Ureteral endometriosis: A systematic literature review.

INTRODUCTION: Ureteral endometriosis is a rare disease affecting women of childbearing age which presents with nonspecific symptoms and it may result in severe morbidity. The aim of this study was to review evidence about incidence, pathogenesis, clinical presentation, diagnosis, and management of ureteral endometriosis.
MATERIALS AND METHODS: PubMed Central database was searched to identify studies reporting cases of ureteral endometriosis. "Ureter" or "Ureteral" and "Endometriosis" were used as key words. Database was searched for articles published since 1996, in English without restrictions regarding the study design.
RESULTS: From 420 studies obtained through database search, 104 articles were finally included in this review, including a total of 1384 patients with ureteral endometriosis. Data regarding age, location, pathological findings, and interventions were extracted. Mean patients' age was 38.6 years, whereas the therapeutic arsenal included hormonal, endoscopic, and/or surgical treatment.
CONCLUSIONS: Ureteral endometriosis represents a diagnostic and therapeutic challenge for the clinicians and high clinical suspicion is needed to identify it.

INTRODUCTION

Endometriosis is an important gynecologic clinical disorder characterized by the ectopic presence and growth of functional endometrial tissue, glands, and stroma, outside the uterus, clinically associated with pelvic pain and infertility.[1] While the true incidence of this clinical entity cannot be exactly known since a large proportion of the affected women are asymptomatic, it is estimated to be about 5%–20%. The organs most commonly involved include the ovaries, the uterosacral ligaments, the fallopian tubes, the cervix, and the cul-de-sac.[2] Endometriosis can be classified as ovarian, peritoneal, or deep infiltraring endometriosis, with the latter defined as the presence of a lesion infiltrating 5 mm or more into the peritoneum.[3] Another classification based on the number, size, and superficial and/or deep location of endometrial implants, plaques, endometriomas and/or adhesions has been established by the American Society for Endometriosis and is as follows: stage I (minimal-points 1–5), stage II (mild-points 6–15), stage III (moderate– points 16–40), and stage IV (severe– points >40).[4] The endometriotic cells may originate from retrograde menstruation, blood and lymphatic dissemination, stem cells, and metaplasia of coelomic epithelium.[4] We present the clinical appearance of endometriosis in the ureter(s), the steps to diagnosis and treatment options through a review of the literature.

MATERIALS AND METHODS

Data collection

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for this systematic review. Medline was systematically searched, and thereafter, we performed a snowball process in the reference lists of the eligible articles for additional titles.

Search methodology

A thorough search of the English language literature published from 1996 until August 2017 was performed to identify studies relative to ureteral endometriosis. The search strategy explored medical subject heading terms in all possible combinations: “Endometriosis” and “ureteral” or “ureter.” Each title and abstract of studies were evaluated and selected according to relevance and inclusion criteria. The electronic search was supplemented and expanded using the “related articles” function of the search engine and with manual search of the relevant articles. The study selection and data extraction were performed by two investigators (VP, GK), and the full texts of the studies were retrieved. Discrepancies were rechecked, and consensus was achieved by discussion. After locating and reading 420 abstracts online, relevant articles were printed to permit thorough reading. After full-texts analysis, 235 articles were excluded because they met exclusion criteria while 185 were selected for inclusion [Figure 1].

Figure 1

Summarizing literature search results

One hundred and four articles were finally included in this review: 5 prospective studies and 99 retrospective, of which 62 were case reports. A total of 1384 patients (mean age 38.6 years) with ureteral endometriosis were evaluated and data on age, side affected, histological type, and management are included in Supplementary Table 1 (available online only at www.indianjurol.com).

Illustrates the main studies with ureteral endometriosis and their characteristics

Click here for additional data file.

Inclusion and exclusion criteria

Eligibility for inclusion was limited to papers referring specifically to patients having ureteral endometriosis, and including data regarding age, side affected, histology, and intervention. Articles were excluded if they referred only to endometriosis located in other organs or when the referable data were mixed. Furthermore, reviews and letters were also excluded.

RESULTS

Epidemiology

Ureteral endometriosis is a rare disease first described by Cullen in 1917, constituting 0.1%–0.4% of genitourinary tract endometriosis.[56] Ureters are the second most common site of the urinary tract affected by endometriosis with a ratio of bladder/ureter/kidney/urethral endometriosis of 40:5:1:1, whereas an increase in incidence is observed over the years probably because of the increased diagnosis.[78] On the other hand, the fact that the disease can also run asymptomatically or present with nonspecific symptoms may lead to an underestimation of the prevalence of this clinical entity.

Pathogenesis and histopathology

The pathogenesis of endometriosis and more specifically of ureteral involvement has been widely investigated; however no single theory explains the clinical entity. The most common theory is that of retrograde menstruation,[910] which also explains the asymmetrical localization of ureteral endometriosis. The sigmoid colon contributes to the creation of an isolated microenvironment around the left adnexa. Macrophages, the first line of the immune system cannot reach the endometrial cells coming from the left fallopian tube into the peritoneal environment. On the right side, the cecum cannot provide such protection because of its more cranial anatomical position. The above-mentioned asymmetry has also been correlated with the presence of ovarian endometriosis indicating a common pathogenesis of ovarian and ureteral endometriosis or the development of ureteral lesions as a subsequent implantation arising from the ovaries. In addition, the propensity for endometriotic lesions to affect the distal ureter more frequently than the proximal ureter could also be explained by the retrograde menstruation theory, explaining the implantation of endometriotic cells under the influence of gravity.[11]

The second theory is the embryonal one. According to this, endometriosis may develop primarily in the retroperitoneum from the embryonic remains of the Mullerian duct. A further spread of the disease up to and around the ureter may be explained by the proliferation of smooth muscle surrounding the ureteral wall.[89]

Benign metastasis could also potentially provide a theory for some cases of endometriosis, wherein endometrial cells from within the uterus circulate through the lymphatic or blood vessels and spread to distant parts of the body.[12]

In addition, other hormonal and molecular pathways play an important and complicated role in the pathophysiology of deep endometriotic lesions in the ureters. The presence and survival of ectopic endometrial tissue in deep endometriotic lesions require a type of immunotolerance. Sphingosine-1-phosphate receptor 1 axis plays a particular role in this process, receiving several stimuli such as growth factors (EGFR, VEGFR, and NGFR), hormones, chemokines, cytokines, and reactive oxygen species and inducing interleukin (IL) 1b, tumor necrosis factor-alpha (TNF-α). Cytokines such as IL-1b or IL-33, which are elevated in deep infiltraring endometriosis (DIE), have further immunomoderative effects. In addition, DIE lesions demonstrate an overexpression of prostaglandin endoperoxide synthase 2 (PTGS2), which in turn leads to an increase in the production of PGF2a and PGE2 from endometrial cells. This fact, in combination with the upregulation of prostaglandin receptors leads to the presence of high concentrations of prostaglandins in DIE.[13141516]

The hormonal background is also different in DIE lesions, which show an increased estrogen biosynthesis and a decreased inactivation through the following mechanisms; upregulation of aromatase (converts androgens to estradiol E2), downregulation of 17b-hydrosteroid dehydrogenase type 2 (HSD17B2) (converts E2 to the less active metabolite estrone), increase of 17b-hydrosteroid dehydrogenase type 1 (HSD17B1) messenger RNA (E2 with increased tissue concentration), and upregulation of the expression of estrogen receptor (ER) β (suppression of ERa expression and consequently E2 inhibition of progesterone expression dominates against its stimulation).

On the other hand, DIE tissues show progesterone resistance, which in turn leads to decreased expression of HSD17B2 and downregulation of estrogen metabolism. In addition, estradiol in combination with TNF-a (Tumor necrosis factor-alpha) induces while progesterone inhibits the activation of NF-kB, which has antiapoptotic functions.

The hormonal milieu of DIE lesions is responsible for their resistance to progesterone's antiproliferative effects and subsequently for survival of the endometriotic cells.

A favorable invasion microenvironment is also created by the upregulation of matrix metalloproteinase MMP-3, TGF-b, and other cytokines. Oxidative stress and neuroangiogenetic mechanisms were also found to be involved in the pathogenesis of DIE increased proliferative (reactive oxygen species), extracellular regulated kinase, and advanced oxidation protein product, and increased expression of neurangiogenesis genes including nerve growth factor, vascular endothelial growth factor, and intercellular adhesion molecule activity of oxidative stress of NF-kB, reactive oxygen species.[4]

Histopathologically, two major types of endometriosis are recognized according to the grade of infiltration of the ureteral wall: intrinsic and extrinsic.[7] In the extrinsic type, the endometrial tissue invades the ureteral adventitia and/or the surrounding connective tissue. As a result, ureteral obstruction and hydronephrosis are common. In the intrinsic type, the ectopic endometrial tissue, apparently through lymphatic or venous metastasis, is found in the muscularis mucosa and the uroepithelium. Nevertheless, the two types may occur simultaneously.[7171819]

Diagnosis

Ureteral endometriosis presents a diagnostic challenge. Many medical specialties may be involved since the patients complain of non-specific symptoms. Most patients present with incapacitating dysmenorrhea, dyspareunia, pelvic pain, symptoms related with the involvement of rectovaginal septum, uterosacral ligaments, broad ligaments, and the ovaries.[202122] Ureteral endometriosis may also cause more specific symptoms associated with the urinary tract such as flank or abdominal pain, renal colic, hematuria associated with flank pain, or cyclic gross hematuria. Unexplained hypertension and silent renal failure may also occur as the disease may run asymptomatic for a long time. Risk of renal failure in this cases is as high as 25%–50%.[1823]

Considering that the symptoms are either non-specific or absent initally, a high index of clinical suspicion is required when patients of childbearing age have such a clinical presentation. This is why evaluation of the urinary tract is suggested when deep infiltrating endometriosis is suspected and more particularly if the rectovaginal septum is affected by nodules of >3 cm.[24] It is found that patients with rectocervical endometriosis have a 7-fold greater chance of having ureteral endometriosis, whereas patients with rectum-sigmoid endometriosis have a 22-fold greater chance.[25]

Physical examination

While there may be no physical findings, large endometriotic nodules may be palpated in the rectovaginal septum and their presence is highly related to ureteral endometriosis.[24]

Investigations

Serum Ca125 may be elevated in endometriosis but is neither sensitive nor specific for ureteral endometriosis.[26] Renal function should be assessed and urine should be examined for hematuria, and cytology to rule out malignant disease.

There are no specific diagnostic tests and the extent of the disease cannot be accurately estimated preoperatively. A step-by-step algorithm is proposed [Table 1]. A vaginal ultrasound may reveal the presence of ovarian endometriomas and/or nodules at the rectovaginal septum. Abdominal ultrasound can identify urinary tract obstruction. In case of normal findings, a kidney ultrasound should be obtained regularly in follow-up. Computed tomography has limited use in the diagnostis of ureteral endometriosis because of the high cost, poor specificity, and high radiation dose, which is avoidable for patients of childbearing age.[7]

Table 1

Step-by-step diagnosis of ureteral endometriosis

Magnetic resonance imaging (MRI) allows assessment of disease extension in the pelvis and ureteric involvement and is the investigation of choice.[27282930] It allows evaluation of all endometriotic locations and can potentially distinguish intrinsic from extrinsic form of ureteral endometriosis and thus help decide the surgical approach.[31] In addition, MRI appears to be more sensitive (91% vs. 82%) but less specific (59% vs. 67%) than surgery for the diagnosis of intrinsic ureteral endometriosis.[32]

Isotope renography should be used to assess any patient with suspected ureteral endometriosis to evaluate renal function.[3334] It is reported that 25%–50% of the nephrons are lost, and almost 30% of the patients present with reduced kidney function at the time of the diagnosis.[35]

Ureteroscopy is used to diagnose intrinsic endometriosis, although negative findings do not exclude the presence of ureteral endometriosis Apart from the macroscopic recognition of endometriotic lesions, which may appear as edematous and irregular with different shapes and colors, ureteroscopy allows biopsy, histological confirmation and ablation.[303637] It may also reveal multifocality of the disease and helps measure the distance between the lower endometriotic margins and ureteral orifices which is of fundamental significance for the choice of surgical approach.[3839]

Most commonly ureteral endometriosis is found accidentally in patients undergoing laparoscopy for infertility and/or endometriosis.

Treatment

Ureteral endometriosis is an uncommon clinical entity that affects young women of childbearing age with severe symptoms and/or infertility. Because of the rarity of the disease and the lack of prospective randomized studies, there are no clear guidelines for treatment. Each patient should be individually managed after a multidisciplinary team approach, including a skilled laparoscopic gynecologist, urologist, and colorectal surgeon. The therapeutic arsenal includes both conservative and operative treatments [Table 2]. The choice depends on the onset and renal function and the issues are: (1) relief of symptoms (2) renal preservation, and (3) prevention of relapse.

Table 2

Ureteral endometriosis: Therapeutic management

Hormonal therapy

Hormonal therapy includes danazol, GnRH agonists (leuprolide, goserelin), medroxyprogesterone, estrogen-progestin combination, and progestin alone. The most popular between are danazol and GnRH agonists, which antagonize the effect of gonadotropin, entailing the eventual effect of inhibition of ovarian function. In addition, local progestogens in the form of intrauterine levonogestrel device lead to a high concentration of the drug at the endometrium and are effective in the management of pelvic and vesicovaginal septum endometriosis. The 5-year effectiveness in combination with preservation of fertility after cessation of therapy is simlar to intrauterine levonorgestrel devices.[4041]

The best candidates for hormonal therapy are: (a) patients of childbearing age who desire pregnancy, with close follow-up with ultrasound at 6-month intervals to rule out an obstruction,[7] (b) patients without significant fibrosis in combination with the suitable surgical intervention,[3036] and (c) postmenopausal women, under close follow-up.[39] Hormonal therapy functions through the shrinkage of affected tissues. It does not prevent the formation of fibrous tissue and adhesions. As a consequence, ureteral obstruction and hydroureteronephrosis may still occur.[4243] Medical management alone is clearly contraindicated in the setting of ureteral obstruction and hydronephrosis, and medical management alone might not be a good option for ureteric endometriosis given the increased incidence of recurrence with the serious potential sequelae of reduced renal function.[7]

Moreover, the response to hormonal therapy may not be complete. A possible explanation is the desmoplastic reaction within the muscle layers and the serosa of the ureter due to repetitive bleeding and resorption of menstrual debris. In addition, the side effects of hormonal therapy are a reason for low compliance. The relapse rate is also high (55%) after treatment cessation.[44] Therefore conservative treatment is considered as palliative for deep infiltrative endometriosis.

Invasive therapy

Endoscopic management

Ureteroscopic management is indicated in patients with intraluminal endometriosis. Ureteroscopy allows ablation with laser, and balloon dilatation with stent placement.[384546] However, this is often not curative and follow-up imaging, including ureteroscopic surveillance and retrograde urography, is recommended to early detect disease recurrence and/or progression.

Operative management

Conventionally, laparotomy was the approach of choice for the treatment of extensive ureteral endometriosis.[47] Laparoscopy, through a magnified view, allows greater ability to identify the extent of the disease.[4849] In both cases, the preoperative ureteric stent is recommended as it functions as a guide for the identification of the ureter and the prevention of ureteral injury.

Operative approaches for ureteral endometriosis include ureterolysis, ureteral resection with ureteral reconstruction, and nephrectomy in cases of renal insufficiency. The choice of the suitable technique is based on the type of ureteral endometriosis (intrinsic vs extrinsic) and the location and the extent of the disease.

Ureterolysis

Ureterolysis is indicated in cases of extrinsic endometriosis with lesions <3 cm when not associated with hydroureteronephrosis.[2050] Intrinsic endometriosis is a contraindication for ureterolysis since it is associated with high recurrence rates (16%) and ureteral restenosis. Patients should be warned about the possible need for reintervention and/or progressive renal failure, in combination with the need for close follow-up.[4851]

Ureteral resection with ureteral reconstruction

Ureteral resection with ureteral reconstruction is considered in cases of intrinsic endometriosis, lesions longer than 3 cm situated below the level of the iliac vessels and hydroureteronephrosis.[48] The two basic techniques include the ureteral-ureteral anastomosis and ureteroneocystostomy.

The first technique should be performed if the ureteral stenosis is limited to the ovarian fossa and distal ureter can be preserved.[525354555657]

Ureteroneocystostomy is the operation of choice in cases of extended disease with ureteral stenosis close to the vesicoureteral junction.[5358596061] The Lich-Gregoire, Leadbetter–Politano or a psoas hitch technique may be used.[626364] Rarely, replacement with bowel segments or bladder flaps may be required.[6566] A successful series of five laparoscopic nonrefluxing extravesical Lich-Gregoir reimplantations with no intra- or post-operative complications and a 100% success rate in accordance with the previous literature for open surgery has been reported.[676869] Ureterocystoneostomy with the vesico-psoas hitch technique places the ureter away from the pelvis, the frequent site of recurrence.[59] Tension-free anastomosis is needed to reduce the risk of postoperative recurrence of stenosis and hydronephrosis.[70] Despite the modification of the anatomy of the urinary tract, the urodynamic parameters do not change.[71] The effectiveness of the psoas hitch and ureteral reimplantation in open surgery has been proven by multiple reports in the literature, with good results at follow-up.[7172737475] On the other hand, Gozen et al. reported their series of laparoscopic psoas hitch and concluded that it is a versatile procedure with multiple indications and associated with excellent results.[69] In addition, Rassweiler et al., in a retrospective comparison with open surgery, report a functional success rate of 10 out of 10 in the laparoscopic group.[74]

Nephrectomy

Nephrectomy is necessary in cases of deteriorated renal function, which unfortunately still occurs despite the surgical techniques developed and in cases when the lesions mimic an urothelial carcinoma.[63]

CONCLUSIONS

Ureteral endometriosis is a challenging disease presenting most commonly with nontypical symptoms and signs and may consequently lead to significant morbidity and most importantly renal function deterioration. The diagnosis should be suspected when women of childbearing age appear with atypical urological symptoms combined with symptoms indicative of deep pelvic endometriosis. Preoperative imaging is helpful for the planning of the operative management. Surgery depends on the type, extent, and location of the disease, and a laparoscopic approach is preferred. Surgical management is effective in relieving symptoms and improving fertility. For the best results, a multidisciplinary approach from an experienced gynecologist, urologist, and general surgeon is advised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.