Malignant transformation is an infrequent complication of endometriosis. The ovary is the primary site in 79 per cent of cases, and extragonadal sites are identified in 21 per cent. Primary involvement of these types of tumors with the colon and/or rectum is a rare clinical entity. Endometrioid carcinoma is a common histologic type that remains a diagnostic challenge-the main differential diagnosis includes colorectal carcinomas. We report a case of malignant transformation arising in colonic endometriosis. The patient had a total abdominal hysterectomy and bilateral salpingo-oophorectomy 10 years before she presented with hematochezia. The patient was ultimately treated by surgical resection. Immunohistochemical staining in addition to the usual histopathology was critical for accurate diagnosis of this endometriosis-associated intestinal tumor.
ENDOMETRIOSIS IS A COMMON benign gynecologic condition affecting about 10 per cent to 25 per cent of women evaluated for gynecologic complaints in the United States.1, 2 Intestinal endometriosis occurs in 3 per cent to 37 per cent of reported cases, typically involving areas where the peritoneum is irregularly folded such as the rectovaginal septum, rectum, and sigmoid colon.3 Malignant transformation of endometriosis is a rare but clinically significant complication, occurring in up to 1 per cent of women.4 The ovary is the primary site in about 79 per cent of known cases, and extragonadal pelvic sites (rectovaginal septum, vagina, omentum, umbilicus, broad ligament, ureter, vesicovaginal septum, etc.) represent about 21 per cent.5 The colon and/or rectum are involved in only 5 per cent of cases.6 In this article, we present a case of endometrioid adenocarcinoma of the rectosigmoid colon wall, originally diagnosed as a rectal cancer.
Case Report
A 60-year-old woman (gravida 4, para 3), who had undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy 10 years earlier because of extensive endometriosis, presented with hematochezia. She was otherwise asymptomatic. Her past medical history was remarkable for type 11 diabetes and hypothyroidism. Her father had a history of colon cancer in his 60s, and her grandfather had an undefined gastrointestinal tumor. No other family members had colorectal or endometrial neoplasms. She was taking oral estrogen replacement (Premarin).
The patient underwent colonoscopy, which revealed a 3.5 to 4 cm sessile polyp on the anterior rectal wall, which was partially excised (Fig. 1). Pathology revealed a moderately differentiated adenocarcinoma presumably of rectal origin. Subsequent computed tomography scan showed no evidence of metastatic disease. She was referred to our institution for definitive therapy. Flexible sigmoidoscopy and rigid proctoscopy revealed a small focus of residual tumor (
Gross pathologic review of the specimen revealed a 2 cm^sup 3^ mural mass extending through the muscularis propria of the upper rectum into the perirectal fat. Histologic review showed areas of benign endometriosis (bland endometrioid glands and associated stroma) as well as foci of well-differentiated endometrioid adenocarcinoma (FIGO grade I of III) over the entirety of the rectal wall mass (Fig. 2). A total of nine mesenteric lymph nodes were examined but did not reveal any evidence of malignancy. In the context of these findings, re-review of the original colonoscopic biopsy specimen showed that its morphology was identical to the present rectal wall tumor. Immunoperoxidase stains were used to confirm the mullerian origin of the tumor. A CDlO stain was used because it selectively highlights endometrial stroma in areas of endometriosis and of adenocarcinoma. The tumor cells were positive for CA-125 and negative for carcinoembryonic antigen. When the keratin subtypes were examined, the tumor displayed an endometrial phenotype with positive cytokeratin 7 and negative cytokeratin 20 (Fig. 3). In contrast, cells of gastrointestinal origin show the opposite immunophenotype: negative cytokeratin 7 and positive cytokeratin 20.7 Overall, the immunostaining pattern from our panel of tumor markers is highly specific for endometrioid adenocarcinoma. The final pathologic diagnosis was primary endometrioid adenocarcinoma arising in rectal wall endometriosis. Pathologic specimens from the patient’s hysterectomy and oophorectomy specimen 10 years earlier were subsequently reexamined and found to contain only benign endometriosis.
FIG. 1. Colonoscopic view of a sessile polyp. A large sessile polyp of the colorectum is shown located in the anterior colon wall (black arrow).
Discussion
Since 1925, when Sampson first described the phenomenon of malignant transformation of endometriosis (both in gonadal and extragonadal sites), a steadily growing number of cases have been reported.5 A subset of these cases had gastrointestinal tract involvement and were classified as endometriosis-associated intestinal tumors (EAITs).8 Because colorectal cancer is far more common than EAIT, it is not uncommon for these tumors to be confused with colorectal carcinoma. Diagnosis of EAIT is based on the following classic criteria: tumor cells arising in benign tissue (not invading from another source), the presence of tissue resembling endometrial stroma surrounding epithelial glands, and microscopic endometriosis contiguous with the malignant tissue. In our case, additional histologie techniques were used to confirm the gynecologic origin of this tumor.
FIG. 2. Microscopic views of endometrioid adenocarcinoma. Top panel: A hematoxylin and eosin-stained low-magnification, cross- sectional view encompassing the colonie tumor mass and layers of colon wall is shown. Bottom panel: An enlarged view of tumor cells is shown from the white box inset. Tumors cells have a mucosal location and are polypoid in shape, thus mimicking the more common colon adenocarcinomas.
EAIT is an extremely rare tumor, and the current case represents only the 19th report of a primary EAIT and 10th report where the patient was using unopposed estrogen.9 All 19 cases of primary adenocarcinomas, to date, occurred at the rectosigmoid colon, likely as a consequence of this anatomic location having the highest incidence of endometriosis.10,11 These tumors typically occur in women from age 30 to 60 years, earlier than most colorectal cancers. The most common signs and symptoms are abdominal and/or pelvic pain, pelvic mass, vaginal bleeding, or bloody stools. However, these tumors are often discovered incidentally as serosal nodules during surgical exploration for other reasons.12 Less commonly, patients may present with small or large bowel obstruction resulting from a mass or an acute abdomen secondary to acute appendicitis,13 intussusception,14 or perforation.15
FIG. 3. Immunostaining of tumor mass reveals a mullerian origin. Cytokeratin (CK) immunostaining was performed. Tumor cells of interest are highlighted (black arrow) and show an endometrial phenotype, staining positive for CK7 and negative for CK20.
On gross exam, endometriosis usually involves the serosa and subserosa (up to 70%8), although involvement of the deeper bowel layers (muscularis propria, submucosa, or even mucosa) may be seen in symptomatic patients.5 Tumors arising in endometriosis are predominantly limited to their site of origin of the benign disease. Transmural tumors show a typical dumbbell shape characterized by a bulky serosal and polypoid mucosal tumor connected by a narrower neoplastic waist that extends through muscle bundles of the muscularis propria.8 The most common histologie subtype is endometrioid adenocarcinoma of low to intermediate grade,5 sometimes with squamous differentiation. Other less common histologie types include sarcoma, clear cell, squamous cell, or mixed germ cell.
Histologie examination of superficial, endoscopie biopsy material may be difficult to assess definitively for multiple reasons. The limited amount of specimen available may not contain diagnostic endometriotic glands and stroma. Nonspecific, chronic changes may be seen and misinterpreted as other pathologies such as inflammatory bowel disease16 or solitary rectal ulcer syndrome.17 In other instances, the tumor may have overgrown the tissue of origin (endometriosis), completely destroying it and thus mimic a primary colon carcinoma.5 Finally, the mucosa is frequently normal or shows minimal changes if sampled endoscopically because endometriosis usually involves the outer bowel wall.
Endometrioid adenocarcinoma is the EAIT most likely to be confused with a colorectal carcinoma, as was the case for our patient. Primary colon carcinoma always involves the bowel mucosa and may be associated with adenomatous changes or a neoplastic polyp. Advanced colon carcinomas may extend from the mucosa throughthe bowel wall and to the serosal surface or adjacent fat. In contradistinction, endometriosis and cancers arising in it show the opposite pattern of growth in the bowel, arising in an extramural location and invading into the bowel wall from the outside. Endometrioid carcinomas typically form tubular glands with “clean” luminal contents. Their neoplastic cells lack mucin and have an Alcian blue-positive glycocalyx. The key morphologic feature, obviously, is the presence of a background of benign endometriosis to differentiate endometrioid adenocarcinoma from colon carcinoma. Despite these criteria to identify EAIT, the practical reality of accurate diagnosis is difficult especially with poorly differentiated tumors. To prevent possible diagnostic errors, we recommend the routine use of immunochemistry in all cases of EAIT for confirmation. The suggested minimal number of markers required is 2, corresponding to the cytokeratin subtypes 7 and 20.7 In a study of 165 tumors, 86 per cent of the endometrioid tumors and none of the colorectal carcinomas showed a positive cytokeratin 7, negative cytokeratin 20 immunostaining pattern, whereas 96 per cent of the colorectal carcinomas and none of the endometrioid tumors showed a negative cytokeratin 7, positive cytokeratin 20 pattern.18
Exogenous estrogen is widely accepted as a contributing factor in the development of premalignant or malignant transformation of endometriosis.19’20 In their review of the literature, Jones et al.9 reported nine cases of primary EAIT arising in the rectosigmoid colon in patients using unopposed estrogen for several years prior to the development of cancer. They concluded that their findings supported a causal, cancercausing role for unopposed estrogen. This has led some authors to recommend a routine short course of a progestin to suppress residual endometriosis before the initiation of estrogen replacement.5,21 Malignancy associated with hyperestrogenism correlated most frequently (69%) with well- differentiated adenocarcinomas.20 Overall, the prognosis for estrogen-stimulated EAIT arising in any gastrointestinal site is highly favorable with a survival rate of 82 per cent at 5 years.5
Treatment for this disease has been variably reported in the literature and is highly individualized. In most cases of nonmetastatic EAIT, if feasible, primary surgical treatment with complete resection of all dis ease should be performed. General indications for surgery include pain, bleeding, altered bowel habits, and intestinal obstruction.22 The therapeutic value of chemoradiation for metastatic EAIT is of unclear value.5 The situation is similar in the adjuvant setting after complete resection of disease because of only sporadic reports.12
In summary, EAIT is a rare but clinically significant disease predominantly affecting postmenopausal patients. Clinical suspicion should arise in patients previously treated for endometriosis who later present with abdominal pain or rectal bleeding, especially in those who have received unopposed estrogen hormone replacement. These tumors can be diagnostically challenging because they can resemble common primary neoplasms of the gastrointestinal tract both clinically and pathologically. More frequent use of confirmatory immunohistochemical panels may reveal that the incidence and prevalence of malignant transformation in endometriosis may be higher than current estimates. Awareness and recognition of these types of tumors by surgeons, therefore, may result in better overall care to affected patients.
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CHUONG D. HOANG, M.D.,* ADAM K. BOETTCHER, B.S.,* JOSE JESSURUN, M.D.,[dagger] STEFAN E. PAMBUCCIAN, M.D.,[dagger] KELLI M. BULLARD, M.D.*,[dagger]
From the Departments of * Surgery and [dagger] Laboratory Medicine and Pathology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota
Address correspondence and reprint requests to Kelli M. Bullard, M.D., University of Minnesota, MMC 450, 420 Delaware Street S.E., Minneapolis, MN 55455.
Copyright The Southeastern Surgical Congress Aug 2005
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