Case 1. Pathology of gynecological cancer. What do we need to know (Case 1) Luca Mazzucchelli Istituto cantonale di patologia Locarno

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1 Case 1 Pathology of gynecological cancer. What do we need to know (Case 1) Luca Mazzucchelli Istituto cantonale di patologia Locarno SAMO Interdisciplinary Workshop on Gynecological Tumors Lucern, October year old women with cystic ovarian tumor measuring 7 cm in diameter Provisional diagnosis: Resection, left uterine adnexe: Serous borderline tumor of the ovary No involvement of the ovarian surface FIGO: IA 1

2 Final diagnosis: Resection, left uterine adnexe: Serous borderline tumor of the ovary Terous tubal intraepithelial carcinoma G3 FIGO: IIC? Disussion points: Are we dealing with one or with two different tumors? What is a tubal intraepithelial carcinoma? How are we going to stage and treat tubal intraepithelial carcinomas? What is the origin and the pathogenesis of ovarian cancer? Do we know precursor lesions of ovarian carcinoma? Open questions The single layer of generally attenuated mesothelium overlying the ovaries bears no resemblance to serous, mucinous, clear cell, or transitional carcinoma Ovarian inclusion cysts bearing mesothelium with metaplastic changes are rare Well documented examples of malignant transformation of inclusion cysts do not exist Inclusion cysts with intestinal type or transitional epithelium are rare Ovarian tumors are derived from the ovarian surface epithelium (mesothelium) Subsequent metaplastic changes of the surface epithelium or of epithelia in inclusion cysts lead to the development of the different cell type (serous, endometroid, clear cell, mucinous, and transitional cell) Müllerian tumors (serous, endometroid, and clear cell) most likely derives from müllerian-type tissue and not from the mesothelium The müllerian-type tissue lines paratubal and paraovarian cysts 2

3 Open questions Well documented examples of malignant transformation of paratubal and paraovarian cysts do not exist Most mucinous tumors display intestinal rather than endocervical mucinous differentiation and do not qualify as müllerian-type tumors A similar problem exists for transitional cell (brenner tumors) The cell of origin of a proportion of epithelial ovarian cancer is not ovarian In 2001 Dutch investigators described tubal dysplasia/ carcinoma in women with a genetic predisposition to ovarian cancer Subsequent studies confirmed that in situ and small invasive tubal carcinomas occurred in women with genetic predisposition for ovarian cancers Fallopian tube carcinoma was included in th spectrum of cancers associated with BRCA mutations A proportion of ovarian carcinomas might develop as a result of implantation of malignant cells from the tubal carcinoma to the ovary Piek JM et al. J Pathol 2001, 195: Piek JM et al.lancet 2001, 358:844 Piek JM et al.gynecol Oncol 2003, 90:491 The cell of origin of most epithelial ovarian cancer is derived from the fallopian tube Normal tubal epithelium Tubal dysplasia/carcinoma Tubal intraepithelial carcinoma (TIC) Am J Surg Pathol 2010, 34,433 TIC in sporadic high grade serous carcinoma TIC can be identified in approximately 70% of high grade serous carcinoma Missing cases Sampling errors of the tubal mucosa, Overgrowth of pelvic carcinoma Dislodgment of tubal mucosa into the ovaries Rarely, progression of low grade borderline tumors may account for the remaining cases 3

4 Serous tubal intraepithelial carcinoma Tubal epithelial alterations High grade atypia of the epitehlium Loss of polarity Mostly overexpress p53 Mostly but not always overexpress p16 The proliferative index (ki67) is typically high A range of biomarkers may be helpful for the diagnosis (Cyclin E, PAX 2, PAX5, PAX8) but... histology remains the gold standard Benign lesions Metaplasia Reactive atypias Pregnancy related changes Salpingolithis Epithelial pseudoneolasia associated with salpingitis Papillary lesions Benign precursor candidates (secretory cell outgrowth, SCOUTs) P53 signatures Proliferative p53 signatures P53 signatures Common findings in the tube More common in association with serous carcinoma No immediate significance from the clinical perspectives Source of overdiagnosis in pathology p53 Benign appearing areas of tubal epithelium that show strong staining for p53 by immunohistochemistry (at least 12 cells) Secretory cell phenotype (with occasional cilia) Low proliferative index (ki67 < 10%) About half of cases of TICs had concurrent p53 signatures P53 signatures are common in the fallopian tube regardless of the BRCA mutation status (up to 30% of women) Proliferative P53 signatures Proposal for a sequence of pathological events Intermediate features between p53 signatures and TICs Genotoxic DNA dmage High grade nuclear atypia but pservation of epithelial polarity and pseudostratification P53 signature P53 up-regiulation High proliferative index (ki67 > 10%) p53 Proliferative p53 signature P53 mutation Interobserver reproducibility has not been established Tubal intraepitehlial carcinoma Loss of cell cycle control The clinical significance of this lesion in isolation is not known High grade serous carcinoma Komplex genetic abnormalities ki67 4

5 However... Proposed development of ovarian endometrioid and clear cell carcinoma P53 mutations, when presnt in p53 signature, are not always identical with the mutations in TICs in the same specimen Women at high risk have the same frequency of p53 signatures as women who are not at high risk The high prevalence of p53 signature (30%) compared with the low prevalence of high grade serous carcinoma suggest low rate progression to carcinoma, or no relation to carcinoma It conceivable that p53 signatures reflect an appropriate and physiologic upregulation of p53 in response to DNA damage Proposed development of ovarian mucinous and transitional cell tumors Mucinous and transitional tumors do not disply müllerian phenotype Mucinous and transitional metaplasia in ovarian inclusion cysts is very rare The association of mucinous and brenner tumor is well known Possibly, they arise from microscopic transitional cell nests at the tubal-mesothelial junction Take home messages Serous tumors develop from the fimbriated portion of the fallopian tube Endometrioid and clear cell tumors develop from endometrial tissue passing trough the fallopian tube Brenner- and mucinous tumors develop from transitional-type epithelium located at the tubal-mesothelial junction where the fimbrias make contact with the peritoneum The majority of epithelial ovarian carcinomas originates outside the ovary Take home messages Ask a second opinion in unusual cases For pathologists: do not mention p53 signatures in a pathology report For oncologists: do not treat p53 signatures TICs probably need chemotherapy but randomized clinical trial are lacking Prophylaxis for ovarian cancer need to be reevaluated Salpingectomy could be effective to prevent serous cancer in women at high risk but randomized clinical trial are lacking Future molecular studies should compare data obtained in ovarian cancer with appropriate normal tissue 5