This woman in her 40s presented with small bowel obstruction and significant weight loss, leading to a clinical concern for inflammatory bowel disease and malignancy. Although histologic diagnosis of the ileo-cecal mass was straightforward and rendered at the time of intra-operative evaluation, clinical presentation was atypical enough to warrant a review of literature on endometriosis of the GI tract.
Endometriosis is defined as the presence of ectopic endometrium-like tissue outside the mucosal lining of the uterus. Both glands and stroma are necessary for diagnosis. The overall prevalence is estimated to be 5-10% of women of child-bearing age. The ovaries are the most common sites of involvement. Endometriosis has been reported in multiple organs including the lungs, urinary bladder, pleura and skin. While the exact incidence at these sites is not known, it is generally considered rare compared to pelvic disease. The gastrointestinal tract is the most common extrapelvic site of involvement, with most cases being reported in the rectosigmoid colon, followed in descending order of frequency, by rectovaginal septum, the ileum, jejunum and cecum. Symptoms including vomiting, diarrhea, constipation and cramps, most often result from obstruction. Involvement of rectum and/or rectovaginal septum may result in pain on defection.
A case report of a 26-year-old woman describes ileocecal endometriosis presenting with cecocolic intussusception, a cecal mass on barium enema, and gastrointestinal hemorrhage (1). Similar to our case, histopathology showed serosal and subserosal endometrial implants, without mucosal involvement. However, the cecal mucosa also showed ulceration and ischemic changes secondary to intussusception. Rarely, endometriosis involving the intestinal mucosal surface presents as a polypoid mass and hematochezia, and may cause diagnostic confusion with a primary colonic malignancy on endoscopic biopsy (2). Villous atrophy resulting in protein-losing enteropathy and anasarca is a less common clinical presentation (3).
In a study of over 1500 patients with pelvic endometriosis diagnosed at laparoscopy, 5.4% also had gastrointestinal tract involvement. However, only 0.7% underwent bowel resection, most commonly due to presence of obstructive gastrointestinal symptoms or inability to exclude malignancy. None of the patients with appendiceal endometriosis (<1% of all cases) showed symptoms of appendicitis suggesting the asymptomatic nature of the disease in this anatomic location (4).
Laparoscopy and laparotomy remain the gold standard for diagnosis. As illustrated by our case, most lesions are extramucosal to the GI tract and therefore may not be identified by endoscopic biopsy procedures. Likewise, radiology may not show any abnormalities until late in the disease process, when enteroclysis or a barium enema can show eccentric deformation of small or large bowel respectively. Data concerning treatment options are limited to case reports and few retrospective studies. Surgical resection appears necessary only when complete obstruction occurs or malignancy is suspected. The need for concurrent hysterectomy and bilateral salpingo-oopherectomy is not well-established, although one study suggests a beneficial effect on "cure rate", which is not statistically significant. Ectopic endometrial tissue responds unpredictably to hormonal manipulation and the exact role of medical treatment of extrapelvic disease is not known.
The other interesting aspect in this case was the presence of "bland" glandular inclusions (BGIs) without the characteristic endometrial stroma in two lymph nodes. Two additional lymph nodes showed typical endometriotic foci, similar to those seen in the ileocecum. BGIs have been described in pelvic and para-aortic lymph nodes (5, 6). They are found exclusively in women, and classically are composed of cystically dilated glands lined by single layer of cuboidal to columnar epithelium that is often ciliated (tubal-type). Cytoplasmic or intraluminal secretions may be present as can periglandular and intraglandular calcifications resembling psammoma bodies. In most cases the glands are located within the fibrous capsule or in the cortical portion of the lymph nodes, although some authors report presence within the capsular sinusoid (5, 7).
Multiple theories have been proposed to explain BGIs in lymph nodes. Sloughing of fallopian tube epithelium with peritoneal implantation and subsequent lymphatic drainage to lymph nodes has led to the term "endosalpingiosis" being applied to these lesions. Although they do not have a stromal component, derivation from endometriotic tissue has been proposed as a possible mechanism as is metaplasia of the secondary mullerian system of coelomic-derived peritoneum. While much of the current literature considers BGIs as benign lesions, their biologic significance is not entirely clear (see below). Difficulties in differentiating them from nodal metastases have been reported (5). Rare cases of serous borderline and malignant tumors arising from these bland lesions have been described as well (8).
Recently, Moore et al. studied the clinicopathologic features of 62 patients with microscopic BGIs (referred to as mullerian inclusion cysts in their paper) present in lymph nodes and peritoneum (9). Their results showed a high prevalence of these lesions in patients with tumors of the ovary compared to other gynecologic conditions/tumors (58% of all cases). Endometriosis was present as an isolated finding in only 5 cases, with 3 cases showing endometriosis outside the ovary. Another study reports BGIs in pelvic lymph nodes in 65% of patients with borderline serous ovarian tumors, with progressively lower incidence of BGIs seen with tumors of higher grade (10). These findings, together with absence of BGIs in ovarian tumors of other histologic subtypes (eg mucinous tumors) as well their distribution predominantly in para-aortic lymph nodes (that primarily drain the ovaries) have led some investigators to hypothesize that BGIs could represent well-differentiated metastases of serous borderline tumors. In a study of 6 serous borderline tumors of the ovary, k-ras oncogene mutations were seen in 2 primary tumors and their associated BGIs, giving weak support to this hypothesis (11).
Currently, the histologic variable that has consistently been shown to be an adverse prognostic indicator in serous borderline tumors of the ovary is the presence of invasive implants (12). In the absence of invasive implants, patients with advanced stage tumors have a relatively favorable outcome with a survival rate of over 95% (12). With this background, it is unlikely that BGIs, irrespective of controversies over their neoplastic nature, would adversely affect prognosis in serous ovarian neoplasms.
Diagnosis and management of BGIs in the absence of a primary ovarian tumor, is also unclear. In addition to morphologic features discussed earlier, immunohistochemical stains may be helpful in differentiating mullerian epithelium from metastases of other organ systems. Majority of BGIs express hormone receptors and this feature may be applied diagnostically (13). In our case, a PCR-based study using a panel of fifteen polymorphic markers associated with tumor suppressor genes was performed to evaluate for loss of heterozygosity and hence cumulative mutational damage in one BGI. The same panel was also applied on the epithelial component of endometriosis in the ileocecal mass. Both the BGI as well as the ileo-cecal endometrioma showed no loss of heterozygosity in any of the markers tested, confirming that the nodal glandular lesions are similar to the ileocecal mass and most likely represent a reactive rather than a neoplastic process.
This case demonstrates that endometriosis should be considered in the clinical differential of obstructive GI symptoms in women of reproductive age-group and also in the histologic differential of intranodal bland glandular inclusions.
Contributed by Hina Sheikh,MD, Uma Krishnamurti, MD, PhD and Swaminathan Rajendiran,MD