154–11159CrossRefGoogle Scholar
Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695CrossRefGoogle Scholar
Hu M, Polyak K (2008) Microenvironmental regulation of cancer development. Curr Opin Genet Dev 18(1):27–34CrossRefGoogle Scholar
Mirantes C, Espinosa I, Ferrer I, Eaton EN, Ayyanan A, Zhou AY, Weinberg RA (2013) Epithelial-to-mesenchymal transition and stem cells in endometrial cancer. Hum Pathol 44(10):1973–1981CrossRefGoogle Scholar
Hollier BG, Evans K, Mani SA The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14(1):29–43Google Scholar
Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213(2):374–383CrossRefGoogle Scholar
Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751CrossRefGoogle Scholar
Mani SA, Guo W, Liao MJ, Dolcet X, Prat J, Matias-Guiu X (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715CrossRefGoogle Scholar
Nakamura M, Kyo S, Zhang B, Zhang X, Mizumoto Y, Takakura M, Inoue M (2010) Prognostic impact of CD133 expression as a tumor-initiating cell marker in endometrial cancer. Hum Pathol 41(11):1516–1529CrossRefGoogle Scholar
Hammond ME, Hayes DE, Dowsett M, Allred DC, Hagerty KL, Badve S American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 134(7):48–72Google Scholar
Koyuncuoglu M, Okysy E, Saatli B, Olgan S, Akin M, Saygili U (2012) Tumor budding and E-Cadherin expression in endometrial carcinoma: are they prognostic factors in endometrial cancer? Gynecol Oncol 125(1):208–213CrossRefGoogle Scholar
Rutella S, Bonanno G, Procoli A, Mariotti A, Corallo M, Prisco MG, Ferrandina G (2009) Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clin Cancer Res 15(13):4299–4311CrossRefGoogle Scholar
Friel AM, Zhang L, Curley MD, Therrien VA, Sergent PA, Belden SE, Rueda BR (2010) Epigenetic regulation of CD133 and tumorigenicity of CD133 positive and negative endometrial cancer cells. Reprod Biol Endocrinol 8:147–160CrossRefGoogle Scholar
Zagorianakou N, Ioachim E, Mitselou A, Kitsou E, Zagorianakou P, Stefanaki S, Agnantis NJ (2003) Glycoprotein CD44 expression in normal, hyperplasic and neoplastic endometrium. An immunohistochemical study including correlations with p53, steroid receptor status and proliferative indices (PCNA, MIB1). Eur J Gynaecol Oncol 24(6):500–504Google Scholar
Murray SK, Young RH, Scully RE (2003) Unusual epithelial and stromal changes in myoinvasive endometrioid adenocarcinoma: a study of their frequency, associated diagnostic problems, and prognostic significance. Int J Gynecol Pathol 22(4):324–333CrossRefGoogle Scholar
Castilla MA, Moreno-Bruno G, Romero-Perez L, Van De Vijver K, Biscuola M, Lopez-Garcia MA, Palacios J (2011) Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J Pathol 223(1):72–80CrossRefGoogle Scholar
Wik E, Raeder MB, Krakstad C, Trovik J, Birkeland E, Hoivik EA, Salvesen HB (2013) Lack of estrogen receptor-alpha is associated with epithelial-mesenchymal transition and PI3K alterations in endometrial carcinoma. Clin Cancer Res 19(5):1094–1105CrossRefGoogle Scholar
Stewart CJ, Little L (2009) Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial-mesenchymal transition. Histopathology 55(1):91–101CrossRefGoogle Scholar
Hanekamp EE, Gielen SC, De Ruiter PE, Chadha-Ajwani S, Brinkmann AO, Blok LJ (2005) Differences in invasive capacity of endometrial cancer cell lines expressing different progesterone receptor isotypes: possible involvement of cadherins. J Soc Gynecol Investig 12(4):278–284CrossRefGoogle Scholar
Dai D, Wolf DM, Litman ES, White MJ, Leslie KK (2002) Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res 62(3):881–886Google Scholar
Hanekamp EE, Kuhne EC, Smid-Koopman E, Chadha-Ajwani S, Huikeshoven FJ, Burger CW, Blok LJ (2002) Loss of progesterone receptor may lead to an invasive phenotype in human endometrial cancer. Eur J Cancer 38(Suppl 6):S71–SS2CrossRefGoogle Scholar
Guarino M, Rubino B, Ballabio G (2007) The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39(3):305–318CrossRefGoogle Scholar
Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454CrossRefGoogle Scholar