Endosalpingiosis

Etiology

The pathophysiology of endosalpingiosis remains poorly understood and warrants further investigation. Several theories have been proposed regarding its etiology, including coelomic or peritoneal metaplasia, Müllerian metaplasia, injury to the fallopian tube, and tubal escape. Among these, the theory of peritoneal cellular metaplasia is one of the most widely supported. This theory proposes that metaplastic changes occur in coelomic or peritoneal cells, transforming them into fallopian tube-like epithelium.[5][8][9]

The Müllerian metaplasia hypothesis proposes that endosalpingiosis is a congenital lesion formed from ectopic latent cells of the Müllerian tract, which differentiate and develop into the fallopian tube-like epithelium characteristic of endosalpingiosis.[10][11] This process is also referred to as Müllerianosis. According to this theory, misplaced embryonic Müllerian tissue during organogenesis leads to the formation of 4 benign conditions—endosalpingiosis, adenomyosis, endometriosis, and endocervicosis.[12]

Another theory suggests that endosalpingiosis results from transplantation during surgery or as a reactive process secondary to tubal damage or inflammation, such as pelvic inflammatory disease, which causes excessive proliferation for repair.[4][13] Esselen et al conducted an extensive retrospective study involving over 58,000 gynecologic patients. They found that 74% of patients with endosalpingiosis had at least one risk factor for tubal inflammation or injury, thereby providing support for the tubal inflammation or injury hypothesis.[4]

Another proposed theory is the tubal escape theory, which suggests that tubal fimbriae, in close proximity to the ovary, disrupt the ovarian surface epithelium during ovulation, leading to the implantation of fallopian tube epithelium on the ovary.[10] Wang et al conducted animal studies to test this hypothesis and they concluded that endosalpingiosis was unlikely to result from the escape of oviduct epithelium, suggesting that other mechanisms are more probable.[10] Overall, the pathogenesis of endosalpingiosis remains a topic of debate, and further research is needed to draw definitive conclusions regarding its etiology and pathogenesis.

Epidemiology

Prevalence rates of endosalpingiosis vary in the literature. A study of 1107 women undergoing laparoscopic surgery over 1 year reported a prevalence of 7.6%.[13] In contrast, a study of over 58,000 women undergoing gynecologic surgery found a prevalence of only 1.4%.[4] These differing prevalence rates may be attributed to the necessity of surgical biopsies for diagnosis confirmation, as well as variations in diagnostic protocols.

A study noted that after implementing the formal Sectioning and Extensively Examining of the Fimbriated End (SEE-Fim) protocol for evaluating adnexal lesions, the prevalence of endosalpingiosis increased from 2.54% before implementation to 22.15% afterward.[7] DeHoop et al also demonstrated variability in pathological diagnosis. In a retrospective review, 35% of patients initially diagnosed with endometriosis were re-examined and found to have either endosalpingiosis with endometriosis or endosalpingiosis alone.[6]

Studies on the age prevalence of endosalpingiosis have yielded conflicting results. Several studies report a higher prevalence in postmenopausal women.[4][7][13] However, other studies have found a lower incidence in this group.[3][13] Data from biopsy-confirmed cases suggest a mean age of diagnosis between 40 and 52.[3][13][14] However, further research is necessary to clarify the age prevalence of this disease.

Current literature suggests an association between the BRCA gene mutation and endosalpingiosis. Gruessner et al found that ovarian endosalpingiosis, particularly endosalpingiosis expressing ErbB4 and CSF-1R, was correlated with a BRCA mutation.[15] In their study, 76% of patients in a high-risk group (which included 40% BRCA carriers) undergoing risk-reducing salpingo-oophorectomy had endosalpingiosis, compared to 56% in a low-risk cohort without BRCA mutations.[15]

Pathophysiology

Similar to endometriosis, where endometrial cells implant outside the uterus, the pathophysiology of endosalpingiosis involves the implantation of fallopian tube cells in sites outside the fallopian tubes. Specifically, endosalpingiosis occurs when ciliated columnar glandular epithelial cells from the fallopian tubes implant in extratubal sites within the pelvis and other areas. As previously mentioned, several hypotheses have been proposed to explain this phenomenon, including coelomic or peritoneal metaplasia, Müllerian metaplasia, secondary damage to the fallopian tube, and tubal escape. However, the exact mechanism remains unknown.

Histopathology

The diagnosis of endosalpingiosis is confirmed through histology obtained from surgical biopsy specimens. Hermens et al described the intraoperative appearance of endosalpingiosis as multiple, punctate, white-yellow, opaque, or translucent fluid-filled cysts with a vesicular or granular surface.[16] Burla et al classified the appearance into subtypes, including vesicular, polypous, fimbrial-like, cystic, or unusual.[3] Notably, these lesions may resemble those of endometriosis, making it challenging to distinguish between the 2 without histological examination. In some cases, endosalpingiosis may present as a tumor-like mass or as extensive lesions throughout the pelvic organs. When extensive, the condition is referred to as FCE.

Histologically, endosalpingiosis is characterized by the presence of ciliated columnar, peg or secretory, and intercalated cells—all of which are typically found in the fallopian tube epithelium.[17] Additionally, the tissue of endosalpingiosis expresses biomarkers similar to those of normal fallopian tube epithelium. Esselen et al identified 3 antigens—phospho-Smad2, BCL2, and FOXJ1—that are present in both normal fallopian tube epithelium and endosalpingiosis, distinguishing them from ovarian surface epithelium.[17] However, importantly, these biomarkers were similarly found in serous neoplasms but not other tumor types, thus furthering the evidence that serous carcinomas may arise from the fallopian tube-like epithelium.[17]

Rarely, endosalpingiosis can be found in axillary lymph nodes, potentially mimicking metastatic adenocarcinoma. Histopathology and immunohistochemistry are crucial for differentiation. White and colleagues highlighted the utility of GATA3 immunohistochemistry in distinguishing metastatic low-grade mammary carcinoma (GATA3+) from nodal endosalpingiosis (GATA3−), helping to avoid diagnostic errors. Corben et al also addressed this potential diagnostic pitfall, emphasizing the importance of identifying ciliated and peg cells histologically, along with the immunohistochemical markers WT1 and PAX8, which aid in differentiating endosalpingiosis from mammary carcinoma.[18]

History and Physical

Endosalpingiosis is often discovered incidentally during surgery or imaging for unrelated conditions. However, some patients may present with symptoms that can overlap with those of other gynecological disorders, such as endometriosis or ovarian cysts. The most commonly reported symptom in patients with endosalpingiosis is pelvic or abdominal pain. That said, literature also documents a variety of symptoms, including: 

• Abnormal uterine bleeding, menorrhagia, and postmenopausal bleeding [16][19][20]
• Dyspareunia [21][22]
• Urinary symptoms such as dysuria, frequency, and hematuria [21]
• Bowel symptoms [16]
• Cyclic pain [16]
• Infertility [16]
• Dysmenorrhea [16]
• Chronic back pain [23]
• Fever, nausea, vomiting, and pain in the right iliac fossa (particularly if the lesion is near the appendix) [24]

Notably, a significant proportion of patients with endosalpingiosis also present with concurrent endometriosis. Prentice et al reported that over one-third of individuals diagnosed with endosalpingiosis had coexisting endometriosis.[13] As a result, endometriosis should remain a key consideration in the differential diagnosis, particularly in patients presenting with common symptoms such as pelvic pain, dysmenorrhea, dyspareunia, heavy menstrual bleeding, and infertility. A comprehensive history, physical examination, and appropriate diagnostic workup are essential to distinguish endosalpingiosis from other conditions with similar presentations. 

The history and physical findings in patients with endosalpingiosis are diverse and may sometimes present asymptomatically, being discovered incidentally during surgery. Burla et al conducted a systematic review of patients with confirmed endosalpingiosis and found that the most common indications for surgery were pelvic pain, surgery for gynecological malignancy, infertility, and a suspicious pelvic mass.[3] Esselen et al also conducted a retrospective review of patients diagnosed with endosalpingiosis, reporting similar preoperative diagnoses. These included, but were not limited to, pelvic masses, gynecologic cancers or preinvasive lesions, and pelvic pain, endometriosis, or infertility.[4]

Notably, pelvic pain is commonly reported as a symptom in patients with endosalpingiosis; however, there is debate regarding its association with chronic pelvic pain. Some studies support a link,[6][25] whereas others have found no such association.[13][26][27] Similarly, although infertility has been reported as a symptom and a reason for surgical exploration, Prentice et al found no significant association between infertility and endosalpingiosis.[13]

Evaluation

Currently, there are no well-established guidelines for the diagnostic workup of patients with endosalpingiosis. Clinical evaluation typically starts with a thorough history and physical examination, focusing on the patient's symptoms. Clinicians should include endosalpingiosis in the differential diagnosis for patients presenting with chronic pelvic and abdominal pain and abnormal uterine bleeding, or other related symptoms. The workup should follow the standard approach for these symptoms, including a detailed history, pelvic examination, and imaging, as needed. Furthermore, there are no established imaging features or preoperative diagnostic criteria for endosalpingiosis; only commonly reported characteristics exist.

Endosalpingiosis typically appears as an anechoic cystic structure without internal blood flow on ultrasound.[19][28] Expansile hyperechoic masses have also been reported sonographically.[2] However, due to the similarity in findings with other gynecological conditions, this can lead to misdiagnosis of an adnexal cyst or leiomyoma on ultrasound.[19][28] If computed tomography (CT) is performed, the findings may show well-circumscribed masses with variable cystic and soft tissue components.[2] In cases where endosalpingiosis is present in the peritoneum, it may appear on plain radiographs or CT as numerous calcified granular nodules.[2]

Magnetic resonance imaging (MRI) findings of endosalpingiosis have been described by Fujii et al, with lesions appearing isointensity to low intensity on T1-weighted images and displaying inhomogeneous high intensity on T2-weighted images.[29] Notably, while imaging findings may suggest endosalpingiosis, other gynecological conditions can present similarly. Intraoperative findings are typically cyst-like, varying in size, and may appear vesicular, polypous, multilobular, or fimbrial-like.[3] The presence of either viscous or clear fluid within the cyst is also commonly observed.[19]

Rarely, endosalpingiosis may present as a mass with a reddish, sarcoma-like appearance.[11] In cases of FCE, there may be numerous cysts that appear tumor-like. If surgeons identify these findings intraoperatively, a biopsy or removal of the mass should be performed and sent to pathology for final diagnosis. Given the varied surgical appearance and similarity to other gynecological conditions, the definitive diagnosis of endosalpingiosis is histological and relies on a surgical biopsy.

Treatment / Management

Currently, there are no established treatment guidelines or recommendations for endosalpingiosis. Depending on the clinical scenario, management strategies may include expectant monitoring, symptom control, or surgical intervention. Treatment should be tailored to the patient’s presentation. Clinicians' initial approach should focus on excluding other conditions with similar presentations. Given the high co-occurrence with endometriosis, treatment options commonly used for endometriosis should be considered. Common treatments offered include oral contraceptives, gonadotropin-releasing hormone (GnRH) agonists, and danazol.

Laufer et al conducted a retrospective review and found that patients with pelvic pain and endosalpingiosis responded similarly to traditional treatments for endometriosis.[30] Notably, research on treatment is limited, and this study had a small sample size. Clinicians may consider initiating therapy for symptomatic patients with oral contraceptives, GnRH agonists, or danazol, provided there are no contraindications to these medications.

Several studies have reported an association between endosalpingiosis and gynecological malignancy, with 40% to 51% of patients diagnosed with endosalpingiosis also having a concurrent gynecological malignancy.[4][13][14][16] Esselen et al identified a statistically significant association between endosalpingiosis and uterine and ovarian cancers, particularly serous borderline, clear cell, and mucinous ovarian carcinomas.[4] Despite this association, insufficient evidence supports definitive surgical interventions such as prophylactic hysterectomy or oophorectomy. Management is typically guided by the patient’s clinical symptoms rather than preventive surgical strategies. 

Current research indicates that no treatment is necessary if the patient is asymptomatic. However, clinicians should be mindful of the reported association between endosalpingiosis and ovarian or uterine cancer and consider long-term follow-up when appropriate. If endosalpingiosis is not found incidentally during surgery, clinicians should reserve surgery for symptomatic patients who do not respond to medical therapy. In a literature review of 16 cases of uterine endosalpingiosis, Yang et al reported that treatment involved total hysterectomy in up to 75% of cases, with 62.5% undergoing bilateral salpingo-oophorectomy simultaneously, except for 2 patients who had concurrent malignancy.[11](B3)

Zhan et al specifically discussed the treatment of FCE and recommended total hysterectomy with bilateral salpingectomy as a reasonable treatment approach due to its similarity to malignancy. However, for patients with FCE who desire future fertility, conservative surgery with removal of as many lesions as possible may be considered. In cases of fertility-sparing surgery, they recommended intraoperative peritoneal washings for cytology and histology of frozen sections to rule out malignancy in patients with FCE.[31] Postoperative surveillance, including labs and imaging, was also recommended to monitor for any potential progression to malignancy.[31] Notably, no specific guidelines exist to direct the methodology for treatment or postoperative surveillance of endosalpingiosis. As a result, clinicians must rely on anecdotal treatment recommendations, as no well-established national guidelines are available.(B3)

Differential Diagnosis

Based on patient symptoms, diagnostic findings, and intraoperative findings, the differential diagnosis includes other causes of similar-appearing lesions such as endometriosis, peritoneal inclusion cysts, hydrosalpinges, mesothelioma, adenocarcinoma, peritoneal borderline serous tumors, and low-grade serous ovarian tumors.[11][32] Including endometriosis in the differential diagnosis is crucial, as just over one-third of patients with endosalpingiosis also present with concurrent endometriosis.[4][13] Histological findings are key to differentiating the 2 conditions.

Endosalpingiosis can also resemble multicystic or peritoneal mesothelioma. Immunohistochemistry aids in differentiating between the 2 conditions, as multicystic mesothelioma stains positive for calretinin and negative for PAX-8, whereas endosalpingiosis is characterized by positive PAX-8 and negative CD10.[33] If endosalpingiosis is found in the lymph nodes, metastasis of adenocarcinoma should be considered in the differential diagnosis. Immunohistochemistry can help distinguish between the 2, with GATA-3 staining negative in nodal endosalpingiosis.[32]

Prognosis

The prognosis of endosalpingiosis is generally favorable, as it is often an incidental surgical finding with no currently recommended treatment guidelines. Clinicians may consider treatment if the patient is symptomatic. However, recent evidence suggests an association with ovarian and uterine cancer. Lewis et al performed a retrospective case-control analysis of over 500 patients diagnosed with endosalpingiosis, reporting concurrent malignancy in 40% of cases, specifically ovarian and uterine cancer.[14]

Esselen et al compared a surgical cohort of over 58,000 patients—838 women with endosalpingiosis and 57,323 without. They found statistically significant associations between endosalpingiosis and concurrent endometriosis, uterine cancer, and ovarian cancer. Among patients with endosalpingiosis and ovarian cancer, the subtype was more likely to be serous borderline, clear cell, or invasive mucinous tumors.[4]

Prentice et al described a smaller sample of 110 patients with endosalpingiosis, finding a high rate of concurrent gynecological malignancy (approximately 51%). The most common malignancies were endometrial adenocarcinoma, cervical cancer, and serous borderline ovarian tumors.[13] Notably, this association was more pronounced in premenopausal patients.[13] Specifically, premenopausal patients with endosalpingiosis were 10 times more likely to have a gynecological malignancy compared to women without endosalpingiosis.[13]

Hermens et al also reported an association between ovarian cancer and endosalpingiosis, particularly with clear cell and endometrioid ovarian cancer subtypes.[16] These findings highlight the importance of the examining pathologist identifying endosalpingiosis and excluding coexisting malignancy. Given these associations, counseling patients with biopsy-proven endosalpingiosis remains challenging. Currently, no guidelines exist recommending risk-reducing surgeries or additional cancer screenings for these patients.

Complications

Potential complications of endosalpingiosis may include pelvic pain, abdominal pain, dyspareunia, infertility, the development of a pelvic mass, and abnormal uterine bleeding. Symptoms can also vary based on the location of the endosalpingiosis. For instance, if located on the bladder, patients may experience urinary symptoms such as dysuria, frequency, and hematuria.

Notably, although patients may present with these symptoms, there is ongoing debate in the literature about whether endosalpingiosis is the definitive cause. As noted in the Prognosis section, endosalpingiosis has been associated with gynecological malignancies, and the potential concurrent presence of malignancy is considered a theoretical complication.