{"paper_id":"6e92b239-feb4-4e5e-a159-7513017846c0","body_text":"Page 1 of 5\nEndometriosis as a Risk Factor for Colorectal Cancer\nVictor Manuel Vargas Hernandez1*, José María Tovar Rodríguez2 and Víctor Manuel Vargas Aguilar2\n1Department of Gynecology and Oncology, Gynecology Service of Hospital Juárez de México, Mexico\n2Hospital Juárez de México, Ministry of Health, Mexico\n*Corresponding author: Victor Manuel Vargas Hernandez, Gynecology Service, \nHospital Juarez de México, SS Women’s Health Clinic, Insurgents Sur 605-1403, \nNaples, CDMX 03810 Mexico.\nReceived Date: January 23, 2020\nPublished Date: January 29, 2020\nISSN: 2641-6247                                                                                                                           DOI: 10.33552/WJGWH.2020.03.000560\nWorld Journal of \nGynecology & Women’s Health\nReview Article Copyright © All rights are reserved by Victor Manuel Vargas Hernandez\nThis work is licensed under Creative Commons Attribution 4.0 License  WJGWH.MS.ID.000560.\nBackground\nEndometriosis is a proliferative disease that is defined as the \npresence of endometrial glands and stroma outside the uterine \ncavity; or in extrauterine sites, it is a common chronic gynecological \ndisease; the incidence in women of reproductive age is 5 to 17%; its \ncause is unknown; But, the accepted hypothesis is the implantation \nof endometrial tissue in the peritoneal cavity due to retrograde \nmenstruation, or when endometrial tissues and cells adhere to the \nsurfaces of the peritoneum, annexes and other pelvic organs [1-4]. \nThe main symptoms are dysmenorrhea, pelvic pain and infertility. \nAlthough endometriosis is considered a benign condition, it shares \nsome characteristics of cancer proliferation, such as invasion, tissue \ndamage, neoangiogenesis and spread to distant organs [3].\nThe development of cancer is a rare complication of \nendometriosis, and mainly in some gynecological cancers 5 and \nothers extragonadal [3], the first case of malignant transformation \nwas described in 1925 1 of endometriosis in the intestinal tract, 17 \ncases have been reported of neoplastic changes 6; the most common \nlocation being the colon and rectum-sigmoid (50 to 90%) 1 small \nintestine (7%), blind (3.6%) and appendix (3%); other locations \nare in the pleura, pericardium, navel, rectovaginal septum (13%) 7, \nbladder, lungs, central nervous system and even skin 1, as in scars \nfrom surgeries or previous episiotomies, [5-8], (Figure 1). Despite  \n \nepidemiological evidence, the association between endometriosis \nand cancer has not been elucidated so far.\nFigure 1: The female pelvis in (a) ventral and (b) lateral views, \nwhich indicate the sites of endometriosis.\n Endometriosis is hormonally dependent on estrogens, it is \nassociated with oxidative stress, inflammatory pathways that are \nactivated in its microenvironment [7,8]; but, molecular events \ninvolved in malignant transformation are under investigation, \nand early molecular alterations have been identified such as the \nalteration of a tumor suppressor gene, the mutation of the ARID1A \nAbstract \nEndometriosis is a common benign disease in women of reproductive age, it has been associated with an increased risk of various malignancies \nthat is defined by certain histological criteria mainly 80% in ovary and 20% in extragonadal sites such as intestine, rectovaginal septum, abdominal \nwall , pleura and others; the greatest risk for colorectal cancer is women with adenomyosis or endometriosis; Several genetic alterations have \nbeen found in the risk of endometriosis associated with cancer; The symptomatology, imaging and endoscopic characteristics simulate other \ninflammatory and malignant lesions that make the preoperative diagnosis of extragonadal endometriosis difficult. This is a review of the knowledge \nabout endometriosis and its potential risk of malignancy, particularly with colorectal cancer.\nKeywords: Endometriosis; Colorectal cancer; Neoplasms associated with endometriosis; Adenomyosis; Malignant transformation; Simulation\n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nCitation: Victor Manuel Vargas Hernandez, José María Tovar Rodríguez, Víctor Manuel Vargas Aguilar. Endometriosis as a Risk Factor for \nColorectal Cancer. W J Gynecol Women’s Health. 3(2): 2020. WJGWH.MS.ID.000560. DOI: 10.33552/WJGWH.2020.03.000560.\nPage 2 of 5\nand loss of its encoded BAF250a [5]. The association between \nendometriosis and other hormone-dependent cancers particularly \nendometrial cancer (EC) and breast cancer (CM), share common \nrisk factors (FR), such as hyperestrogenism, some reproductive \ncharacteristics, obesity, the administration of menopausal \nhormone therapy (THM) and Type 2 diabetes mellitus (DM2) \n[8-10]; When clinical-pathological characteristics are compared \nbetween primary CE and synchronous epithelial ovarian cancer \n(EOC) [10], the incidence of endometriosis is higher in patients \nwith EC than in EOC (100% vs. 35%), other malignant neoplasms \nsuch as colorectal cancer which is one of the most frequent intra-\nabdominal cancers in women that could exist in association with \nendometriosis. Uterine adenomyosis or internal endometriosis is \nwhen the ectopic endometrial glands and stroma are impregnated \nto the myometrium that can also be associated with an increased \nrisk of cancer [3,9,10].\nThe clinical presentation of intestinal endometriosis is usually \nasymptomatic, or with gastrointestinal bleeding, nausea, vomiting, \nabdominal pain, defecation pain; diarrhea, constipation, rectum-\nvaginal colonic mass, intussusception, intestinal obstructions and \nintestinal perforation are observed; Symptomatology worsens \nduring menstruation by 40%: Imaging and endoscopy of the \nintestinal tract simulates other inflammatory and malignant lesions; \nthe definitive diagnosis before surgery is difficult, only clinical \nsuspicion can prevent it [2]; consider patients with endometriosis, \nespecially postmenopausal patients with a recurrence of symptoms \n[11,12 ] (Table 1).\nTable 1: General characteristics of endometriosis.\nSites  % Symptomatology          Differential Diagnosis or MRI\nBladder 6.4-20 Dysuria, hematuria, urinary retention \nSymptoms, suprapubic  pain                   \nUranus remnant, epithelial and mesenchymal  \ntumors\nUreters 0.01–1 Dysmenorrhea, dyspareunia, flank                         \npain (hydronephrosis) CC obstruction\nOvaries 20–40 Nonspecific pelvic pain Teratomas or hemorrhagic ovarian cysts, \nendometrioid cancers or clear ovarian cells\nRound ligaments         0.3–14 Painful inguinal mass, nonspecific pelvic pain                cysts, endometrioid cancers \nRetro cervical region \nUterosacral ligaments 6-9.2 Painful symptoms, dyspareunia           clear ovarian cells.\n Vagina 14.5 dysmenorrhea, dyspareunia, postcoital  \nRectosigmoid colon   Dysquecia, Cyclic pain, \nrectorrhagia Dysquecia, cyclic pain, rectorrhagia Colorectal cancer, metastatic implants\nRM (Magnetic Resonance imaging)\nCC (Cervical Cancer)\nEndometriosis and Cancer Risk\nWomen with endometriosis are at risk of developing cancer \nof 87.2 per 10,000 patients / year, or risk ratio of (OR) 1.8 with \na 95% CI of 1.4 to 2.4; the time to develop endometriosis cancer \nwas 34.3 months (18.7–46.8 months) and that is when they have \nadenomyosis; and increases with age, with OR 2.3 for those aged \n31 to 40, 2.9; for 41 to 50 years and 4.2 for those 50 years of age or \nolder [10,11,13].\nImaging and Pathology Studies of Intestinal \nEndometriosis\nFigure 2: Image of computed tomography (CT) with contrast \nshowing eccentric thickening of the wall of the rectum-sigmoid \njunction.\nThe diagnostic suspicion of intestinal endometriosis is \nmainly clinical, based on symptomatology; however, the lack of \npathological signs makes diagnosis difficult; even during surgery \nintestinal endometriosis is confused with neoplasms, despite the \nuse of computed tomography (CT) tomography [1,14], Figure 2 or \nmagnetic resonance imaging (MRI), lto detection of wall nodules \nwithin the attached masses, when the atypical characteristics in the \nMRI sequences suggest a possible malignant Figure 3. It is generally \ndiagnosed by histological findings after surgical resection [12] \n(Figures 4-6).\nFigure 3: Magnetic resonance imaging (MRI) (a) Sagittal, (b) \naxial oblique and (c) coronal oblique T2 weighted at T2 show \nspeculated hypointense areas arranged at confluent angles (white \narrows) with loss of cleavage planes between the anterior surface \nof the sigmoid, the posterior serosa of the uterus and bilateral \nendometriomas (white arrowheads).\n\n\nCitation: Victor Manuel Vargas Hernandez, José María Tovar Rodríguez, Víctor Manuel Vargas Aguilar. Endometriosis as a Risk Factor for \nColorectal Cancer. W J Gynecol Women’s Health. 3(2): 2020. WJGWH.MS.ID.000560. DOI: 10.33552/WJGWH.2020.03.000560.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nPage 3 of 5\nFigure 4: Macroscopic appearance of endometriotic nodule of \nsigmoid colon. The arrows indicate the intact mucous layer.\nFigure 5: Adenocarcinoma that infiltrates the colon. Tumor cells \nform irregular glands.\nFigure 6: Small focus of endometriosis near the tumor in the \nmuscles of the colon.\nPathological and immunohistochemical staining (IHQ) is \nessential to make a diagnosis, IHQ stains, which include CK 7, \nCK 20, vimentin and estrogen receptors (RE) [6], are useful to \ndistinguish between adenocarcinoma arising from endometriosis \nand adenocarcinoma Primary intestinal [1,6]. The endometrioid \nglands are usually immunoreactive for CK7, RE, and stromal cells \nare positive for CD10 and RE. The intestinal glands express CDX2 \nand CK20, while showing a negative expression of CK7, RE or CD10. \nPAX8 was shown to be expressed in gynecological cancers [1].\nDiscussion\nEndometriosis is defined histologically as the presence of \nendometrial glands and stroma outside the uterine cavity; common \nbenign disease in women of reproductive age, the frequency of \nintestinal endometriosis varies from 3 to 34% 16; it affects the \nintestinal tract in 15 to 37% of patients with pelvic endometriosis \n[13]. Many theories about its pathogenesis have been proposed, the \nmost accepted proposes retrograde menstruation and subsequent \nimplantation of endometrial cells implanted in the peritoneum \nand pelvic viscera, which is facilitated by immune alterations; It \nis located in various anatomical sites, peritoneum, ovary, fallopian \ntubes, cervix, vagina, vulva, rectovaginal septum, uterus-sacral \nligaments, intestine, rectosigmoid, bladder, uterus and skin [13].\nCancer develops in 5.5% of patients with endometriosis; 21.3% \nof cases originate in extragonadal pelvic sites, intestinal tumors \nassociated with endometriosis are even more rare; in patients \nwith pelvic endometriosis, it mainly affects the rectosigmoid \ncolon, followed by the proximal colon, small intestine, blind and \nappendix. Malignant transformation of endometriosis without \npelvic involvement is rare and its actual incidence is unknown; \nbut, it simulates a neoplasm of the gastrointestinal tract [1,6], in a \nreview of endometrioid adenocarcinomas that arise in colorectal \nendometriosis, of 50 cases only in 22 neoplastic transformation, it \nwas an adenocarcinoma.\nThe others included sarcomas and mixed Müllerian tumors; \nprogression to cancer has been linked to hyperestrogenism \nand to classify cancer as a result of endometriosis, it requires \nhistopathological criteria; proposed by Sampson for the first time \nin 1925 and are: 1) presence of malignant and benign endometrial \ntissue in the same organ; 2) that the cancer arises from the tissue \nand does not invade it from another place; and 3) the finding \nof tissue similar to the endometrial stroma surrounding the \ncharacteristic glands [6].\nThe symptoms of intestinal endometriosis include abdominal \npain, abdominal distension, signs and symptoms of gastrointestinal \nobstruction, rectorrhagia, etc., depending on the segment of \nthe affected intestine, they can be cyclic in 40% that are usually \naggravated during menstruation. Preoperative diagnosis of \nintestinal endometriosis through imaging is difficult and rare \ndue to other common intestinal pathologies [15]. Treatments \nof intestinal endometriosis depend on presentation symptoms \nand operative findings. Medical hormone therapy with surgery \nprovides less recurrence of endometriosis [15,16]; it is rarely \nsuccessful in severe symptomatic disease or intestinal obstruction, \nsurgery with intestinal resection and anastomosis is necessary, \nSuperficial lesions can be removed and definitive treatment \nis excision is hysterectomy with bilateral salpingooporectomy \nand total excision of endometrial foci by laparoscopy or by \nlaparotomy, with multidisciplinary team; it is associated with \nimprovements in the quality of life, it represents a safe approach to \nthe treatment of intestinal endometriosis or colorectal cancer; the \nrisk of subsequent colorectal cancer was elevated in patients with \ncoexisting adenomyosis with other extragonadal endometriosis, \nOR, 13.04, not including carcinoma in situ; of cancers related to \nendometriosis, colorectal is the second most common extragonadal \nsite for malignant transformation of endometriosis [1,2] this \n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nCitation: Victor Manuel Vargas Hernandez, José María Tovar Rodríguez, Víctor Manuel Vargas Aguilar. Endometriosis as a Risk Factor for \nColorectal Cancer. W J Gynecol Women’s Health. 3(2): 2020. WJGWH.MS.ID.000560. DOI: 10.33552/WJGWH.2020.03.000560.\nPage 4 of 5\nmalignant transformation is associated with hyperestrogenism [3]; \nthe theory of malignant endometrial transformation only explains \na small proportion of patients with colorectal cancer; In women \nwith coexisting adenomyosis, there are shared etiological factors \nfor these 2 sequential events [17]. 80% of all neoplasms associated \nwith extragonadal endometriosis occurred in the rectum and \nsigmoid colon, mostly are adenocarcinomas. Adenocarcinoma \nthat arises from endometriosis often mimics primary intestinal \nadenocarcinoma [1].\nThe possible association between endometriosis and cancer by \ncurrent molecular studies through routes related to inflammation, \noxidative stress and hyperestrogenism [3,7]and alterations \nmutations of the tumor suppressor gene PTEN or ARID1A for \nmalignant transformation 12 and the microenvironment of \nendometriosis and Associated cancer share similar cytokines and \nmediators [1,2]. Epidemiological evidence supports molecular \ncarcinogenesis with a link between adenomyosis and gynecological \ncancers, including colorectal cancer. Personalized treatment of \nwomen with endometriosis / adenomyosis is required through \nadvice on early detection of cancer. There is no consensus on the \ntherapeutic approach to treat malignant neoplasms associated with \nendometriosis, it is recommended that patients diagnosed with \ncarcinomas associated with extragonadal endometriosis, which \nare limited to the lower pelvic cavity, can benefit from adjuvant \npelvic radiotherapy, hormone therapy, may have a similar efficacy \nin malignant neoplasms associated with endometriosis with \nprogesterone receptors [1].\nRecently a new concept has been developed in the pathogenesis \nof endometriosis: the “neurological hypothesis” . showed an absolute \ncorrelation with the anatomic distribution of the pelvic sympathetic \nnervous system showed that there is a close histological relationship \nbetween endometriotic lesions of the large intestine and nerves \nin this area. Endometrioid lesions appear to infiltrate the wall of \nthe large intestine preferably along the nerves, even at a distance \nfrom the palpated lesion. Endometriosis and its possible malignant \nchanges should be taken into account in the differential diagnosis \nof intestinal masses in women. In addition, the clinical suspicion of \nmalignancy should be aroused in patients with abdominal pain or \nrectal bleeding and a history of quiescent endometriosis [6].\nGlobally, cancer-associated endometriosis is very rare, and \nit is really appropriate to consider it a premalignant condition; \nbut there is considerable controversy in the literature about the \nrelationship between endometriosis and cancer 6. Due to the \nmalignant potential, patients with endometriosis should have \nadequate hormonal management even after surgery and estrogens \nwithout opposition should generally be avoided in these patients \n[8,18].\nConclusions\nEndometriosis is associated with an increased risk of \ncancer, including colorectal cancer mainly when coexisting with \nadenomyosis. Studies on the association of adenomyosis and the \nrisk of colorectal cancer are needed to clarify whether the malignant \ntransformation of colorectal endometrial implants [19-22].\nAcknowledgement\nNone.\nConflict of Interest\nAuthors declare no conflict of interest.\nReferences\n1. Li N, Zhou W, Zhao L, Zhou J (2018) Endometriosis-associated recto-\nsigmoid cancer: a case report BMC Cancer 18(1): 905. \n2. Muthyala T , Sikka P , Aggarwal N, Suri V, Gupta R, et al. (2015) \nEndometriosis presenting as carcinoma colon in a perimenopausal \nwoman J Midlife Health 6(3): 122-124.\n3. Krawczyk N, Paluchowski MB, Fehm T (2016) Endometriosis-associated \nMalignancy. Geburtsh Frauenheilk 76: 176-181.\n4. Vaarala MH, Hellstrom P , Santala M (2010) Is the incidence of urinary \nbladder endometriosis increasing? Figures from Finland. Gynecol Obstet \nInvest 70(1): 55-59.\n5. Vargas-Hernández VM (2013) Endometriosis as a risk factor for \novariancancer. Cir 81: 163-168.\n6. Marchena-Gomez J, Conde-Martel A, Hemmersbach-Miller M, Alonso-\nFernandez A (2006) Metachronic malignant transformation of small \nbowel and rectal endometriosis in the same patient World J Surg Oncol \n4: 93. \n7. Vargas-Hernández VM (2015) Rectovaginal endometriosis: medical or \nsurgical treatment? Mexican Journal of Digestive Device Surgery 4(2): \n62-67.\n8. Kobayashi S, Sasaki M, Goto T , Asakage N, Sekine M, et al. (2010) \nEndometrioid adenocarcinoma arising from endometriosis of the \nrectosigmoid. Dig Endos 22(1): 59-63.\n9. Katsikogiannis N, Tsaroucha A, Dimakis K, Sivridis E, Simopoulos C \n(2011) Rectal endometriosis causing colonic obstruction and concurrent \nendometriosis of the appendix: a case report. J Med Case Rep 5:320. \n10. Pisanu A, Deplano D, Angioni S, Ambu R, Uccheddu A (2010) Rectal \nperforation from endometriosis in pregnancy: case report and literature \nreview. World J Gastroenterol 16(5): 648-651.\n11. Worley MJ, Welch WR, Berkowitz RS, Ng SW (2013) Endometriosis-\nassociated ovarian cancer: a review of pathogenesis. Int J Mol Sci 14(3): \n5367-5379.\n12. Lai CR, Hsu CY, Chen YJ, Yen MS, Chao KC, et al. (2013) Ovarian cancers \narising from endometriosis: a microenvironmental biomarker study \nincluding ER, HNF1ss, p53, PTEN, BAF250a, and COX-2. J Chin Med Assoc \n76(11): 629-634.\n13. Yamanoi K, Mandai M, Suzuki A, Matsumura N, Baba T , et al. (2012) \nSynchronous primary corpus and ovarian cancer: high incidence of \nendometriosis and thrombosis. Oncol Lett 4(3): 375-380.\n14. Nomelini RS, Ferreira FA, Borges RC, Adad SJ, Murta EFC (2013) \nFrequency of endometriosis and adenomyosis in patients with \nleiomyomas, gynecologic premalignant, and malignant neoplasias. Clin \nExp Obst Gynecol 40(1): 40-44.\n15. Ishii M, Yamamoto M, Tanaka K, Asakuma M, Masubuchi S, et al. (2018) \nIntestinal endometriosis combined with colorectal cancer: a case series. \nJ Med Case Rep 12(1): 21. \n16. Uchiyama S, Haruyama Y, Asada T , Nagaike K, Hotokezaka M, et al. (2010) \nRectal endometriosis masquerading as dissemination in a patient with \nrectal cancer: report of a case. Surg Today 40(7): 672-675. \n17. Foti PV, Farina R, Palmucci S, Agata Vizzini IA, Libertini N, et al. (2018) \nEndometriosis: clinical features, MR imaging findings and pathologic \ncorrelation Insights Imaging 9(2): 149-172.\n\nCitation: Victor Manuel Vargas Hernandez, José María Tovar Rodríguez, Víctor Manuel Vargas Aguilar. Endometriosis as a Risk Factor for \nColorectal Cancer. W J Gynecol Women’s Health. 3(2): 2020. WJGWH.MS.ID.000560. DOI: 10.33552/WJGWH.2020.03.000560.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 3-Issue 2\nPage 5 of 5\n18. Charatsi D, Koukoura O, Ntavela IG, Chintziou F, Gkorila G, et al. (2018) \nGastrointestinal and Urinary Tract Endometriosis: A Review on the \nCommonest Locations of Extrapelvic Endometriosis Adv Med 2018: \n3461209.\n19. Young S, Burns MK, DiFrancesco L, Nezhat A, Nezhat C (2017) Diagnostic \nand treatment guidelines for gastrointestinal and genitourinary \nendometriosis. J Turk Ger Gynecol Assoc 18(4): 200-209.\n20. Chen PC, Chao SC, Hsu KF, Lee CT , Lee JC (2012) Endometrioid \nadenocarcinoma arising from colonic endometriosis in a Lynch \nsyndrome patient. Int J Colorectal Dis 27: 681–682.\n21. Nasu K, Okamato M, Kawano Y, Hirakawa T , Yada N, et al. (2014) \nEndometrioid adenocarcinoma arising from intestinal endometriosis. \nJournal of Endometriosis and Pelvic Pain Disorders 6(2): 112-118.\n22. Hernandez VMV, Rodriguez JMT , Aguilar VMV (2015) Oncogenic Risk of \nEndometriosis. Austin J Reprod Med Infertil 2(5): 1028.","source_license":"CC0","license_restricted":false}