Müllerianosis of the Urinary Bladder: A Rare Tumorlike Lesion

Müllerianosis 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 müllerian glands to hormonal stimuli. The major interest of müllerianosis 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. Müllerianosis may be responsive to gonadotropin-releasing hormone agonists. Surgical resection may be justified in the case of clinical symptoms refractory to hormone therapy. Müllerianosis of the Urinary Bladder: A Rare Tumorlike Lesion Müllerianosis was first described by Young and Clement1 in 1996 as a rare entity consisting of an admixture of at least 2 types of müllerian tissues—cervical, tubaric, or endometrial—in the lamina propria and muscularis propria of the urinary bladder. At present, fewer than 20 cases of müllerianosis 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 müllerianosis of the urinary bladder resides in its potential to mimic a neoplastic lesion from clinical, cytologic, and histologic viewpoints.10,18 Though müllerianosis is extremely rare, its correct identification is crucial for appropriate management, because patients may benefit from hormonal therapy and radical cystectomy may be avoided. CLINICAL FEATURES Müllerianosis 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, müllerianosis may simulate many other pathologic conditions of the urinary tract, including neoplasias. A novel case of müllerianosis 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. GROSS FINDINGS A definitive gross description of müllerianosis 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 müllerianosis 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 müllerianosis 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. HISTOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS AND DIFFERENTIAL DIAGNOSIS At histologic examination by hematoxylin-eosin stain, müllerianosis of the urinary bladder appears as a lesion consisting of an admixture of variably sized, bland-appearing glands that are deeply situated within the lamina propria and the muscularis propria of the urinary bladder 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 müllerianosis may also show an admixture of urothelium and müllerian 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 müllerianosis, 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 müllerianosis is diffusely stained by anti-CD10 antibody, and the glandular epithelia stain positively for Ca-125 (Figure 2, B). The histologic differential diagnosis of müllerianosis 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 minimal-deviation 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 müllerianosis, 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 müllerianosis 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 müllerianosis are negative for this protein.20 Müllerianosis 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 müllerianosis, 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 müllerianosis and urachal adenocarcinoma, as both are characterized by a sharp demarcation from intact bladder epithelium. The preferential 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 müllerianosis 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 müllerianosis of the urinary bladder may be attributed to the deep localization of the müllerian 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 müllerian-type epithelia. In the only report describing the cytologic appearance of müllerianosis 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. Müllerian 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 müllerianosis is characteristic 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 low-grade urothelial carcinoma may be more complex,22,23 the evidence of macrophages, which are found in endosalpingiosis, supports the hypothesis of müllerianosis. 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 müllerianosis is still unclear. As for endometriosis, implantation and metaplastic origins have been contemplated.1,2 Implantation might give an explanation for müllerianosis 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, müllerianosis of the urinary bladder in the absence of previous surgery, as in our case, or müllerianosis observed at more distant sites, as in the spine,17 is hardly referable to this mechanism. Also, the presence of 2 or more müllerian tissues, rather than 1, as seen in endometriosis, seems to argue against the implantation theory. Donne et al2 preferred a metaplastic origin of müllerianosis, suggesting that the presence of various types of müllerian tissue might have resulted from the differentiation of a müllerian epithelium toward tubal, endometrial, or endocervical phenotypes. In favor of a metaplastic derivation of müllerianosis 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 müllerianosis of the urinary bladder may be the morphologic continuity between the müllerian glands and the urothelium, as described in the report by Koren and colleagues.7 Hence müllerianosis involving pelvic and lower abdominal structures might derive from the so-called secondary müllerian system, which includes pelvic and lower abdominal mesothelium and the subjacent mesenchyme of females. Indeed, during embryogenesis this gives rise to the müllerian 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 müllerian structures in the adult. Recently, Batt et al25 redefined müllerianosis as “an organoid structure of embryonic origin; a choristoma composed of müllerian 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 müllerianosis and endometriosis are deeply different, as endometriosis is endometrium shed outside the uterine cavity that invades the outer surface of organs, whereas müllerianosis is endometrium (and at times also endosalpinx 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 TREATMENT AND PROGNOSIS Few data are available on the management of bladder müllerianosis.1,2 The efficacy of gonadotropin-releasing 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 müllerianosis arisen in sites, such as the spinal compartment, 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, müllerianosis 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 müllerianosis 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. Contributor Notes The authors have no relevant financial interest in the products or companies described in this article.