ORIGINAL ARTICLE
Appendiceal or Cecal Endometriosis With Intestinal Metaplasia A Potential Mimic of Appendiceal Mucinous Neoplasms Joseph Misdraji, MD,* Gregory Y. Lauwers, MD,* Julie A. Irving, MD,w Kenneth P. Batts, MD,z and Robert H. Young, MD*
Abstract: Appendiceal or cecal endometriosis uncommonly presents diagnostic challenges, but rare cases with intestinal metaplasia can mimic mucinous tumors of the appendix. We describe 6 cases of appendiceal or cecal endometriosis with intestinal metaplasia that grossly and microscopically mimicked appendiceal mucinous tumors. The cases were characterized by marked mural hypertrophy and elastosis, with distortion of the appendix, and virtual obliteration of the lumen of the appendix. All cases had conventional endometriosis, together with varying amounts of endometriosis with intestinal-type epithelium. In 2 cases, scant or virtually no stroma around some mucin-filled glands made their recognition as endometriosis more difficult. None of the cases had dysplasia of the mucinous epithelium. All patients had benign follow-up (mean 3.6 y). Endometriosis with intestinal metaplasia is a rare phenomenon that, when it occurs in the appendix or cecum, may lead to misdiagnosis as a lowgrade appendiceal mucinous neoplasm or mucinous carcinoma. Key Words: appendix, cecum, endometriosis, intestinal metaplasia, low-grade appendiceal mucinous neoplasm, mucinous adenocarcinoma (Am J Surg Pathol 2014;38:698–705)
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ndometriosis involves the appendix rarely, often in the context of intestinal involvement by endometriosis.1 When it does involve the appendix, it may produce interesting clinical situations, such as appendiceal perforation in pregnant women,2,3 intussusception of the appendix,4–9 or retention mucocele.10–12 Although these manifestations can cause diagnostic challenges for surgeons, endometriosis rarely causes diagnostic confusion From the *James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA; zHospital Pathology Associates, Virginia Piper Cancer Institute, Minneapolis, MN; and wDepartment of Pathology, University of British Columbia, BC, Canada. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Joseph Misdraji, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Warren Building, Boston, MA 02114 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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for pathologists when it is typical. However, endometriosis can be associated with less common microscopic appearances, such as stromal endometriosis, decidual change, or neoplastic changes, that can cause diagnostic challenges for pathologists. One particular additional uncommon microscopic change that may cause confusion with a neoplasm is the subject of this report, specifically, endometriosis of the appendix and cecum in which the endometrial glands are partly replaced by intestinal epithelium, a process reported rarely as either intestinal metaplasia or intestinal colonization.13–16 These examples of appendiceal endometriosis have several features that mimic appendiceal mucinous neoplasms, particularly lowgrade appendiceal mucinous neoplasms (LAMNs), and have the potential for serious diagnostic error. We report our experience with 6 cases of appendiceal or cecal endometriosis with intestinal metaplasia to highlight this rare phenomenon and to describe features that distinguish this entity from LAMN.
METHODS Cases of appendiceal endometriosis with intestinal metaplasia were compiled from the consultation files of several of the authors. One of the cases was contributed from the consultation files of Dr Philip B. Clement. All slides were reviewed by one of us (J.M.), and, when available, immunohistochemistry was reviewed. Clinical data were obtained by contacting referring pathologists, surgeons, or gynecologists.
RESULTS Clinical Findings The 6 women ranged in age from 39 to 71 years (mean 52 y). Three of them were surgically explored for an appendiceal abnormality or mass; 1 of these was found to have a perforated appendix. Two were operated on for a cecal mass at the appendiceal orifice. One of these 2 women had a history of endometriosis and a remote history of having undergone appendectomy, the pathology of which was not available, and the other woman was presumed to have congenital absence of the appendix. One patient (case 2) was described as having a “pelvic mass” and was found to have a complex right adnexal mass adherent to the cecum, Am J Surg Pathol
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Appendix Endometriosis With Intestinal Metaplasia
TABLE 1. Clinical Data on 6 Women With Appendiceal or Cecal Endometriosis With Intestinal Metaplasia Case Age
Relevant History
Presentation
Surgical Procedure
1
52
—
2
53
—
3
39
—
4
49 Endometriosis and remote history of appendectomy 71 —
Rectal bleeding; pericecal mass Abnormal appendix
Right colectomy, left ovarian cystectomy, and omentectomy Right hemicolectomy
50 Presumed congenital absence of appendix
Cecal mass
Cecectomy
5 6
Appendiceal mass with Appendectomy and cecectomy normal ovaries Pelvic mass Appendectomy, hysterectomy, and bilateral oophorectomy Perforated appendix Appendectomy
encompassing the appendix, with mucin extruding from it at the time of surgery (Table 1). Three patients had the appendix, cecum, or both removed. The patient with the complex right adnexal mass had appendectomy, hysterectomy, and bilateral oophorectomy. Two patients underwent right hemicolectomy. The referring pathologic diagnosis was known in 5 cases, and in all 5 there was concern for a mucinous neoplasm arising from endometriosis or independent of endometriosis, but the exact type of mucinous tumor varied from cystadenoma to mucinous borderline tumor or LAMN, to low-grade mucinous adenocarcinoma. Follow-up information is available for 5 patients, and the other case is recent. One patient had a second procedure at 6 months that revealed conventional endometriosis in the ovaries and on the uterine serosa. All patients are alive and without evidence of mucinous neoplasia at 1 to
Interval (y)
Follow-up No evidence of mucinous neoplasia or pseudomyxoma No evidence of mucinous neoplasia or pseudomyxoma No evidence of mucinous neoplasia or pseudomyxoma —
3 2 7 Recent
No evidence of mucinous neoplasia or pseudomyxoma No evidence of mucinous neoplasia or pseudomyxoma
4 1
7 years (mean 3.6 y). None developed pseudomyxoma peritonei.
Pathology Four cases had gross features suggestive of a cystic mucinous tumor of the appendix. In case 2, the right ovary was described as a complex cystic mass with mucin, adherent to the cecum and incorporating the appendix. The patient with a history of a prior appendectomy had an appendiceal stump that segued into a mucin-filled cyst alongside a multinodular cecal mass. In 1 case, the appendix was described as white and rubbery with a 1 cm mucin-filled cyst. The patient with presumed congenital absence of the appendix had a 2.3 cm mural mass in the cecum. The appendix was submitted in its entirety in all 6 cases (Table 2).
TABLE 2. Pathologic Findings in 6 Cases of Appendiceal or Cecal Endometriosis With Intestinal Metaplasia
Case 1 2
3 4
5 6
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Gross Findings Distorted, red appendix with 3 cm cystic gelatinous mass Irregular nodular appendix and attached to a 6 cm cyst. Right adnexal mass was adherent to cecum and appendix, and contained mucin Appendix white and rubbery with 1 cm cyst filled with mucin 3.5 cm multinodular pink-tan cecal mass with appendiceal stump along 1 aspect and adjacent cyst resembling mucocele Dilated appendix filled with thick mucin 2.3 cm mural mass in cecum
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Immunophenotype of Endometrial Glands and Stroma
Immunophenotype of Intestinal Metaplastic Epithelium
Other Sites of Endometriosis
Goblet mucinous cells only Goblet mucinous cells only
Not done
Not done
—
Not done
Not done
Right ovary (with focal intestinal phenotype), uterine serosa, left adnexa
Goblet mucinous cells only
Not done
Not done
Bilateral ovaries and uterine serosa
Goblet mucinous cells and focal endocrine cells
Not done
Not done
Left ovary and omentum
Cytokeratin 7, ER, PR positive Stroma: CD10 positive. Glands: cytokeratin 7, CA125, and ER positive
Cytokeratin 20, CDX2 positive Cytokeratin 20 and CDX2 positive
Intestinal Cell Types in Endometriosis
Goblet mucinous cells only Goblet mucinous cells and focal Paneth cells
— —
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Three cases had similar microscopic features, with marked distortion of the appendix secondary to fibromuscular hyperplasia and elastosis, making it impossible to identify a lumen or normal appendiceal mucosa microscopically. All 3 specimens had foci of conventional or atrophic endometriosis. Scattered among the endometriosis in a buckshot pattern were glands lined by tall mucinous cells resembling goblet cells and partly or completely invested in endometrial-type stroma (Fig. 1). In each case, some foci of endometriosis had only glands composed exclusively of goblet-like mucinous cells, and some foci had both endometrial-type and intestinal-type glands (Fig. 2). In some glands, the mucinous epithelium appeared hyperplastic with tall mucin vacuoles. In 2 cases, the 2 epithelia lined the same gland with an abrupt transition between the 2 types. Some endometriotic foci with intestinal phenotype were only partially invested by endometrial-type stroma, with some intestinal-type glands abutting muscularis propria or elastotic stroma. Most of the glandular units were small to medium sized, typical of endometriosis, although several mucinous glands assumed a larger more tortuous appearance. The distortion of the appendiceal architecture in these cases made it impossible to determine with certainty whether the intestinal epithelium involved endometriotic foci only
close to the lumen or throughout the appendiceal wall. All cases were associated with at least a moderate amount of extruded mucin in the mesoappendix or on the serosal surface. No case had endocrine cells or Paneth cells. None of these 3 cases had dysplasia of the endometriotic epithelium or of the mucinous epithelium. None showed other forms of metaplasia that occur in endometriosis. The case with an appendiceal stump (case 4) showed a recognizable appendiceal orifice at the proximal end of the specimen, with endometriosis and mural thickening. In this case, the endometriosis focally extended into the base of the appendiceal mucosa at the appendiceal orifice. Distally, there was a cystic structure partly surrounded by attenuated muscularis propria and partly lined by fibrotic tissue with dystrophic calcifications. The cyst was filled with mucin and focally lined by reactive-appearing intestinal epithelium. The endometriosis with intestinal phenotype comprised goblet cells and, focally, cells with subnuclear eosinophilic granules resembling colonic endocrine cells. The mucinous epithelium showed mild nuclear stratification interpreted as reactive. In 2 cases, some of the mucinous epithelium dissecting the appendix or cecal wall was not clearly invested with endometrial stroma, and a second process was more difficult to exclude. In 1 of these 2 cases, the appendiceal
FIGURE 1. Low-power view of appendiceal endometriosis with intestinal metaplasia with a buckshot pattern of scattered glands, some of which are lined by mucinous cells.
FIGURE 2. Endometriosis with glands lined by endometrialtype epithelium (upper right) and by hyperplastic goblet-like mucinous epithelial cells (lower left).
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lumen appeared dilated, and the mucosa was partially denuded with an inflammatory reaction. Focally, the flat mucosa lining the dilated lumen showed nuclear stratification and superficially eroded through the muscularis mucosae with an elastotic reaction. It was unclear whether this process represented a retention cyst with reactive atypia or a LAMN. No villous mucinous proliferation was present. The endometriosis in this case was atrophic with minimal stroma and involved the appendix, cecum, and ileocecal region. Focal intestinal metaplasia was noted, with intestinal-type epithelium abutting on endometrial-type epithelium. Separately, several large mucin-filled glands lined mostly by intestinal-type epithelium but focally by attenuated epithelium lacked stroma and dissected the muscle of the cecum and ileocecum (Fig. 3). These glands were difficult to confirm as endometriosis and suggested the possibility of dissecting LAMN, but careful study of the immunohistochemical stains showed that the attenuated portion of the lining epithelium marked for keratin 7 and ER, and small clusters of CD10-positive stromal cells undermined these areas.
FIGURE 3. Example of endometriosis with intestinal metaplasia in which the intestinal component produces large mucin-filled glands with virtually no stroma, mimicking a dissecting LAMN. Note the endometriosis at the lower left. Immunohistochemistry in a similar gland nearby showed areas of the gland lined by ER-positive endometrial-type epithelium. r
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In the second of these 2 cases (case 6), the cecal mass consisted of nodular smooth muscle and elastotic tissue with endometriosis. The overlying cecal mucosa was distorted, ulcerated, and puckered. In the submucosa, several mucinous glands were invested by lamina propria, and, in the muscularis propria, several cystic intestinal glands were either devoid of stroma or cuffed by edematous lamina propria with eosinophils and plasma cells, consistent with colitis cystica profunda due to the distortion of the muscularis propria secondary to endometriosis. Endometriosis focally involved the overlying mucosa (Fig. 4). In isolated areas, endometriosis merged with intestinal-type glands with focal Paneth cells (Fig. 5), with both types of epithelium in the same endometriosis deposit and even in the same gland accompanied by pools of mucin. Several mucinous glands had stratification and mitotic figures, interpreted as reactive. Immunohistochemical staining analyses were performed on 2 cases (cases 5 and 6) and demonstrated an inverse staining pattern for the endometrial and intestinal epithelia. In 1 case, endometrial glands stained for keratin 7, estrogen, and progesterone receptors, whereas intestinalized areas stained with cytokeratin 20 and CDX2 (Fig. 6). The other case showed staining of endometrial stroma with CD10, endometrial glands with cytokeratin
FIGURE 4. Endometriosis merging with the base of the overlying cecal mucosa. www.ajsp.com |
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FIGURE 5. Endometriosis with intestinal metaplasia and focal Paneth cells (arrowheads).
7, estrogen receptor, and CA125, and intestinalized glands with cytokeratin 20 and CDX2. Three women had endometriosis documented outside the appendix or cecum. The patient whose appendix was cystic and adherent to the right ovary had endometriosis in the right ovary, left adnexa, and uterine serosa. In the right ovary, the endometriosis showed focal intestinal-type epithelium, but the relationship of this area to the appendix was not apparent from the sections as the 2 organs had been separated before submission to pathology. In the other 2 patients, only conventional endometriosis was seen in extraintestinal sites.
DISCUSSION Appendiceal endometriosis may produce an array of confusing clinical complications. Decidualized endometriosis in pregnancy can cause symptoms of acute appendicitis.17 More dramatically, involution of decidualized endometriosis can lead to appendiceal perforation.2,3 The fibromuscular expansion typical of intestinal involvement by endometriosis can create a mass-like lesion that can become the lead point of appendiceal intussusception.4–9 This same muscular expansion can obstruct the appendiceal lumen and cause a retention mucocele.10–12 Pathologically, endometriosis rarely proves diagnostically challenging as its classic appearance with scattered endometrial glands surrounded
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by variable amounts of endometrial-type stroma is familiar to most pathologists. However, occasionally, endometriosis can have unusual appearances, including a variety of metaplasias, absence of an epithelial component (stromal endometriosis), intravascular growth, or polypoid growth pattern in the gastrointestinal tract or appendix,18–21 and then can cause diagnostic confusion with other processes, either benign or malignant. In addition, endometriosis can be the origin of extraovarian or extrauterine mu¨llerian-type tumors in women, which can present another set of challenges to pathologists.20,22 LAMNs are low-grade mucinous adenocarcinomas of the appendix that show a distinctive pattern of invasion of the appendix and that have the potential to spread to the peritoneum as pseudomyxoma peritonei and cause cystic ovarian masses.23,24 These tumors dissect into the appendix wall or show pushing invasion but not the destructive invasion of usual intestinal adenocarcinoma. These tumors, when confined to the appendix, are generally biologically benign. However, rupture of a LAMN with extrusion of mucin beyond the appendiceal serosa carries a low risk for recurrence as pseudomyxoma peritonei. Extrusion of mucin with mucinous epithelial cells outside the appendix confers a high risk for progressing to disseminated peritoneal disease.25,26 Obviously, a LAMN can coexist with appendiceal endometriosis.16,27 However, we have seen several examples of appendiceal endometriosis with intestinal metaplasia that mimicked low-grade appendiceal mucinous neoplasia. Previously, we reported our experience with diverticular disease of the appendix mimicking LAMNs.28 Appendiceal endometriosis with intestinal metaplasia represents another, rarer mimic of LAMN. As with appendiceal diverticular disease, endometriosis with intestinal metaplasia can lead to mucin extrusion on the appendiceal serosa, causing confusion with a ruptured LAMN. Unwary pathologists may report this as localized pseudomyxoma peritonei and may suggest that the patient is at high risk for developing disseminated pseudomyxoma peritonei. Depending on the approach to peritoneal neoplasia of the surgical team at the institution in which this patient is treated, this may, in extreme examples, subject the patient to additional surgery in an attempt to reduce that risk. Features common to all of our cases that may be mistaken for LAMNs include extrusion of mucin—sometimes abundant—in the mesoappendix or on the appendiceal serosa, marked distortion of the appendix, and intestinal-type mucinous epithelium dissecting through the appendiceal muscularis propria. However, other features of these cases were helpful in distinguishing them from LAMN (Table 3). Endometriosis is well known to be the origin of a subset of mu¨llerian tumors in women, and the gastrointestinal tract is no exception.20,22 This phenomenon has not been reported in endometriosis with intestinal colonization. It is, however, theoretically possible that endometriosis with intestinal colonization might develop dysplasia or neoplasia of the mucinous component and be the source of appendiceal or cecal mucinous tumors. One r
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FIGURE 6. Immunohistochemical profile of a gland in endometriosis lined by both intestinal-type and endometrial-type epithelium. The intestinal-type epithelium marks with cytokeratin (CK) 20 and CDX2, whereas the endometrial lining marks with CK7, ER, and PR.
report describes a case in which low-grade mucinous epithelial dysplasia arose in endometriosis with intestinal metaplasia in the appendix.14 Another report describes an appendiceal mucinous tumor occurring concurrently with endometriosis with intestinal metaplasia,16 but the r
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authors do not suggest that the mucinous tumor arose from the endometriosis. The possibility of reactive atypia in these distorted, inflamed appendices makes diagnosis of low-grade neoplasia difficult, and we would caution against overinterpretation of reactive changes in these www.ajsp.com |
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TABLE 3. Features of Endometriosis With Intestinal Metaplasia That Are Useful in the Distinction With LAMN Lack of a recognizable lumen or a mucinous tumor within the appendiceal lumen Presence of conventional endometriosis A buckshot pattern of small to medium-sized mucinous glands admixed with endometrial glands A cuff of endometrial stroma surrounding mucinous glands Hybrid glands with both endometrial and mucinous epithelium Immunohistochemistry for mu¨llerian and intestinal markers in difficult cases to demonstrate the hybrid nature of mucinous glands
cases as preneoplastic or neoplastic changes. The difficulty in distinguishing reactive epithelial changes in hyperplastic mucinous epithelium from LAMN is one of the reasons that appendiceal diverticular disease is often mistaken for LAMN,28 and this challenge is relevant in endometriosis as well. Others have commented on the ability of endometriosis with intestinal colonization to suggest a mucinous carcinoma that destroyed the appendix or in mistaking endometriosis with intestinal metaplasia as invasive neoplastic glands,15,16 emphasizing that the greater concern in these cases is overinterpretation of reactive atypia in hyperplastic mucinous epithelium lining these dissecting glands as an invasive low-grade mucinous tumor. Another entity that might enter into the differential diagnosis is a mucinous cystic neoplasm with ovarian-type stroma. These tumors occur most often in the pancreas, but have been described in the mesentery.29,30 We have seen a single case in the mesoappendix. However, these tumors occur as cystic tumors rather than scattered glands within the muscularis of the appendix and are lined by cuboidal or columnar mucinous cells that lack the gobletlike appearance of intestinal metaplasia seen in our cases. Endometriosis with mucinous metaplasia is a welldescribed phenomenon, although typically this is of endocervical type, and intestinal metaplasia is rare.1,20 Although intestinal metaplasia is included in comprehensive descriptions of endometriosis,1,31 a literature search of this phenomenon reveals only a few appendiceal or cecal examples and only isolated examples in other sites.32 The mechanism of intestinalization of endometriosis is unknown, but 2 theories have been proposed: metaplasia and colonization of endometriosis.14,15 Although intestinal metaplasia certainly occurs in endometriosis, the predilection for intestinal metaplasia to occur in endometriosis of the appendix leads us to conclude that mechanical colonization of endometriosis by appendiceal mucosa may be responsible for some cases. First, a wellknown phenomenon that occurs in the colon is colonization of the mucosa by epithelia from other sources, such as colonization of the intestinal mucosa by metastatic tumors.33 In addition, mucosal involvement of the gastrointestinal tract or appendix by endometriosis can show colonization of the mucosal surface with endometrial-type epithelium or hybrid glands in the mucosa.13,20,34 Furthermore, the appendix is a small organ, and endometriosis is associated with marked distortion of that organ and, often, obliteration of the lumen. Other
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reported examples of intestinalized endometriosis in the appendix share this marked distortion or even obliteration of the appendix.14,15 The presence of colitis cystica profunda in 1 of our cases and 1 reported case13 raises another interesting mechanism by which the 2 epithelial types might merge. Therefore, it is highly probable that the process of colonization, which might remain limited to the mucosa in the colon or intestine, more often involves deeper portions of the appendix due to the marked distortion of that organ, diverticula, or colitis cystica profunda secondary to the muscular hyperplasia induced by endometriosis itself. In only 1 of our cases was intestinal-type epithelium found in endometriosis outside the appendix. In that case, the endometriosis in the right ovary had focal intestinal metaplasia but that ovary had been adherent to the appendix, and extension of the process into the ovary might account for this finding. It is worth noting that this patient had only conventional endometriosis in the contralateral adnexa and on the uterine serosa. Immunohistochemistry data were limited to 2 cases in our study, but the endometrial and intestinal epithelium each showed hormone receptor, CDX2, and cytokeratin 7/20 immunoprofiles typical of mu¨llerian and intestinal-type epithelium without dual expression. Others have suggested that the microenvironment of the appendix might be uniquely conducive to intestinal metaplasia of endometriosis, but we think this is unlikely. Endometriosis of the intestinal tract is not usually accompanied by intestinal metaplasia of endometriotic glands,20 and it is unlikely that the microenvironment of the appendix is altogether different from the colon. Some authors have noted that intestinal metaplasia in the appendix occurs more often in superficial endometriosis deposits than in deeper ones.14 In our cases, inability to identify the lumen of the appendix usually made this evaluation impossible; however, the presence of mucinous glands closer to the lumen of the appendix favors colonization. The presence of Paneth cells and endocrine cells together with the mucinous cells in intestinalized foci of endometriosis has also been quoted as an argument in favor of metaplasia over colonization.14 Most of our cases lacked cells other than goblet mucinous cells, although 2 cases had other cell types. Regardless, either colonization or metaplasia could account for 1 or multiple cell types, and superimposed mucinous hyperplasia might alter the epithelial cellular composition. In summary, we describe 6 cases of endometriosis of the appendix with at least focal and in many cases extensive intestinal metaplasia. These cases were often associated with marked distortion of the appendix, obliteration of the lumen, and mucin extrusion, causing concern for a LAMN. Inability to identify a luminal mucinous neoplasm, the presence of intestinal glands in continuity with endometrialtype glands, a cuff of endometrial-type stroma, and a buckshot pattern of scattered clusters of glands in the specimen are clues to the diagnosis of endometriosis with intestinal metaplasia. However, mucinous epithelial atypia and the absence of endometrial stroma around some dissecting glands make distinction from a LAMN difficult in some instances. r
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REFERENCES 1. Irving JA, Clement PB. Diseases of the peritoneum. In: Kurman RJ, Ellenson LH, Ronnett BM, eds. Blaustein’s Pathology of the Female Genital Tract. New York: Springer; 2011:649–678. 2. Gini PC, Chukudebelu WO, Onuigbo WI. Perforation of the appendix during pregnancy: a rare complication of endometriosis. Case report. Br J Obstet Gynaecol. 1981;88:456–458. 3. Nakatani Y, Hara M, Misugi K, et al. Appendiceal endometriosis in pregnancy. Report of a case with perforation and review of the literature. Acta Pathol Jpn. 1987;37:1685–1690. 4. Lauwers GY, Prendergast NC, Wahl SJ, et al. Invagination of vermiform appendix. Dig Dis Sci. 1993;38:565–568. 5. Jevon GP, Daya D, Qizilbash AH. Intussusception of the appendix. A report of four cases and review of the literature. Arch Pathol Lab Med. 1992;116:960–964. 6. Mann WJ, Fromowitz F, Saychek T, et al. Endometriosis associated with appendiceal intussusception. A report of two cases. J Reprod Med. 1984;29:625–629. 7. Langsam LB, Raj PK, Galang CF. Intussusception of the appendix. Dis Colon Rectum. 1984;27:387–392. 8. Schmidt FR, McCarthy JD. Intussusception of the appendix with endometriosis presenting as a cecal tumor. Arch Surg. 1971;103:515–517. 9. Hill BJ, Schmidt KD, Economou SG. The “inside-out” appendix. Radiology. 1970;95:613–617. 10. Hapke MR, Bigelow B. Mucocele of the appendix secondary to obstruction by endometriosis. Hum Pathol. 1977;8:585–589. 11. Nopajaroonsri C, Mreyoud N. Retention mucocele of appendix due to endometriosis. South Med J. 1994;87:833–835. 12. Driman DK, Melega DE, Vilos GA, et al. Mucocele of the appendix secondary to endometriosis. Report of two cases, one with localized pseudomyxoma peritonei. Am J Clin Pathol. 2000;113:860–864. 13. Kim J, Russell P, Arendse M, et al. Endometriosis in appendix and adjacent caecum with intestinal gland differentiation. Pathology (Phila). 2013;45:513–516. 14. Mai KT, Burns BF. Development of dysplastic mucinous epithelium from endometriosis of the appendix. Histopathology. 1999;35:368–372. 15. Tipps AM, Weidner N. Colonization of intestinal endometriosis by benign colonic mucosa: a pattern potentially misdiagnosed as invasive mucinous carcinoma. Int J Surg Pathol. 2011;19:259–262. 16. Libbrecht L, Snauwaert C, De Vos M, et al. Intestinal metaplasia and colonization of endometriosis in a case of an appendiceal mucinous neoplasm. Virchows Arch. 2012;461:227–229. 17. Suster S, Moran CA. Deciduosis of the appendix. Am J Gastroenterol. 1990;85:841–845. 18. Daya D, O’Connell G, DeNardi F. Rectal endometriosis mimicking solitary rectal ulcer syndrome. Mod Pathol. 1995;8:599–602. 19. Yantiss RK, Clement PB, Young RH. Endometriosis of the intestinal tract: a study of 44 cases of a disease that may cause
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Appendiceal or Cecal Endometriosis With Intestinal Metaplasia A Potential Mimic of Appendiceal Mucinous Neoplasms Joseph Misdraji, MD,* Gregory Y. Lauwers, MD,* Julie A. Irving, MD,w Kenneth P. Batts, MD,z and Robert H. Young, MD*
Abstract: Appendiceal or cecal endometriosis uncommonly presents diagnostic challenges, but rare cases with intestinal metaplasia can mimic mucinous tumors of the appendix. We describe 6 cases of appendiceal or cecal endometriosis with intestinal metaplasia that grossly and microscopically mimicked appendiceal mucinous tumors. The cases were characterized by marked mural hypertrophy and elastosis, with distortion of the appendix, and virtual obliteration of the lumen of the appendix. All cases had conventional endometriosis, together with varying amounts of endometriosis with intestinal-type epithelium. In 2 cases, scant or virtually no stroma around some mucin-filled glands made their recognition as endometriosis more difficult. None of the cases had dysplasia of the mucinous epithelium. All patients had benign follow-up (mean 3.6 y). Endometriosis with intestinal metaplasia is a rare phenomenon that, when it occurs in the appendix or cecum, may lead to misdiagnosis as a lowgrade appendiceal mucinous neoplasm or mucinous carcinoma. Key Words: appendix, cecum, endometriosis, intestinal metaplasia, low-grade appendiceal mucinous neoplasm, mucinous adenocarcinoma (Am J Surg Pathol 2014;38:698–705)
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ndometriosis involves the appendix rarely, often in the context of intestinal involvement by endometriosis.1 When it does involve the appendix, it may produce interesting clinical situations, such as appendiceal perforation in pregnant women,2,3 intussusception of the appendix,4–9 or retention mucocele.10–12 Although these manifestations can cause diagnostic challenges for surgeons, endometriosis rarely causes diagnostic confusion From the *James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA; zHospital Pathology Associates, Virginia Piper Cancer Institute, Minneapolis, MN; and wDepartment of Pathology, University of British Columbia, BC, Canada. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Joseph Misdraji, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Warren Building, Boston, MA 02114 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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for pathologists when it is typical. However, endometriosis can be associated with less common microscopic appearances, such as stromal endometriosis, decidual change, or neoplastic changes, that can cause diagnostic challenges for pathologists. One particular additional uncommon microscopic change that may cause confusion with a neoplasm is the subject of this report, specifically, endometriosis of the appendix and cecum in which the endometrial glands are partly replaced by intestinal epithelium, a process reported rarely as either intestinal metaplasia or intestinal colonization.13–16 These examples of appendiceal endometriosis have several features that mimic appendiceal mucinous neoplasms, particularly lowgrade appendiceal mucinous neoplasms (LAMNs), and have the potential for serious diagnostic error. We report our experience with 6 cases of appendiceal or cecal endometriosis with intestinal metaplasia to highlight this rare phenomenon and to describe features that distinguish this entity from LAMN.
METHODS Cases of appendiceal endometriosis with intestinal metaplasia were compiled from the consultation files of several of the authors. One of the cases was contributed from the consultation files of Dr Philip B. Clement. All slides were reviewed by one of us (J.M.), and, when available, immunohistochemistry was reviewed. Clinical data were obtained by contacting referring pathologists, surgeons, or gynecologists.
RESULTS Clinical Findings The 6 women ranged in age from 39 to 71 years (mean 52 y). Three of them were surgically explored for an appendiceal abnormality or mass; 1 of these was found to have a perforated appendix. Two were operated on for a cecal mass at the appendiceal orifice. One of these 2 women had a history of endometriosis and a remote history of having undergone appendectomy, the pathology of which was not available, and the other woman was presumed to have congenital absence of the appendix. One patient (case 2) was described as having a “pelvic mass” and was found to have a complex right adnexal mass adherent to the cecum, Am J Surg Pathol
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Appendix Endometriosis With Intestinal Metaplasia
TABLE 1. Clinical Data on 6 Women With Appendiceal or Cecal Endometriosis With Intestinal Metaplasia Case Age
Relevant History
Presentation
Surgical Procedure
1
52
—
2
53
—
3
39
—
4
49 Endometriosis and remote history of appendectomy 71 —
Rectal bleeding; pericecal mass Abnormal appendix
Right colectomy, left ovarian cystectomy, and omentectomy Right hemicolectomy
50 Presumed congenital absence of appendix
Cecal mass
Cecectomy
5 6
Appendiceal mass with Appendectomy and cecectomy normal ovaries Pelvic mass Appendectomy, hysterectomy, and bilateral oophorectomy Perforated appendix Appendectomy
encompassing the appendix, with mucin extruding from it at the time of surgery (Table 1). Three patients had the appendix, cecum, or both removed. The patient with the complex right adnexal mass had appendectomy, hysterectomy, and bilateral oophorectomy. Two patients underwent right hemicolectomy. The referring pathologic diagnosis was known in 5 cases, and in all 5 there was concern for a mucinous neoplasm arising from endometriosis or independent of endometriosis, but the exact type of mucinous tumor varied from cystadenoma to mucinous borderline tumor or LAMN, to low-grade mucinous adenocarcinoma. Follow-up information is available for 5 patients, and the other case is recent. One patient had a second procedure at 6 months that revealed conventional endometriosis in the ovaries and on the uterine serosa. All patients are alive and without evidence of mucinous neoplasia at 1 to
Interval (y)
Follow-up No evidence of mucinous neoplasia or pseudomyxoma No evidence of mucinous neoplasia or pseudomyxoma No evidence of mucinous neoplasia or pseudomyxoma —
3 2 7 Recent
No evidence of mucinous neoplasia or pseudomyxoma No evidence of mucinous neoplasia or pseudomyxoma
4 1
7 years (mean 3.6 y). None developed pseudomyxoma peritonei.
Pathology Four cases had gross features suggestive of a cystic mucinous tumor of the appendix. In case 2, the right ovary was described as a complex cystic mass with mucin, adherent to the cecum and incorporating the appendix. The patient with a history of a prior appendectomy had an appendiceal stump that segued into a mucin-filled cyst alongside a multinodular cecal mass. In 1 case, the appendix was described as white and rubbery with a 1 cm mucin-filled cyst. The patient with presumed congenital absence of the appendix had a 2.3 cm mural mass in the cecum. The appendix was submitted in its entirety in all 6 cases (Table 2).
TABLE 2. Pathologic Findings in 6 Cases of Appendiceal or Cecal Endometriosis With Intestinal Metaplasia
Case 1 2
3 4
5 6
r
Gross Findings Distorted, red appendix with 3 cm cystic gelatinous mass Irregular nodular appendix and attached to a 6 cm cyst. Right adnexal mass was adherent to cecum and appendix, and contained mucin Appendix white and rubbery with 1 cm cyst filled with mucin 3.5 cm multinodular pink-tan cecal mass with appendiceal stump along 1 aspect and adjacent cyst resembling mucocele Dilated appendix filled with thick mucin 2.3 cm mural mass in cecum
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Immunophenotype of Endometrial Glands and Stroma
Immunophenotype of Intestinal Metaplastic Epithelium
Other Sites of Endometriosis
Goblet mucinous cells only Goblet mucinous cells only
Not done
Not done
—
Not done
Not done
Right ovary (with focal intestinal phenotype), uterine serosa, left adnexa
Goblet mucinous cells only
Not done
Not done
Bilateral ovaries and uterine serosa
Goblet mucinous cells and focal endocrine cells
Not done
Not done
Left ovary and omentum
Cytokeratin 7, ER, PR positive Stroma: CD10 positive. Glands: cytokeratin 7, CA125, and ER positive
Cytokeratin 20, CDX2 positive Cytokeratin 20 and CDX2 positive
Intestinal Cell Types in Endometriosis
Goblet mucinous cells only Goblet mucinous cells and focal Paneth cells
— —
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Three cases had similar microscopic features, with marked distortion of the appendix secondary to fibromuscular hyperplasia and elastosis, making it impossible to identify a lumen or normal appendiceal mucosa microscopically. All 3 specimens had foci of conventional or atrophic endometriosis. Scattered among the endometriosis in a buckshot pattern were glands lined by tall mucinous cells resembling goblet cells and partly or completely invested in endometrial-type stroma (Fig. 1). In each case, some foci of endometriosis had only glands composed exclusively of goblet-like mucinous cells, and some foci had both endometrial-type and intestinal-type glands (Fig. 2). In some glands, the mucinous epithelium appeared hyperplastic with tall mucin vacuoles. In 2 cases, the 2 epithelia lined the same gland with an abrupt transition between the 2 types. Some endometriotic foci with intestinal phenotype were only partially invested by endometrial-type stroma, with some intestinal-type glands abutting muscularis propria or elastotic stroma. Most of the glandular units were small to medium sized, typical of endometriosis, although several mucinous glands assumed a larger more tortuous appearance. The distortion of the appendiceal architecture in these cases made it impossible to determine with certainty whether the intestinal epithelium involved endometriotic foci only
close to the lumen or throughout the appendiceal wall. All cases were associated with at least a moderate amount of extruded mucin in the mesoappendix or on the serosal surface. No case had endocrine cells or Paneth cells. None of these 3 cases had dysplasia of the endometriotic epithelium or of the mucinous epithelium. None showed other forms of metaplasia that occur in endometriosis. The case with an appendiceal stump (case 4) showed a recognizable appendiceal orifice at the proximal end of the specimen, with endometriosis and mural thickening. In this case, the endometriosis focally extended into the base of the appendiceal mucosa at the appendiceal orifice. Distally, there was a cystic structure partly surrounded by attenuated muscularis propria and partly lined by fibrotic tissue with dystrophic calcifications. The cyst was filled with mucin and focally lined by reactive-appearing intestinal epithelium. The endometriosis with intestinal phenotype comprised goblet cells and, focally, cells with subnuclear eosinophilic granules resembling colonic endocrine cells. The mucinous epithelium showed mild nuclear stratification interpreted as reactive. In 2 cases, some of the mucinous epithelium dissecting the appendix or cecal wall was not clearly invested with endometrial stroma, and a second process was more difficult to exclude. In 1 of these 2 cases, the appendiceal
FIGURE 1. Low-power view of appendiceal endometriosis with intestinal metaplasia with a buckshot pattern of scattered glands, some of which are lined by mucinous cells.
FIGURE 2. Endometriosis with glands lined by endometrialtype epithelium (upper right) and by hyperplastic goblet-like mucinous epithelial cells (lower left).
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lumen appeared dilated, and the mucosa was partially denuded with an inflammatory reaction. Focally, the flat mucosa lining the dilated lumen showed nuclear stratification and superficially eroded through the muscularis mucosae with an elastotic reaction. It was unclear whether this process represented a retention cyst with reactive atypia or a LAMN. No villous mucinous proliferation was present. The endometriosis in this case was atrophic with minimal stroma and involved the appendix, cecum, and ileocecal region. Focal intestinal metaplasia was noted, with intestinal-type epithelium abutting on endometrial-type epithelium. Separately, several large mucin-filled glands lined mostly by intestinal-type epithelium but focally by attenuated epithelium lacked stroma and dissected the muscle of the cecum and ileocecum (Fig. 3). These glands were difficult to confirm as endometriosis and suggested the possibility of dissecting LAMN, but careful study of the immunohistochemical stains showed that the attenuated portion of the lining epithelium marked for keratin 7 and ER, and small clusters of CD10-positive stromal cells undermined these areas.
FIGURE 3. Example of endometriosis with intestinal metaplasia in which the intestinal component produces large mucin-filled glands with virtually no stroma, mimicking a dissecting LAMN. Note the endometriosis at the lower left. Immunohistochemistry in a similar gland nearby showed areas of the gland lined by ER-positive endometrial-type epithelium. r
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In the second of these 2 cases (case 6), the cecal mass consisted of nodular smooth muscle and elastotic tissue with endometriosis. The overlying cecal mucosa was distorted, ulcerated, and puckered. In the submucosa, several mucinous glands were invested by lamina propria, and, in the muscularis propria, several cystic intestinal glands were either devoid of stroma or cuffed by edematous lamina propria with eosinophils and plasma cells, consistent with colitis cystica profunda due to the distortion of the muscularis propria secondary to endometriosis. Endometriosis focally involved the overlying mucosa (Fig. 4). In isolated areas, endometriosis merged with intestinal-type glands with focal Paneth cells (Fig. 5), with both types of epithelium in the same endometriosis deposit and even in the same gland accompanied by pools of mucin. Several mucinous glands had stratification and mitotic figures, interpreted as reactive. Immunohistochemical staining analyses were performed on 2 cases (cases 5 and 6) and demonstrated an inverse staining pattern for the endometrial and intestinal epithelia. In 1 case, endometrial glands stained for keratin 7, estrogen, and progesterone receptors, whereas intestinalized areas stained with cytokeratin 20 and CDX2 (Fig. 6). The other case showed staining of endometrial stroma with CD10, endometrial glands with cytokeratin
FIGURE 4. Endometriosis merging with the base of the overlying cecal mucosa. www.ajsp.com |
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FIGURE 5. Endometriosis with intestinal metaplasia and focal Paneth cells (arrowheads).
7, estrogen receptor, and CA125, and intestinalized glands with cytokeratin 20 and CDX2. Three women had endometriosis documented outside the appendix or cecum. The patient whose appendix was cystic and adherent to the right ovary had endometriosis in the right ovary, left adnexa, and uterine serosa. In the right ovary, the endometriosis showed focal intestinal-type epithelium, but the relationship of this area to the appendix was not apparent from the sections as the 2 organs had been separated before submission to pathology. In the other 2 patients, only conventional endometriosis was seen in extraintestinal sites.
DISCUSSION Appendiceal endometriosis may produce an array of confusing clinical complications. Decidualized endometriosis in pregnancy can cause symptoms of acute appendicitis.17 More dramatically, involution of decidualized endometriosis can lead to appendiceal perforation.2,3 The fibromuscular expansion typical of intestinal involvement by endometriosis can create a mass-like lesion that can become the lead point of appendiceal intussusception.4–9 This same muscular expansion can obstruct the appendiceal lumen and cause a retention mucocele.10–12 Pathologically, endometriosis rarely proves diagnostically challenging as its classic appearance with scattered endometrial glands surrounded
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by variable amounts of endometrial-type stroma is familiar to most pathologists. However, occasionally, endometriosis can have unusual appearances, including a variety of metaplasias, absence of an epithelial component (stromal endometriosis), intravascular growth, or polypoid growth pattern in the gastrointestinal tract or appendix,18–21 and then can cause diagnostic confusion with other processes, either benign or malignant. In addition, endometriosis can be the origin of extraovarian or extrauterine mu¨llerian-type tumors in women, which can present another set of challenges to pathologists.20,22 LAMNs are low-grade mucinous adenocarcinomas of the appendix that show a distinctive pattern of invasion of the appendix and that have the potential to spread to the peritoneum as pseudomyxoma peritonei and cause cystic ovarian masses.23,24 These tumors dissect into the appendix wall or show pushing invasion but not the destructive invasion of usual intestinal adenocarcinoma. These tumors, when confined to the appendix, are generally biologically benign. However, rupture of a LAMN with extrusion of mucin beyond the appendiceal serosa carries a low risk for recurrence as pseudomyxoma peritonei. Extrusion of mucin with mucinous epithelial cells outside the appendix confers a high risk for progressing to disseminated peritoneal disease.25,26 Obviously, a LAMN can coexist with appendiceal endometriosis.16,27 However, we have seen several examples of appendiceal endometriosis with intestinal metaplasia that mimicked low-grade appendiceal mucinous neoplasia. Previously, we reported our experience with diverticular disease of the appendix mimicking LAMNs.28 Appendiceal endometriosis with intestinal metaplasia represents another, rarer mimic of LAMN. As with appendiceal diverticular disease, endometriosis with intestinal metaplasia can lead to mucin extrusion on the appendiceal serosa, causing confusion with a ruptured LAMN. Unwary pathologists may report this as localized pseudomyxoma peritonei and may suggest that the patient is at high risk for developing disseminated pseudomyxoma peritonei. Depending on the approach to peritoneal neoplasia of the surgical team at the institution in which this patient is treated, this may, in extreme examples, subject the patient to additional surgery in an attempt to reduce that risk. Features common to all of our cases that may be mistaken for LAMNs include extrusion of mucin—sometimes abundant—in the mesoappendix or on the appendiceal serosa, marked distortion of the appendix, and intestinal-type mucinous epithelium dissecting through the appendiceal muscularis propria. However, other features of these cases were helpful in distinguishing them from LAMN (Table 3). Endometriosis is well known to be the origin of a subset of mu¨llerian tumors in women, and the gastrointestinal tract is no exception.20,22 This phenomenon has not been reported in endometriosis with intestinal colonization. It is, however, theoretically possible that endometriosis with intestinal colonization might develop dysplasia or neoplasia of the mucinous component and be the source of appendiceal or cecal mucinous tumors. One r
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FIGURE 6. Immunohistochemical profile of a gland in endometriosis lined by both intestinal-type and endometrial-type epithelium. The intestinal-type epithelium marks with cytokeratin (CK) 20 and CDX2, whereas the endometrial lining marks with CK7, ER, and PR.
report describes a case in which low-grade mucinous epithelial dysplasia arose in endometriosis with intestinal metaplasia in the appendix.14 Another report describes an appendiceal mucinous tumor occurring concurrently with endometriosis with intestinal metaplasia,16 but the r
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authors do not suggest that the mucinous tumor arose from the endometriosis. The possibility of reactive atypia in these distorted, inflamed appendices makes diagnosis of low-grade neoplasia difficult, and we would caution against overinterpretation of reactive changes in these www.ajsp.com |
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TABLE 3. Features of Endometriosis With Intestinal Metaplasia That Are Useful in the Distinction With LAMN Lack of a recognizable lumen or a mucinous tumor within the appendiceal lumen Presence of conventional endometriosis A buckshot pattern of small to medium-sized mucinous glands admixed with endometrial glands A cuff of endometrial stroma surrounding mucinous glands Hybrid glands with both endometrial and mucinous epithelium Immunohistochemistry for mu¨llerian and intestinal markers in difficult cases to demonstrate the hybrid nature of mucinous glands
cases as preneoplastic or neoplastic changes. The difficulty in distinguishing reactive epithelial changes in hyperplastic mucinous epithelium from LAMN is one of the reasons that appendiceal diverticular disease is often mistaken for LAMN,28 and this challenge is relevant in endometriosis as well. Others have commented on the ability of endometriosis with intestinal colonization to suggest a mucinous carcinoma that destroyed the appendix or in mistaking endometriosis with intestinal metaplasia as invasive neoplastic glands,15,16 emphasizing that the greater concern in these cases is overinterpretation of reactive atypia in hyperplastic mucinous epithelium lining these dissecting glands as an invasive low-grade mucinous tumor. Another entity that might enter into the differential diagnosis is a mucinous cystic neoplasm with ovarian-type stroma. These tumors occur most often in the pancreas, but have been described in the mesentery.29,30 We have seen a single case in the mesoappendix. However, these tumors occur as cystic tumors rather than scattered glands within the muscularis of the appendix and are lined by cuboidal or columnar mucinous cells that lack the gobletlike appearance of intestinal metaplasia seen in our cases. Endometriosis with mucinous metaplasia is a welldescribed phenomenon, although typically this is of endocervical type, and intestinal metaplasia is rare.1,20 Although intestinal metaplasia is included in comprehensive descriptions of endometriosis,1,31 a literature search of this phenomenon reveals only a few appendiceal or cecal examples and only isolated examples in other sites.32 The mechanism of intestinalization of endometriosis is unknown, but 2 theories have been proposed: metaplasia and colonization of endometriosis.14,15 Although intestinal metaplasia certainly occurs in endometriosis, the predilection for intestinal metaplasia to occur in endometriosis of the appendix leads us to conclude that mechanical colonization of endometriosis by appendiceal mucosa may be responsible for some cases. First, a wellknown phenomenon that occurs in the colon is colonization of the mucosa by epithelia from other sources, such as colonization of the intestinal mucosa by metastatic tumors.33 In addition, mucosal involvement of the gastrointestinal tract or appendix by endometriosis can show colonization of the mucosal surface with endometrial-type epithelium or hybrid glands in the mucosa.13,20,34 Furthermore, the appendix is a small organ, and endometriosis is associated with marked distortion of that organ and, often, obliteration of the lumen. Other
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reported examples of intestinalized endometriosis in the appendix share this marked distortion or even obliteration of the appendix.14,15 The presence of colitis cystica profunda in 1 of our cases and 1 reported case13 raises another interesting mechanism by which the 2 epithelial types might merge. Therefore, it is highly probable that the process of colonization, which might remain limited to the mucosa in the colon or intestine, more often involves deeper portions of the appendix due to the marked distortion of that organ, diverticula, or colitis cystica profunda secondary to the muscular hyperplasia induced by endometriosis itself. In only 1 of our cases was intestinal-type epithelium found in endometriosis outside the appendix. In that case, the endometriosis in the right ovary had focal intestinal metaplasia but that ovary had been adherent to the appendix, and extension of the process into the ovary might account for this finding. It is worth noting that this patient had only conventional endometriosis in the contralateral adnexa and on the uterine serosa. Immunohistochemistry data were limited to 2 cases in our study, but the endometrial and intestinal epithelium each showed hormone receptor, CDX2, and cytokeratin 7/20 immunoprofiles typical of mu¨llerian and intestinal-type epithelium without dual expression. Others have suggested that the microenvironment of the appendix might be uniquely conducive to intestinal metaplasia of endometriosis, but we think this is unlikely. Endometriosis of the intestinal tract is not usually accompanied by intestinal metaplasia of endometriotic glands,20 and it is unlikely that the microenvironment of the appendix is altogether different from the colon. Some authors have noted that intestinal metaplasia in the appendix occurs more often in superficial endometriosis deposits than in deeper ones.14 In our cases, inability to identify the lumen of the appendix usually made this evaluation impossible; however, the presence of mucinous glands closer to the lumen of the appendix favors colonization. The presence of Paneth cells and endocrine cells together with the mucinous cells in intestinalized foci of endometriosis has also been quoted as an argument in favor of metaplasia over colonization.14 Most of our cases lacked cells other than goblet mucinous cells, although 2 cases had other cell types. Regardless, either colonization or metaplasia could account for 1 or multiple cell types, and superimposed mucinous hyperplasia might alter the epithelial cellular composition. In summary, we describe 6 cases of endometriosis of the appendix with at least focal and in many cases extensive intestinal metaplasia. These cases were often associated with marked distortion of the appendix, obliteration of the lumen, and mucin extrusion, causing concern for a LAMN. Inability to identify a luminal mucinous neoplasm, the presence of intestinal glands in continuity with endometrialtype glands, a cuff of endometrial-type stroma, and a buckshot pattern of scattered clusters of glands in the specimen are clues to the diagnosis of endometriosis with intestinal metaplasia. However, mucinous epithelial atypia and the absence of endometrial stroma around some dissecting glands make distinction from a LAMN difficult in some instances. r
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