Endosalpingiosis

INTRODUCTION — Endosalpingiosis is the presence of ectopic, cystic glands outside the fallopian tube that are lined with fallopian tube-type ciliated epithelium [1]. Endosalpingiosis may occur in pelvic organs, including ovaries, fallopian tube serosa, uterine serosa, myometrium, or pelvic peritoneum. It may also occur in the bladder or in a retroperitoneal or axillary lymph node [2].

Endosalpingiosis is not well-studied, and the clinical features remain uncertain. It has been reported to be associated with pelvic pain, infertility, pelvic mass, and/or urinary symptoms [3-6]. It is also often found concurrently with endometriosis or pelvic serous neoplasms. However, the diagnosis of endosalpingiosis can be made only after surgical biopsy.

Another notable feature of endosalpingiosis is its histologic relationship to pelvic serous neoplasms (eg, lesions of low malignant potential, low-grade pelvic serous carcinoma). However, the role of endosalpingiosis as a risk factor or as part of the pathogenesis of these conditions is unknown.

The pathology, diagnosis, and management of endosalpingiosis will be reviewed here. Topics regarding endometriosis are discussed separately. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact" and "Endometriosis: Treatment of pelvic pain".)

EPIDEMIOLOGY — The prevalence of endosalpingiosis is difficult to establish since it is diagnosed only through surgical biopsy. The median age of diagnosis is between 50 and 52 years; other characteristics are as follows [6-8]:

●Postmenopausal patients – 40 to 59 percent

●Nulliparous patients – 27 to 31 percent

●History of tubal disease – 34 to 37 percent

●Concurrent endometriosis – 35 to 40 percent; lower rates have been reported [9].

Some data suggest that endosalpingiosis is more common in women with BRCA mutations. This was reported in one study that found endosalpingiosis in 86 percent of BRCA carriers undergoing risk-reducing salpingo-oophorectomy compared with 56 percent of women at low risk of ovarian cancer undergoing salpingo-oophorectomy for other indications [10].

In addition, prevalence may be affected by the sectioning method (ie, interval) of the histologic specimen. In a retrospective study of over 1100 ovarian and fallopian tube pathology specimens, the prevalence of endosalpingiosis with standard compared with 2 to 3 mm interval sections was 2.5 and 22.0 percent, respectively [11]. Prevalence also increased with age; patients >30 years compared with patients <30 years had a 4.7-fold increased risk of developing endosalpingiosis (28.0 versus 6.6 percent, respectively).

Rates of concurrent ovarian or uterine cancer are discussed below. (See 'Relationship to pelvic serous neoplasms' below.)

HISTOPATHOLOGY AND PATHOGENESIS — Endosalpingiosis is the presence at ectopic sites of ciliated cells, secretory cells, and intercalated cells similar to those seen in the normal fallopian tube epithelium [12]. Endosalpingiosis lesions and normal fallopian tube epithelium express similar biomarkers [12].

As noted above, endosalpingiosis may occur in female reproductive organs, including ovaries, fallopian tube serosa, uterine serosa, myometrium, or pelvic peritoneum. It may also occur in the bladder, appendix, gallbladder, or in a retroperitoneal or axillary lymph node [2,13-16].

Endosalpingiosis can occur as an isolated pathologic finding, or it can be associated with foci of endometriosis or endocervicosis. Some experts have proposed the term "Mullerianosis" to describe the co-occurrence of endosalpingiosis, endometriosis, and endocervicosis (cells resembling the endocervical cells on the peritoneal surface) [1].

Similar to endometriosis, endosalpingiosis is thought to arise in ectopic locations either through metaplasia or ectopic transport. In addition, transplantation of ciliated fallopian tube cells to peritoneal surfaces may occur as a result of surgical intervention on the tubes or ovary [5]. Interestingly, in one series, three patients with endosalpingiosis alone at time of initial diagnosis were found to also have endometriosis at a subsequent surgery [3].

Endosalpingiosis differs from endometriosis in that it has ciliated glandular elements and no endometrial stroma and is not associated with a local inflammatory response. Small vesicles of endometriosis and endosalpingiosis can have a similar surgical appearance, presenting as small vesicular cystic lesions that are clear, white, or tan in color.

Relationship to pelvic serous neoplasms — Endosalpingiosis is one of a group of peritoneal serous lesions that include peritoneal borderline serous tumors and low-grade serous neoplasms; it can, therefore, be challenging to differentiate among the three lesions when only a small biopsy is provided or a large specimen is undersampled [17].

In addition, endosalpingiosis can be found concurrently with pelvic serous neoplasms, and there is increasing evidence that there may be a direct association between endosalpingiosis and ovarian cancer, though additional studies are needed. Given that this relationship remains poorly understood and that there are no known effective screening methods for ovarian cancer, patients with endosalpingiosis do not receive postoperative evaluation or surveillance for malignancy.

Representative studies that show an association between endosalpingiosis and ovarian cancer are as follows:

●In a series of 110 cases of endosalpingiosis, endometrial adenocarcinoma and serous borderline ovarian tumors were also present in 16 and 7 percent of cases, respectively. Among the patients with borderline ovarian tumors, concurrent endosalpingiosis was identified on the ovary (37 percent), fallopian tube (21 percent), omentum (9 percent), uterine serosa (7 percent), and other sites, including the uterovesical reflection, lymph nodes, cervix, bladder, peritoneum, and appendix [6].

●Another series of 838 cases reported that patients with endosalpingiosis compared with a population control group were more likely to have serous borderline (odds ratio [OR] 10.2, 95% CI 5.1-20.7), invasive mucinous (OR 5.0, 95% CI 1.5-6.6), and clear cell tumors (OR 3.0, 95% CI 1.1-8.0) [7]. These differences were present even after controlling for age, race, menopausal status, parity, tubal ligation, and endometriosis.

●In a retrospective cohort study of 2490 patients, those with a histologic diagnosis of endosalpingiosis and endometriosis had a higher incidence of ovarian cancer than controls with a benign dermal nevus (837 versus 23 per 100,000 person-years; age-adjusted incidence rate ratio [IRR] 43.7, 95% CI 35.1-54.3); the increased risk persisted when patients with endometriosis (an independent risk factor for ovarian cancer) were excluded in subgroup analysis [8]. When patients with synchronous ovarian cancer (ie, endosalpingiosis and ovarian cancer diagnosed within six months of each other) were excluded, incidents rates for those with and without endometriosis were lower (2.4 and 1.8, respectively). Further, when IRRs were calculated based on ovarian cancer histologic subtype, there was an increased risk of clear cell and endometrioid ovarian cancer subtypes in patients with prior diagnosis of endosalpingiosis; no such association was found with mucinous or serous ovarian cancer subtypes. The study was unable to evaluate low-grade serous neoplasms due to heterogeneous reporting of grading in their national database.

●In a retrospective case-control study including 967 patients undergoing gynecologic surgery and confirmed endosalpingiosis or endometriosis on pathology report (1.2 percent of patients had both), those with endosalpingiosis (53 percent) compared with endometriosis had higher rates of concurrent malignancy (40 versus 18 percent; OR 2.48, 95% CI 1.78-3.46) and greater risk of death (OR 1.69, 95% CI 1.1-2.6) [9]. The majority (>80 percent) of these malignancies were gynecologic in origin. In addition, 32 patients were diagnosed with a malignancy postoperatively during the 55-month (mean; range 0 to 208 months) follow-up period; the majority of these malignancies were non-gynecologic and occurred equally in both groups. Thus, while there appears to be an increased frequency of concurrent malignancy in patients with endosalpingiosis compared with endometriosis, further study is needed to understand whether there is an underlying molecular relationship.

The histopathology of pelvic serous neoplasms is discussed in detail separately. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology".)

CLINICAL FEATURES AND EVALUATION — Endosalpingiosis is seldom suspected preoperatively and is typically diagnosed incidentally in patients undergoing surgery for pelvic pain, infertility, urinary symptoms, or a pelvic mass. This is for several reasons: (1) the incidence is unclear; (2) preoperative symptoms and findings have not been well-studied; (3) many clinicians are not familiar with it; and (4) it is often found concurrently with endometriosis, so it is unclear which symptoms are caused by endosalpingiosis alone.

Clinical manifestations — Endosalpingiosis has been associated with pelvic pain and infertility. Patients with bladder endosalpingiosis may also present with urinary symptoms (eg, hematuria, dysuria) [18-21]. Hematuria is typically what brings the patient to medical attention. Rarely, endosalpingiosis presents as large, tumor-like cystic masses involving the uterine serosa (figure 1) or bladder epithelium (picture 1) [17,22].

It is not clear if endosalpingiosis causes pelvic pain or is an incidental histologic finding in patients with pelvic pain [23]. The observation that some patients with chronic pelvic pain have endosalpingiosis (in the absence of endometriosis) identified at laparoscopy suggests that endosalpingiosis may be a cause of pelvic pain [3-6]. However, pain may not be as severe as those with endometriosis. In the largest case-control study including 967 patients who underwent gynecologic surgery, those with histologic-confirmed endosalpingiosis (53 percent) compared with endometriosis were less likely to have a diagnosis of chronic pain (25 versus 47 percent) or pelvic pain as the primary indication for their surgery (16 versus 35 percent, odds ratio [OR] 0.51, 95% CI 0.34-0.78); 12 patients in the endosalpingiosis group also had endometriosis [24].

Evaluation — The preoperative evaluation for endosalpingiosis has not been established. Based on the current understanding of the condition, the evaluation should be the same as for endometriosis or other conditions associated with pelvic pain, urinary symptoms, or pelvic mass. This should include a medical history, pelvic examination, and pelvic imaging. However, as noted, the diagnosis is made with surgical biopsy. (See "Chronic pelvic pain in adult females: Evaluation" and "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact" and "Endometriosis of the bladder and ureter" and "Approach to the patient with an adnexal mass".)

Imaging findings that are specific for pelvic endosalpingiosis have not been identified. On bladder ultrasound, the bladder lesions are often 1 to 4 cm in size and have prominent vascular signals on Doppler imaging [18-21,25-27]. Urinalysis or cystoscopy may be performed if indicated for evaluation of dysuria or hematuria. (See "Etiology and evaluation of hematuria in adults".)

Surgical exploration and biopsy are the key diagnostic procedures. Endosalpingiosis lesions vary in size [28]. A large lesion is shown in the image (figure 1 and picture 2). Endosalpingiosis can also appear as smaller, cystic blebs on the peritoneum and on pelvic and abdominal surfaces that are clear to white in color.

Endosalpingiosis is a difficult pathologic diagnosis, and the specimen is often sent to a consultant pathologist who has expertise in this diagnosis.

DIAGNOSIS — Endosalpingiosis is a histologic diagnosis based on tissue biopsies obtained during surgery. Typically, this is at the time of laparoscopy for endometriosis, oophorectomy, salpingectomy, or hysterectomy.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of endosalpingiosis includes endometriosis and other vesicles or tumor-like lesions of the peritoneum including ovarian cortical inclusion cysts, peritoneal inclusion cysts, peritoneal borderline serous tumors, and low-grade serous ovarian tumors. The differentiation is made solely based on the histologic diagnosis, since the clinical characteristics of endosalpingiosis may overlap with other peritoneal lesions.

In addition, endosalpingiosis must be differentiated from mesothelioma. The diagnosis is by histology, and on histology, the two entities are easy to differentiate, particularly with use of immunohistochemistry. Mesothelioma will stain positive for calretinin and negative for PAX8, while endosalpingiosis will stain positive for PAX8 and negative for calretinin [29,30].

When identified in axillary (or other) lymph nodes, it may be difficult to differentiate endosalpingiosis from metastatic low grade mammary carcinoma. GATA-binding protein 3 (GATA3) immunohistochemistry may be a useful tool in such patients as GATA3 is typically present in breast carcinoma but is notably absent in endosalpingiosis [31].

These conditions are discussed in detail separately. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact" and "Adnexal mass: Differential diagnosis" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology".)

MANAGEMENT — There are few data to guide the management of endosalpingiosis. The clinical profile of the condition and the frequency with which these lesions are found concurrent with endometriosis suggests that the treatment should be the same as endometriosis.

In general, for all sites, there appears to be a high recurrence rate unless the endosalpingiosis tissue is completely removed. In some cases, this may result in an extensive resection. The surgeon needs to balance the goal of complete excision against the risks of surgical morbidity, particularly as the link to pelvic pain, infertility, and its relationship to pelvic neoplasms is not well understood.

For patients with pelvic pain and endosalpingiosis alone or with concurrent endometriosis lesions, management may include standard treatments for endometriosis (eg, estrogen-progestin contraceptives, progestin-only treatments including norethindrone or medroxyprogesterone acetate). The only study to evaluate such treatment was a series of 15 patients with pelvic pain found to have endosalpingiosis (with no endometriosis), in whom symptoms were controlled with hormonal treatment (oral contraceptives, danazol, gonadotropin releasing hormone agonist) and repeat surgery [3]. As some endocrine therapies can have considerable side effects, a careful review of other possible causes of pain should be made. (See "Endometriosis: Treatment of pelvic pain".)

Regarding infertility, the association with endosalpingiosis is uncertain and there are no studies regarding treatment in this clinical context. In our practice, we treat infertility and endosalpingiosis alone (without endometriosis) with standard fertility interventions for patients with unexplained infertility. (See "Female infertility: Treatments".)

For patients with a bladder tumor proven to be endosalpingiosis, removal of the mass in its entirety will typically be curative. Partial removal of the tumor will often result in continued growth. Small vesicular lesions of endosalpingiosis on the peritoneum often do not grow significantly over long-term follow-up.

If endosalpingiosis is identified in a patient with a gynecologic malignancy, appropriate treatment should be given for the malignancy and no changes in treatment are made based on the presence of the endosalpingiosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian and fallopian tube disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Chronic pelvic pain in females (The Basics)")

●Beyond the Basics topics (see "Patient education: Chronic pelvic pain in females (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Endosalpingiosis is the presence of ectopic, cystic glands outside the fallopian tube that are lined with fallopian tube-type ciliated epithelium. Endosalpingiosis may occur at many sites, including the female reproductive organs (figure 1 and picture 2) or bladder (picture 1). (See 'Histopathology and pathogenesis' above.)

●Concurrent pathology – Endosalpingiosis is often found concurrently with endometriosis or pelvic serous neoplasms. It differs from endometriosis in that it has ciliated glandular elements, no endometrial stroma, and is not associated with a local inflammatory response. Endosalpingiosis is one of a group of peritoneal serous lesions that include peritoneal borderline serous tumors and low-grade serous neoplasms. It can be challenging to differentiate endosalpingiosis from peritoneal borderline serous tumors and low-grade serous carcinoma. (See 'Epidemiology' above and 'Histopathology and pathogenesis' above.)

●Clinical manifestations – Endosalpingiosis has been associated with pelvic pain, infertility, and urinary symptoms. It is not clear if endosalpingiosis causes these symptoms or is an incidental histologic finding in patients with these symptoms. Rarely, endosalpingiosis presents as a cystic pelvic mass. (See 'Clinical manifestations' above.)

●Diagnosis – Endosalpingiosis is never a preoperative diagnosis. It is a histologic diagnosis based on tissue biopsies obtained during surgery for pelvic pain, infertility, or the evaluation of a pelvic cystic lesion identified on an imaging study. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of endosalpingiosis includes endometriosis and other vesicles or tumor-like lesions of the peritoneum including peritoneal inclusion cysts, peritoneal borderline serous tumors, and low-grade serous ovarian tumors. (See 'Differential diagnosis' above.)

●Management

•Patients with pelvic pain and endosalpingiosis alone or with concurrent endometriosis may be managed with standard treatments for endometriosis; however, there are few data to guide management. In our practice, we treat patients with unexplained infertility and endosalpingiosis alone (without endometriosis) with standard fertility interventions. (See 'Management' above.)

•For patients with a bladder tumor caused by endosalpingiosis, removal of the mass in its entirety will typically be curative. Partial removal of the tumor will often result in continued growth. If endosalpingiosis is identified in a patient with a gynecologic malignancy, appropriate treatment should be given for the malignancy and no changes in treatment are made based on the presence of the endosalpingiosis. (See 'Management' above.)