Minimally Invasive Diagnosis of Endometriosis

General articles

Ref: Ro J Med Pract. 2021;16(1) DOI: 10.37897/RJMP.2021.1.5 Minimally invasive diagnosis of endometriosis Cătălina Diana STANICA, Adrian NEACSU, Romina Marina SIMA, Raluca Gabriela IOAN Departament of Obstetrics and Gynecology, ”Carol Davila” University of Medicine and Pharmacy, Bucharest

Abstract Endometriosis is a common condition among women of reproductive age that can cause chronic pelvic pain and infertility. Rapid establishment of a positive diagnosis of endometriosis is essential for effective management. The positive diagnosis of endometriosis is difficult to establish and requires invasive methods. The "golden standard" for diagnosis is still laparoscopy. Current research has not yet established specific non-invasive diagnostic methods for endometriosis. Imaging techniques, endometrial or serum markers facilitate diagnosis and are useful in monitoring the patient's progress. A number of noninvasive investigations, such as imaging techniques, or biomarkers are currently being evaluated for use in routine practice. A combination of these noninvasive tests could be the standard for diagnosing endometriosis in the future.

Keywords: endometriosis, noninvasive diagnosis, imaging diagnosis

INTRODUCTION menstrual pain), infertility, dysuria, rectal tenesmus, hematuria, hemoptysis, the diagnosis of endometriosis Endometriosis is a common gynecological condi- should be considered. The symptoms have a cyclical tion, found in women of reproductive age, with impor- character, similar to the menstrual cycle (1). tant implications for their quality of life and married The positive diagnosis of endometriosis involves life. The costs involved in the diagnosis and treatment the use of invasive methods that allow the visualization of endometriosis, not negligible, have special so- of lesions and the taking of tissue samples from suspi- cio-economic consequences. cious lesions. The anatomo-pathological examination The exact pathophysiological mechanisms involved of the samples taken establishes the diagnosis of cer- in the onset and progression of the disease are not tainty. This is currently the „gold standard” in the diag- known. Endometriosis can be classified as adenomyo- nosis of endometriosis (2). There is currently no mini- sis (endometriosis developed in the thickness of the mally invasive paraclinical test to establish a definite myometrium) and endometriosis itself (development diagnosis of endomertiosis. Currently available investi- of ectopic endometrial tissue outside the uterus), with gations supplement only clinical data, strengthening genital or extragenital location, can affect the large in- the suspicion of the diagnosis of endometriosis and testine at different levels, appendix, urinary tract, res- also allowing monitoring of treatment. piratory tract brain, skin etc. About 10% of women of reproductive age suffer In the case of a woman of childbearing age who has from endometriosis, and recent epidemiological data chronic pelvic pain (dysmenorrhea, dyspareunia, inter- show an increase in the incidence of the disease (3).

Corresponding author: Article History: Catalina Diana Stanica Received: 08 March 2021 E-mail: [email protected] Accepted: 16 March 2021

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The condition affects a woman’s quality of life and re- (10,11). However, its sensitivity and specificity are low, productive potential, by decreasing fertility. The dis- with elevated plasma levels being found in other condi- covery of non-invasive diagnostic tests, of population tions (epithelial neoplasms, pericarditis, pancreatitis screening methods, which would allow the start of etc.). treatment from an early stage, would therefore be very Serological markers such as the antigens CA-72, CA useful. 15-3, CA 19-9, TAG-72 have not yet demonstrated their The development of imaging methods, the extraor- utility in the diagnosis of endometriosis (12-14). In the dinary advances registered in the field of genetics, of case of placental protein 14 (PP14) there is a very good the study of biological, cellular and molecular markers, correlation with the stage of the disease (15,16). Also, constitute premises for the discovery of new efficient the specificity for diagnosing endometriosis when de- methods of diagnosis and treatment in endometriosis. termining antiendometrial antibodies can reach almost 100% (17,18). OBJECTIVE AND METHOD In endometriosis, cytokines (19,20) appear to have a profound effect on the implantation of endometriotic The objective of this paper was to identify in the sources by reducing immunological surveillance and literature new minimally invasive methods for diagnos- identifying and destroying endometrial cells. Of these, ing endometriosis. IL-6 has been the most studied in recent decades, with We searched in electronic databases (PubMed, good sensitivity and specificity. However, it is better Google Scholar) articles and clinical studies published that future studies focus on the diagnostic efficacy of in recent years, which identify minimally invasive meth- IL-6 combined with other cytokines. ods for diagnosing endometriosis. We selected only In an attempt to pinpoint the existence and location the materials that specify that they went through the of endometriotic implants as accurately and less inva- peer review procedure. sively as possible, the use as markers of substances that specifically combine with surface receptors of ec- BIOMARKERS USED TO DETECT topic endometrial tissue is tested. Laser-induced lumi- nescence is based on the fact that a tissue, exposed to ENDOMETRIOSIS light of a certain wavelength, emits fluorescence in a The definite diagnosis of endometriosis still involves specific spectrum, as well as some tissue-specific drugs. invasive techniques (laparoscopy and laparotomy). It was found that tamoxifen has the best concentration Current research seeks to establish non-invasive, relia- in endometriotic implants, its highlighting can be done ble, relatively low-cost methods for diagnosing endo- with an argon-ion laser (21). A similar method is based metriosis. on the use of 5-aminolevulinic acid that accumulates in Understanding the pathophysiological mechanisms endometriotic tissue, where it is converted to pro- involved in the onset and progression of endometriosis toporphyrin IX, which has the ability to emit fluores- has led to the study of a large number of possible bio- cent (22). logical, cellular or molecular markers that could have There are studies of monoclonal antibodies that practical utility in the diagnosis of endomertiosis (4,5). bind specifically to target endometriotic cells that facil- Hormonal, immunological mechanisms are studied, itate the definite diagnosis of endometriosis, but also which involve adhesion molecules and cellular recep- open up new therapeutic options for the use of cyto- tors, as well as biochemical changes in the eutopic or toxic substances or inhibitors of ectopic endometrial ectopic endometrium. Many of the studies have had activity related to these “carrier” (23). promising results in animal or in vitro models, not in Studies have found that miRNAs obtained from dis- human patient studies, but research is ongoing. eased tissues and other body fluids have been able to In recent years, a number of serological markers, detect various diseases (24). MiRNA deregulation is in- peritoneal fluid, or menstrual flow have been studied volved in the pathophysiology of endometriosis and (6-9). has been investigated as potential biomarkers, howev- The most widely used serological marker today is er additional validations in a large population using a the CA-125 antigen. This is a high molecular weight sur- standardized reproducible methodology to further face glycoprotein (20 Kilodaltons), whose serum con- clarify the diagnostic potential of miRNAs. centration increases in women with endometriosis, There are studies on the altered expression of cer- correlated with the stage of the disease. The marker is tain genes in endometriotic implants, or protein sub- useful in monitoring treatment (values decrease after sets secreted by ectopic endometrial tissue (25-27). administration of danazol or GnRh agonists), or in mon- Out of a total number of 4,133 genes studied, 8 genes itoring the recurrence of post-therapeutic disease were identified as altered in endometriotic tissue.

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IMAGING METHODS FOR DIAGNOSING Another useful investigation in the positive diagno- ENDOMETRIOSIS sis of endomeriosis is sonohisterography. This was pro- posed for further study of salpinges (41), being a com- The two-dimensional transvaginal ultrasound ex- bination of transvaginal ultrasound and instillation into amination proved to be very useful in detecting ovarian the uterine cavity of a saline or opaque solution follow- endometriomas with a diameter greater than 10 mm, ing the passage of its tubal passage and the appear- but also in differentiating them from other adnexal ance of fluid in the bottom of the Douglas sac. Sono- masses, as well as in following their evolution under histerography is useful in differentiating endometriosis drug treatment. adenomyosis and in investigating tubal infertility, being The cystic character with homogeneous hypoechoic an alternative to hysterosalpingography. appearance, with the presence of echoes of low inten- Ultrasound remains the initial choice in the assess- sity, are considered the basic ultrasound characteristics ment of adnexal masses, but nuclear magnetic reso- of ovarian endometriomas (28-30). In addition, other nance (NMR), also a non-invasive method, can be much elements were identified that increased the specificity more useful, with better sensitivity and specificity (in and sensitivity of the method: cystic wall thickness, the case of peritoneal implants or adhesions), with the multilocularity, the presence of parietal hyperechoic possibility of perform sections on several planes and nodules (31-33). The differential diagnosis of ovarian with good reproducibility. However, it is a more expen- endometrioma is made with other ultrasound-like ad- sive investigation technique with less accessibility. nexal masses: hemorrhagic cyst, functional luteal cyst, Identification of endometriosis by MRI is based on the dermoid cyst, neoplasms. As suggestive ultrasound el- detection of chronic bleeding in suspicious lesions. The ements for neoplasms we mention high wall thickness, presence of degraded blood in the endometriotic ovar- irregularity, inhomogeneity, the presence of septa or ian cyst appears as a homogeneous image, hyperin- vegetation etc. tense in T1 and hypointense, with small hyperintense The use of Doppler ultrasound (color Doppler, areas in T2. In case of recent bleeding, the signal is hy- pulsed Doppler, Power Doppler) can increase the accu- perintense in both T1 and T2. Peritoneal lesions appear racy of the diagnosis, allowing the study of parietal vas- as nodules, with hyperintense signal in T1 and T2, and cularization, more developed in the case of malignant adhesions can be identified by changing the position of formations (34-36). the organs involved (42-46). Deep lesions in the rec- Transvaginal ultrasound can visualize endometriotic tovaginal septum may have a signal similar to the myo- nodules (solid hyperechoic lesions) from 0.5 cm in size, located at the level of the recto-vaginal septum, the metrial one in T1, with small areas of signal intensifica- bottom of the Douglas sac, or the anterior rectal wall. tion indicating the presence of microendometriomas. The sensitivity of detection, in the case of deep involve- In some cases there is a transition zone adjacent to the ment of the rectal wall, is higher for echoendoscopy, or node, an area with a hyperintense signal, called the transrectal ultrasound (37). 7.5 MHz or 10 MHz probes “safety zone”, probably represented by interposed adi- are used which ensure a better resolution, increasing pose tissue, especially anterior to the rectum (47,48). the sensitivity of the ultrasonographic investigation. The use of the so-called lipid subtraction technique (in- The examination is more painful if it occurs during hibition of the lipid signal) can facilitate the differential menstruation. Bladder lesions can be visualized by ul- diagnosis of ovarian endometriomas with dermoid trasound in the form of hyperechoic nodules with re- cysts. The sensitivity and specificity of the method can duced vascularization, most commonly located in the be increased by administering a contrast agent (gado- posterior bladder wall (38). Ultrasound also allows linium) (49). minimally invasive investigations, avoiding unneces- High-resolution devices are currently used, as well sary surgery. Thus, biopsy puncture can be performed as three-dimensional reconstruction programs, which under ultrasound guidance, of the ovarian endometri- ensure a better view of the pelvic structures and a oma, or its aspiration, a useful procedure in case of dif- more correct interpretation of the relationships be- ferential diagnosis, or monitoring the evolution, in case tween the organs, useful in the case of adhesions. MRI of recurrence of cystic formation (39). The sensitivity examination also allows therapeutic monitoring, espe- and specificity of ultrasonography is very low in the de- cially in the case of ovarian endometriosis (50). tection of superficial ovarian or peritoneal endometri- Interest in radiological investigations in the diagno- otic implants. sis of endometriosis has declined recently due to irradi- Therefore, new techniques with contrast substance, ation, poor sensitivity and specificity, as well as due to harmonic Power Doppler, tissue Doppler and even the existence of other methods that provide more ac- three-dimensional reconstruction of pelvic structures curate information about the number and location of have emerged, useful especially in the case of adhe- lesions. Hysterography/hysterosalpingography has lost sions (40). ground to sonohysterography or MRI, being used only

27 Romanian Journal of Medical Practice – Vol. XVI, No. 1 (75), 2021 in centers where no other methods are available to intact or with erosions. Blue-blackish or reddish-brown highlight indirect signs of pelvic endometriosis, to dif- areas often appear. If the location of the implant is in ferentiate adenomyosis and to investigate tubal per- the thickness of the bladder wall, towards the superfi- meability. Barium esophagus-gastro-duodenal transit, cial tunics, the appearance of the mucosa is quasi-nor- or irigography, may be useful in some situations of mal, or has a small prominence on the surface. The le- damage to the digestive tract. IV urography or retro- sions are often 1-4 cm in size and are located in the grade pyelography may reveal endometriotic lesions at posterior wall or in the bladder trine. Examination al- the ureteral or bladder level, possibly deviation or ob- lows biopsy of suspicious lesions necessary for histo- struction due to the involvement of the ureter in se- pathological examination (58). vere adhesion processes (51,52). Chest radiological ex- Laparoscopy is still the “gold standard” in the posi- amination may be useful in the presence of tive diagnosis of endometriosis. Laparoscopy requires pleuropulmonary endometriotic implants (53). cold light, a double-pointed technique, and instrumen- Computed tomography (CT) is superior to radiolog- tation for biopsies. The recent introduction of minia- ical examination, but inferior to MRI in terms of sensi- turized instruments (less than 5 mm) allows the proce- tivity and specificity, and it may provide useful informa- dure to be performed even on an outpatient basis. tion in the thoracic, abdominal, cerebral, or pelvic Sometimes extended adhesions prevent visualization locations of endometriotic lesions (54). and characterization of lesions, or biopsies. In this case a subsequent laparotomy is indicated. On laparoscopic examination, the lesions appear as small spots on the MINIMALLY INVASIVE METHODS OF peritoneum, about 2 mm in size, blue, purple or dark DIAGNOSING ENDOMETRIOSIS brown-brown, which can be seen on the surface of the ovary that looks “burned by gunpowder” in the ovarian Methods of direct visualization of endometriotic le- fossae, uterine sacrates ligaments, uterus, fallopian sions include: hysteroscopy, salpingoscopy (falloposcopy), tubes and peritoneum of the bladder and recto-uterine colposcopy, rectosigmoidoscopy, colonoscopy, cystos- sac bottoms (59). copy. The 1985 American Fertility and Sterility Society Direct visualization of the interior of the uterine classification (60) took into account these “typical” le- cavity and the tubal lumen is used not only in the diag- sions for the 4 stages of endometriosis: minimal, mild, nosis of endometriosis, but also of other diseases: sub- moderate, or severe. Subsequent studies (61) have mucosa fibroids, endometrial carcinoma, polyps, infer- shown that other lesions are considered to be atypical tility. Salpingoscopy can investigate the tubal lumen (small, white, opaque peritoneal areas; areas with sub- from its uterine ostium to the level of the fimbriae. It ovarian adhesions, circular peritoneal defects with the can thus highlight the existence of tubal obstructions, surrounding surface pleated and retracted; bright red intraluminal adhesions, endotubic polyps, hydrosalpinx spots, ecchymotic, surrounded by a congestive area or intraluminal endometriotic lesions (55). The minimi- vesicles of different colors) are positive for endometri- zation of the instrumentation and the possibility of us- osis on histopathological examination in a proportion ing prostaglandins to dilate the cervix, have facilitated of more than 81%. As a result, the revised Classification the application of this technique even on an outpatient of the World Endometriosis Society also took into ac- basis, with minimal discomfort for the patient. count these types of lesions to establish the lesion Colposcopy identifies endometriotic lesions with score (62). high cervical or vaginal localization (56). Another relatively recently introduced technique is Rectosigmoidoscopy and colonoscopy are used in hydrolaparoscopy, in which the video camera is insert- case of suspicion of endometriotic foci located in the ed through the bottom of the posterior vaginal sac, af- wall of the lower digestive tract, with varying degrees ter instilling a saline solution into the bottom of the of penetration. Submucosal lesions, however, can Douglas sac (63). cause bleeding, visible especially if the examination is Contact peritoneoscopy uses an image magnifica- performed during menstruation. They appear as mu- tion system (20x-40x) that allows a more detailed anal- cosal folds, usually pigmented. These examinations al- ysis of the appearance of the lesion and the assessment low the collection of tissue material from the suspi- of its vascularity. In a study of 140 patients, the authors cious areas, necessary for the histopathological described the existence of two major types of lesions, examination. The biopsy can also be guided by echoen- active and less active, depending on the appearance of doscopy, which provides great accuracy (57). the perilesional vessels, the degree of impregnation Cystoscopy is an investigation that addresses pa- with hemosiderin and the presence of fibrous, scarring tients with urinary symptoms. In the case of bladder tissue (64). endometriosis, the appearance of endometriosis is Another recent use of laparoscopy in the diagnosis that of congestive edematous mucosa, which may be of endometriosis is the construction of maps of painful

28 Romanian Journal of Medical Practice – Vol. XVI, No. 1 (75), 2021 areas by touching the lesion areas and perilesional are- of the immunological and biochemical mechanisms in- as, the patient being only slightly sedated, conscious. It volved, can improve current methods of diagnosis of has been shown that there are painless lesions, but this complex condition. Many of the ongoing studies also areas with a normal appearance, located at a dis- have had extraordinary results on in vitro cell cultures, tance of 2.5 cm from the lesion and whose touch causes or on animal models. pain. In 30% of cases the adhesions are the painful Particular emphasis is placed on cellular and bio- ones, hence the need to excise the lesions while main- chemical markers. An ideal marker is characterized by taining a perilesional safety zone, as well as to perform high sensitivity and specificity, high prognostic value, viscerolysis (65). This probably explains the persistence the possibility of correlation between its serum levels or recurrence of postoperative pain. and the severity of the disease. Laparotomy has rapidly lost ground in favor of less Minimally invasive imaging methods are studied to invasive laparoscopy, with fewer postoperative compli- compare accuracy and costs as diagnostic tests. cations, with much faster recovery. A wide range of factors have been studied exten- sively, but none of them can accurately identify the disease alone. A combination of different minimally inva- CONCLUSIONS sive diagnostic methods is probably a promising target Despite decades of research, the diagnosis and for the future diagnosis of endometriosis. Until then, treatment of endometriosis is an ongoing challenge. laparoscopy followed by histopathological examination Elucidating the etiological factors and pathophysiologi- of biopsy samples from suspicious lesions remains the cal mechanisms involved in the occurrence and devel- gold standard for the positive diagnosis of endometrio- opment of endometriotic foci, a deeper understanding sis.

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