1595
Letters to the Editor
Redwine DB, Yocom L. A serial section study of visually normal peritoneum in patients with endometriosis. Fertil Steril 1990;54:648 – 651. Roman H, Bridoux V, Tuech JJ, Marpeau L, da Costa C, Savoye G, Puscasiu L. Bowel dysfunction before and after surgery for endometriosis. Am J Obstet Gynecol 2013;209:524– 530. Somigliana E, Vercellini P, Vigano P, Benaglia L, Besnelli A, Fedele L. Postoperative medical therapy after surgical treatment for endometriosis: from adjuvant therapy to tertiary prevention. J Minim Invasive Gynecol 2013. doi:10.1016/ j.jmig.2013.10.007. Horace Roman* Department of Obstetrics and Gynecology, Groupe de Recherche EA 4308 ‘Spermatogenesis and Gamete Quality’, Rouen University Hospital, 1 rue de Germont, Rouen 76031, France
doi:10.1093/humrep/deu100 Advanced Access publication on May 16, 2014
Reply: Searching for truth Sir, Accurate identification of endometriosis during surgery is essential. The notion of occult microscopic endometriosis (OME) is at the extreme low end of the visual spectrum, where macroscopic and microscopic features become blurred. The prime importance of the criteria of normal peritoneum is often overlooked in discussions about OME. In order to identify visually normal peritoneum, one must first distinguish peritoneum that is abnormal from peritoneum that is normal. Peritoneum that is thought to be normal is then removed for histology in order to prove how visually ‘normal’ it really is. The studies by Redwine (1988); Redwine and Yocom (1990) were the first to establish and validate simple, comprehensive criteria of normal peritoneum. Can visual criteria of normal peritoneum be readily applied to larger expanses of peritoneum? Conducting complete peritoneal excision without clinical indication raises ethical considerations. Since the rate of OME is measured in patients visually diagnosed with endometriosis, complete peritoneal excision will necessarily include areas of visually detectable disease. The larger the area of tissue removed, the harder the surgeon’s task of ensuring that all areas of biopsied tissue are free of visual abnormalities. Endometriosis has been found to follow predictable patterns in its location of occurrence, with the posterior cul-de-sac the most common location (Redwine, 1987). Biopsying visually normal tissue from this anatomical location would have the greatest chance of confirming the existence of OME. Expanding the search to areas less commonly affected by endometriosis is unlikely to further improve upon results. Given the dozens of biopsies taken in the studies by Redwine (1988); Redwine and Yocom (1990), the selection criteria used have been shown to be highly reproducible. Approaching the question of OME without criteria of normal peritoneum replaces science with opinion. The ‘science’ resulting from such an opinion-based approach can be imprecise and contradictory.
Figure 1 Microscope slide with macroscopically identifiable individual endometriotic gland/stroma complexes (arrows) alongside a human hair, which is 100 mm in diameter. Photo courtesy of DB Redwine.
Downloaded from http://humrep.oxfordjournals.org/ by guest on November 15, 2015
*Correspondence address. Tel: +33-232-888-643; Fax: +33-235-981-149; E-mail: [email protected]
Dr Roman’s complaint that since other investigators have found a small incidence of OME therefore OME exists, is tautological; other investigators did not use defined criteria for normal peritoneum and therefore their results cannot be used to nullify the results of Redwine (1988); Redwine and Yocom (1990). Surgical experience is not a proxy for sound experimental methodology in the search for normal peritoneum devoid of OME. Decreasing the viewing distance of the tip of the laparoscope from the peritoneal surface has been shown to reduce the rate of OME (Redwine, 2003), presumably due to the avoidance of abnormal peritoneum for biopsy. As microscopy has proved (Redwine, 1988; Redwine and Yocom, 1990), decreasing the viewing distance will not increase the rate of OME by finding ever-smaller deposits of ‘microscopic’ endometriosis. Dr Roman’s concern that smaller deposits of OME might exist that could have been missed by laparoscopy had already been dispelled decades before his letter was written. The histologically proven absence of OME in visually normal tissue obtained with a viewing distance of ,1 cm instead supports the proposition that endometriosis is a macroscopic entity (Fig. 1) regardless of stage of evolution. Dr Roman states that Evers’ work (1987) that endometriosis becomes invisible presents a paradox with our assertion that OME does not exist. In that study, however, the observation at surgery of hemorrhage resulting from destabilization of capillaries adjacent to active endometriosis was decreased at the end of ovarian suppressive therapy compared with observation conducted at surgeries performed several months later. Although the hemorrhagic footprint adjacent to endometriosis was decreased, nothing was said about the endometriotic lesions themselves shrinking or disappearing. Biopsies were not
1596
References Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004;82:878 – 884.
Evers JL. The second-look laparoscopy for evaluation of the result of medical treatment of endometriosis should not be performed during ovarian suppression. Fertil Steril 1987;47:502– 504. Meigs JV. Endometriosis; etiologic role of marriage age and parity; conservative treatment. Obstet Gynecol 1953;2:46 – 53. Redwine DB. Age related evolution in color appearance of endometriosis. Fertil Steril 1987;48:1062– 1063. Redwine DB. Is ‘microscopic’ peritoneal endometriosis invisible? Fertil Steril 1988;50:665 – 666. Redwine DB. Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of reoperation and persistent or recurrent disease. Fertil Steril 1991;56:628 – 634. Redwine DB. ‘Invisible’ microscopic endometriosis. A Review. Gynecol Obstet Invest 2003;55:63 – 67. Redwine DB, Yocom L. A serial section study of visually normal peritoneum in patients with endometriosis. Fertil Steril 1990;54:648 – 651. Wheeler JM, Malinak LR. Recurrent endometriosis. Contrib Gynecol Obstet 1987;16:13 – 21. Yeung P Jr, Sinervo K, Winer W, Albee RB Jr. Complete laparoscopic excision in teenagers: Is postoperative hormonal suppression necessary? Fertil Setril 2011;95:1909 – 1912. D.B. Redwine1 and E.N. Hopton2,* 1 Chandler, AZ, USA 2 Maastricht University, Maastricht, The Netherlands *Correspondence address. E-mail: [email protected] doi:10.1093/humrep/deu098 Advanced Access publication on May 16, 2014
Criticizing the effect of ovarian suspension on adhesions in laparoscopic surgery for endometriosis Sir, We enjoyed studying the recent paper by Dr Hoo et al. (2014). Despite containing many strong points, there are some limitations, or perhaps misunderstandings on our part, which are discussed here. First of all, it seems that the ovaries, and not the women (as was claimed), underwent randomization. The authors mentioned that the cases had bilateral endometriosis, which is the main prerequisite for ovarian randomization; however, Table II shows that only 25 (48.1%) and 24 (46.2%) cases had right and left endometrioma, respectively. These are not consistent with each other; albeit, they mean bilateral endometrioma. On the other hand, if they mean bilateral endometriosis, the study needed to be randomized in such a way that each side of endometriosis involvement (that is more affected) was equal in both the suspended and non-suspended groups, which was not considered. As an additional point, a joint study has previously shown that left side endometrioma is more common (Matalliotakis et al., 2009). In addition, we are not aware of the equality of ovarian involvement, which is another prerequisite for randomization. This could also be another reason for the similar results found between the suspended and placebo groups.
Downloaded from http://humrep.oxfordjournals.org/ by guest on November 15, 2015
taken to prove (or disprove) that the peritoneum lacked endometriosis at the conclusion of therapy. The results were based on visualization alone. Dr Roman switches from the concept of OME to proper therapy for endometriosis. There is no evidence to support his statement that it is impossible to remove all endometriosis in the pelvis. This opinion is held by many surgeons, but is too often used to rationalize incomplete surgery or as a reason not to attempt surgery at all. Nothing we wrote implied that symptom response is synonymous with response of endometriosis to aggressive excisional surgery. Women can have multiple causes of pelvic pain. Our hope is that better identification and surgical removal of endometriosis will help remove this diagnosis from consideration and break the cycle of repetitive surgeries and medical therapies that are the unfortunate modern hallmark of endometriosis treatment. Dr Roman’s proposed study would have predictable results: inducing amenorrhea with ovarian suppression will improve uterine dysmenorrhea, which will add to the pain relief of excision of endometriosis alone. While overall symptom improvement is important, ovarian suppression may result in improvement of any estrogen-dependent symptom produced by a variety of diseases. Given the difficulty of detecting adenomyosis without hysterectomy, how can one reliably identify study candidates who do not have adenomyosis, a potential silent confounding variable? In addition to symptom response it would be important to check robust measurements of ovarian function before and ≥6 months after cessation of ovarian suppression. This would help to determine if symptom improvement might be due to prolonged or permanently reduced ovarian function. The concept of OME has important implications for the surgical cure of endometriosis. While it is true that endometriosis requires microscopy for accurate histologic diagnosis, this does not render its sometimes extremely subtle morphologies invisible during surgery. Clinicians applying the Redwine criteria of normal peritoneum have recently documented lack of recurrent disease in reoperated adolescents following excision of endometriosis, (Yeung et al., (2011) For a disease, which has long been considered incurable, these results underscore the previous studies: most patients undergoing aggressive excision of endometriosis do not have endometriosis at reoperation. If the absence of a disease after treatment is defined as cure, it can be said that most patients undergoing excision of endometriosis by experienced surgeons are cured by surgery (Meigs, 1953; Wheeler & Malinak, 1987; Redwine, 1991; Abbott et al., 2004; Yeung et al., 2011). This fact should be embraced and all means available should be used to identify endometriosis accurately at surgery, thus improving surgical outcomes in all endometriosis patients. Note: In a proprietary study from the 1980s which helped bring Lupron to market and which is now under a USA federal court seal, the sponsor of Lupron found prolonged or permanent impairment to ovarian function in the majority of follow-up participants in the experimental arm of the study.
Letters to the Editor
Letters to the Editor
Redwine DB, Yocom L. A serial section study of visually normal peritoneum in patients with endometriosis. Fertil Steril 1990;54:648 – 651. Roman H, Bridoux V, Tuech JJ, Marpeau L, da Costa C, Savoye G, Puscasiu L. Bowel dysfunction before and after surgery for endometriosis. Am J Obstet Gynecol 2013;209:524– 530. Somigliana E, Vercellini P, Vigano P, Benaglia L, Besnelli A, Fedele L. Postoperative medical therapy after surgical treatment for endometriosis: from adjuvant therapy to tertiary prevention. J Minim Invasive Gynecol 2013. doi:10.1016/ j.jmig.2013.10.007. Horace Roman* Department of Obstetrics and Gynecology, Groupe de Recherche EA 4308 ‘Spermatogenesis and Gamete Quality’, Rouen University Hospital, 1 rue de Germont, Rouen 76031, France
doi:10.1093/humrep/deu100 Advanced Access publication on May 16, 2014
Reply: Searching for truth Sir, Accurate identification of endometriosis during surgery is essential. The notion of occult microscopic endometriosis (OME) is at the extreme low end of the visual spectrum, where macroscopic and microscopic features become blurred. The prime importance of the criteria of normal peritoneum is often overlooked in discussions about OME. In order to identify visually normal peritoneum, one must first distinguish peritoneum that is abnormal from peritoneum that is normal. Peritoneum that is thought to be normal is then removed for histology in order to prove how visually ‘normal’ it really is. The studies by Redwine (1988); Redwine and Yocom (1990) were the first to establish and validate simple, comprehensive criteria of normal peritoneum. Can visual criteria of normal peritoneum be readily applied to larger expanses of peritoneum? Conducting complete peritoneal excision without clinical indication raises ethical considerations. Since the rate of OME is measured in patients visually diagnosed with endometriosis, complete peritoneal excision will necessarily include areas of visually detectable disease. The larger the area of tissue removed, the harder the surgeon’s task of ensuring that all areas of biopsied tissue are free of visual abnormalities. Endometriosis has been found to follow predictable patterns in its location of occurrence, with the posterior cul-de-sac the most common location (Redwine, 1987). Biopsying visually normal tissue from this anatomical location would have the greatest chance of confirming the existence of OME. Expanding the search to areas less commonly affected by endometriosis is unlikely to further improve upon results. Given the dozens of biopsies taken in the studies by Redwine (1988); Redwine and Yocom (1990), the selection criteria used have been shown to be highly reproducible. Approaching the question of OME without criteria of normal peritoneum replaces science with opinion. The ‘science’ resulting from such an opinion-based approach can be imprecise and contradictory.
Figure 1 Microscope slide with macroscopically identifiable individual endometriotic gland/stroma complexes (arrows) alongside a human hair, which is 100 mm in diameter. Photo courtesy of DB Redwine.
Downloaded from http://humrep.oxfordjournals.org/ by guest on November 15, 2015
*Correspondence address. Tel: +33-232-888-643; Fax: +33-235-981-149; E-mail: [email protected]
Dr Roman’s complaint that since other investigators have found a small incidence of OME therefore OME exists, is tautological; other investigators did not use defined criteria for normal peritoneum and therefore their results cannot be used to nullify the results of Redwine (1988); Redwine and Yocom (1990). Surgical experience is not a proxy for sound experimental methodology in the search for normal peritoneum devoid of OME. Decreasing the viewing distance of the tip of the laparoscope from the peritoneal surface has been shown to reduce the rate of OME (Redwine, 2003), presumably due to the avoidance of abnormal peritoneum for biopsy. As microscopy has proved (Redwine, 1988; Redwine and Yocom, 1990), decreasing the viewing distance will not increase the rate of OME by finding ever-smaller deposits of ‘microscopic’ endometriosis. Dr Roman’s concern that smaller deposits of OME might exist that could have been missed by laparoscopy had already been dispelled decades before his letter was written. The histologically proven absence of OME in visually normal tissue obtained with a viewing distance of ,1 cm instead supports the proposition that endometriosis is a macroscopic entity (Fig. 1) regardless of stage of evolution. Dr Roman states that Evers’ work (1987) that endometriosis becomes invisible presents a paradox with our assertion that OME does not exist. In that study, however, the observation at surgery of hemorrhage resulting from destabilization of capillaries adjacent to active endometriosis was decreased at the end of ovarian suppressive therapy compared with observation conducted at surgeries performed several months later. Although the hemorrhagic footprint adjacent to endometriosis was decreased, nothing was said about the endometriotic lesions themselves shrinking or disappearing. Biopsies were not
1596
References Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004;82:878 – 884.
Evers JL. The second-look laparoscopy for evaluation of the result of medical treatment of endometriosis should not be performed during ovarian suppression. Fertil Steril 1987;47:502– 504. Meigs JV. Endometriosis; etiologic role of marriage age and parity; conservative treatment. Obstet Gynecol 1953;2:46 – 53. Redwine DB. Age related evolution in color appearance of endometriosis. Fertil Steril 1987;48:1062– 1063. Redwine DB. Is ‘microscopic’ peritoneal endometriosis invisible? Fertil Steril 1988;50:665 – 666. Redwine DB. Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of reoperation and persistent or recurrent disease. Fertil Steril 1991;56:628 – 634. Redwine DB. ‘Invisible’ microscopic endometriosis. A Review. Gynecol Obstet Invest 2003;55:63 – 67. Redwine DB, Yocom L. A serial section study of visually normal peritoneum in patients with endometriosis. Fertil Steril 1990;54:648 – 651. Wheeler JM, Malinak LR. Recurrent endometriosis. Contrib Gynecol Obstet 1987;16:13 – 21. Yeung P Jr, Sinervo K, Winer W, Albee RB Jr. Complete laparoscopic excision in teenagers: Is postoperative hormonal suppression necessary? Fertil Setril 2011;95:1909 – 1912. D.B. Redwine1 and E.N. Hopton2,* 1 Chandler, AZ, USA 2 Maastricht University, Maastricht, The Netherlands *Correspondence address. E-mail: [email protected] doi:10.1093/humrep/deu098 Advanced Access publication on May 16, 2014
Criticizing the effect of ovarian suspension on adhesions in laparoscopic surgery for endometriosis Sir, We enjoyed studying the recent paper by Dr Hoo et al. (2014). Despite containing many strong points, there are some limitations, or perhaps misunderstandings on our part, which are discussed here. First of all, it seems that the ovaries, and not the women (as was claimed), underwent randomization. The authors mentioned that the cases had bilateral endometriosis, which is the main prerequisite for ovarian randomization; however, Table II shows that only 25 (48.1%) and 24 (46.2%) cases had right and left endometrioma, respectively. These are not consistent with each other; albeit, they mean bilateral endometrioma. On the other hand, if they mean bilateral endometriosis, the study needed to be randomized in such a way that each side of endometriosis involvement (that is more affected) was equal in both the suspended and non-suspended groups, which was not considered. As an additional point, a joint study has previously shown that left side endometrioma is more common (Matalliotakis et al., 2009). In addition, we are not aware of the equality of ovarian involvement, which is another prerequisite for randomization. This could also be another reason for the similar results found between the suspended and placebo groups.
Downloaded from http://humrep.oxfordjournals.org/ by guest on November 15, 2015
taken to prove (or disprove) that the peritoneum lacked endometriosis at the conclusion of therapy. The results were based on visualization alone. Dr Roman switches from the concept of OME to proper therapy for endometriosis. There is no evidence to support his statement that it is impossible to remove all endometriosis in the pelvis. This opinion is held by many surgeons, but is too often used to rationalize incomplete surgery or as a reason not to attempt surgery at all. Nothing we wrote implied that symptom response is synonymous with response of endometriosis to aggressive excisional surgery. Women can have multiple causes of pelvic pain. Our hope is that better identification and surgical removal of endometriosis will help remove this diagnosis from consideration and break the cycle of repetitive surgeries and medical therapies that are the unfortunate modern hallmark of endometriosis treatment. Dr Roman’s proposed study would have predictable results: inducing amenorrhea with ovarian suppression will improve uterine dysmenorrhea, which will add to the pain relief of excision of endometriosis alone. While overall symptom improvement is important, ovarian suppression may result in improvement of any estrogen-dependent symptom produced by a variety of diseases. Given the difficulty of detecting adenomyosis without hysterectomy, how can one reliably identify study candidates who do not have adenomyosis, a potential silent confounding variable? In addition to symptom response it would be important to check robust measurements of ovarian function before and ≥6 months after cessation of ovarian suppression. This would help to determine if symptom improvement might be due to prolonged or permanently reduced ovarian function. The concept of OME has important implications for the surgical cure of endometriosis. While it is true that endometriosis requires microscopy for accurate histologic diagnosis, this does not render its sometimes extremely subtle morphologies invisible during surgery. Clinicians applying the Redwine criteria of normal peritoneum have recently documented lack of recurrent disease in reoperated adolescents following excision of endometriosis, (Yeung et al., (2011) For a disease, which has long been considered incurable, these results underscore the previous studies: most patients undergoing aggressive excision of endometriosis do not have endometriosis at reoperation. If the absence of a disease after treatment is defined as cure, it can be said that most patients undergoing excision of endometriosis by experienced surgeons are cured by surgery (Meigs, 1953; Wheeler & Malinak, 1987; Redwine, 1991; Abbott et al., 2004; Yeung et al., 2011). This fact should be embraced and all means available should be used to identify endometriosis accurately at surgery, thus improving surgical outcomes in all endometriosis patients. Note: In a proprietary study from the 1980s which helped bring Lupron to market and which is now under a USA federal court seal, the sponsor of Lupron found prolonged or permanent impairment to ovarian function in the majority of follow-up participants in the experimental arm of the study.
Letters to the Editor
