PRECEDENTE CONSTITUCIONAL RESPECTO DE LA PRUEBA DE OFICIO JUEZ DE CONOCIMIENTO SENTENCIA C-396 DE 23 DE MAYO DE

identified in the endometrium. STIC was significantly more often found in concurrence to EIC, atypical hyperplasia, and/or invasive endometrial carcinoma compared with normal endometrium (p=0.010; Pearson’s Chi square). In 64% of cases identified with STIC, an EIC and/or atypical hyperplasia was found in the endometrium, whereas in 28% of cases with STIC the endometrium was benign. Of the latter, in four cases non-atypical hyperplasia was found in the endometrium.

Discussion

Table 7: The coexistence of STIC and EIC and/or endometrial atypical hyperplasia in

serous ovarian cancer patients (N=54)

STIC Endometrium N N (%) Benign 32 9 (28%) Premalignancy 22 14 (64%) Atypical hyperplasia 13 8 (62%) EIC 3 2 (67%)

EIC + atypical hyperplasia 6 4 (67%)

Malignancy 5 3 (60%)

p=0.010 (Pearson’s Chi square test)

Abbreviations: EIC, endometrial intraepithelial carcinoma; STIC, serous tubal intraepithe- lial carcinoma.

100

in the last decade and STIC has been found in serous ovarian carcinomas in a mean overall prevalence of 41%6,8-10_{. The current study is unique, as the entire epithelium of the endometrium}

and the tubal epithelium were extensively assessed, as well as representative sections of the cervix. In 52% of cases, a STIC, EIC, and/or endometrial atypical hyperplasia was found. In the endocervical tissue, one CIN3 lesion was found. In the fallopian tubes, STIC was present in 43%, and in the endometrium an intraepithelial carcinoma was found in 15% of cases and atypical hyperplasia in 32%. In a quarter of cases, a lesion was found in the tubes as well as in the endometrium. Serous tubal intraepithelial carcinoma occurred significantly more often in women diagnosed with an EIC and/or atypical hyperplasia compared with women with a benign endometrium, regardless of the type of endometrial lesion (p=0.010).

To the best of our knowledge, the surprisingly high prevalence of atypical hyperplasia and EIC in serous ovarian cancer patients has not been previously described. The few studies that investigated the endometrium in pathology reports of asymptomatic women, reported a much lower prevalence of atypical hyperplasia (0.5–1.1%) and no EIC29-31_{. We recently reported the}

prevalence of atypical hyperplasia in 6% of women who underwent a hysterectomy because of uterovaginal prolapse, after embedding the endometrial tissue in accordance with the SEE- End protocol32_{. In none of these women, EIC was found.}

The prevalence of STIC in the current study was comparable to other studies that extensively examined the fallopian tubes in accordance with the SEE-Fim protocol6,9_{. In these studies,}

STIC was found restrictive to ovarian cancers of serous histology type, which supports its suggested role in the development of serous carcinoma10,33_{. Tubal hyperplasia and minor}

epithelial atypia were equally present in women at risk of ovarian carcinoma compared with women from normal populations and considered as variants of normal tubal epithelial proliferation22_.

Recently, the introduction of the SEE-Fim protocol resulted in a significant increase of the identification of STIC, as it enabled optimal microscopic view of the tubal plicae19_{. The}

endometrium is not particularly difficult to visualize microscopically, but its heterogeneous aspect and the small size of some lesions necessitates meticulous screening20_{. The}

introduction of the SEE-End protocol might contribute to a more accurate identification of endometrial pathology, as shown by the higher prevalence of endometrial pathology found in asymptomatic women after introduction of the new protocol32_{. Especially for the identification}

of EIC, the SEE-End protocol is recommended, as it can occur only unifocal and can be easily missed with routine sampling.

Further, identification of invasive endometrial carcinoma seems slightly increased in the current study (8%), compared with the prevalence reported after routine sampling (2–5%)15,34_.

This might be because of the introduction of the SEE-End protocol. In half of the cases additional serous tubal carcinoma was found and in one case even a lesion in the endocervix. Prevalence of extensive carcinoma is high and we cannot exclude that some of these cases

5

might be misclassified as primary ovarian instead of primary tubal or endometrial. However, diagnostic criteria for extensive serous carcinoma have not been well defined.

The high prevalence of endometrial atypical hyperplasia in this group of serous ovarian cancer patients is remarkable, as atypical hyperplasia is known as a precursor of endometrioid endometrial carcinoma and its development is influenced by genetic predisposition and increased, unopposed, estrogen35_{. Some endometrioid ovarian cancers have been described}

to cause increased estrogen levels, and this has even been reported for a few cases with serous ovarian cancer36-38_{. However, we have no information on estrogen levels from cases}

included in the current study.

Endometrial intraepithelial carcinoma is involved in the development of serous endometrial carcinoma, and is occasionally found concurrent to serous ovarian or extra-ovarian carcinoma, without presence of invasive endometrial carcinoma11,39-41_{. An EIC has the capability of}

disseminating throughout the peritoneal cavity, and could putatively be responsible for a proportion of serous epithelial ovarian cancers42,43_{. Interestingly, we often identified}

simultaneous prevalence of STIC, EIC, and/or atypical hyperplasia in patients with serous ovarian carcinoma. Several hypotheses can be put forward to explain their coexistence. Endometrial atypical hyperplasia represents most likely a synchronous precursor of endometrioid endometrial carcinoma in these women with serous ovarian carcinoma, instead of a lesion involved in the development of serous ovarian cancer. This is supported by the different immunophenotypes for atypical hyperplasia and coexisting EIC. However, STIC and EIC are both involved in the development of serous carcinoma, and their coexistence is in contrast with the assumption that serous carcinoma develops from one location, from where it can develop into invasive carcinoma or spread to other locations in the peritoneal cavity.

An explanation for coexisting STIC and EIC is that one lesion represents the primary location from where the tumor spreads, and that the other lesion is a direct product of implantation of migrating cells. Spread of tumor cells from an EIC into the uterine cavity, through the tubes, toward the peritoneal cavity seems a plausible explanation, as it follows the route of retrograde menstruation11,43,44_{. However, as suggested by Jarboe et al}40_{, STIC}

might also represent the primary location, as cells may exfoliate toward the peritoneal cavity as well as toward the uterine cavity45_{. They reported on a few cases diagnosed as endometrial}

serous carcinoma with coexistence of STIC and EIC40_{. However, most cases were without}

invasive endometrial carcinoma, but with tumor involvement of both ovaries. Therefore, cases seem comparable to the ones diagnosed in the current study as serous ovarian cancer with coexisting STIC and EIC. Jarboe et al40_{, analyzed the tumor origin of four cases with coexisting}

102

development does not occur in only one specific area of the Müllerian duct, but that the entire tract is susceptible for tumor development in these women. This could explain for the discordant WT1 staining in some of the coexisting STIC and EIC. A similar mechanism of field carcinogenesis has been described in many cancers, as for example in colonic and head and neck cancers, and has occasionally been described for ovarian cancers46-48_{. This}

mechanism could also explain that gynecologic carcinomas, of comparable or different histological subtypes, are often identified synchronously. Additional molecular genetic studies are necessary to differentiate primary carcinomas from metastases and to elucidate the route of carcinogenesis in these women.

Clinical and pathological characteristics were almost comparable for women with and without a STIC and/or EIC in the current study. However, clinical variables were retrieved retrospectively and not always complete. The majority of women included in this study underwent chemotherapy before debulking surgery. Although, no significant difference in prevalence of EIC, STIC or atypical hyperplasia was found between both groups, we cannot exclude that chemotherapy might have an impact on the prevalence of pathologic lesions. Another limitation of the current study is that the cervical tissue was not completely embedded.

In conclusion, the current study provided an overview of pathology in tissues derived from the Müllerian duct in women with serous ovarian cancer, embedded in accordance with the SEE-Fim and SEE-End protocol. Atypical hyperplasia, STIC, and EIC were commonly identified in these women, and often occurred simultaneously. The clinical significance and biological potential of these lesions in women diagnosed with serous ovarian carcinoma may be of utmost importance in understanding tumor development of ovarian cancers.

5

van Altena AM, Karim-Kos HE, de Vries E, Kruitwagen RF, Massuger LF, Kiemeney LA. Trends in therapy and survival of advanced stage epithelial ovarian cancer patients in the Netherlands. Gynecol Oncol. 2012;125: 649-54.

Registration WNC. www.cijfersoverkanker.nl (IKNL; Integraal Kankercentrum Nederland). 2013. Gross AL, Kurman RJ, Vang R, Shih Ie M, Visvanathan K. Precursor lesions of high-grade serous ovarian carcinoma: morphological and molecular characteristics. J Oncol. 2010;2010: 126295. Marquez RT, Baggerly KA, Patterson AP, Liu J, Broaddus R, Frumovitz M, et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin Cancer Res. 2005;11: 6116-26.

Dubeau L. The cell of origin of ovarian epithelial tumours. Lancet Oncol. 2008;9: 1191-7.

Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol. 2007;31: 161-9.

Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195: 451-6.

Przybycin CG, Kurman RJ, Ronnett BM, Shih I, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34: 1407-16.

Roh MH, Kindelberger D, Crum CP. Serous tubal intraepithelial carcinoma and the dominant ovarian mass: clues to serous tumor origin? Am J Surg Pathol. 2009;33: 376-83.

Tang S, Onuma K, Deb P, Wang E, Lytwyn A, Sur M, et al. Frequency of serous tubal intraepithelial carcinoma in various gynecologic malignancies: a study of 300 consecutive cases. Int J Gynecol Pathol. 2012;31: 103-10.

Roelofsen T, van Kempen LC, van der Laak JA, van Ham MA, Bulten J, Massuger LF. Concurrent endometrial intraepithelial carcinoma (EIC) and serous ovarian cancer: can EIC be seen as the precursor lesion? Int J Gynecol Cancer. 2012;22: 457-64.

Bafghi A, Zafrani Y, Pautier P, Lhomme C, Duvillard P, Castaigne D, et al. Endometrial disorders in patients with peritoneal serous papillary carcinoma. Eur J Obstet Gynecol Reprod Biol. 2007;134: 101-4.

Silverman BB, O’Neill RT, Mikuta JJ. Multiple malignant tumors associated with primary carcinoma of the ovary. Surg Gynecol Obstet. 1972;134: 243-8.

Soliman PT, Slomovitz BM, Broaddus RR, Sun CC, Oh JC, Eifel PJ, et al. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol Oncol. 2004;94: 456-62.

van Altena AM, Geels YP, Bulten J, Kiemeney LA, de Hullu JA, Massuger LF. Why do women with double primary carcinoma of the endometrium and ovary have a favorable prognosis? Int J Gynecol Pathol. 2012;31: 344-51.

Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

104

McCluggage WG. Benign Diseases of the Endometrium, In: Kurman RJ, Ellenson HL, (eds). Blaustein’s Pathology of the Female Genital Tract. 6th edn. Springer: New York. 2011: 305-58. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006;30: 230-6.

Mills AM, Longacre TA. Endometrial hyperplasia. Semin Diagn Pathol. 2010;27: 199-214.

Ambros RA, Sherman ME, Zahn CM, Bitterman P, Kurman RJ. Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation. Hum Pathol. 1995;26: 1260-7.

Mingels MJ, Roelofsen T, van der Laak JA, de Hullu JA, van Ham MA, Massuger LF, et al. Tubal epithelial lesions in salpingo-oophorectomy specimens of BRCA-mutation carriers and controls. Gynecol Oncol. 2012;127: 88-93.

Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, et al. The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol. 2007;19: 3-9.

Piek JM, Verheijen RH, Kenemans P, Massuger LF, Bulten H, van Diest PJ. BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis. Gynecol Oncol. 2003;90: 491.

Mehrad M, Ning G, Chen EY, Mehra KK, Crum CP. A pathologist’s road map to benign, precancerous, and malignant intraepithelial proliferations in the fallopian tube. Adv Anat Pathol. 2010;17: 293-302. Kommoss S, Schmidt D, Kommoss F, Hedderich J, Harter P, Pfisterer J, et al. Histological grading in a large series of advanced stage ovarian carcinomas by three widely used grading systems: consistent lack of prognostic significance. A translational research subprotocol of a prospective randomized phase III study (AGO-OVAR 3 protocol). Virchows Arch. 2009;454: 249-56.

Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28: 496-504.

Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA. 2006;296: 185-92.

Bonnar J, Kraszewski A, Davis WB. Incidental pathology at vaginal hysterectomy for genital prolapse. J Obstet Gynaecol Br Commonw. 1970;77: 1137-9.

Frick AC, Walters MD, Larkin KS, Barber MD. Risk of unanticipated abnormal gynecologic pathology at the time of hysterectomy for uterovaginal prolapse. Am J Obstet Gynecol. 2010;202: 507-4. Mahajan G, Kotru M, Batra M, Gupta A, Sharma S. Usefulness of histopathological examination in uterine prolapse specimens. Aust N Z J Obstet Gynaecol. 2011;51: 403-5.

Mingels MJ, Geels PG, Pijnenborg JM, van der Wurff AA, van Tilborg AA, van Ham MA, et al. Histopathologic assessment of the entire endometrium in asymptomatic women. Hum Pathol. 2013;44: 2293-301.

Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, et al. Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol. 2008;27: 1-9.

Bunting MW, Jaaback KS, McNally OM. Routine hysterectomy in the surgical management of ovarian cancer: a retrospective case series, physician opinion survey, and review of the literature. Int J Gynecol Cancer. 2011;21: 1579-84.

Kurman RJ, McConnell TG. Precursors of endometrial and ovarian carcinoma. Virchows Arch. 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

36 37 38 39 40 41 42 43 44 45 46 47 48 2010;456: 1-12.

Jongen VH, Sluijmer AV, Heineman MJ. The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer. Maturitas. 2002;43: 77-85.

Poels LG, Jap PH, Ramaekers FF, Scheres JM, Thomas CM, Vooijs PG, et al. Characterization of a hormone-producing ovarian carcinoma cell line. Gynecol Oncol. 1989;32: 203-14.

Ridderheim M, Mahlck CG, Selstam G, Stendahl U, Backstrom T. Steroid production in different parts of malignant and benign ovarian tumors in vitro. Cancer Res. 1993;53: 2309-12.

Baergen RN, Warren CD, Isacson C, Ellenson LH. Early uterine serous carcinoma: clonal origin of extrauterine disease. Int J Gynecol Pathol. 2001;20: 214-9.

Jarboe EA, Miron A, Carlson JW, Hirsch MS, Kindelberger D, Mutter GL, et al. Coexisting intraepithelial serous carcinomas of the endometrium and fallopian tube: frequency and potential significance. Int J Gynecol Pathol. 2009;28: 308-15.

Soslow RA, Pirog E, Isacson C. Endometrial intraepithelial carcinoma with associated peritoneal carcinomatosis. Am J Surg Pathol. 2000;24: 726-32.

Zheng W, Schwartz PE. Serous EIC as an early form of uterine papillary serous carcinoma: recent progress in understanding its pathogenesis and current opinions regarding pathologic and clinical management. Gynecol Oncol. 2005;96: 579-82.

Massuger L, Roelofsen T, Ham M, Bulten J. The origin of serous ovarian cancer may be found in the uterus: a novel hypothesis. Med Hypotheses. 2010;74: 859-61.

Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34: 433-43.

Seidman JD, Zhao P, Yemelyanova A. “Primary peritoneal” high-grade serous carcinoma is very likely metastatic from serous tubal intraepithelial carcinoma: assessing the new paradigm of ovarian and pelvic serous carcinogenesis and its implications for screening for ovarian cancer. Gynecol Oncol. 2011;120: 470-3.

Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6: 963-8.

Buller RE, Skilling JS, Sood AK, Plaxe S, Baergen RN, Lager DJ. Field cancerization: why late “recurrent” ovarian cancer is not recurrent. Am J Obstet Gynecol. 1998;178: 641-9.

Damania D, Roy HK, Kunte D, Hurteau JA, Subramanian H, Cherkezyan L, et al. Insights into the field carcinogenesis of ovarian cancer based on the nanocytology of endocervical and endometrial epithelial cells. Int J Cancer. 2013; 133: 1143-52.

Chapter 6

Value of immunohistochemical WT1