DIAGNOSIS OF ENDOMETRIOSIS

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1 ,,,,,,,,,,,,,,,,,,,,,,,, Chapter 5 DIAGNOSIS OF ENDOMETRIOSIS This section will review the evidence for the different methods used to make a correct diagnosis of endometriosis. While there may be confusion or controversy regarding the appropriate treatment, making a diagnosis of endometriosis remains the first step in management. Beyond this, establishing a classification system for endometriosis which includes consideration of the amount of disease, its natural history and correlations with pain and infertility, is a goal yet to be achieved. Published reports provide data to support different methods for making a diagnosis. There is less evidence to support the multiple classification systems currently used in different parts of the world. Recent studies, for example the EndoCan study, l have been useful in the development of a more complete and universally accepted classification system. MAKING A DIAGNOSIS Endometriosis is a common gynaecological condition. However, making a diagnosis of endometriosis may be delayed or missed, as the frequently associated symptoms, especially pain and infertility, may direct clinicians towards different paths of investigation. The "gold standard" test for endometriosis is to see it and biopsy it. Visualization of pelvic endometriosis is achieved best by means of laparoscopy, provided that there are no contra-indications to performing it. Despite the fact that laparoscopy is the most universally used diagnostic method, it is not foolproof. Laparotomy also provides an opportunity for adequate visualization. A detailed history and careful physical examination will lead to suspicion of a diagnosis of endometriosis, but these alone cannot make the diagnosis. Screening methods have been used to select those women at higher risk, but these also have been unable to confirm a diagnosis of endometriosis. Laboratory screens and imaging techniques used for ancillary assessment are discussed below. LABORATORY TESTS All the laboratory examinations used as screening tests have shown limitations; however, measurement of serum CA-125 levels, and of a number of other proteins, may be helpful in evaluating certain populations at risk. This may also be useful for following the course of the disease and to monitor the response to medical or surgical treatment. CA-125 This a cell surface antigen. It is present in the cervix, endometrium, Fallopian tube, peritoneum, pleura and pericardial tissue. Elevated levels of CA-125 are observed in the serum, menstrual effluent and peritoneal fluid of women with endometriosis. 2 The sensitivity and specificity of the test are variable, depending on the stage of the disease. In minimal and mild disease, the sensitivity may be as low as 17 JOURNAL SOGe 480 MAY 1999

2 percent, with a specificity of 75 percent. 3 - S The reliability of serum CA-125 levels in the diagnosis of endometriosis could be altered by other clinical situations, for example pregnancy, epithelial ovarian cancer or pelvic inflammatory disease. 6 More recent studies have shown that serum CA-125 levels correlate with the severity of endometriosis, its natural course, and the response to medical and surgical treatments in patients with documented endometriosis. 2 Serum levels of CA-125 (>35 U/ml), in combination with positive pelvic findings (nodularities palpable during menses), achieved excellent sensitivity (87%) and specificity (83%) in the detection of pelvic endometriosis in some studies. s The assay may also help to distinguish between endometriomas (which show high serum levels of CA-125 in 78% of cases S ) and corpus luteal cysts. Levels that remain elevated postoperatively indicate a poor prognosis in patients with infertility. 7 OTHER MARKERS Other markers assessed for their value in identifying patients with endometriosis include CA-n (sensitivity 2%8), CA-15-3, TAG nand CA-19. These have all shown poor sensitivity. One promising marker is PP -14, the most abundant product of the late secretory endometrium, which has shown a reported 59 percent sensitivity and 96 percent specificity;9 nevertheless, these findings need substantiation. Serum levels of anti-endometrial antibodies are elevated in women with endometriosis, but there is poor correlation with the severity of disease. 10 Further clinical data are required before a conclusion about the value of such markers can be reached. IMAGING Selective use of imaging techniques can be useful in identifying patients with endometriosis. ULTRASOUND The reliability of ultrasound for diagnosis and monitoring of endometriosis depends on the nature of the lesions. The endovaginal approach for ultrasound is superior to the transvesical approach. For the diagnosis and management of ovarian endometriomas, it is a very reliable method (sensitivity up to 83%, with specificity of 98% ).11 On the other hand, it has poor sensitivity in the detection of focal implants (sensitivity as low as 11 %).12 Diagnostic accuracy may be enhanced by colour Doppler flow studies, serum CA-125 assays, and the use of such clinical parameters as the patient's age, her symptoms and clinical signs (sensitivity and specificity above 99%).13 Ovarian endometriomas detected by ultrasound examination will be visualized as solid or cystic, but with thick walls compared with functional cysts. 14 Scattered internal echoes or septa are seen in most endometriomas. MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) has proven to be a useful investigation in detecting pigmented haemorrhagic lesions. It has been shown to be useful in detecting changes in lesions through the menstrual cycle, changes in the number of lesions during therapy, the possibility of nerve involvement, or residual tissue in the abdominal wall. 1S The sensitivity and specificity of MRI vary, and the findings do not always correlate with the stage of disease. The sensitivity for detecting endometriotic implants could be as low as 13 percent and, for the detection of all lesions, varies from 64 to 90 percent; specificity averages 50 to 60 percent. 1S,16 The value of MRI overall, therefore, remains uncertain, particularly as accessibility to MRI may be limited in Canada. COMPUTERIZED TOMOGRAPHY AND BARIUM ENEMA Lesions of the pleura can be detected by computerized tomography (CT). Endometriotic lesions affecting the bowel, when large enough, are clearly detectable by means of a barium enema. Both of these tests lack specificity, and their findings must be supported by the results of complementary investigations. 6 Lesions detected by CT must be large enough to allow visualization. Additional investigations including cystoscopy, rectosigmoidoscopy, colonoscopy or intravenous pyelography are used occasionally according to the possible extension of the disease, or when endometriosis is associated with other medical conditions. JOURNAL SOGC 481 MAY 1999

3 SURGICAL PROCEDURES In most cases of suspected endometriosis, the diagnosis will be confirmed or excluded by performing laparoscopy. In the unusual situations where laparoscopy is contra-indicated, performing laparotomy is an option. The most important step in confirming the diagnosis is to visualize and obtain tissue for histological examination. 6 Endometriotic tissue may have a typical or atypical appearance. Focal deposits may have the classical blue or black appearance, but may also appear yellow, brown, white or red (81 % of such areas show histological evidence of endometriosis 17), and may also appear as translucent adhesions or peritoneal defects (45% of such areas showing endometriosis on biopsy).18 Histological confirmation of a diagnosis of endometriosis will require at least two of the following: endometrial epithelium, endometrial glands, endometrial stroma and haemosiderin-iaden macrophages. To assist in visualizing atypical lesions, some specific techniques can be useful. These include the "bubble test", in which small volumes of crystalloid solution are squirted into the cul-de-sac. 19 "Peritoneal blood painting" involves dripping blood-stained peritoneal fluid over the parietal peritoneum to demonstrate irregularities in the contour of the peritoneal surface. 20 If a diagnosis of deep endometriosis or if endometriotic tissue is suspected in an abnormal site, clinical examination and 1aparoscopy or laparotomy will need to be supplemented by such tests as an assay of serum CA-1255, X-ray or CT, or MRI. CLASSI FICATIONS Classifying endometriosis should be simple, rapid, objective and reproducible. A classification method should contain some assessment of symptoms, and scoring should correlate with a change in lesions and the effects of treatment. Although many classifications have been proposed, there is still no satisfactory system; this has also been the case with the classification of different forms of cancer.21 The major problem with classifying endometriosis is that there appears to be no direct correlation between the volume of endometriotic tissue and the severity of symptoms. This is the case with both endometriosis-associated pain and endometriosis-associated infertility.22 Visual assessment permits an estimation of the extent of the disease, but not of its activity. Thus, there are limitations to any classification system in using it to predict the potential for fertility, for example. 22,23 Although classifications have their limitations, it must be strongly emphasized that the use of any uniform method of staging should allow for better continuity in the treatment and management of the disease, and its possible recurrence,21 Many classifications have been developed so far. Published classifications include the following: Acosta;24 Kistner;25 AFS (American Fertility Society) 1979;26 r-afs (revised American Fertility Society) 1985;27 r-afs (revised American Fertility Society) 1993;28 EndoCan (Canadian Collaborative Group on Endometriosis). I Most classifications have been developed to stage endometriosis in the setting of infertility. The r-afs (1985)27 classification addressed the deeply infiltrating disease in many patients with endometriosisassociated pain, but emphasized the role of adhesions in pain symptoms. The classification was reviewed by a subcommittee of the AFS (1993 )28 to address the limitations of the r-afs classification with respect to pelvic pain. This subcommittee developed an instrument to be used by clinicians and investigators in documenting the extent of endometriosis and pelvic pain. The instrument allows for consistency in the management of pelvic pain. There is currently another subcommittee of the American Society for Reproductive Medicine (formerly the American Fertility Society) undertaking a further revision of the r-afs classification. 21,22 OUTCOMES Deeply infiltrating disease is more frequently associated with pelvic pain, particularly implants with a depth of more than lomm. There is a strong correlation between the depth of invasion and the total volume of typical endometriosis. 29 There is a reduced likelihood of pregnancy in women with r-afs (1985) classification endometriosis scores of more than JOURNAL SOGC 482 MAY 1999

To allow for accurate prediction of the probability of pregnancy, it is likely that other endometriosisassociated factors will need to be incorporated in the classification system.

4 To allow for accurate prediction of the probability of pregnancy, it is likely that other endometriosisassociated factors will need to be incorporated in the classification system. Existing classifications may not predict outcome but will evolve towards more accuracy. Better and simpler classifications will help both the patient and the medical team in the difficult, management of this elusive disease. 22 CONCLUSION Making a diagnosis of endometriosis requires careful integration of the clinical presentation, laboratory data, imaging studies and, in almost all situations, laparoscopic observations. Histologic confirmation is the most reliable diagnostic step. Endometriosis remains an enigma. In order to make the diagnosis, the tools used to support clinical suspicion and clinical examination are, in decreasing order of usefulness: laparoscopic visualization and biopsy, measurement of serum CA-125 (but especially in following the effects of treatment), endovaginal ultrasound, MRI, X-ray and CT. Complementary endoscopic tests (rectosigmoidoscopy, cystoscopy, colonoscopy) might occasionally be needed. In the future, diagnosis may be facilitated by such specific tests as the identification of chemotactile factors in peritoneal fluid; specific endometrial integrins; or laser-induced immunescence, which will highlight ectopic endometrial cells. There will likely be increased use of more easily-obtained samples (saliva or urine) for screening purposes. CONSENSUS STATEMENTS 1. A suspicion of the presence of endometriosis based on history and physical examination alone is not adequate to establish the diagnosis. 2. The "gold standard" for diagnosis of endometriosis is to visualize the lesions, either by laparoscopy or laparotomy, and to biopsy them. 3. Adjunctive tests, including serum markers and imaging techniques, are appropriate for use in specific situations. 4. Existing classifications are poor predictors of pain severity and treatment outcome, and are of limited value in predicting the potential for fertility. 5. A revised American Fertility Society (r-afs) endometriosis score27 of greater than 70 indicates a poor fertility prognosis. 6. Proper staging of endometriosis with the help of documents (photographs, video) enhances the quality of care. REFERENCES 1, Marcoux S, Maheux R, Berube S and the Canadian Collaborative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 1997;337: , 2. Hornstein MD, Harlow BL, Thomas Pp, Check JH. Use of a new CA-125 assay in the diagnosis of endometriosis. Hum Reprod 1995;10: , Barbieri RL, Niloff JM, Bast RC Jr, Scaetze E, Kistner RW, Knapp RC. Elevated serum concentrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986;45:630-4, 4. Homstein MD, Thomas PP, Gleason RE, Barbieri RL. Menstrual cyclicity of CA-125 in patients with endometriosis. Fertil Steril 1992;58: Koninckx PR, Meuleman C, Oosterlynck D. Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration. Fertil Steril 1996;65: , Duleba AJ. Diagnosis of endometriosis. Obstet Gynecol Clin North Am 1997;24: Pittaway DE. CA-125 in women with endometriosis. Obstet Gynecol Clin North Am 1989;16: Molo MW, Kelly M, Radwanska E, Binor Z. Preoperative serum CA-125 and CA-72 in predicting endometriosis in infertility patients. J Reprod Med 1994;39: Telimaa S, Kauppilla A. Ronnberg L, Suikkari A. Seppala M. Elevated serum levels of endometrial secretory protein PP14 in patients with advanced endometriosis: suppression by treatment with danazol and high-dose medroxyprogesterone acetate. Am J Obstet Gynecol 1989;161 : , Evers JLH, Dunselman GAJ, van der Linden PJQ. New Markers for Endometriosis. In: Coutinho EM, Spinola P, de Moura LH (Eds), Progress in the Management of Endometriosis. Parthenon Publishing, Camforth, 1995: pp, Guerriero S, Mais V. Ajossa S, Paoletti AM, Angiolucci M, Lubate F. Melis GB. The role of endovaginal ultrasound in differentiating endometriomas from other ovarian cysts. Clin Exp Obstet GynecoI1995;22: Friedman H, Vogelzang RL, Mendelson EB, Neiman HL, Cohen M. Endometriosis detection by US with laparoscopic correlation. Radiology 1985;157: Kurjak A. Kupesic S. Scoring system for prediction of ovarian endometriosis based on transvaginal color and pulsed Doppler sonography. Fertil Steril1994;62:81-8. JOURNAL SOGe 483 MAY 1999

14. Athey PA, Diment DD. The spectrum of sonographic findings in endometriomas. JUltrasound Med 1989;8:487-91. 15. Zawin M, McCarthy S, Scoutt L, Comite F.

Endometrial cysts: diagnosis with MR imaging. Radiology 1991 ;180(1 ):73-8. 17. Nisolle M, Paindaveine B, Bourdon A, Berliere M, Casanas-Roux F, Donnez J.

Nonpigmented endometriosis: clinical, laparoscopic and pathological definition. Am J Obstet GynecoI1986;155:1154-9. 19. Gleicher N, Karande V, Rabin D, Dudkiewicz A, Pratt D.

5 14. Athey PA, Diment DD. The spectrum of sonographic findings in endometriomas. JUltrasound Med 1989;8: Zawin M, McCarthy S, Scoutt L, Comite F. Endometriosis appearance and detection at MR imaging. Radiology 1989;171 : Togashi K, Nishimura K, Kimura I, Tsuda Y, Yamashita K, Shibata T, Nakano Y, Konishi J, Konishi I, Mori T. Endometrial cysts: diagnosis with MR imaging. Radiology 1991 ;180(1 ): Nisolle M, Paindaveine B, Bourdon A, Berliere M, Casanas-Roux F, Donnez J. Histologic study of peritoneal endometriosis in infertile women. Fertil Steril 1990;53: Jansen RPS, Russe ll P. Nonpigmented endometriosis: clinical, laparoscopic and pathological definition. Am J Obstet GynecoI1986;155: Gleicher N, Karande V, Rabin D, Dudkiewicz A, Pratt D. The bubble test: a new tool to improve the diagnosis of endometriosis. Hum Reprod 1995;10: Redwine DB. Peritoneal blood painting : an aid in the diagnosis of endometriosis. Fertil Steril 1989; 161 : Hoeger KM, Guzick DS. Classification of endometriosis. Obstet Gynecol Clin North Am 1997;24: Olive DL. Classification of endometriosis. Infertil Reprod Med Clin North Am 1992;3: Wiegerinck M, Van Dop P. Brosens I. The staging of peritoneal endometriosis by the type of active lesions in addition to the revised American Fertility Society classification. Fertil Steril 1993;60: Acosta AA, Buttram VC, Besch PK, Malinak LR, Franklin RR, Vanderheyden JD. A proposed classification of endometriosis. Obstet GynecoI1973;42: Kistner RW, Siegler AM, Behrman SJ. Suggested classification for endometriosis: relationship to infertility. Fertil SteriI1977;28: The American Fertility Society. Classification of Endometriosis. Fertil Steril 1979;32: The American Fertility Society. Revised American Fertility Society Classification of Endomet riosis, Fertil Steril 1985;43: The American Fertility Society. Management of endometriosis in the presence of pelvic pain. Fertil Steril 1993;60: Vercellini P. Vendola N, Bocciolone L, Rognoni MT, Carinelli SG, Candiani GB. Reliability of the visual diagnosis of ovarian endometriosis. Fertil Steril 1991 ;56: Visit the endometriosis Z NE on the Internet at: new! What's Editorial Board On-line bibliography Endometriosis in the news Case history topic Hot Education Links Encouraging world-wide debate on the current issues in endometriosis endometriosis Z NE Panel of experts from Belgium, UK, and USA ZENECA The Endometriosis Zone is upported s by an unconditional grant from Zenec a Pharmaceuticals

Smita Jain, M.B., M.S.* and Maureen E. Dalton, F.R.C.O.G. Sunderland Royal Hospital, Sunderland, Tyne and Wear, United Kingdom

Smita Jain, M.B., M.S.* and Maureen E. Dalton, F.R.C.O.G. Sunderland Royal Hospital, Sunderland, Tyne and Wear, United Kingdom ENDOMETRIOSIS FERTILITY AND STERILITY VOL. 72, NO. 5, NOVEMBER 1999 Copyright 1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Chocolate