Morphological and immunohistochemical pattern of tubo-ovarian dysplasia and serous tubal intraepithelial carcinoma

Published:October 13, 2014DOI:



      Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous “ovarian dysplasia” and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls.

      Study design

      Morphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO).


      Morphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p < 0.0001, for ovaries and 6.54 vs 1.58, p < 0.0001 for tubes). Increased γH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs.


      The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Chene G.
        • Penault-Llorca F.
        • Le Bouedec G.
        • et al.
        Ovarian epithelial dysplasia and prophylactic oophorectomy for genetic risk.
        Int J Gynecol Cancer. 2009; 19: 65-72
        • Schloosshauer P.W.
        • Cohen C.J.
        • Penault-Lllorca F.
        • et al.
        Prophylactic oophorectomy.
        Cancer. 2003; 98: 2599-2606
        • Mehrad M.
        • Ning G.
        • Chen E.Y.
        • Mehra K.K.
        • Crum C.P.
        A pathologist's road map to benign, precancerous, and malignant intraepithelial proliferations in the fallopian tube.
        Adv Anat Pathol. 2010; 17: 293-302
        • Kurman R.J.
        • Ming-Shih I.
        Pathogenesis of ovarian cancer, lessons from morphology and molecular biology and their clinical implications.
        Int J Gynecol Pathol. 2008; 27: 151-160
        • Salazar H.
        • Godwin A.K.
        • Daly M.B.
        • et al.
        Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies.
        J Natl Cancer Inst. 1996; 88: 1810-1820
        • Stratton J.F.
        • Buckey C.H.
        • Lowe D.
        • Ponder B.A.J.
        Comparison of prophylactic oophorectomy specimens from carriers and non carriers of a BRCA1 or BRCA2 gene mutation.
        J Natl Cancer Inst. 1999; 91: 626-628
        • Werness B.A.
        • Afify A.M.
        • Bielat K.L.
        • Eltabbakh G.H.
        • Piver M.S.
        • Paterson J.M.
        Altered surface and cyst epithelium of ovaries removed prophylactically from women with a family history of ovarian cancer.
        Hum Pathol. 1999; 30: 151-157
        • Plaxe S.
        • Deligdish L.
        • Dottino P.
        • Cohen C.
        Ovarian intraepithelial neoplasia demonstrated in patients with stage I ovarian carcinoma.
        Gynecol Oncol. 1990; 38: 367-372
        • Resta L.
        • Russo S.
        • Colucci G.A.
        • Prat J.
        Morphologic precursors of ovarian epithelial tumors.
        Obstet Gynecol. 1993; 82: 181-186
        • Mittal K.R.
        • Jacquotte A.Z.
        • Cooper J.L.
        • Demopoulos R.
        Controlateral ovary in unilateral ovarian carcinoma: a search for preneoplastic lesions.
        Int J Gynecol Patho. 1993; 12: 59-63
        • Tressera F.
        • Grases P.J.
        • Labastida R.
        • Ubeda A.
        Histological features of the controlateral ovary in patients with unilateral ovarian cancer: a case control study.
        Gynecol Oncol. 1998; 71: 437-441
        • Chene G.
        • Penault-Llorca F.
        • Le Bouedec G.
        • et al.
        Ovarian epithelial dysplasia after ovulation induction: time and dose effect.
        Human Reprod. 2009; 24: 132-138
        • Nieto J.J.
        • Crow J.
        • Sundaresan M.
        • et al.
        Ovarian epithelial dysplasia in relation to ovulation induction and nulliparity.
        Gynecol Oncol. 2001; 82: 344-349
        • Cargangiu M.L.
        • Radice P.
        • Manoukian S.
        • et al.
        Atypical epithelial proliferation in Fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA 1 and BRCA 2 germline mutation carriers.
        Int J Gynecol Pathol. 2003; 23: 35-40
        • Yanai-Inbar I.
        • Siriaunkgul S.
        • Silverberg S.G.
        Mucosal epithelial proliferation of the fallopian tube: a particular association with ovarian serous tumor of low malignant potential?.
        Int J Gynecol Pathol. 1995; 14: 107-113
        • Ginestier C.
        • Hur M.H.
        • Charafe-Jauffret E.
        • et al.
        ALDH1 is a marker of normal and malignant human mammary sterm cells and a predictor of poor clinical outcome.
        Cell Stem Cell. 2007; 1: 555-567
        • Chang B.
        • Liu G.
        • Xue F.
        • et al.
        ALDH1 expression correlates with favorable prognosis in ovarian cancers.
        Modern Pathol. 2009; 22: 817-823
        • Folkins A.K.
        • Jarboe E.A.
        • Saleemuddin A.
        • et al.
        A candidate precursor to pelvic serous cancer (p53 signature) and their prevalence in ovaries and fallopian tubes from women with BRCA mutations.
        Gynecol Oncol. 2008; 109: 168-173
        • Powell C.B.
        • Kenley E.
        • Chen L.M.
        • et al.
        Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy.
        J Clin Oncol. 2005; 23: 127-132
        • Crum C.P.
        Intercepting pelvic cancer in the distal fallopian tube: theories and realities.
        Mol Oncol. 2009; 3: 165-170
        • Deligdisch L.
        • Gil J.
        Characterization of ovarian dysplasia by interactive morphometry.
        Cancer. 1989; 63: 748-755
        • Deligdisch L.
        • Miranda C.
        • Barba J.
        • Gil J.
        Ovarian dysplasia: nuclear texture analysis.
        Cancer. 1993; 72: 3253-3257
        • Chene G.
        • Dauplat J.
        • Raoelfils I.
        • et al.
        Ovarian epithelial dysplasia: description of a dysplasia scoring scheme.
        Ann Pathol. 2011; 31: 3-10
        • Piek J.M.
        • van Diest P.J.
        • Zweemer R.P.
        Dysplastic changes in prophylactic removed fallopian tubes of women predisposed to developping ovarian cancer.
        J Pathol. 2001; 195: 451-456
        • Chene G.
        • Dauplat J.
        • Robin N.
        • Caure A.
        • Penault-Llorca F.
        Tu-be or tu-be: that is the question… About serous ovarian carcinogenesis.
        Crit Rev Oncol Hematol. 2013; 88: 134-143
        • Mah L.J.
        • El-Osta A.
        • Karagiannis T.C.
        γH2AX as a molecular marker of aging and disease.
        Epigenetics. 2010; 2: 129-136)-L
        • Clingen P.H.
        • Wu J.Y.H.
        • Miller J.
        • et al.
        Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy.
        Bioch Pharmacol. 2008; 76: 19-27
        • Chene G.
        • Tchirkov A.
        • Eymard-Pierre E.
        • et al.
        Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.
        Clin Cancer Res. 2013; 19: 2873-2882
        • Chene G.
        • Ouellet V.
        • Rahimi K.
        • et al.
        DNA damage signalling and apoptosis in preinvasive tubal lesions of ovarian carcinoma.
        Int J Gynecol Cancer. 2014; (Epub ahead of print) PMID 24987917
        • Liu S.
        • Ginestier C.
        • Charafe-Jauffret E.
        • et al.
        BRCA1 regulates human mammary stem/progenitor cell fate.
        PNAS. 2008; 105: 1680-1685
        • Penumatsa K.
        • Edassery S.L.
        • Barua A.
        • Bradaric M.J.
        • Luborsky J.L.
        Differential expression of aldehyde dehydrogenase 1a1 (ALDH1) in normal ovary and serous ovarian tumors.
        J Ovarian Res. 2010; 28: 1-13
        • Charafe-Jauffret E.
        • Ginestier C.
        • Iovino F.
        • et al.
        Aldehyde dehydrogenase 1 positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer.
        Clin Cancer Res. 2010; 16: 45-55
        • Foulkes W.D.
        BRCA1 functions as a breast stem cell regulator.
        J Med Genet. 2004; 41: 1-5
        • Chene G.
        • Radosevic-Robin N.
        • Tardieu A.S.
        • et al.
        Morphological and immunohistochemical study of ovarian and tubal dysplasia associated with Tamoxifen.
        Eur J Histochem. 2014; 58: 2251
        • Auersperg N.
        The stem-cell profile of ovarian surface epithelium is reproduced in the oviductal fimbriae, with increased stem-cell marker density in distal parts of the fimbriae.
        Int J Gynecol Pathol. 2013; 32: 444-453
        • Bowen N.J.
        • Walker L.D.
        • Matyunina L.V.
        Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells.
        BMC Med Genomics. 2009; 2: 71
        • Flesken-Nikitin A.
        • Hwang Cl.
        • Cheng C.Y.
        • Michurina T.V.
        • Enikolopov G.
        • Nikitin A.Y.
        Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.
        Nature. 2013; 495: 241-245
        • Deng S.
        • Yang X.
        • Lassus H.
        • et al.
        Distinct expression levels and atterns of sterm cell marker Aldehyde Dehydrogenase Isoform 1 (ALDH1), in human epithelial cancers.
        PLoS One. 2010; 5: e10277