Resident Short Review
Mullerianosis ¨ of the Urinary Bladder A Rare Tumorlike Lesion Giovanni Branca, MD; Valeria Barresi, MD
Mullerianosis ¨ was first described as a rare entity consisting of an admixture of cervical, tubaric, or endometrial epithelium within the lamina propria and muscularis propria of the urinary bladder. This lesion occurs mainly in the dome or posterior wall of the urinary bladder in women of fertile age. Its clinical presentation is characterized by hematuria, pelvic pain, and dysuria, nonspecific symptoms that are related to the responsiveness of mullerian ¨ glands to hormonal stimuli. The major interest of mullerianosis ¨ resides in its similarity, from clinical, cytologic, and histologic viewpoints, to more threatening conditions, such as neoplasias. The clinical context and the identification of periglandular endometrial stroma at histologic examination with conventional hematoxylin-eosin stain, as well as the immunohistochemical demonstration of estrogen and progesterone receptors in the glands, are of diagnostic utility in the differential diagnosis. Mullerianosis ¨ may be responsive to gonadotropin-releasing hormone agonists. Surgical resection may be justified in the case of clinical symptoms refractory to hormone therapy. (Arch Pathol Lab Med. 2014;138:432–436; doi: 10.5858/ arpa.2012-0681-RS)
crucial for appropriate management, because patients may benefit from hormonal therapy and radical cystectomy may be avoided. CLINICAL FEATURES Mullerianosis of the urinary bladder originates mainly in ¨ women of fertile age, sometimes in association with a previous history of pelvic surgery or cesarean delivery.3–5 According to published reports, the age at diagnosis ranges between 28 and 53 years.1–12 Because of its clinical presentation, characterized by nonspecific symptoms, such as hematuria, pelvic pain, and dysuria,10 occurring or not occurring in association with menstruation, mullerianosis ¨ may simulate many other pathologic conditions of the urinary tract, including neoplasias. A novel case of mullerianosis of the urinary bladder, ¨ which we recently diagnosed, affected a fertile 50-year-old woman who complained of gross hematuria and dysuria. In this case the past clinical history was negative for pelvic surgery or cesarean section.
ullerianosis was first described by Young and Clement1 ¨ in 1996 as a rare entity consisting of an admixture of at least 2 types of mullerian tissues—cervical, tubaric, or ¨ endometrial—in the lamina propria and muscularis propria of the urinary bladder. At present, fewer than 20 cases of mullerianosis of the urinary bladder have been reported,1–12 ¨ though this lesion has also been rarely observed in the ureter,13,14 mesosalpinx,15 inguinal lymph nodes,16 and spinal cord.17 The main interest of mullerianosis of the urinary bladder ¨ resides in its potential to mimic a neoplastic lesion from clinical, cytologic, and histologic viewpoints.10,18 Though mullerianosis is extremely rare, its correct identification is ¨
GROSS FINDINGS A definitive gross description of mullerianosis of the ¨ urinary bladder cannot be deduced from most of the existing reports. Indeed, in most of the cases the lesion is submitted to transurethral endoscopic resection2,6,7 and only non– grossly descriptive fragments are sent for the histologic examination. To the best of our knowledge, the gross findings of mullerianosis of the urinary bladder have been ¨ reported only by Guan and colleagues,10 who described this lesion as a mass showing an internal cystic structure, with dark blue to black cysts.10 In the remaining cases, the macroscopic aspect of mullerianosis of the urinary bladder ¨ may be inferred only from cystoscopy, which reveals the presence of polypoid, masslike lesions ranging from 1 to 4.5 cm in size, predominantly involving the dome or posterior wall of the bladder.10 Also in our case, cystoscopy had shown an exophytic lesion, located at the posterior bladder wall.
Accepted for publication April 2, 2013. From the Department of Pathology, University of Messina, Messina, Italy. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Valeria Barresi, MD, Dipartimento di Patologia Umana, Policlinico G. Martino, Pad D, Via Consolare Valeria, 98125 Messina, Italy (e-mail: [email protected]).
HISTOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS AND DIFFERENTIAL DIAGNOSIS At histologic examination by hematoxylin-eosin stain, mullerianosis of the urinary bladder appears as a lesion ¨ consisting of an admixture of variably sized, blandappearing glands that are deeply situated within the lamina propria and the muscularis propria of the urinary bladder
M
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wall, and which resemble the tubal, endocervical, and endometrial epithelia (Figure 1). The presence of an endometrial-like stroma surrounding the endometrial-like glands usually makes the histologic diagnosis straightforward (Figure 1, A through D). Some of the glands of mullerianosis may also show an admixture of urothelium ¨ and mullerian epithelium, which suggests a metaplastic ¨ process in the pathogenesis of the disease.7 All of the glands within the lesion look benign and neither cytologic atypia nor mitoses are evident. In line with their derivation, the glands of mullerianosis, as well as the ¨ endometrial stroma, are responsive to hormones, because of their nuclear expression of estrogen and progesterone receptors, which may be demonstrated by immunohistochemistry7 (Figure 2, A). Also, similar to the orthotopic endometrium, the stroma surrounding the endometrial glands of mullerianosis is diffusely stained by anti-CD10 ¨ antibody, and the glandular epithelia stain positively for Ca125 (Figure 2, B). The histologic differential diagnosis of mullerianosis of the ¨ urinary bladder encompasses several benign and neoplastic conditions, including cystitis glandularis, urachal remnants, nephrogenic adenoma, primary adenocarcinomas of the urinary bladder, and secondary spread from a minimaldeviation adenocarcinoma of the uterine cervix. Cystitis glandularis consists of glands lined by cuboidal to columnar cells, which may contain abundant mucin. Goblet cells are also found in the intestinal form of the disease. Unlike mullerianosis, the glands of cystitis glandularis are ¨ superficially located in the bladder wall, with preservation of the muscularis propria, and no staining for estrogen and progesterone receptors is observed.7 The hypothesis of urachal remnants should also be excluded in the presence of glandular structures within the bladder wall. The demonstration of endometrial stroma around the glands, through CD10 immunostaining, is of significant help in the differential diagnosis. Nephrogenic adenoma is a benign process that may involve the urinary bladder. In light of its histologic aspect, with small tubules lined by cuboidal and hobnail cells, it enters the differential diagnosis with mullerianosis of the ¨ urinary bladder. Nonetheless, differently from the latter, it does not feature mucinous cells, deep location in the muscularis propria of the urinary bladder, and immunoreactivity for hormone receptors. In addition, although nephrogenic adenoma stains positive for racemase,19 the endometrial glands of mullerianosis are negative for this ¨ protein.20 Mullerianosis may also simulate an infiltrating primary or ¨ metastatic adenocarcinoma of the urinary bladder, especially if glands without surrounding endometrial stroma are predominant. Based on the site of origin, 2 major types of primary adenocarcinoma of the urinary bladder are recognized: adenocarcinoma arising in the bladder proper, and that arising from the urachal remnants. In comparison with mullerianosis, which arises in women of fertile age, ¨ adenocarcinoma of both types is more characteristic of older individuals, with a mean age of 59 years at presentation.21 The presence of a normal or ulcerated overlying urothelium generally excludes the hypothesis of primary nonurachal adenocarcinoma, which shows a surface neoplastic epithelium. However, it leaves unsolved the differential diagnosis between mullerianosis and urachal ¨ adenocarcinoma, as both are characterized by a sharp demarcation from intact bladder epithelium. The preferenArch Pathol Lab Med—Vol 138, March 2014
tial location of both lesions in the dome of the bladder may further complicate the distinction between the 2 entities. Nonetheless, the evidence of endometrial glands with periglandular endometrioid stroma, the lack of cytonuclear atypia, and absence of mitoses and desmoplasia argue against a malignant lesion. Finally, the possibility of secondary bladder involvement by endocervical adenocarcinoma may be ruled out by a negative clinical history and other diagnostic studies as appropriate. CYTOLOGIC FINDINGS AND DIFFERENTIAL DIAGNOSIS To the best of our knowledge, the cytologic findings relative to mullerianosis of the urinary bladder have been ¨ described in only one case among those reported in the literature.10 The rarity of reports on the cytologic appearance of mullerianosis of the urinary bladder may be attributed to the ¨ deep localization of the mullerian glands within the bladder ¨ wall, with consequent low probability of their desquamation in the urine. Consistent with this hypothesis, in our case the cytologic examination of urine failed to detect any mullerian-type epithelia. ¨ In the only report describing the cytologic appearance of mullerianosis of the urinary bladder, only endometrial-type ¨ glands could be recognized in the urinary smear. They appeared as cohesive, 3-dimensional aggregates of glandular cells with scant cytoplasm and slightly irregular nuclei with vesicular, fine chromatin, and visible small nucleoli.10 The cytologic appearance of tubal-type epithelium in urinary cytology may be inferred from a report of endosalpingiosis of the urinary bladder.3 According to this report, in urine samples tubal epithelium figures as large, monolayered epithelial aggregates of uniform cells, showing slightly irregular nuclei with nucleoli and scanty cytoplasm. Also, papillary aggregates, isolated cells with signet-ring shape, and histiocytes may be observed.3 No cytologic descriptions of bladder endocervicosis are available. It seems, however, that the endocervical nature of the cells may be recognizable on cytologic smears. Mullerian benign lesions should be distinguished from ¨ several benign and neoplastic entities in the urinary cytology. First of all, menstrual contamination should be excluded, especially in the presence of an abundant squamous cell population. Among other benign conditions entering the differential diagnosis, the hypothesis of reactive urothelium should be considered in the presence of an inflammatory background. Undoubtedly, the most important differential diagnosis for the subsequent management of the patient regards urinary bladder neoplasias. Indeed, the presence of cells with nuclear atypia and evident nucleoli, as well as that of papillary clusters, may simulate urothelial tumors. Nonetheless, attention should be paid to the age of the patient, as urothelial neoplasias are very unusual in young women, whereas mullerianosis is charac¨ teristic of patients of fertile age. On the other hand, a necrotic background, single epithelial cell, or prominent nuclear atypia favors the diagnosis of high-grade urothelial carcinoma. Though the differential diagnosis toward lowgrade urothelial carcinoma may be more complex,22,23 the evidence of macrophages, which are found in endosalpingiosis, supports the hypothesis of mullerianosis. ¨ Mullerianosis—Branca & Barresi 433 ¨
Figure 1. A, Glands lined by endocervical epithelium in the lamina propria of endoscopically resected fragments of urinary bladder wall. B, Endocervical and endometrial glands surrounded by endometrial stroma deeply located in bladder wall. C, Endometrial gland with surrounding stroma within muscularis propria of bladder fragments. D, Gland lined by ciliated tubal-type epithelium in the bladder wall (hematoxylin-eosin, original magnifications 3100 [A and B], 3200 [C], and 3400 [D]).
The occurrence of isolated signet-ring cells in the urine of patients with endosalpingiosis3 may suggest adenocarcinoma of the urinary bladder. Nonetheless, the neoplastic cells of adenocarcinoma display a more abundant and vacuolated cytoplasm than those of benign tubal-type epithelium.3 HISTOGENESIS The pathogenesis of mullerianosis is still unclear. As for ¨ endometriosis, implantation and metaplastic origins have been contemplated.1,2 Implantation might give an explanation for mullerianosis in those patients with a previous ¨ history of pelvic surgery, especially cesarean delivery, as reported in some of the cases in the literature.1,3–5 Nonetheless, mullerianosis of the urinary bladder in the ¨ absence of previous surgery, as in our case, or mullerianosis ¨ observed at more distant sites, as in the spine,17 is hardly referable to this mechanism. Also, the presence of 2 or more mullerian tissues, rather than 1, as seen in endometriosis, ¨ seems to argue against the implantation theory. Donne et al2 preferred a metaplastic origin of mullerianosis, suggest¨ ing that the presence of various types of mullerian tissue ¨ 434 Arch Pathol Lab Med—Vol 138, March 2014
might have resulted from the differentiation of a mullerian ¨ epithelium toward tubal, endometrial, or endocervical phenotypes. In favor of a metaplastic derivation of mullerianosis is its invariable location in the posterior wall ¨ and dome of the bladder, an area that topographically corresponds to its peritoneal covering24 and that may be particularly receptive to female hormones. Further supporting a metaplastic derivation of mullerianosis of the urinary ¨ bladder may be the morphologic continuity between the mullerian glands and the urothelium, as described in the ¨ report by Koren and colleagues.7 Hence mullerianosis ¨ involving pelvic and lower abdominal structures might derive from the so-called secondary mullerian system, ¨ which includes pelvic and lower abdominal mesothelium and the subjacent mesenchyme of females. Indeed, during embryogenesis this gives rise to the mullerian ducts, the ¨ epithelium of which then differentiates into endocervical, endometrial, and tubal epithelium. We may speculate that peritoneal mesothelium might retain its potential and thus, under unknown stimuli, it might be able to further differentiate into mullerian structures in the adult. Recently, ¨ Mullerianosis—Branca & Barresi ¨
TREATMENT AND PROGNOSIS Few data are available on the management of bladder 1,2 The efficacy of gonadotropin-releasing mullerianosis. ¨ hormone agonists in the treatment of this lesion is controversial.1,2 Indeed, though disappearance of the symptoms is observed following therapy, the lesion remains unchanged in size and appearance.2 Pharmacologic treatment might be the most appropriate in the case of mullerianosis arisen in sites, such as the spinal compart¨ ment, where surgical intervention may lead to life-threatening complications.17 Nonetheless, extensive endoscopic transurethral resection may be preferable in cases involving the urinary bladder. Importantly, a strict follow-up is warranted following surgical resection, because, though rarely, the malignant transformation of endometriosis versus endometrioid carcinoma has been reported in urinary bladder.6 CONCLUSIONS In conclusion, mullerianosis of the bladder is a rare benign ¨ condition that may be clinically, cytologically, and histologically mistaken for a tumor lesion. This entity should be added to the list of pseudoneoplastic bladder lesions potentially responsible for a false-positive diagnosis of carcinoma. The clinical context and specific cytologic, histologic, and immunohistochemical findings may allow its differentiation from carcinoma. The identification of mullerianosis is of crucial importance for its correct ¨ management, which may include the use of a pharmacologic treatment, though the risk of its progression toward carcinoma is still unknown because of the small number of reported cases. References
Figure 2. A, Nuclear staining for estrogen receptors in the endometrial epithelial and stromal cells found within the fragments of urinary bladder wall. B, CD10 stain in the stroma surrounding endometrial glands (estrogen receptor stain, original magnification 3200 [A]; CD10 stain, original magnification 3200 [B]).
Batt et al25 redefined mullerianosis as ‘‘an organoid structure ¨ of embryonic origin; a choristoma composed of mullerian ¨ rests—normal endometrium, normal endosalpinx, and normal endocervix—singly or in combination, incorporated within other normal organs during organogenesis.’’ A choristoma is a mass of histologically normal tissue that is ‘‘not normally found in the organ or structure in which it is located.’’ 25 Thus, according to Batt et al,25 the pathogeneses of mullerianosis and endometriosis are deeply different, as ¨ endometriosis is endometrium shed outside the uterine cavity that invades the outer surface of organs, whereas mullerianosis is endometrium (and at times also endosal¨ pinx and endocervix) misplaced within other organs during organogenesis. In support of this hypothesis is the finding of ectopic endometrium in human fetuses, misplaced outside the uterine cavity during the earlier steps of organogenesis, in the rectovaginal septum, in the proximity of the Douglas pouch, in the mesenchymal tissue, close to the posterior wall of the uterus, in the rectal tube at the level of muscularis propria, and in the wall of the uterus with no macroscopic or microscopic defects of the genital system.26 Arch Pathol Lab Med—Vol 138, March 2014
1. Young RH, Clement PB. Mullerianosis of the urinary bladder. Mod Pathol. ¨ 1996;9(7):731–737. 2. Donne C, Vidal M, Buttin X, et al. Mullerianosis of the urinary bladder: ¨ clinical and immunohistochemical findings. Histopathology. 1998;33(3):290– 292. 3. Jimenez-Heffernan JA, Sanchez-Piedra D, Bernaldo de Quiros L, Martinez V. Endosalpingiosis (mullerianosis) of the bladder: a potential source of error in ¨ urinary cytology. Cytopathology 2000;11(5):348–353. 4. Margulis V, Lemack GE, Molberg K, Saboorian MH. Bladder ‘‘Mullerianosis’’ in a woman with lower urinary tract symptoms and hematuria. ¨ J Urol. 2001;165(6, pt 1):1996–1997. 5. Islam S, Tumman JJ, McMahon RF, Payne SR. Mullerianosis of the urinary ¨ bladder. BJU Int. 2003;92(suppl 3):e23. 6. Garavan F, Grainger R, Jeffers M. Endometrioid carcinoma of the urinary bladder complicating vesical Mullerianosis: a case report and review of the literature. Virchows Arch. 2004;444(6):587–589. 7. Koren J, Mensikova J, Mukensnabl P, Zamecnik M. Mullerianosis of the urinary bladder: report of a case with suggested metaplastic origin. Virchows Arch. 2006;449(2):268–271. 8. Cruz Guerra NA, Gomez Raposo MD, Baizan Garcia MJ, Prieto Nogal SB, Juan AG, Sierra MP. Mullerianosis of the urinary bladder: a rare entity. Arch Esp Urol. 2009;62(2):150–152. 9. Olivia Vella JE, Nair N, Ferryman SR, Athavale R, Latthe P, Hirschowitz L. Mullerianosis of the urinary bladder. Int J Surg Pathol. 2011;19(4):548–551. ¨ 10. Guan H, Rosenthal DL, Erozan YS. Mullerianosis of the urinary bladder: report of a case with diagnosis suggested in urine cytology and review of literature. Diagn Cytopathol. 2012;40(11):997–1001. 11. Ogah K, Hartis R, Hilton P. Mullerianosis involving the urinary bladder. Int Urogynecol J. 2012;23(1):123–125. 12. Kudva R, Hegde P. Mullerianosis of the urinary bladder. Indian J Urol. 2012;28(2):206–207. 13. Nogales FF, Zuluaga A, Arrabal M, Dhakal HP, Aguilar D. Mullerianosis of ¨ the ureter: a metaplastic lesion. J Urol. 1999;162(6):2090–2091. 14. Li WM, Yang SF, Lin HC et al. Mullerianosis of ureter: a rare cause of ¨ hydronephrosis. Urology. 2007;69(6):1208.e9–e11. 15. Lim S, Kim JY, Park K, Kim BR, Ahn G. Mullerianosis of the mesosalpinx: a case report. Int J Gynecol Pathol. 2003;22(2):209–212. 16. Sinkre P, Hoang MP, Albores-Saavedra J. Mullerianosis of inguinal lymph nodes: report of a case. Int J Gynecol Pathol. 2002;21(1):60–64.
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17. Barresi V, Cerasoli S, Vitarelli E, Donati R. Spinal intradural mullerianosis: ¨ a case report. Histol Histopathol. 2006;21(10):1111–1114. 18. Whitworth SA, Subhawong AP, Rosenthal DL, Ali SZ. Clear cell adenocarcinoma of the lower urinary tract: cytopathologic characteristics and differential diagnoses. Cancer Cytopathol. 2012;120(5):308–312. 19. Skinnider BF, Oliva E, Young RH, Amin MB. Expression of alphamethylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol. 2004;28(6):701–705. 20. Jiang Z, Fanger GR, Woda BA, et al. Expression of alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: a study of 761 cases. Hum Pathol. 2003;34(8):792–796. 21. Bentley G, Grignon D. Non-transitional epithelial tumors. In: Foster CS, Ross JS, eds. Pathology of the Urinary Bladder. Philadelphia, PA: Saunders; 2004: 129–134.
22. Schneider V, Smith MJV, Frable WJ. Urinary cytology in endometriosis of the bladder. Acta Cytol. 1980;24(1):30–33. 23. Bohlmeyer TJ, Shroyer KR. Endometriosis of the bladder: cytologic findings and differentiation from transitional cell carcinoma. Acta Cytol. 1996;40(2):380– 382. 24. Clement PB, Young RH. Endocervicosis of the urinary bladder: a report of six cases of a benign mullerian lesion that may mimic adenocarcinoma. Am J ¨ Surg Pathol. 1992;16(6):533–542. 25. Batt RE, Smith RA, Buck Louis GM, et al. Mullerianosis. Histol Histopathol. ¨ 2007;22(10):1161–1166. 26. Signorile PG, Baldi F, Bussani R, D’Armiento M, De Falco M, Baldi A. Ectopic endometrium in human foetuses is a common event and sustains the theory of mullerianosis in the pathogenesis of endometriosis, a disease that ¨ predisposes to cancer. J Exp Clin Cancer Res. 2009;28(1):49.
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Mullerianosis—Branca & Barresi ¨
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Mullerianosis ¨ of the Urinary Bladder A Rare Tumorlike Lesion Giovanni Branca, MD; Valeria Barresi, MD
Mullerianosis ¨ was first described as a rare entity consisting of an admixture of cervical, tubaric, or endometrial epithelium within the lamina propria and muscularis propria of the urinary bladder. This lesion occurs mainly in the dome or posterior wall of the urinary bladder in women of fertile age. Its clinical presentation is characterized by hematuria, pelvic pain, and dysuria, nonspecific symptoms that are related to the responsiveness of mullerian ¨ glands to hormonal stimuli. The major interest of mullerianosis ¨ resides in its similarity, from clinical, cytologic, and histologic viewpoints, to more threatening conditions, such as neoplasias. The clinical context and the identification of periglandular endometrial stroma at histologic examination with conventional hematoxylin-eosin stain, as well as the immunohistochemical demonstration of estrogen and progesterone receptors in the glands, are of diagnostic utility in the differential diagnosis. Mullerianosis ¨ may be responsive to gonadotropin-releasing hormone agonists. Surgical resection may be justified in the case of clinical symptoms refractory to hormone therapy. (Arch Pathol Lab Med. 2014;138:432–436; doi: 10.5858/ arpa.2012-0681-RS)
crucial for appropriate management, because patients may benefit from hormonal therapy and radical cystectomy may be avoided. CLINICAL FEATURES Mullerianosis of the urinary bladder originates mainly in ¨ women of fertile age, sometimes in association with a previous history of pelvic surgery or cesarean delivery.3–5 According to published reports, the age at diagnosis ranges between 28 and 53 years.1–12 Because of its clinical presentation, characterized by nonspecific symptoms, such as hematuria, pelvic pain, and dysuria,10 occurring or not occurring in association with menstruation, mullerianosis ¨ may simulate many other pathologic conditions of the urinary tract, including neoplasias. A novel case of mullerianosis of the urinary bladder, ¨ which we recently diagnosed, affected a fertile 50-year-old woman who complained of gross hematuria and dysuria. In this case the past clinical history was negative for pelvic surgery or cesarean section.
ullerianosis was first described by Young and Clement1 ¨ in 1996 as a rare entity consisting of an admixture of at least 2 types of mullerian tissues—cervical, tubaric, or ¨ endometrial—in the lamina propria and muscularis propria of the urinary bladder. At present, fewer than 20 cases of mullerianosis of the urinary bladder have been reported,1–12 ¨ though this lesion has also been rarely observed in the ureter,13,14 mesosalpinx,15 inguinal lymph nodes,16 and spinal cord.17 The main interest of mullerianosis of the urinary bladder ¨ resides in its potential to mimic a neoplastic lesion from clinical, cytologic, and histologic viewpoints.10,18 Though mullerianosis is extremely rare, its correct identification is ¨
GROSS FINDINGS A definitive gross description of mullerianosis of the ¨ urinary bladder cannot be deduced from most of the existing reports. Indeed, in most of the cases the lesion is submitted to transurethral endoscopic resection2,6,7 and only non– grossly descriptive fragments are sent for the histologic examination. To the best of our knowledge, the gross findings of mullerianosis of the urinary bladder have been ¨ reported only by Guan and colleagues,10 who described this lesion as a mass showing an internal cystic structure, with dark blue to black cysts.10 In the remaining cases, the macroscopic aspect of mullerianosis of the urinary bladder ¨ may be inferred only from cystoscopy, which reveals the presence of polypoid, masslike lesions ranging from 1 to 4.5 cm in size, predominantly involving the dome or posterior wall of the bladder.10 Also in our case, cystoscopy had shown an exophytic lesion, located at the posterior bladder wall.
Accepted for publication April 2, 2013. From the Department of Pathology, University of Messina, Messina, Italy. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Valeria Barresi, MD, Dipartimento di Patologia Umana, Policlinico G. Martino, Pad D, Via Consolare Valeria, 98125 Messina, Italy (e-mail: [email protected]).
HISTOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS AND DIFFERENTIAL DIAGNOSIS At histologic examination by hematoxylin-eosin stain, mullerianosis of the urinary bladder appears as a lesion ¨ consisting of an admixture of variably sized, blandappearing glands that are deeply situated within the lamina propria and the muscularis propria of the urinary bladder
M
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Mullerianosis—Branca & Barresi ¨
wall, and which resemble the tubal, endocervical, and endometrial epithelia (Figure 1). The presence of an endometrial-like stroma surrounding the endometrial-like glands usually makes the histologic diagnosis straightforward (Figure 1, A through D). Some of the glands of mullerianosis may also show an admixture of urothelium ¨ and mullerian epithelium, which suggests a metaplastic ¨ process in the pathogenesis of the disease.7 All of the glands within the lesion look benign and neither cytologic atypia nor mitoses are evident. In line with their derivation, the glands of mullerianosis, as well as the ¨ endometrial stroma, are responsive to hormones, because of their nuclear expression of estrogen and progesterone receptors, which may be demonstrated by immunohistochemistry7 (Figure 2, A). Also, similar to the orthotopic endometrium, the stroma surrounding the endometrial glands of mullerianosis is diffusely stained by anti-CD10 ¨ antibody, and the glandular epithelia stain positively for Ca125 (Figure 2, B). The histologic differential diagnosis of mullerianosis of the ¨ urinary bladder encompasses several benign and neoplastic conditions, including cystitis glandularis, urachal remnants, nephrogenic adenoma, primary adenocarcinomas of the urinary bladder, and secondary spread from a minimaldeviation adenocarcinoma of the uterine cervix. Cystitis glandularis consists of glands lined by cuboidal to columnar cells, which may contain abundant mucin. Goblet cells are also found in the intestinal form of the disease. Unlike mullerianosis, the glands of cystitis glandularis are ¨ superficially located in the bladder wall, with preservation of the muscularis propria, and no staining for estrogen and progesterone receptors is observed.7 The hypothesis of urachal remnants should also be excluded in the presence of glandular structures within the bladder wall. The demonstration of endometrial stroma around the glands, through CD10 immunostaining, is of significant help in the differential diagnosis. Nephrogenic adenoma is a benign process that may involve the urinary bladder. In light of its histologic aspect, with small tubules lined by cuboidal and hobnail cells, it enters the differential diagnosis with mullerianosis of the ¨ urinary bladder. Nonetheless, differently from the latter, it does not feature mucinous cells, deep location in the muscularis propria of the urinary bladder, and immunoreactivity for hormone receptors. In addition, although nephrogenic adenoma stains positive for racemase,19 the endometrial glands of mullerianosis are negative for this ¨ protein.20 Mullerianosis may also simulate an infiltrating primary or ¨ metastatic adenocarcinoma of the urinary bladder, especially if glands without surrounding endometrial stroma are predominant. Based on the site of origin, 2 major types of primary adenocarcinoma of the urinary bladder are recognized: adenocarcinoma arising in the bladder proper, and that arising from the urachal remnants. In comparison with mullerianosis, which arises in women of fertile age, ¨ adenocarcinoma of both types is more characteristic of older individuals, with a mean age of 59 years at presentation.21 The presence of a normal or ulcerated overlying urothelium generally excludes the hypothesis of primary nonurachal adenocarcinoma, which shows a surface neoplastic epithelium. However, it leaves unsolved the differential diagnosis between mullerianosis and urachal ¨ adenocarcinoma, as both are characterized by a sharp demarcation from intact bladder epithelium. The preferenArch Pathol Lab Med—Vol 138, March 2014
tial location of both lesions in the dome of the bladder may further complicate the distinction between the 2 entities. Nonetheless, the evidence of endometrial glands with periglandular endometrioid stroma, the lack of cytonuclear atypia, and absence of mitoses and desmoplasia argue against a malignant lesion. Finally, the possibility of secondary bladder involvement by endocervical adenocarcinoma may be ruled out by a negative clinical history and other diagnostic studies as appropriate. CYTOLOGIC FINDINGS AND DIFFERENTIAL DIAGNOSIS To the best of our knowledge, the cytologic findings relative to mullerianosis of the urinary bladder have been ¨ described in only one case among those reported in the literature.10 The rarity of reports on the cytologic appearance of mullerianosis of the urinary bladder may be attributed to the ¨ deep localization of the mullerian glands within the bladder ¨ wall, with consequent low probability of their desquamation in the urine. Consistent with this hypothesis, in our case the cytologic examination of urine failed to detect any mullerian-type epithelia. ¨ In the only report describing the cytologic appearance of mullerianosis of the urinary bladder, only endometrial-type ¨ glands could be recognized in the urinary smear. They appeared as cohesive, 3-dimensional aggregates of glandular cells with scant cytoplasm and slightly irregular nuclei with vesicular, fine chromatin, and visible small nucleoli.10 The cytologic appearance of tubal-type epithelium in urinary cytology may be inferred from a report of endosalpingiosis of the urinary bladder.3 According to this report, in urine samples tubal epithelium figures as large, monolayered epithelial aggregates of uniform cells, showing slightly irregular nuclei with nucleoli and scanty cytoplasm. Also, papillary aggregates, isolated cells with signet-ring shape, and histiocytes may be observed.3 No cytologic descriptions of bladder endocervicosis are available. It seems, however, that the endocervical nature of the cells may be recognizable on cytologic smears. Mullerian benign lesions should be distinguished from ¨ several benign and neoplastic entities in the urinary cytology. First of all, menstrual contamination should be excluded, especially in the presence of an abundant squamous cell population. Among other benign conditions entering the differential diagnosis, the hypothesis of reactive urothelium should be considered in the presence of an inflammatory background. Undoubtedly, the most important differential diagnosis for the subsequent management of the patient regards urinary bladder neoplasias. Indeed, the presence of cells with nuclear atypia and evident nucleoli, as well as that of papillary clusters, may simulate urothelial tumors. Nonetheless, attention should be paid to the age of the patient, as urothelial neoplasias are very unusual in young women, whereas mullerianosis is charac¨ teristic of patients of fertile age. On the other hand, a necrotic background, single epithelial cell, or prominent nuclear atypia favors the diagnosis of high-grade urothelial carcinoma. Though the differential diagnosis toward lowgrade urothelial carcinoma may be more complex,22,23 the evidence of macrophages, which are found in endosalpingiosis, supports the hypothesis of mullerianosis. ¨ Mullerianosis—Branca & Barresi 433 ¨
Figure 1. A, Glands lined by endocervical epithelium in the lamina propria of endoscopically resected fragments of urinary bladder wall. B, Endocervical and endometrial glands surrounded by endometrial stroma deeply located in bladder wall. C, Endometrial gland with surrounding stroma within muscularis propria of bladder fragments. D, Gland lined by ciliated tubal-type epithelium in the bladder wall (hematoxylin-eosin, original magnifications 3100 [A and B], 3200 [C], and 3400 [D]).
The occurrence of isolated signet-ring cells in the urine of patients with endosalpingiosis3 may suggest adenocarcinoma of the urinary bladder. Nonetheless, the neoplastic cells of adenocarcinoma display a more abundant and vacuolated cytoplasm than those of benign tubal-type epithelium.3 HISTOGENESIS The pathogenesis of mullerianosis is still unclear. As for ¨ endometriosis, implantation and metaplastic origins have been contemplated.1,2 Implantation might give an explanation for mullerianosis in those patients with a previous ¨ history of pelvic surgery, especially cesarean delivery, as reported in some of the cases in the literature.1,3–5 Nonetheless, mullerianosis of the urinary bladder in the ¨ absence of previous surgery, as in our case, or mullerianosis ¨ observed at more distant sites, as in the spine,17 is hardly referable to this mechanism. Also, the presence of 2 or more mullerian tissues, rather than 1, as seen in endometriosis, ¨ seems to argue against the implantation theory. Donne et al2 preferred a metaplastic origin of mullerianosis, suggest¨ ing that the presence of various types of mullerian tissue ¨ 434 Arch Pathol Lab Med—Vol 138, March 2014
might have resulted from the differentiation of a mullerian ¨ epithelium toward tubal, endometrial, or endocervical phenotypes. In favor of a metaplastic derivation of mullerianosis is its invariable location in the posterior wall ¨ and dome of the bladder, an area that topographically corresponds to its peritoneal covering24 and that may be particularly receptive to female hormones. Further supporting a metaplastic derivation of mullerianosis of the urinary ¨ bladder may be the morphologic continuity between the mullerian glands and the urothelium, as described in the ¨ report by Koren and colleagues.7 Hence mullerianosis ¨ involving pelvic and lower abdominal structures might derive from the so-called secondary mullerian system, ¨ which includes pelvic and lower abdominal mesothelium and the subjacent mesenchyme of females. Indeed, during embryogenesis this gives rise to the mullerian ducts, the ¨ epithelium of which then differentiates into endocervical, endometrial, and tubal epithelium. We may speculate that peritoneal mesothelium might retain its potential and thus, under unknown stimuli, it might be able to further differentiate into mullerian structures in the adult. Recently, ¨ Mullerianosis—Branca & Barresi ¨
TREATMENT AND PROGNOSIS Few data are available on the management of bladder 1,2 The efficacy of gonadotropin-releasing mullerianosis. ¨ hormone agonists in the treatment of this lesion is controversial.1,2 Indeed, though disappearance of the symptoms is observed following therapy, the lesion remains unchanged in size and appearance.2 Pharmacologic treatment might be the most appropriate in the case of mullerianosis arisen in sites, such as the spinal compart¨ ment, where surgical intervention may lead to life-threatening complications.17 Nonetheless, extensive endoscopic transurethral resection may be preferable in cases involving the urinary bladder. Importantly, a strict follow-up is warranted following surgical resection, because, though rarely, the malignant transformation of endometriosis versus endometrioid carcinoma has been reported in urinary bladder.6 CONCLUSIONS In conclusion, mullerianosis of the bladder is a rare benign ¨ condition that may be clinically, cytologically, and histologically mistaken for a tumor lesion. This entity should be added to the list of pseudoneoplastic bladder lesions potentially responsible for a false-positive diagnosis of carcinoma. The clinical context and specific cytologic, histologic, and immunohistochemical findings may allow its differentiation from carcinoma. The identification of mullerianosis is of crucial importance for its correct ¨ management, which may include the use of a pharmacologic treatment, though the risk of its progression toward carcinoma is still unknown because of the small number of reported cases. References
Figure 2. A, Nuclear staining for estrogen receptors in the endometrial epithelial and stromal cells found within the fragments of urinary bladder wall. B, CD10 stain in the stroma surrounding endometrial glands (estrogen receptor stain, original magnification 3200 [A]; CD10 stain, original magnification 3200 [B]).
Batt et al25 redefined mullerianosis as ‘‘an organoid structure ¨ of embryonic origin; a choristoma composed of mullerian ¨ rests—normal endometrium, normal endosalpinx, and normal endocervix—singly or in combination, incorporated within other normal organs during organogenesis.’’ A choristoma is a mass of histologically normal tissue that is ‘‘not normally found in the organ or structure in which it is located.’’ 25 Thus, according to Batt et al,25 the pathogeneses of mullerianosis and endometriosis are deeply different, as ¨ endometriosis is endometrium shed outside the uterine cavity that invades the outer surface of organs, whereas mullerianosis is endometrium (and at times also endosal¨ pinx and endocervix) misplaced within other organs during organogenesis. In support of this hypothesis is the finding of ectopic endometrium in human fetuses, misplaced outside the uterine cavity during the earlier steps of organogenesis, in the rectovaginal septum, in the proximity of the Douglas pouch, in the mesenchymal tissue, close to the posterior wall of the uterus, in the rectal tube at the level of muscularis propria, and in the wall of the uterus with no macroscopic or microscopic defects of the genital system.26 Arch Pathol Lab Med—Vol 138, March 2014
1. Young RH, Clement PB. Mullerianosis of the urinary bladder. Mod Pathol. ¨ 1996;9(7):731–737. 2. Donne C, Vidal M, Buttin X, et al. Mullerianosis of the urinary bladder: ¨ clinical and immunohistochemical findings. Histopathology. 1998;33(3):290– 292. 3. Jimenez-Heffernan JA, Sanchez-Piedra D, Bernaldo de Quiros L, Martinez V. Endosalpingiosis (mullerianosis) of the bladder: a potential source of error in ¨ urinary cytology. Cytopathology 2000;11(5):348–353. 4. Margulis V, Lemack GE, Molberg K, Saboorian MH. Bladder ‘‘Mullerianosis’’ in a woman with lower urinary tract symptoms and hematuria. ¨ J Urol. 2001;165(6, pt 1):1996–1997. 5. Islam S, Tumman JJ, McMahon RF, Payne SR. Mullerianosis of the urinary ¨ bladder. BJU Int. 2003;92(suppl 3):e23. 6. Garavan F, Grainger R, Jeffers M. Endometrioid carcinoma of the urinary bladder complicating vesical Mullerianosis: a case report and review of the literature. Virchows Arch. 2004;444(6):587–589. 7. Koren J, Mensikova J, Mukensnabl P, Zamecnik M. Mullerianosis of the urinary bladder: report of a case with suggested metaplastic origin. Virchows Arch. 2006;449(2):268–271. 8. Cruz Guerra NA, Gomez Raposo MD, Baizan Garcia MJ, Prieto Nogal SB, Juan AG, Sierra MP. Mullerianosis of the urinary bladder: a rare entity. Arch Esp Urol. 2009;62(2):150–152. 9. Olivia Vella JE, Nair N, Ferryman SR, Athavale R, Latthe P, Hirschowitz L. Mullerianosis of the urinary bladder. Int J Surg Pathol. 2011;19(4):548–551. ¨ 10. Guan H, Rosenthal DL, Erozan YS. Mullerianosis of the urinary bladder: report of a case with diagnosis suggested in urine cytology and review of literature. Diagn Cytopathol. 2012;40(11):997–1001. 11. Ogah K, Hartis R, Hilton P. Mullerianosis involving the urinary bladder. Int Urogynecol J. 2012;23(1):123–125. 12. Kudva R, Hegde P. Mullerianosis of the urinary bladder. Indian J Urol. 2012;28(2):206–207. 13. Nogales FF, Zuluaga A, Arrabal M, Dhakal HP, Aguilar D. Mullerianosis of ¨ the ureter: a metaplastic lesion. J Urol. 1999;162(6):2090–2091. 14. Li WM, Yang SF, Lin HC et al. Mullerianosis of ureter: a rare cause of ¨ hydronephrosis. Urology. 2007;69(6):1208.e9–e11. 15. Lim S, Kim JY, Park K, Kim BR, Ahn G. Mullerianosis of the mesosalpinx: a case report. Int J Gynecol Pathol. 2003;22(2):209–212. 16. Sinkre P, Hoang MP, Albores-Saavedra J. Mullerianosis of inguinal lymph nodes: report of a case. Int J Gynecol Pathol. 2002;21(1):60–64.
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17. Barresi V, Cerasoli S, Vitarelli E, Donati R. Spinal intradural mullerianosis: ¨ a case report. Histol Histopathol. 2006;21(10):1111–1114. 18. Whitworth SA, Subhawong AP, Rosenthal DL, Ali SZ. Clear cell adenocarcinoma of the lower urinary tract: cytopathologic characteristics and differential diagnoses. Cancer Cytopathol. 2012;120(5):308–312. 19. Skinnider BF, Oliva E, Young RH, Amin MB. Expression of alphamethylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol. 2004;28(6):701–705. 20. Jiang Z, Fanger GR, Woda BA, et al. Expression of alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: a study of 761 cases. Hum Pathol. 2003;34(8):792–796. 21. Bentley G, Grignon D. Non-transitional epithelial tumors. In: Foster CS, Ross JS, eds. Pathology of the Urinary Bladder. Philadelphia, PA: Saunders; 2004: 129–134.
22. Schneider V, Smith MJV, Frable WJ. Urinary cytology in endometriosis of the bladder. Acta Cytol. 1980;24(1):30–33. 23. Bohlmeyer TJ, Shroyer KR. Endometriosis of the bladder: cytologic findings and differentiation from transitional cell carcinoma. Acta Cytol. 1996;40(2):380– 382. 24. Clement PB, Young RH. Endocervicosis of the urinary bladder: a report of six cases of a benign mullerian lesion that may mimic adenocarcinoma. Am J ¨ Surg Pathol. 1992;16(6):533–542. 25. Batt RE, Smith RA, Buck Louis GM, et al. Mullerianosis. Histol Histopathol. ¨ 2007;22(10):1161–1166. 26. Signorile PG, Baldi F, Bussani R, D’Armiento M, De Falco M, Baldi A. Ectopic endometrium in human foetuses is a common event and sustains the theory of mullerianosis in the pathogenesis of endometriosis, a disease that ¨ predisposes to cancer. J Exp Clin Cancer Res. 2009;28(1):49.
Submissions Now Accepted for CAP ’14 Abstract Program Abstract and case study submissions are now being accepted for the College of American Pathologists (CAP) 2014 meeting, which will be held September 7th through the 10th in Chicago, Ill. Submissions for the CAP ’14 Abstract Program will be accepted from:
Monday, January 13, 2014 through Friday, March 14, 2014 Accepted submissions will be published as a Web-only supplement to the September 2014 issue of the Archives of Pathology & Laboratory Medicine and will be posted on the Archives Web site. Visit the CAP ’14 Web site at www.cap.org/cap14 to access the abstract submission site and additional abstract program information as it becomes available.
436 Arch Pathol Lab Med—Vol 138, March 2014
Mullerianosis—Branca & Barresi ¨
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