{"paper_id":"8e34d3b5-75ce-46f3-9b89-466d1ba04927","body_text":"120\nThe Korean Journal of Pathology  2009; 43: 120-5\nDOI: 10.4132/KoreanJPathol.2009.43.2.120\nBackground :Since many patients with intestinal endometriosis present with gastrointestinal\nsymptoms without a history of endometriosis, endoscopic examination of the intestinal tract is\ninitially performed, often leading to a misdiagnosis. Methods :We reviewed the clinicopatho-\nlogic findings of 18 samples from 15 patients with intestinal endometriosis who underwent endo-\nscopic biopsy and/or surgical resection to identify diagnostically helpful findings. Results :All\n7 biopsy specimens displayed relatively well-defined submucosal lesions, with non-mucinous\nglands lined by ciliated epithelium and surrounding cellular stroma containing spiral arteriole-\nlike blood vessels. The stroma was immunopositive for CD10 in all cases. All but one speci-\nmen exhibited immunopositivity for ER and PR in both glandular and stromal components. In\ncontrast to the overlying normal colonic mucosa, glandular epithelium with endometriosis was\nimmunopositive for cytokeratin (CK) 7, but immunonegative for CK20 in all cases. Three cases\nwere associated with adenocarcinoma in the same or different segments; specifically, two\nprimary rectal adenocarcinomas and one endometrioid adenocarcinoma arising from endometrio-\nsis. Conclusions :The characteristic features of endometrial glands and stroma, including non-\nmucinous glands without goblet cells, ciliated columnar epithelium, and cellular stroma with\nspiral arterioles, facilitate the accurate diagnosis of intestinal endometriosis, which can be con-\nfirmed by immunohistochemical staining.\nKey Words : Endometriosis; Intestine; Endometrioid adenocarcinoma \nHeejin Lee\n Kyu-Rae Kim\n 120\nIntestinal Endometriosis: Clinicopathologic Analysis of 15 Cases\nIncluding a Case of Endometrioid Adenocarcinoma\n 120 120\nCorresponding Author\nKyu-Rae Kim, M.D.\nDepartment of Pathology, Asan Medical Center,\nUniversity of Ulsan College of Medicine, 388-1\nPungnap-dong, Songpa-gu, Seoul 138-736, Korea\nTel: 02-3010-4514\nFax: 02-472-7898\nE-mail: krkim@amc.seoul.kr\nDepartment of Pathology, University of\nUlsan College of Medicine, Asan\nMedical Center, Seoul, Korea\nReceived : July 4, 2008\nAccepted : December 16, 2008\nEndometriosis is defined as the growth of endometrial glands\nor stroma outside the uterine cavity.1 Intestinal endometriosis is\nrelatively uncommon, occurring in 5% of women with endom-\netriosis,\n1,2 and the involved sites include the rectum, sigmoid,\nappendix, terminal ileum, and cecum, in descending order of\nfrequency.\n3 Patients usually experience abdominal or rectal pain,\ntenesmus, constipation, diarrhea, loose stools, and hematochezia,\ndepending on the site involved.\n1,2 Because many patients pre-\nsent with gastrointestinal symptoms, radiologic examination or\nendoscopy of the intestinal tract is usually performed at the ini-\ntial presentation,\n4 often leading to misdiagnoses as various inflam-\nmatory lesions or tumors of the intestine based on the findings\nof obstructive or infiltrative masses.2,5,6 We therefore sought to\nidentify the pathologic characteristics of intestinal endometrio-\nsis by assessing the histopathologic and immunohistochemical\nproperties of endoscopic biopsy and resected specimens. Since\ndiagnosis of intestinal endometriosis in the resected specimens\nis rarely a problem, we particularly focused on endoscopic biop-\nsy specimens.\nMATERIALS AND METHODS\nThe surgical pathology files of the Department of Pathology,\nAsan Medical Center (Seoul, Korea), contained 18 verified sam-\nples of intestinal endometriosis from 15 patients between 1996\nand 2006. Among these patients, 4 had been diagnosed with\nintestinal endometriosis based on endoscopic biopsy alone, one\nhad surgical resection after repeated endoscopic biopsies (case 5),\nand 10 underwent surgical resection only (cases 1-4 and 6-11).\nThe gross and microscopic findings and the patients’clinical re-\ncords were reviewed in all cases. \nIn 17 samples, immunohistochemical staining was performed\non formalin-fixed and paraffin-embedded tissue sections using\nan autostainer (Ventana Medical Systems Inc., Tucson, AZ, USA).\nThe primary antibodies used were cytokeratin (CK) 7 (1:200\ndilution; DAKO, Glostrup, Denmark), CK20 (1:200 dilution;\nDAKO), CD10 (1:50 dilution; NOVO, Newcastle, UK), estro-\ngen receptor (ER, 1:400 dilution; NeoMarkers, Fremont, CA,\nUSA), and progesterone receptor (PR, 1:400 dilution; NeoMark-\n\nIntestinal Endometriosis  121\ners).After incubation with the primary antibodies, immunode-\ntection was performed with biotinylated anti-mouse immuno-\nglobulin followed by peroxidase-labeled streptavidin, using the\nLSAB kit (DAKO) and 3,3\n′-diaminobenzidine chromogen as the\nsubstrate. An endogenous biotin blocking kit was used to reduce\nnon-specific immunopositivity (Ventana Medical Systems Inc.).\nDiaminobenzidine was used as a chromogen, and tissues were\ncounterstained with hematoxylin. \nRESULTS\nClinical findings\nThe median patient age at the time of diagnosis was 41 years\n(Table 1). The presenting clinical symptoms included abdomi-\nnal pain (8/15 [53.3%]), hematochezia (6/15 [40.0%]), tenesmus\n(2/15 [13.3%]), and constipation (2/15 [13.3%]). Two patients\n(cases 4 and 10) exhibited no clinical symptoms, but intestinal\nendometriosis was incidentally detected during surgery for a vil-\nlotubular adenoma and an infertility work-up, respectively. Based\non radiologic and clinical findings, 5 patients (33.3%) were diag-\nnosed with colon cancer, 5 patients (33.3%) with ovarian cysts,\n3 patients (20%) with submucosal tumors of the large intestine,\n1 patient (6.7%) with invasion of ovarian cancer, and 1 patient\n(6.7%) with appendicitis. Endometriosis was located in the rec-\ntum in 8 (53.3%) patients, the appendix in 6 patients (40.0%),\nand the sigmoid colon in 1 patient (6.7%). In 8 patients (53.3%),\nintestinal endometriosis was associated with histologically-proven\novarian endometriosis, and 1 patient (6.7%) with adenomyosis,\nwhile the remaining 6 patients had no history of endometriosis.\nTAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; LAR, low anterior resection; RSO, right salpingo-oophorectomy, LOC, left\novarian cystectomy; BOC, bilateral ovarian cystectomy; LSO, left salpingo-oophorectomy; ROC, right ovarian cystectomy; P, perirectal soft tissue; S,\nserosa; M, proper muscle layer; Sm, submucosa; NT, not tested.\nCase Age Symptoms Clinical Associated Procedure Location Involved ER/PR/CD10/\nNo. impression endometriosis layers CK7/CK20\n1 50 Constipation Colon cancer Ovarian TAH, BSO, Appendix S, M +/+/+/+/ -\nendometriosis Appendectomy,\nSegmentectomy\n2 43 Abdominal pain, Colon cancer - LAR, Rectum P +/+/+/+/ -\nTenesmus, Appendectomy\nHematochezia\n3 53 Constipation, Colon cancer Ovarian LAR Rectum P, M +/+/+/+/\n-\nHematochezia endometriosis\n4 42 None Colon cancer - LAR Rectum P +/+/+/+/ -\n5 36 Tenesmus, Submucosal - Biopsy (x2), LAR, Rectum P, M, Sm +/+/+/+/ -\nDyspareunia tumor TAH\n6 42 Abdominal pain Appendicitis - Appendectomy Appendix S, M +/+/+/+/ -\n7 36 Abdominal pain Ovary cyst Ovarian RSO, LOC,\nendometriosis Appendectomy Appendix S, M NT\n8 39 Abdominal pain Ovary cyst Ovarian BOC, Appendix S, M +/+/+/+/ -\nendometriosis Appendectomy\n9 31 Abdominal pain Ovary cyst Ovarian LOC, Appendix S, M +/+/+/+/ -\nendometriosis Appendectomy\n10 35 None Ovary cyst Ovarian LSO,ROC, Appendix S, M +/+/+/+/ -\nendometriosis Appendectomy\n11 41 Abdominal pain, Ovary cyst Ovarian LSO, Sigmoid S, M, Sm +/+/+/+/ -\nHematochezia endometriosis Appendectomy,\nSegmentectomy\n12 41 Abdominal pain, Submucosal Adenomysosis Biopsy Rectum Sm -/-/+/+/-\nHematochezia tumor\n13 45 Hematochezia Colon cancer - Biopsy Rectum Sm +/+/+/+/ -\n14 47 Hematochezia Invasion Ovarian Biopsy Rectum Sm +/+/+/+/ -\novary cancer endometriosis\n15 38 Abdominal pain Submucosal - Biopsy (x2) Rectum Sm +/+/+/+/ -\ntumor\nTable 1.Clinicopathological and immunohistochemical findings in patients with intestinal endometriosis\n\n 122 Heejin Lee\n Kyu-Rae Kim\nPathologic findings\nEndoscopic biopsy specimens\nAmong the 4 patients diagnosed using endoscopic biopsy alone,\n1 was clinically suspected to have colon cancer, 2 with submu-\ncosal tumors, and 1 with colonic invasion of ovarian cancer. Seven\nendoscopic biopsy specimens were obtained from 5 patients (cases\n5, 12-15). Each specimen contained 2-5 pieces (average, 3.5) of\ncolonoscopic-biopsied mucosa. Endometriotic foci were relative-\nly well-delineated from the surrounding normal intestinal mucosa\n(Fig. 1A). All 7 biopsy specimens were characterized by non-muci-\nnousglandular structures lined by ciliated columnar epithelium\nand surrounded by cellular stroma containing abundant thin-\nwalled vasculature (Fig. 1B). Glands were irregular and larger\nin shape and size compared to the adjacent colonic mucosa, and\nlined by tall columnar epithelium cells with elongated nuclei\nshowing regular vertical orientation. Goblet cells were absent,\nin contrast to the adjacent normal colonic mucosa. The epithe-\nlium displayed immunopositivity for CK7 (Fig. 2A), but imm-\nunonegativity for CK20 (Fig. 2B), in contrast to overlying nor-\nmal colonic mucosa, which was negative for CK7 and positive\nfor CK20. In all samples, periglandular stroma was distinguished\nfrom the lamina propria of normal colonic mucosa by the pres-\nence of short, spindle-shaped cells with inconspicuous cytoplasm\nand abundant small vasculature. The stroma was immunoposi-\ntive for CD10 in the endometriotic foci, but negative in the lam-\nina propria of the colon (Fig. 2C). All but one case (case 12) sh-\nowed diffuse immunopositivity for ER in the endometrial glands\nand stroma (Fig. 2D), but endometriosis was confirmed in an\nER- and PR-negative case (case 12) based on the strong imm-\nunopositivity for CD10 in the stroma.\nSurgically-resected specimens\nAmong the 11 surgically-resected cases, the pre-operative diag-\nnoses were as follows: colon cancer in 4 patients, submucosal tu-\nmors (such as a gastrointestinal tumor) in 1 patient, acute appen-\ndicitis in 1 patient, and ovarian cysts in 5 patients. Grossly, all\n11 specimens had multifocal hemorrhagic spots on the serosal\nsurfaces. Apart from 4 cases with adenocarcinomas or villotubu-\nlar adenomas, the overlying mucosa of the resected specimens\nremained intact. Two patients (18.2%) displayed serosal surface\ninvolvement only, 7 patients (63.6%) showed involvement of\nthe serosa and muscle layers, and 2 patients (18.2%) had involve-\nment of the serosa to the submucosa. In cases 5 and 11, the intesti-\nnal walls were irregularly thickened and fibrotic. Moreover, in\ncase 5, focal cystic changes containing gray-brown material were\nidentified in the thickened wall. \nEndometriosis specimens associated with adenocarcinoma\nIntestinal endometriosis was associated with adenocarcinoma\nin the same segment in 2 patients (cases 2 and 3) and in differ-\nent segments in 1 patient (case 1). In cases 2 and 3, lesions of\nendometriosis and adenocarcinoma involved different layers of\nthe same segment, and 1 patient (case 3) contained an endometri-\noid adenocarcinoma arising from endometriosis in the same seg-\nment involving the entire thickness of the rectal wall from the\nmucosa to the perirectal soft tissue. \nClinical and pathological findings of the latter closely mim-\nicked those of primary colorectal cancer, with ulceration of the\noverlying mucosa (Fig. 3A, B), and the neoplastic glands focal-\nFig. 1. Endoscopic biopsy specimen showing rectal endometriosis. (A) Endometriotic focus in the submucosa (arrows) is relatively well\ndelineated from the surrounding normal colonic mucosa. (B) Non-mucinous ciliated epithelium and cellular stroma containing spiral arte-\nriole-like blood vessels are characteristic findings. \nA B\n\nIntestinal Endometriosis  123\nly contained mucinous epithelium (Fig. 3C). However, the mass\ngrew into the cystic space of endometriosis lined by endometri-\notic glands and stroma. The epicenter of the tumor was located\nin the deep muscle layer and perirectal soft tissue with only a\nsmall mucosal opening (Fig. 3A, B). In contrast to primary col-\norectal adenocarcinoma and overlying normal rectal mucosa,\nendometrioid adenocarcinoma was strongly immunopositive for\nER (Fig. 3D) and CK7 (Fig. 3E), but negative for CK20. \nDISCUSSION\nClinically, intestinal endometriosis can simulate irritable bowel\nsyndrome, acute appendicitis, inflammatory bowel disease, diver-\nticulitis, submucosal tumors, or intestinal carcinoma.\n7,8 While\nintestinal endometriosis is frequently associated with pelvic en-\ndometriosis,\n9 gastrointestinal symptoms may be the first mani-\nfestation of the disease.3 In our series, 4 patients (cases 5, 6, 13,\nand 15) presented with intestinal symptoms, such as abdominal\npain, tenesmus, and hematochezia, with no history of endometrio-\nsis. Therefore, intestinal endometriosis should be considered dur-\ning the differential diagnosis of intestinal lesions.\n4,10,11While intesti-\nnal endometriosis occurs more frequently in women of reproduc-\ntive age, this factor is not critical since disease onset in 2 of our\npatients occurred after 50 years of age, and one had surgical me-\nnopause 10 years before presentation. \nAdenocarcinoma can arise in endometriosis, albeit rarely.\n4,6,10-12\nThe histopathologic criteria for the diagnosis of primary adeno-\ncarcinoma arising in endometriosis include the following: 1)\nclear evidence of endometriosis within close proximity to the\ntumor, 2) no other primary site of adenocarcinoma, and 3) his-\ntologic appearance similar to native endometrium of the uterus.\nAdenocarcinoma in endometriosis is easily confused with prima-\nry colorectal carcinoma since tumor cells often contain mucin-\nFig. 2.Immunohistochemical findings in intestinal endometriosis. Endometrial glands are immunopositive for cytokeratin 7 (A) and negative\nfor cytokeratin 20 (B), in contrast to the surrounding normal colonic epithelium. (C) Dense periglandular stroma shows strong immunoposi-\ntivity for CD10 antibody. (D) Glandular epithelium and/or stroma are immunopositive for ER, in contrast to the surrounding colonic mucosa.\nA B\nC D\n\n 124 Heejin Lee\n Kyu-Rae Kim\nsecreting epithelium. However, the growth patterns are usually\ndifferent, as in our case.4 The epicenter of the tumor is usually\noutside the intestinal wall, but these tumors ultimately invade\nthe intestinal wall. Compared with primary colorectal carcino-\nma, the extent of mucosal involvement or the mucosal opening\nis generally smaller (Fig. 3A). Differentiation between adeno-\ncarcinoma arising in endometriosis and primary colorectal carci-\nnoma is crucial owing to better prognosis of the former and dis-\ntinct treatment plans.\n13\nIn conclusion, characteristic features of endometrial glands and\nstroma, including non-mucinous glands without goblet cells, cili-\natedcolumnar epithelium, and cellular stroma with spiral arte-\nrioles, are helpful in the diagnosis of intestinal endometriosis,\nwhich can be confirmed by immunohistochemical staining for\nFig. 3.Endometrioid adenocarcinoma arising in rectal endometriosis.\n(A, B) Gross and microscopic findings of the cut surface of the tumor\nshow its epicenter located in the deep muscle layer and perirectal\nsoft tissue with a narrow mucosal opening. (C) Adenocarcinoma focal-\nly contains mucinous epithelium (arrows), which mimics primary colonic\nadenocarcinoma. (D, E) Tumor cells are strongly immunopositive for\nER (D) and CK7 (E).\nA B\nC\nE\nD\n\nIntestinal Endometriosis  125\nCK7, CK20, ER, PR, and CD10.14-19\nREFERENCES\n1. Robboy JR, Anderson MC, Russell P. Endometriosis. In: Robboy JR,\nAnderson MC, Russell P, eds. Pathology of the female reproductive\ntract. London: Churchill Livingstone, 2002; 445-70.\n2. Kanthimathinathan V, Elakkary E, Bleibel W, Kuwajerwala N, Con-\njeevaram S, Tootla F. Endometrioma of the large bowel. Dig Dis Sci\n2007; 52: 767-9.\n3. Clement PB. Diseases of the peritoneum. In: Kurman RJ, ed. Blaus-\ntein’s pathology of the female genital tract. 5th ed. New York: Sp-\nringer-Verlag, 2002; 761-2.\n4. Hoang CD, Boettcher AK, Jessurun J, Pambuccian SE, Bullard KM.\nAn unusual rectosigmoid mass: endometrioid adenocarcinoma aris-\ning in colonic endometriosis: case report and literature review. Am\nSurg 2005; 71: 694-7.\n5. Varras M, Kostopanagiotou E, Katis K, Farantos C, Angelidou-Mani-\nka Z, Antoniou S. 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Mod Pathol 1996; 9: 1040-4.","source_license":"CC0","license_restricted":false}