Müllerianosis of the urinary bladder in pre- and postmenopausal women: a literature review

Introduction

Müllerianosis of the urinary bladder is an unusual pathological entity where Müllerian-derived tissues such as the endometrium, endocervix and endosalpinx are found within the bladder [1]. Müllerianosis appears to pose a diagnostic problem not only due to its disease etiology, which is generally benign, but due to its clinical presentation, while in many cases, Müllerianosis can resemble other more prevalent or even malignant diseases, such as endometriosis, cystitis glandularis, and bladder carcinoma [1–3]. The first report of this condition was published by Young and Clement in 1996, and this disease mainly affects premenopausal women; however, postmenopausal women may also experience the onset of the disease [3–5].

Diagnosis is often delayed due to the nonspecific nature of symptoms, which commonly include hematuria, dysuria, and pelvic pain that can be exacerbated during menstruation [3, 6]. The rarity of Müllerianosis, combined with its nonspecific symptoms, often leads to underdiagnosis or misdiagnosis, complicating its clinical management [1, 7]. Therefore, it is important to have comprehensive knowledge of its clinical manifestations, diagnostic difficulties, and management approaches in order to enhance the course of patients’ disease.

This review aims at reviewing in detail Müllerianosis through 36 cases that have been documented in the literature, detailing patients’ characteristics, symptoms, imaging, and pathological findings for a systematic understanding of this rare clinical presentation. Müllerianosis is a rare and complex pathological condition characterized by the presence of ectopic Müllerian-derived tissues, such as endometrium, endocervix, and endosalpinx, within the urinary bladder.

Literature search strategy

A comprehensive review of the literature was conducted to investigate the rare clinical entity known as Müllerianosis. A search was performed using the PubMed database with the keywords “müllerianosis” and “müllerianosis of the urinary bladder”. The search focused on identifying all relevant case reports and studies published on this topic. The inclusion criteria were original studies and case reports that detailed the clinical presentation, imaging findings, surgical intervention, and histopathological confirmation of Müllerianosis.

The search yielded a total of 32 studies with 36 cases reported in the literature. For the purpose of this review, data were extracted from each case regarding the following parameters: year of publication, number of cases, patient age, location and size of the lesions, history of previous pelvic surgery, presenting symptoms, imaging studies performed, treatment administered, and histopathological features observed. The extracted data were compiled into a summary table to allow for a comprehensive analysis of the clinical patterns, diagnostic challenges, and treatment outcomes associated with Müllerianosis (Table 1) [1–4, 6–32]. The review primarily focused on the descriptive synthesis of these findings to provide a detailed understanding of the condition and to identify any commonalities or trends that could inform clinical practice.

Results

The patient demographics for the reviewed cases of Müllerianosis indicate that the mean age of the women was 42.4 years, ranging from 25 to 70 years. The standard deviation of the ages was 11.8 years, indicating some variability in the age distribution, but with a concentration around middle age. Of the women reviewed, 8 (22.2%) were postmenopausal and 28 (77.8%) were premenopausal. This distribution suggests that Müllerianosis is more frequently observed in premenopausal women, although it is also present in postmenopausal women.

The symptoms associated with Müllerianosis are diverse and reflect the complexity of this clinical entity. The most commonly reported symptoms include dysmenorrhea and catamenial dysuria. In addition to these predominant symptoms, patients often reported a variety of other complaints, further complicating the clinical picture. Lower abdominal discomfort was frequently mentioned, a symptom that can be easily mistaken for other gynecological or gastrointestinal conditions. Recurrent urinary tract infections (UTIs) were also common, with some patients experiencing persistent dysuria, suprapubic tenderness, and even gross hematuria. These symptoms often led to significant diagnostic challenges, as they mimic more common urological disorders. Moreover, some patients experienced urgency and urge incontinence, particularly during menstruation, further indicating the cyclical and hormonal influence on symptomatology. Others reported intermittent hematuria and pelvic pain, which were sometimes associated with the presence of a bladder mass, as seen in imaging studies or during cystoscopy.

Various imaging modalities were utilized to identify lesions in the urinary bladder. However, it is important to note that while these imaging studies were crucial in detecting the presence of abnormal masses, they were not definitive in diagnosing Müllerianosis. The imaging findings provided essential information about the size, location, and characteristics of the lesions. Magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound were most frequently employed to visualize the masses. In the cases reviewed, MRI and CT scans revealed the presence of solid masses, often with scattered cystic areas, mostly in the posterior wall of the urinary bladder. These findings indicated the presence of a lesion, but they were not specific enough to confirm Müllerianosis, as similar imaging features could be seen in other conditions such as bladder cancer, endometriosis, or benign cysts. In several instances, imaging studies were combined with cystoscopy to detect the presence of the mass, and to possibly allow the biopsy of the suspicious area.

The lesions associated with Müllerianosis are typically located in the posterior wall (n = 18 cases) of the urinary bladder, which was the most common site of involvement across the reported cases. Other locations were the lateral wall of the bladder (n = 5), the dome (n = 6), the anterior wall (n = 1), the trigone (n = 1), the base (n = 1) and the ureterovesical junction (n = 1). In four cases no specific location was provided. The size of these lesions varied, generally ranging from 2 cm to 4 cm in diameter, although larger lesions have been documented. The lesions were frequently described as solid masses, occasionally exhibiting scattered cystic areas, reflecting the complex and heterogeneous nature of the ectopic Müllerian tissue.

In some cases, the lesions presented as well-circumscribed masses that could be visualized on imaging studies or during surgical exploration. The presence of cystic components within these lesions suggests a degree of morphological diversity, with both glandular (cystic) and stromal (solid) elements being present. This variation in the lesion’s appearance can contribute to diagnostic challenges, as it might mimic other neoplastic or inflammatory conditions affecting the bladder or adjacent pelvic structures.

A history of previous pelvic surgery was a significant factor in many of the patients. Out of the total cases reviewed, 21 women had a documented history of previous pelvic surgery. These procedures included cesarean sections in 8 cases, hysterectomy (vaginal, laparoscopic) in 6 cases, and other pelvic procedures (salpingo-oophorectomy, cyst removal, ectopic pregnancy, cervical polypectomy) in 4 cases. Moreover, four women had a history of endometriosis. Conversely, 8 women did not have any history of previous pelvic surgery, indicating that Müllerianosis can occur even in the absence of surgical intervention.

The treatment strategies for Müllerianosis varied across the reviewed cases. The most common intervention was transurethral resection (TUR) of the lesion, which was carried out in 28 cases. TUR was typically the initial surgical approach used either to remove the lesions or to obtain tissue for biopsy. In 7 cases, particularly where lesions were extensive, there were recurrence (n = 5) [20–22, 24, 26], or there was a suspicion of malignancy (n = 1) [12], TUR was followed by more radical procedures, such as partial cystectomy (n = 5), or partial cystectomy combined with total hysterectomy (n = 2). In 3 cases, only the lesion was excised, while in one case, a total hysterectomy was performed combined with a partial cystectomy. Additionally, in 2 cases, partial cystectomy was undertaken without further procedures. Finally, in one instance, following TUR, treatment was supplemented with a GnRH analogue.

The histopathological examination of the lesions in Müllerianosis revealed a consistent pattern of ectopic Müllerian tissue, with a complex mix of endosalpingiosis, endocervicosis, and endometriosis identified across the majority of cases. Endosalpingiosis was the most frequently observed feature, present in 22 cases. This tissue type typically displayed ciliated columnar epithelium similar to that of the fallopian tubes. Endocervicosis was noted in 19 cases. This component resembled the endocervical glands, showing glandular epithelium embedded in a fibromuscular stroma, which is characteristic of the cervical tissue. Endometriosis was identified in 17 cases. This involved the presence of endometrial glands and stroma, often accompanied by signs of hemorrhage and hemosiderin-laden macrophages, indicative of cyclic hormonal activity. Eleven cases demonstrated all three components (endosalpingiosis, endocervicosis, and endometriosis) within a single lesion, underscoring the heterogeneity of Müllerianosis. Moreover, additional histopathological findings were reported in some cases, indicating secondary changes or complications. For instance, chronic glandular cystitis was noted in 2 cases, suggesting a reactive inflammatory response in the surrounding bladder tissue. Similarly, solid von Brunn’s nests, which are benign proliferations of urothelial cells, were found in 2 cases, indicating possible secondary epithelial changes due to the presence of the ectopic Müllerian tissue. In one case, a rare finding of endometrioid carcinoma arising from the Müllerian tissue was documented, highlighting the potential, albeit rare, for malignant transformation within these lesions.

Discussion

Müllerianosis of the urinary bladder is a rare and complex pathological entity characterized by the presence of at least two of the three Müllerian-derived tissues, endometrium, endocervix, and endosalpinx within the bladder wall. While benign, the rarity of Müllerianosis, combined with its nonspecific symptoms, often leads to delays in diagnosis and challenges in management [1–3].

Müllerianosis was first described by Young and Clement in 1996 and is predominantly seen in women of reproductive age, although cases have been reported in postmenopausal women as well [3–5]. The condition is typically discovered incidentally during investigations for urinary symptoms such as hematuria, dysuria, and pelvic pain, which can be exacerbated during menstruation [3, 6]. The exact prevalence of Müllerianosis is not well documented due to its rarity and potential underdiagnosis or misdiagnosis as other conditions such as endometriosis or bladder neoplasms [1, 7].

This review included 36 cases from 32 studies. The mean age of the affected women was 42.4 years, with a notable prevalence in premenopausal women. This age distribution, coupled with the observation that 77.8% of the cases were premenopausal, suggests a significant hormonal component in the pathogenesis of Müllerianosis. The cyclical nature of symptoms, such as dysmenorrhea and catamenial dysuria, observed in multiple cases, further supports this hypothesis, drawing parallels with conditions like endometriosis.

Two primary theories have been proposed to explain the pathogenesis of Müllerianosis: the implantation theory and the metaplastic theory. The implantation theory suggests that Müllerian tissue is displaced and implanted in ectopic locations, such as the bladder, during pelvic surgery or cesarean sections. This theory is supported by the observation that a significant number of patients with Müllerianosis have a history of such procedures. However, this theory does not fully explain the occurrence of Müllerianosis in patients with no history of surgery [3, 5, 27, 33]. The metaplastic theory posits that Müllerian tissues develop from the metaplasia of the peritoneal mesothelium under the influence of hormonal factors [13, 33]. This theory is favored in cases where there is no history of pelvic surgery, suggesting that Müllerianosis can arise de novo from embryological Müllerian remnants during development. The metaplastic theory is also supported by the presence of estrogen and progesterone receptors in the ectopic tissues, indicating a hormonal influence on the development of these lesions [3, 5].

The diagnosis of Müllerianosis is notably difficult due to the overlap of its symptoms with other more common conditions and the lack of specific diagnostic criteria. Imaging studies such as ultrasound, CT, and MRI can reveal mass lesions within the bladder, but these findings are nonspecific and can easily be mistaken for malignancies such as transitional cell carcinoma or other benign conditions like cystitis glandularis [1, 2, 5, 17]. Cystoscopy, often performed to investigate these bladder masses, may show nodular lesions that are difficult to distinguish from malignant tumors. This review found that while imaging is crucial for identifying the presence of abnormal masses, it is not definitive for diagnosing Müllerianosis. The lesions were predominantly located in the posterior wall of the bladder, yet other sites were also involved, adding to the diagnostic challenge. The imaging characteristics of these lesions often mimic other urological conditions, underscoring the need for histopathological examination to confirm the diagnosis.

Histopathological examination remains the gold standard for diagnosis, where the identification of Müllerian components of endometrial, endocervical, and tubal epithelium within the bladder wall confirms the condition. Immunohistochemical staining showing positivity for estrogen and progesterone receptors can further support the diagnosis [7]. Tumor markers such as CA-125 can be helpful in differentiating benign from malignant conditions; however, their limited sensitivity and specificity for malignancy highlight the need for a comprehensive diagnostic approach that incorporates multiple modalities to ensure accurate evaluation and prompt treatment [33]. Recent literature has highlighted butyrylcholinesterase (BChE) as a promising biomarker in inflammatory and malignant conditions, including its utility in predicting surgical complications and systemic inflammatory responses. BChE is an enzyme widely distributed in various tissues, and its serum levels are indicative of inflammatory status, nutritional health, and hepatic function. In the context of Müllerianosis of the urinary bladder, which can mimic neoplastic or inflammatory lesions, BChE may offer value as an adjunctive diagnostic tool [34].

The management of Müllerianosis is not standardized due to its rarity, and the treatment approach is often individualized based on the patient’s symptoms, the extent of the disease, and the presence of any associated complications. Both surgical and medical management strategies have been employed, each with its own indications and outcomes [2, 3, 35]. Surgical intervention seems, according to the literature, the preferred approach, especially in cases where the lesion presents as a suspicious mass or when the patient experiences significant symptoms such as severe dysuria, hematuria, or pelvic pain. The goal of surgery is typically to remove the lesion to confirm the diagnosis and to alleviate symptoms. Common surgical procedures include transurethral resection, partial cystectomy, hysterectomy or combination surgery.

Transurethral resection is often the first line of surgical treatment, especially when the lesion is accessible and confined to the bladder wall. TUR allows for both diagnostic and therapeutic resection of the mass. In many cases, this procedure is sufficient to relieve symptoms and provide a definitive diagnosis [1, 5]. In cases where the lesion is extensive or involves deeper layers of the bladder wall, a partial cystectomy may be necessary. This procedure involves the removal of a portion of the bladder and is typically reserved for larger or recurrent lesions that are not fully resectable via TUR. The aim is to achieve complete resection of the lesion while preserving bladder function [3, 27]. In certain cases, particularly when Müllerianosis is associated with other pelvic pathologies or when it involves areas outside the bladder (such as in the case of endometriosis), a more extensive surgical approach may be required. Laparoscopic surgery allows for a minimally invasive approach to resect the lesion, while open surgery might be necessary for more complex cases [5, 7].

Post-surgical outcomes are generally favorable, with most patients experiencing significant relief of symptoms. However, close follow-up is essential, as there have been rare cases of recurrence, even years after surgery. In the literature, only one case of recurrence has been reported following complete resection, indicating that while recurrence is uncommon, it remains a possibility [2, 3].

For patients who are not ideal candidates for surgery or those who prefer a non-surgical approach, medical management may be considered. Hormonal therapies are the cornerstone of medical management, particularly in patients with a known history of endometriosis or those with hormone-sensitive lesions. Gonadotropin-releasing hormone (GnRH) agonists are used to suppress ovarian function, thereby reducing the production of estrogen, which is believed to stimulate the growth of Müllerian tissue. GnRH agonists can effectively reduce the size of the lesions and alleviate symptoms such as dysmenorrhea and pelvic pain [5, 7]. Continuous use of oral contraceptives or progestins can help manage symptoms by maintaining a steady hormone level, thereby preventing the cyclical changes that exacerbate symptoms. This approach is often used in patients with mild symptoms or as an adjunct to surgical treatment [7]. Aromatase inhibitors and selective estrogen receptor modulators (SERMs) have also been explored in the treatment of endometriosis and related conditions, including Müllerianosis. These agents work by inhibiting estrogen production or blocking estrogen receptors, thereby reducing the growth and activity of Müllerian tissue [3].

While medical management can be effective, it is often considered a temporary solution, particularly in younger women who may desire fertility or in those with extensive disease. The efficacy of medical treatments in preventing post-surgical recurrence remains uncertain, and in many cases, surgical intervention may ultimately be required [3, 7].

The prognosis for patients with Müllerianosis is generally favorable, given the benign nature of the condition. However, the potential for recurrence or the development of new lesions necessitates careful long-term follow-up. Patients should undergo regular monitoring, including imaging and cystoscopic evaluations, especially if they continue to experience symptoms or if there was incomplete resection of the initial lesion [2, 3, 31]. Although Müllerianosis itself is benign, there is a theoretical risk of malignant transformation, particularly in cases where the condition coexists with other Müllerian-derived lesions such as endometriosis. Thus, any new or worsening symptoms should prompt further investigation to rule out malignancy [3, 7, 31].

Conclusions

In conclusion, Müllerianosis, while rare, requires a nuanced approach to management, balancing the need for definitive treatment with the preservation of bladder function and the minimization of recurrence risk. Continued research and accumulation of case reports will be essential for refining these management strategies and improving outcomes for affected patients.