Superficial Endometriosis

Endometriosis is an enigmatic,  chronic inflammatory disease of unknown etiology, characterized by ectopic growth of endometrial-like cells outside the uterus ¹. There are three primary subtypes of endometriosis that vary in their epidemiology, location, diagnostic considerations, and treatment, which include: 1) ovarian endometriomas (OE; dark fluid-filled ovarian cysts), 2) deep endometriosis (DE; subperitoneal invasion within surrounding organs such as the bowel and bladder), and 3) superficial endometriosis (SE; thin lesions formed on the wall of the peritoneum) ². The manifestation of the disease varies amongst patients, although common clinic presentations include dysmenorrhea (pain during menstruation), dysuria, dyspareunia, and infertility. In certain instances, endometriosis may present with atypical symptoms, particularly when deposits are present in distant organs, including the lung, liver, and spleen via the blood or lymphatic systems ³.

Several classification systems have been adopted internationally to improve diagnosis, prognosis, and clinical management. The most widely adopted classification system, the revised American Society for Reproductive Medicine (rASRM), is typically used to stage the disease (I-IV) and distinguish the morphology of lesions. However, limitations of the classification system remain due to heavy criticism amongst the patients with endometriosis due to unclear treatment pathways and poor predictive prognosis ⁴.

Due to the limitations posed by the widely adopted rASRM staging guidelines, additional classification systems have been proposed. The revised Enzian staging guidelines, #Enzian, offers a comprehensive classification guideline for DE and newly provides mapping for both OE and SE, through mapping the size, location, and degree of involvement of the implants with adjacent organs ⁵. The ultrasound-based endometriosis staging system (UBESS) developed by Menakaya et al., utilizes transvaginal ultrasound (TVUS) to determine the level of complexity of laparoscopic surgery for endometriosis ⁶. The classification system maps and assesses the mobility of organs, as well as the state of the pouch of Douglas (POD). The most comparable staging system to rASRM includes the new American Association of Gynecologic Laparoscopists (AAGL), similarly attempting to discriminate levels of endometriosis by surgical complexity⁷, based on objective description of lesions and adhesions noted at surgery.

N80.0 - Endometriosis of uterus

N80.1 - Endometriosis of ovary

N80.2 - Endometriosis of fallopian tube

N80.3 - Endometriosis of pelvic peritoneum

Endometriosis is a public health concern due to the large burden associated with the disease. Qualitative studies have shown that endometriosis has a large impact on women and people assigned female at birth (henceforth collectively referred to as people) irrespective of age, including marital/sexual relationships, social life, and mental health ^8,9. However, additional impacts are seen, varying by age groups, such as education, employment, and finances.

The prevalence of endometriosis has been estimated to range between 10% and 15% globally ^10,11 although it has been postulated that the prevalence may be higher due to a large population of asymptomatic women ¹². Other gynecological conditions have been found to be associated with endometriosis which may further affect the global prevalence, such as chronic pelvic pain (CPP), where 2% to 74% of women with CPP have endometriosis ¹³. The disease typically affects people of all ethnic backgrounds, although a higher prevalence is seen amongst women within reproductive age. The prevalence  of endometriosis also varies by classification with SE being the most common subtype, found in approximately 80% of people with endometriosis ¹⁴. The epidemiology of endometriosis is poorly understood, particularly regarding the subtypes. One study evaluated the risk factors associated with SE, where amongst histologically confirmed cases, low body mass index, frequent smoking, and a family history of endometriosis, were associated with SE ¹⁵.

Although many theories within the last two decades have emerged, the etiology of endometriosis remains enigmatic and elusive. For over a century, Sampson's retrograde menstruation was the most widely adopted theory of origin, where menstrual blood flows back through fallopian tubes and into the pelvic cavity and ovaries ¹⁶.The theory is highly supported due to the anatomic distribution of endometriotic implants, where menstrual effluent compartmentalizes under the influence of gravity ¹. Superficial lesions typically develop in the posterior compartment of the pelvis and posterior rectouterine pouch ^17,18. However, the theory was quickly brought into question, as most if not all people with a uterus and fallopian tubes experience retrograde flow. Further questions arise when evaluating the etiology between disease subtypes, due to the coexistence of SE with OE and DE, which suggests that the classifications may have a mutually exclusive origin and pathogenesis. It is likely that the etiology behind endometriosis is  multifactorial, including environmental toxicant exposure, (epi)genetics, immune changes, and the microbiome ^19,20.

Grossly, SE is typically diagnosed as a non-infiltrative lesion lining the peritoneum and can be a variety of colours: black powder-burn, red, white, or clear/vesicular, depending on the degree of vascularization and fibrosis. Although debate remains whether endometriosis is a progressive disease, lesion colour has also been associated with the age of the lesion, progressing from red, black, and finally white/clear ^21,22.

Upon implantation, the disease has been appreciated clinically for its estrogen-dependent nature. Relative to healthy endometrium, endometriosis lesions have an extraordinarily higher expression of estrogen receptor (ER) in ectopic and eutopic cells ^23,24. It has been well understood that endometriosis is driven by hormonal milieu changes where hormones, such as 17β-Estradiol (E2), promote growth, inflammation, and pain ^25–27. Circulating and particularly, locally produced estradiol, bind to ERs and in turn promote the development and progression of the disease ^23,28. Interestingly, SE lesions can synthesize their own E2 due to a high expression of estrogen biosynthesis enzymes, including aromatase or estrogen synthetase (CYP19A1/B1) and steroidogenic acute regulatory protein (StAR), relative to healthy endometrium ^23,29,30. Although the pathobiological role of estrogen in endometriosis is well understood, debate remains regarding the role progesterone plays in endometriosis development. Progesterone carries a critical role in the healthy endometrium, such as driving decidualization and decreasing inflammation ^31,32. In endometriosis, there is a reduction in progesterone receptors which leads to progesterone resistance ^33,34. Together, estrogen dominance and progesterone resistance are the key driving forces for the disease, and classical pharmacological therapies attempt to suppress endogenous estrogen or increase progesterone.

In addition to being considered an estrogen-driven disease, endometriosis has been considered a chronic inflammatory condition with dysregulation of the immune milieu. In juxtaposition to immune dysregulation, recent studies have shown that endometriosis lesions are able to evade the immune system undetected, allowing for disease progression. ^35–38.

One of the major complications of endometriosis, affecting approximately 30-50% of those with the disease, is infertility ³⁹. The cause for infertility in endometriosis may be enigmatic or quite obvious. During laparoscopy, obvious perturbation and distortion of the pelvic anatomy, such as those seen in DE and OE, may influence tubo-ovarian liaison or impair oocyte release in the ovary. However, with SE, the origin of infertility remains unclear. It is most likely that the cause for infertility is a complex interaction between hormonal imbalances, molecular changes, and immune dysfunction, leading to a reduction in endometrial receptivity ³⁹. Particularly, women with endometriosis have been shown to have an increase in prostaglandin, which leads to abnormal uterine contractions in response to irritation and inflammation ⁴⁰.

Although the pathobiology of endometriosis may be generalized, there has been long-term debate regarding whether each subtype of endometriosis should be considered as a separate disease due to divergence in symptoms, epidemiology, and treatment. Additional investigation is required of the pathobiology and etiology for subtypes, particularly for SE, to improve treatment and preventive measures.

Laparoscopy

The most widely adopted technique for detecting endometriosis globally is laparoscopy. Diagnostic laparoscopy allows the surgeon to explore the pelvic environment and evaluate the severity of the disease. Laparoscopy is a gatekeeper to histological assessment – that is, without laparoscopy, abnormalities cannot be biopsied and assessed histologically.

Although the technique remains widely used, several studies suggest that laparoscopy is subjected to several limitations. The accuracy of laparoscopy has been heavily debated over the last two decades, due to inconsistent reporting amongst diagnostic studies. Approximately only 50% of laparoscopic biopsies of possible endometriosis are confirmed histologically, with accuracy depending on the type and location of the lesion  ^41,42. A study by Mettler et al, suggested inaccuracy when evaluating the colour of the lesion, where red lesions had the highest accuracy at 100%, and only 31% of white lesions were endometriosis ⁴². On the other hand, some SE lesions can be extremely difficult to visualize because they are clear lesions, or they are microscopic. Similar findings have been reported, where inconsistencies remain between laparoscopic findings and histology. While this may be secondary to incorrectly diagnosing endometriosis via direct visualization at surgery, we must also accept that histopathological assessment remains operator-dependent and certain variables may limit assessment (e.g., crush or cautery artifact). In summary, laparoscopy remains a comparatively invasive procedure and is limited in accuracy when performed alone.

Ultrasound

Ultrasound offers a relatively inexpensive, rapid, and non-invasive technique to diagnose endometriosis. Over the last decades, advances in TVUS have allowed for accurate diagnosis and currently act as a first-line investigative tool for pelvic pain and other gynecological complaints. In 2016, the International Deep Endometriosis Analysis (IDEA) group consensus was published to improve diagnostic accuracy and to provide standardization in ultrasound mapping for OE and DE ⁴³.

Recent reviews and meta-analyses reveal that ultrasound is comparable to and may be better suited for diagnosing endometriosis relative to laparoscopy, with a sensitivity of 93% and specificity of 96% for OE ^44–46. Comparatively, when evaluating DE using the IDEA group approach, similar location-dependent variances are seen as per laparoscopy, where the accuracy of TVUS is dependent on the location of the deep lesion. Areas such as the upper rectum had a specificity and sensitivity of 100%. However, when evaluating other regions, including the bladder, uterosacral ligaments (UCL), vagina, and the rectovaginal septum, the sensitivity ranged from 55 to 89% and a specificity of 67% to 100% ⁴⁷. When comparing TVUS with bowel preparation versus diagnostic laparoscopy, a study by Goncalves et al, found no differences in specificity or sensitivity for OE, bladder, and rectocervical endometriosis, with a higher sensitivity in the rectosigmoid using TVUS (Goncalves et al., 2021). The findings also suggest that diagnostic laparoscopy is unable to detect vaginal endometriosis (sensitivity and specificity 0%), whereas TVUS depicted a sensitivity and specificity of 85.7% and 99.1%. Furthermore, TVUS was able to predict approximately 71% of ASRM staging, with no false positives in patients with no endometriosis (100% specificity for the ‘no endometriosis’ group), and showed an increase in accuracy with stage severity. When utilizing the ENZIAN classification system, TVUS showed the highest accuracy in compartment A and C (vaginal/rectovaginal septum and rectum/sigmoid colon; 96.7% and 83.3% respectively) (Goncalves et al., 2021).

Recent research has attempted to optimize the sonographic accuracy of diagnosis of SE. Firstly, researchers attempted to diagnose SE via visualization of and correlation with soft markers of the disease, i.e. via correlation of features on ultrasound that might signify SE but do not directly identify it. When utilizing TVS, ovarian immobility was found to be indicative of ipsilateral pelvic pain, USL disease, pelvic sidewall SE, posterior compartment DE, and POD obliteration ⁴⁹. With isolated SE, left ovarian immobility was shown to be indicative of left USL SE and left adnexal site-specific tenderness due to left pelvic sidewall SE ⁴⁹. However, additional studies found no soft marker had appropriate test characteristics for diagnosing SE with TVS ⁵⁰.

It has more recently been proposed that some SE can be visualized on TVUS when there is fluid within the pelvic cavity. A recent pilot study has shown that a novel technique, saline-infusion sonoPODography (SPG) ⁵¹ where fluid is introduced into the POD to create an acoustic window, may allow for diagnosis of SE ⁵².

The appearance of SE relative to peritoneal surfaces on TVUS has been preliminarily defined as follows ⁵³:

1. Hyperechoic projections
2. Hypoechoic areas
3. Cystic areas
4. Filmy adhesions 
5. Peritoneal pockets

The findings of the study suggest that when assessing SE via SPG for allcomers, the current accuracy is 69.1%, with a sensitivity of 64.9%, specificity 100.0%, and confirmed in 57.1% of patients relative to 88.1% through laparoscopy. However, when patients with OE, DE, and POD obliteration are excluded, diagnostic performance improves. In these cases of isolated SE, SPG showed an accuracy of 80% with no false positives. This technique needs to be validated in  larger studies to ensure external validation and generalizability of the technique. Further investigation is needed to determine the tolerability, limitations, and pain experiences associated with the technique.

Limitations of TVUS

Although it may be optimistic to suggest that non-invasive diagnostic tools such as TVUS will become the new gold standard for diagnosing all endometriosis, including SE, in the future, several limitations remain. To diagnose endometriosis using ultrasound with high specificity and sensitivity, extensive training and experience are required. Increased awareness of the utility of these non-invasive tools for this indication is also needed amongst both healthcare providers and patients ^55,56. Further research is needed to evaluate the diagnostic test performance for ultrasound for SE. In the meantime, due to high accuracy in diagnosing OE and DE, the European Society of Human Reproduction and Embryology (ESHRE) have updated their 2022 guidelines to state laparoscopy is no longer the gold standard diagnostic test and imaging should be prioritized ⁵⁴.

There is currently no cure for endometriosis, although most forms of treatment encompass pharmaceutical interventions for pain management, such as nonsteroidal anti-inflammatory drugs (NSAIDs), or to reduce disease progression and severity ^2,57–59. Due to the estrogen-dependent and progesterone-resistant nature of the disease, hormonal contraceptives and gonadotropin-releasing hormone (GnRH) analogs are typically given to suppress the symptoms experienced. In many cases, patients with endometriosis are unresponsive or have contraindications to medication where additional treatment is needed. Most endometriosis societies suggest that laparoscopic excision should be considered when SE and symptoms are present and are unresponsive to medication. However, patient autonomy must be respected and all options including their benefits and risks should be discussed openly with patients to enable proper informed consent. Currently, there is a trial ongoing comparing laparoscopic surgery vs sham surgery for SE to assess the effectiveness and safety of laparoscopic surgery for endometriosis ⁶⁰. In a recent study by Nirgianakis et al (2020), when evaluating the recurrence of individual types of endometriosis, those who were initially diagnosed with SE or OE were likely to have the same diagnosis upon secondary visit for their recurrent surgery. Interestingly, a large portion of the patients who initially had SE subsequently presented with OE (17.9%) and DE (48.2%), with similar trends seen with OE, irrespective of time post-surgery ⁶¹.

To reduce the recurrence of lesions, the success of laparoscopy is dictated by the surgeon’s ability to remove all residual visible lesions and microscopic implants. However, this may prove to be difficult with very small lesions that are hard to see or DE nodules that are infiltrating deep within the peritoneum (e.g. parametrial DE nodules). Alongside potentially missed implants or lesions, endometriosis may also arise from de novo cells through genetic alterations or retrograde menstruation, where new cells are supported within a provocative inflammatory environment ⁶².

There has been increasing interest in multidisciplinary and alternative therapies to treat and manage the disease. Particularly, improving self-management strategies for endometriosis, which may further be divided into problem-focused and emotion-focused strategies ⁶³. Problem-focused strategies attempt to improve quality of life through a change in their environment to alleviate pain, which include endometriosis education and maintaining social support, as well direct lifestyle changes, such as sleep, dietary changes, cannabis, physiotherapy, and physical exercise. Comparatively, emotion-focused strategies aim to mitigate and improve the psychology associated with living with endometriosis, which includes mindfulness and commitment to therapy.

Due to the extensive prevalence of the disease, education amongst clinicians remains imperative, which includes specific training on endometriosis and related symptoms. On a similar note, with the development and advances of TVUS, sonographic training for detection of endometriosis should be enhanced to allow for rapid and non-invasive detection.

Globally, endometriosis remains as one of the most pressing gynecological conditions globally and  both the etiology and pathogenesis of SE remain poorly understood. Due to the extensive prevalence of SE amongst endometriosis patients, it is imperative to improve the diagnostics and management associated with the disease. While promising advances in sonographic diagnosis of  all subtypes of endometriosis, including SE, have been reported,  additional research is necessary  to validate these techniques,  prior to  widespread  adoption.

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