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Endometriosis: Correlation between histologic and visual findings at laparoscopy
Endometriosis: Correlation between histologic and visual findings at laparoscopy Andrew J. Walter, MD,a Joseph G. Hentz, MS,b Paul M. Magtibay, MD,a Jeffrey L. Cornella, MD,a and Javier F. Magrina, MDa Scottsdale, Arizona OBJECTIVE: The purpose of this study was to correlate the diagnosis of endometriosis on the basis of visualization at laparoscopy with the pathologic diagnosis. STUDY DESIGN: A prospective study of 44 patients undergoing laparoscopy for the evaluation of chronic pelvic pain was carried out. All areas suggestive of endometriosis were excised and examined pathologically. Peritoneal biopsy specimens were obtained from areas of normal-appearing peritoneum to rule out microscopic endometriosis. All lesions were identified by anatomic site. Visual and histologic American Fertility Society scores were compared. The positive predictive value, sensitivity, negative predictive value, and specificity were determined for visually identified endometriosis versus the histologic correlate. RESULTS: The mean prevalence of abnormalities visually consistent with endometriosis was 36%, with 18% confirmed histologically. The positive predictive value was 45%; sensitivity, 97%; negative predictive value, 99%; and specificity, 77%; for visual versus histologic diagnosis of endometriosis. Thirty-six percent of the diagnoses were downstaged on the basis of histologic findings. CONCLUSION: A diagnosis of endometriosis should be established only after histologic confirmation. (Am J Obstet Gynecol 2001;184:1407-13.)
Key words: Endometriosis, histology, laparoscopy
Endometriosis, defined as the ectopic presence of normal endometrial glands and stroma, has been widely implicated as one of the causes of chronic pelvic pain, dysmenorrhea, and infertility.1-3 Traditionally, the definitive diagnosis of endometriosis has been determined from visualization of typical or atypical lesions during laparoscopic evaluations of the pelvic organs and peritoneum. Biopsy specimens of peritoneal lesions suggestive of endometriosis provide histologic confirmation in 3.1% to 100% of cases (depending on lesion type and location).4-8 Unfortunately, diverse patient populations, the limited number and small size of the specimens, inconsistencies in biopsy technique, or inconsistencies in the visual classes of endometriosis being sampled mar all of these studies. In addition, other studies have
From the Department of Obstetrics and Gynecologya and the Section of Biostatistics,b Mayo Clinic Scottsdale. Presented at the Sixty-eighth Annual Meeting of The Central Association of Obstetricians and Gynecologists, Chicago, Illinois, October 18-21, 2000. The opinions and conclusions in this article are those of the authors and are not intended to represent the official position of the Department of Defense, United States Air Force, or any other government agency. Reprint requests: Andrew J. Walter, MD, 60 MDG/SGCG 101 Bodin Circle, Travis AFB, CA 94535. 0002-9378/2001 $35.00+0 6/6/115747 doi:10.1067/mob.2001.115747
shown that biopsy specimens of normal-appearing peritoneum provide histologic confirmation of endometriosis in 0% to 13% of cases.1, 5, 9 Thus it is not clear how accurate visualization of abnormal peritoneal lesions is in terms of the diagnosis and staging of endometriosis. The purpose of our study was to define the correlation between the visual and histologic diagnoses of endometriosis from peritoneal findings identified at laparoscopy in a prospective trial with a standardized technique, including complete excision of lesions suggestive of endometriosis and systematic biopsies of normal-appearing pelvic peritoneum. Methods This was a prospective observational study of all women who presented to the Department of Gynecologic Surgery at Mayo Clinic Scottsdale between July 1997 and March 1999 for evaluation of chronic pelvic pain or known endometriosis (diagnosed histologically or by visualization) refractory to medical management. Nonsurgical diagnosis and therapy were managed by the staff medical gynecologists. Patients were excluded only if they had recently completed therapy with gonadotropinreleasing hormone (GnRH) agonists (within 6 months of laparoscopic evaluation), because this may affect the visual appearance of endometriosis at laparoscopy. At laparoscopy, all areas of typical and atypical endometriosis were documented on a pelvic diagram for 1407
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Table I. Prevalence of previous treatments for endometriosis
Table II. Visual versus histologic AFS stage Histologic stage
Patients (n = 44) Treatment
No.
%
Laparoscopy and ablation or excision Once Twice Three times Hysterectomy Leuprolide
7 6 1 7 6
16 14 2 16 14
lesion type and location, completely excised, fixed in formalin, and evaluated pathologically for the presence or absence of endometriosis (defined as the presence of glands and stroma) in a standard fashion by Mayo pathologists who were blinded to the type of lesion (if any). Lesions were defined as puckered pigmented lesions, scarred lesions, red lesions, vesicular lesions, peritoneal pockets, adhesions, and yellow lesions.6-8, 10 Additionally, areas of normal-appearing pelvic peritoneum were sampled with multiple, site-specific biopsies. These sites included the right and left uterosacral ligaments, the posterior and anterior areas of the cul-de-sac, both ovarian fossae, and the peritoneum overlying the right psoas muscle. If all of these sites contained only abnormal-appearing peritoneum, then additional biopsies were not performed. If there were no abnormal peritoneal lesions, then 9 biopsy specimens (~0.5 cm) were taken at the sites specified. To define disease stage, the revised American Fertility Society (AFS) classification was used. Scores were determined from lesion size (determined by pathologic measurement of the excised specimen), depth of penetration (determined during the excision), status of the posterior cul-de-sac, presence and size of ovarian endometriomas, and presence and nature of tubo-ovarian adhesions. All ovarian endometriomas were removed at laparoscopy and evaluated histologically.11 Visual AFS scores were calculated. In addition, a histologic AFS score was obtained by subtracting the score of lesions that were visually consistent with endometriosis but not confirmed on pathologic examination. Approval from our institutional review board (July 1997) was obtained, and all patients provided informed consent for participation in the study. Data collected at the time of the operative procedure included demographic information, presenting complaints, previous method(s) for the diagnosis and treatment of endometriosis, and the location and visual class of any identified lesions. Pathologic examination was performed by 1 of 6 pathologists and re-reviewed by one pathologist. The biopsy specimens were evaluated in the standard fashion. The specimens were fixed in formalin and embedded in
Visual stage
0
I
II
III
IV
Total
0 I II III IV TOTAL
7 6 3 3 0 19
0 4 1 1 0 6
0 0 7 2 0 9
0 0 0 5 0 5
0 0 0 0 5 5
7 10 11 11 5 44
paraffin, and 3- to 4-µm sections were obtained every 50 to 60 µm. The sections were stained with hematoxylin and eosin. Four to 6 sections per specimen were evaluated by means of light microscopy. Data collected from the pathology report and pelvic diagram included the visual and histologic AFS score and correlation of lesion type with final histologic diagnosis. The sample size was determined by the number of patients we thought could be enrolled during a 2-year period (30 to 60). The difference between the visual and histologic AFS scores was assessed by the Wilcoxon signed rank test. The prevalence of endometriosis was compared among sites by the χ2 test of homogeneity of distributions. Diagnostic characteristics were described by using positive predictive value (PPV) (percentage of positive histologic findings of endometriosis among the positive visual findings), sensitivity (percentage of positive visual findings among the positive histologic findings), negative predictive value (percentage of normal histologic findings among the negative visual findings), and specificity (percentage of negative visual findings among the negative histologic findings). Exact binomial confidence intervals (CIs) were calculated for the diagnostic characteristics. Overall stratified values for the diagnostic characteristics were calculated by averaging the values for the 9 biopsy sites. Results The sample consisted of 44 patients who underwent laparoscopic evaluation between July 16, 1997, and March 3, 1999. No patients were excluded because of recent GnRH agonist use. Age at operation ranged from 14 to 48 years (mean age, 33 years; SD, 9). Parity was 0 for 57% of patients (25), 1 for 11% (5), 2 for 30% (13), and 4 for 2% (1). All patients presented with a primary complaint of pelvic pain, dysmenorrhea, or dyspareunia. Previous types of treatments for endometriosis or pelvic pain are summarized in Table I. AFS scores based on histologic findings ranged from 0 to 66 (mean, 11; median, 2). AFS scores from visual findings (mean, 15; median, 8; range, 0-72) were 4.0 points higher on average than the scores from histologic findings (median difference, 2; range of difference, 0-25; P < .001
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Table III. Prevalence of visual findings Finding [% (No.)]
Site Anterior cul-de-sac (n = 44) Broad ligament, left (n = 42) Broad ligament, right (n = 42) Fossa ovarica, left (n = 43) Fossa ovarica, right (n = 41) Posterior cul-de-sac (n = 42) Psoas muscle, right (n = 42) Uterosacral ligament, left (n = 42) Uterosacral ligament, right (n = 42) All sites* (n = 380)
Normal
Abnormal
Puckered pigmented lesion
57 (25) 64 (27) 79 (33) 65 (28) 61 (25) 52 (22) 83 (35) 57 (24) 55 (23) 64 (242)
43 (19) 36 (15) 21 (9) 35 (15) 39 (16) 48 (20) 17 (7) 43 (19) 45 (19) 36 (138)
11 (5) 17 (7) 5 (2) 16 (7) 15 (6) 14 (6) 5 (2) 24 (10) 24 (10) 15 (55)
Scarred lesion
Red vesicular lesion
Other vesicular lesion
9 (4) 10 (4) 12 (5) 5 (2) 5 (2) 17 (7) 5 (2) 7 (3) 7 (3) 9 (32)
9 (4) 0 (0) 0 (0) 2 (1) 5 (2) 7 (3) 2 (1) 7 (3) 10 (4) 5 (18)
5 (2) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (10)
Peritoneal defect Adhesion 2 (1) 0 (0) 0 (0) 0 (0) 2 (1) 2 (1) 0 (0) 0 (0) 0 (0) 0.7 (3)
7 (3) 5 (2) 2 (1) 9 (4) 10 (4) 5 (2) 2 (1) 2 (2) 0 (0) 5 (18)
Yellow lesion 0 (0) 2 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 0.4 (2)
*Mean of 9 sites.
from the Wilcoxon signed rank test). The distributions and agreement of AFS stages are illustrated in Table II. The visually determined stage was higher than the histologic stage for 36% (16) of the patients, including 12 patients whose diagnoses were downstaged from stage I, II, or III to 0. Visual findings for each site are summarized in Table III. The most common visually detected abnormality was a puckered pigmented lesion (40%, 55 of 138). Visually detected abnormalities were most common in the right posterior cul-de-sac and least common in the right psoas muscle. Histologic findings for each site are summarized in Table IV. The prevalence of endometriosis varied significantly among sites (χ2 = 20, P < .001 from the χ2 test of homogeneity), ranging from 31% for the posterior culde-sac to 2% for the right psoas muscle. Overall, 18% of the biopsy specimens provided a histologic diagnosis of endometriosis. PPV and sensitivity of abnormal visual findings for each biopsy site are summarized in Table V. Although sensitivities were high, the PPVs were not and varied considerably among the sites. Negative predictive value and specificity of normal visual findings for each site are summarized in Table VI. Specificity ranged from 66% for the anterior cul-de-sac to 85% for the right psoas muscle. Negative predictive values were high. Endometriosis was found in only 2 biopsy specimens (from 2 different patients), which had been described as normal on visual examination. Both patients had visual and histologic evidence of pelvic endometriosis elsewhere. PPV of each type of abnormal visual finding is summarized in Table VII. PPV was highest for lesions described as puckered pigmented (76%). Diagnostic characteristics for patients, rather than for individual biopsy specimens, are summarized in Table VIII. Eighty-four percent of the patients (37) had at least one site that was classified as abnormal on visual examination. However, the histologic findings indicated that only 52% (23) of the patients had
Table IV. Prevalence of histologic diagnoses of endometriosis for each biopsy site (with 95% CIs) Site
Mean (%)
No.
CI (%)
Anterior cul-de-sac Broad ligament, left Broad ligament, right Fossa ovarica, left Fossa ovarica, right Posterior cul-de-sac Psoas muscle, right Uterosacral ligament, left Uterosacral ligament, right All sites* Crude measure
14 21 7 19 17 31 2 26 26 18 18
6/44 9/42 3/42 8/43 7/41 13/42 1/42 11/42 11/42
5-27 10-37 2-19 8-33 7-32 18-47 0-13 14-42 14-42
69/380
*Mean of 9 sites.
Table V. PPV and sensitivity of abnormal visual findings versus histologic diagnosis of endometriosis (with 95% CIs) Site Anterior cul-de-sac Broad ligament, left Broad ligament, right Fossa ovarica, left Fossa ovarica, right Posterior cul-de-sac Psoas muscle, right Uterosacral ligament, left Uterosacral ligament, right All sites* Crude measure
PPV [% (No.)] CI (%)
Sensitivity [% (No.)]
CI (%)
32 (6/19) 53 (8/15) 33 (3/9)
13-57 100 (6/6) 27-79 89 (8/9) 7-70 100 (3/3)
54-100 52-100 29-100
47 (7/15) 44 (7/16) 65 (13/20) 14 (1/7) 61 (11/18)
21-73 20-70 41-85 0-58 36-83
47-100 59-100 75-100
88 (7/8) 100 (7/7) 100 (13/13) 100 (1/1) 100 (11/11)
72-100
58 (11/19) 34-80 100 (11/11) 72-100 45 49 (67/138)
97 97 (67/69)
*Mean of 9 sites.
at least one biopsy specimen with endometriosis. Among the patients with at least one abnormal site detected by visual examination, only 62% (23 of 37) had histologic confirmation of the abnormality. At least one puckered pig-
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Table VI. Negative predictive value and specificity of normal visual findings versus negative histologic diagnoses (with 95% CIs) NPV [% (No.)]
Site Anterior cul-de-sac Broad ligament, left Broad ligament, right Fossa ovarica, left Fossa ovarica, right Posterior cul-de-sac Psoas muscle, right Uterosacral ligament, left Uterosacral ligament, right All sites* Crude measure
CI (%)
Table VIII. Patient diagnostic characteristics for visual findings versus histologic diagnosis of endometriosis (with 95% CIs)
Specificity [% (No.)] CI (%)
Finding
100 (25/25) 86-100 66 (25/38) 96 (26/27) 81-100 79 (26/33)
49-80 61-91
100 (33/33) 89-100 85 (33/39)
69-94
96 (27/28) 100 (25/25) 100 (22/22) 100 (35/35) 100 (24/24)
77 (27/35) 74 (25/34) 76 (22/29) 85 (35/41) 77 (24/31)
60-90 56-87 56-90 71-94 59-90
Any visually detected abnormality PPV Sensitivity NPV Specificity Puckered pigmented lesions only PPV Sensitivity NPV Specificity
100 (23/23) 85-100 74 (23/31)
55-88
NPV, Negative predictive value.
82-100 86-100 85-100 90-100 86-100
99 99 (240/242)
77 77 (240/311)
NPV, Negative predictive value. *Mean of 9 sites.
Table VII. PPV of specific visual findings versus histologic diagnosis of endometriosis (with 95% CIs) Visual finding Puckered pigmented lesion All sites* Crude measure Scarred lesion All sites* Crude measure Red vesicular lesion All sites* Crude measure Other vesicular lesion All sites* Crude measure Peritoneal defect All sites* Crude measure Adhesion All sites* Crude measure Yellow lesion All sites* Crude measure
Positive predictive value (%)
76 76 (42/55) 22 25 (8/32)0 NA 61 (11/18) 00 00 (0/10)0 NA 00 (0/3)00 NA 28 (5/18)0 NA 50 (1/2)00
NA, Not available. *Mean of 9 sites.
mented lesion was noted in 45% (20) of the patients. Of those with puckered pigmented lesions, 85% (17 of 20) had the diagnosis of endometriosis confirmed histologically. All 7 patients with no visually detected abnormality had negative histologic diagnoses. Various pathologic diagnoses composed the falsepositive group. The most common was endosalpingiosis. The status of these patients will be the subject of a separate report.
Patients [% (No.)]
CI (%)
62 (23/37) 100 (23/23) 100 (7/7) 33 (7/21)
45-78 85-100 59-100 15-57
85 (17/20) 74 (17/23) 75 (18/24) 86 (18/21)
62-97 52-90 53-90 64-97
Comment Laparoscopic visualization of peritoneal lesions consistent with endometriosis has a low PPV for histologic confirmation of disease in our patient population with chronic pelvic pain. Use of histologic rather than visual criteria significantly decreases AFS scores, AFS stage, and frequency of diagnosis of endometriosis. Conversely, microscopic endometriosis is rare (2 of 380 biopsy specimens, both from patients with endometriosis in other pelvic sites), and therefore normal-appearing peritoneum is highly specific for the absence of endometriosis. The prevalence of histologically diagnosed endometriosis for our patients with chronic pelvic pain was 52%. Visual diagnosis of endometriosis on the basis of puckered pigmented lesions alone had higher PPV than visual diagnosis that included the other types of visually detected abnormalities. AFS scores and stages determined from the visual findings were substantially higher than those determined from histologic diagnosis. Of special concern are the 12 patients whose diagnoses were downstaged to 0 (3 of whom had visual AFS stage III), implying that these patients had single to multiple sites that were suggestive of endometriosis on visualization without any site being confirmed histologically. The prevalence of endometriosis and PPVs varied considerably among the 9 biopsy sites. For sites such as the posterior cul-de-sac, a visually detected abnormality was more likely to be endometriosis than a false-positive finding. However, for sites such as the right psoas muscle, a visually detected abnormality was more likely to be histologically negative for endometriosis. The highest PPV of any site was 65% for any visually detected abnormality in the posterior cul-de-sac, still insufficient to justify visual diagnosis alone. Others have studied peritoneal biopsy specimens from patients with histologically confirmed endometriosis. Although most studies confirmed moderate PPVs at best for histologic confirmation, serious methodologic flaws exist,
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including inconsistencies in definition of lesion types, patient populations, and biopsy specimen size and type.4-7 In an extensive study published in 1989, Martin et al8 noted findings similar to ours in terms of correlation between visually detected abnormalities and histologic confirmation. However, they concluded that lesions that were visually suggestive of endometriosis resulted in histologic confirmation in 97% to 99% of cases. The reason for the discrepancy between their results and conclusions is unclear, but they seem to suggest that visualization of classic and subtle lesions is adequate. Our data indicate otherwise. Various pathologic diagnoses are responsible for falsepositive visually detected abnormalities. In our study, the most common diagnosis was endosalpingiosis. Other diagnoses in our study and in other studies include normal peritoneum, mesothelial hyperplasia, fibrosis, hemosiderin deposition (not hemosiderin-laden macrophages), hemangiomas, suture granulomas, adrenal rests, malignancies (breast or ovarian), residual carbon from previous ablations, reaction to oil-based hysterosalpingogram dye, inflammatory changes, and splenosis. Laparoscopic excision of peritoneal lesions visually consistent with endometriosis provides histologic diagnosis, as well as removal of the diseased tissue. Some surgeons may be concerned that excisional biopsy will result in postoperative adhesion formation. However, from this case series, we are reassured: Of 3 patients who had complete excision of all lesions before inclusion in this study at our institution, none had any evidence of pelvic adhesive disease on subsequent laparoscopic exploration performed because of recurrent symptoms. All of these patients had histologically confirmed disease by findings on both laparoscopic procedures. Surgical complications in the 44 patients were limited to one retroperitoneal hematoma, which resolved with conservative management. Our recommendation is for histologic evaluation of visually detected abnormalities suggestive of endometriosis before a definitive diagnosis is made. The poor PPV on the basis of individual lesion type (0%-76% in our series) and per patient diagnosis (62%; overall 12 patients misdiagnosed) suggests that visual diagnosis alone is unreliable and should be abandoned, at least in patient populations with the primary complaint of chronic pelvic pain. The appearance of normal peritoneum is highly reliable for the absence of endometriosis, and it seems to be reasonable to omit biopsy to rule out microscopic endometriosis in these cases. However, we used only magnification to ×400 to confirm the presence or absence of microscopic endometriosis. Other authors have noted the incidence to be increased when normal-appearing peritoneum is subject to examination with electron microscopy.12 The clinical implications of endometriosis diagnosed in this manner and microscopic disease identified solely by light microscopic examination are unclear.
Recently, an algorithm has been espoused that eliminates laparoscopy (and thus histologic or visual confirmation of disease) in the diagnosis and management of chronic pelvic pain suspected of being caused by endometriosis.13 The advantages of this form of management when compared with excisional therapy with or without the use of postoperative GnRH agonists are unclear and will require further randomized prospective studies. At this point, when laparoscopic evaluation is performed in women with chronic pelvic pain for the specific purpose of ruling out endometriosis, we recommend that all visually detected abnormalities that are suggestive of endometriosis be excised or at least sampled before ablative therapy is initiated. This will significantly reduce the overdiagnosis of endometriosis. REFERENCES
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;53:984-8. 2. Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol 1990;162:568-9. 3. Williams TJ. Endometriosis. In: Thompson JD, Rock JA, editors. Te Linde’s operative gynecology. 7th ed. Philadelphia: JB Lippincott; 1992. p. 463-97. 4. Balasch J, Creus M, Fabregues F, Carmona F, Ordi J, MartinezRoman S, et al. Visible and non-visible endometriosis at laparoscopy in fertile and infertile women and in patients with chronic pelvic pain: a prospective study. Hum Reprod 1996;11:387-91. 5. Chatman DL, Zbella EA. Biopsy in laparoscopically diagnosed endometriosis. J Reprod Med 1987;32:855-7. 6. Ueki M, Saeki M, Tsurunaga T, Ueda M, Ushiroyama N, Sugimoto O. Visual findings and histologic diagnosis of pelvic endometriosis under laparoscopy and laparotomy. Int J Fertil Menopausal Stud 1995;40:248-53. 7. Jansen RP, Russell P. Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition. Am J Obstet Gynecol 1986;155:1154-9. 8. Martin DC, Hubert GD, Vander Zwaag R, el-Zeky FA. Laparoscopic appearances of peritoneal endometriosis. Fertil Steril 1989;51:63-7. 9. Redwine DB, Yocom LB. A serial section study of visually normal pelvic peritoneum in patients with endometriosis. Fertil Steril 1990;54:648-51. 10. Martin DC. Laparoscopic appearance of endometriosis: a color atlas. Philadelphia: Resurge Press; 1991. 11. Vercellini P, Vendola N, Bocciolone L, Rognoni MT, Carinelli SG, Candiani GB. Reliability of the visual diagnosis of ovarian endometriosis. Fertil Steril 1991;56:1198-2000. 12. Murphy AA, Green WR, Bobbie D, de la Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986;46: 522-4. 13. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999; 93:51-8.
Discussion DR FRANK LING, Memphis, Tennessee. First, I congratulate Dr Walter and his co-authors on a well-conceived clinical investigation and an excellent presentation. The Central Association has traditionally been a forum for papers of significant clinical relevance, and this paper certainly qualifies. The conclusion from the abstract reads:
1412 Walter et al
“A diagnosis of endometriosis should be established only after histologic confirmation.” With just today’s data, it is hard to argue with this conclusion. As we are told in the paper, publications of the past have already provided reports of marked discrepancies between visual diagnosis and histologic confirmation. I have no concerns with the study’s methodology, nor is there concern about data analyses. In fact, the statistical analysis of these findings should be complimented. The red flag for me is the potential clinical misapplication of these findings. Are the authors advocating that laparoscopy or some surgical procedure to access tissue be mandatory to diagnose endometriosis? For example, should the clinician’s judgment be relegated to a secondary role because only histologic examination can establish the diagnosis of endometriosis? What member of the audience has not performed a biopsy on what, on visual examination, was classic endometriosis, only to have the pathologist report that none was seen on the specimen? What clinician has not gone to the operating room suspecting endometriosis, only to see nothing abnormal? How many of us have been told by third-party carriers that we could not prescribe a GnRH agonist unless there was a tissue diagnosis of endometriosis? If we are limited in our ability to diagnose endometriosis, are we limiting our potential to successfully treat patients whose biopsy specimens fall short of the histologic gold standard? It is for situations such as these that the potential use of GnRH agonist on an empiric basis should be considered, before laparoscopy, or, in some cases, in spite of normal findings on laparoscopy. The authors have presented a comprehensive histologic view of patients that does not address the clinical dilemmas they face. These data do reaffirm our long-held suspicions that visual confirmation of endometriosis is not all that it is cracked up to be. Some, including myself, would argue that laparoscopy should not be mandatory to make the diagnosis but, instead, limited to those cases that do not respond to empiric medical treatment. As I reported in the January 1999 issue of Obstetrics and Gynecology, empiric use of GnRH agonist is an effective treatment before laparoscopy in cases of clinically suspected endometriosis.1 I bring the following 5 issues to the attention of the authors so that some of my cynicism about the limited applicability of their results might be addressed. Issue 1 concerns the study design. What evaluations were done to rule out other causes of chronic pelvic pain? Were patients with gastrointestinal, genitourinary, musculoskeletal, and/or psychiatric conditions included or excluded? Or were all patients scheduled for laparoscopy? What if patients who received GnRH agonist within the past 6 months had not been excluded? Why were subjects allowed if the medication had been received more than 6 months previously? Issue 2 concerns Table I, entitled “Prevalence of previous treatments for endometriosis,” although the text reads “Previous types of treatments for endometriosis or pelvic pain are summarized in Table I.” What, if any, non–endometriosis–related treatments were even sought? Issue 3 addresses the authors’ statement that patients
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were “downstaged” from stage I or higher to zero. In a practical sense, what does this mean from a clinical standpoint in a patient who still has pain? Issue 4 concerns the authors’ statement that “microscopic endometriosis is rare (2 of 380 biopsy specimens).” Does this mean that endometriosis is only a visible disease? Are these 2 biopsy specimens clinically therefore as the others that were grossly visible? How do the authors interpret their findings in light of the 1986 report of Murphy et al2 in which endometriosis was found in normalappearing biopsy specimens by means of electron microscopy? Issue 5 focuses on those patients who had complete excision of all endometriotic lesions at the authors’ institution before entry into the study. None had evidence of adhesive disease during laparoscopy in this series. What do the authors propose to be the cause of these patients’ pain? How do the authors recommend these patients be treated? In summary, this is an admirable addition to our knowledge about the limitations of the visual diagnosis of endometriosis. It does not, however, aid us very much in our ongoing struggle to better diagnose and treat chronic pelvic pain. I totally agree with the authors in saying patients who do not have endometriosis should not be labeled and treated as if they do. On the other hand, focusing too much on endometriosis alone might lead one to develop a case of “Gynevision,” in which the gynecologist gets too caught up in looking for and treating solely gynecologic abnormalities.3 Until more data are forthcoming, the practicing physician would be well advised to advocate the multidisciplinary approach to the diagnosis and management of chronic pelvic pain for which laparoscopy is used selectively, a management scheme that has been proven superior to the universal use of laparoscopy in all patients.1 I appreciate the opportunity to comment on this fine presentation. REFERENCES
1. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol 1999;93:51-8. 2. Murphy AA, Green WR, Bobbie D, de la Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986;46: 522-4. 3. Smith RP, Ling FW. Gynevision. Obstet Gynecol 1991;78:708-9.
DR WALTER (Closing). I would like to thank Dr Ling for his commentary. First, I have one general comment. This is not a treatment article. We are not recommending surgical excision as the only method of treatment for women who present with chronic pelvic pain. Clearly, pelvic pain is a multidimensional disease with gynecologic, urologic, gastrointestinal, psychiatric, neurologic, and musculoskeletal components that are well beyond the scope of this particular paper. The question we have attempted to answer is, if a gynecologic surgeon is performing a laparoscopy with the intention of diagnosing endometriosis, is visualization of peritoneal lesions
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adequate? The PPV of visualized peritoneal abnormalities for histologic confirmation, the gold standard of endometriosis, is insufficient. In regard to the specific questions, the first two issues from Dr Ling referred to our preoperative evaluation and the previous therapies the patients had received. We have a division of medical gynecology, and all preoperative workups were done by this division. This included the various workups that Dr Ling was suggesting. All patients who underwent surgery met the criteria that were outlined in Dr Ling’s article.1 The third issue was the significance of downstaging. Clearly, it is not significant when patients’ diagnoses are downstaged from stage III or II to stage I. That occurred in 4 of our patients. What is more significant are the 12 patients whose diagnoses were downstaged from visual stage I, stage II, and even stage III to stage 0. That is clearly significant because these patients did not have endometriosis according to accepted histologic criteria, despite visual evidence to the contrary. Issue 4, microscopic endometriosis, is very unclear. The incidence has been reported to be between 0% and 13% with light microscopy. I have not read the article on electron microscopy, so I cannot comment on that. The question clearly is, does microscopic endometriosis, if it is
a true ubiquitous phenomenon in patients who do not have visual evidence or histologic evidence of disease elsewhere, cause pain? Again, the last issue was in regard to the patients who underwent repeat laparoscopic evaluation because prior excisional therapy had failed. This was merely to address the potential for adhesions with aggressive excision of endometriosis, which we did not see in our patient population. All 3 of these patients had recurrent pain and recurrent histologic and visual evidence of endometriosis in the pelvis, and they benefitted from excision, followed by postoperative GnRH agonist therapy. We used only the sine qua non gold standard for the histologic diagnosis of endometriosis, that is, glands and stroma. There is some disagreement about whether hemosiderin in tissue does represent endometriosis. In the slide that I presented, that was probably a postsurgical change; also, incorporation of retrograde menstrual blood into the peritoneal lining may cause hemosiderin deposition only. REFERENCE
1. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999;93: 51-8.
Key words: Endometriosis, histology, laparoscopy
Endometriosis, defined as the ectopic presence of normal endometrial glands and stroma, has been widely implicated as one of the causes of chronic pelvic pain, dysmenorrhea, and infertility.1-3 Traditionally, the definitive diagnosis of endometriosis has been determined from visualization of typical or atypical lesions during laparoscopic evaluations of the pelvic organs and peritoneum. Biopsy specimens of peritoneal lesions suggestive of endometriosis provide histologic confirmation in 3.1% to 100% of cases (depending on lesion type and location).4-8 Unfortunately, diverse patient populations, the limited number and small size of the specimens, inconsistencies in biopsy technique, or inconsistencies in the visual classes of endometriosis being sampled mar all of these studies. In addition, other studies have
From the Department of Obstetrics and Gynecologya and the Section of Biostatistics,b Mayo Clinic Scottsdale. Presented at the Sixty-eighth Annual Meeting of The Central Association of Obstetricians and Gynecologists, Chicago, Illinois, October 18-21, 2000. The opinions and conclusions in this article are those of the authors and are not intended to represent the official position of the Department of Defense, United States Air Force, or any other government agency. Reprint requests: Andrew J. Walter, MD, 60 MDG/SGCG 101 Bodin Circle, Travis AFB, CA 94535. 0002-9378/2001 $35.00+0 6/6/115747 doi:10.1067/mob.2001.115747
shown that biopsy specimens of normal-appearing peritoneum provide histologic confirmation of endometriosis in 0% to 13% of cases.1, 5, 9 Thus it is not clear how accurate visualization of abnormal peritoneal lesions is in terms of the diagnosis and staging of endometriosis. The purpose of our study was to define the correlation between the visual and histologic diagnoses of endometriosis from peritoneal findings identified at laparoscopy in a prospective trial with a standardized technique, including complete excision of lesions suggestive of endometriosis and systematic biopsies of normal-appearing pelvic peritoneum. Methods This was a prospective observational study of all women who presented to the Department of Gynecologic Surgery at Mayo Clinic Scottsdale between July 1997 and March 1999 for evaluation of chronic pelvic pain or known endometriosis (diagnosed histologically or by visualization) refractory to medical management. Nonsurgical diagnosis and therapy were managed by the staff medical gynecologists. Patients were excluded only if they had recently completed therapy with gonadotropinreleasing hormone (GnRH) agonists (within 6 months of laparoscopic evaluation), because this may affect the visual appearance of endometriosis at laparoscopy. At laparoscopy, all areas of typical and atypical endometriosis were documented on a pelvic diagram for 1407
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Table I. Prevalence of previous treatments for endometriosis
Table II. Visual versus histologic AFS stage Histologic stage
Patients (n = 44) Treatment
No.
%
Laparoscopy and ablation or excision Once Twice Three times Hysterectomy Leuprolide
7 6 1 7 6
16 14 2 16 14
lesion type and location, completely excised, fixed in formalin, and evaluated pathologically for the presence or absence of endometriosis (defined as the presence of glands and stroma) in a standard fashion by Mayo pathologists who were blinded to the type of lesion (if any). Lesions were defined as puckered pigmented lesions, scarred lesions, red lesions, vesicular lesions, peritoneal pockets, adhesions, and yellow lesions.6-8, 10 Additionally, areas of normal-appearing pelvic peritoneum were sampled with multiple, site-specific biopsies. These sites included the right and left uterosacral ligaments, the posterior and anterior areas of the cul-de-sac, both ovarian fossae, and the peritoneum overlying the right psoas muscle. If all of these sites contained only abnormal-appearing peritoneum, then additional biopsies were not performed. If there were no abnormal peritoneal lesions, then 9 biopsy specimens (~0.5 cm) were taken at the sites specified. To define disease stage, the revised American Fertility Society (AFS) classification was used. Scores were determined from lesion size (determined by pathologic measurement of the excised specimen), depth of penetration (determined during the excision), status of the posterior cul-de-sac, presence and size of ovarian endometriomas, and presence and nature of tubo-ovarian adhesions. All ovarian endometriomas were removed at laparoscopy and evaluated histologically.11 Visual AFS scores were calculated. In addition, a histologic AFS score was obtained by subtracting the score of lesions that were visually consistent with endometriosis but not confirmed on pathologic examination. Approval from our institutional review board (July 1997) was obtained, and all patients provided informed consent for participation in the study. Data collected at the time of the operative procedure included demographic information, presenting complaints, previous method(s) for the diagnosis and treatment of endometriosis, and the location and visual class of any identified lesions. Pathologic examination was performed by 1 of 6 pathologists and re-reviewed by one pathologist. The biopsy specimens were evaluated in the standard fashion. The specimens were fixed in formalin and embedded in
Visual stage
0
I
II
III
IV
Total
0 I II III IV TOTAL
7 6 3 3 0 19
0 4 1 1 0 6
0 0 7 2 0 9
0 0 0 5 0 5
0 0 0 0 5 5
7 10 11 11 5 44
paraffin, and 3- to 4-µm sections were obtained every 50 to 60 µm. The sections were stained with hematoxylin and eosin. Four to 6 sections per specimen were evaluated by means of light microscopy. Data collected from the pathology report and pelvic diagram included the visual and histologic AFS score and correlation of lesion type with final histologic diagnosis. The sample size was determined by the number of patients we thought could be enrolled during a 2-year period (30 to 60). The difference between the visual and histologic AFS scores was assessed by the Wilcoxon signed rank test. The prevalence of endometriosis was compared among sites by the χ2 test of homogeneity of distributions. Diagnostic characteristics were described by using positive predictive value (PPV) (percentage of positive histologic findings of endometriosis among the positive visual findings), sensitivity (percentage of positive visual findings among the positive histologic findings), negative predictive value (percentage of normal histologic findings among the negative visual findings), and specificity (percentage of negative visual findings among the negative histologic findings). Exact binomial confidence intervals (CIs) were calculated for the diagnostic characteristics. Overall stratified values for the diagnostic characteristics were calculated by averaging the values for the 9 biopsy sites. Results The sample consisted of 44 patients who underwent laparoscopic evaluation between July 16, 1997, and March 3, 1999. No patients were excluded because of recent GnRH agonist use. Age at operation ranged from 14 to 48 years (mean age, 33 years; SD, 9). Parity was 0 for 57% of patients (25), 1 for 11% (5), 2 for 30% (13), and 4 for 2% (1). All patients presented with a primary complaint of pelvic pain, dysmenorrhea, or dyspareunia. Previous types of treatments for endometriosis or pelvic pain are summarized in Table I. AFS scores based on histologic findings ranged from 0 to 66 (mean, 11; median, 2). AFS scores from visual findings (mean, 15; median, 8; range, 0-72) were 4.0 points higher on average than the scores from histologic findings (median difference, 2; range of difference, 0-25; P < .001
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Table III. Prevalence of visual findings Finding [% (No.)]
Site Anterior cul-de-sac (n = 44) Broad ligament, left (n = 42) Broad ligament, right (n = 42) Fossa ovarica, left (n = 43) Fossa ovarica, right (n = 41) Posterior cul-de-sac (n = 42) Psoas muscle, right (n = 42) Uterosacral ligament, left (n = 42) Uterosacral ligament, right (n = 42) All sites* (n = 380)
Normal
Abnormal
Puckered pigmented lesion
57 (25) 64 (27) 79 (33) 65 (28) 61 (25) 52 (22) 83 (35) 57 (24) 55 (23) 64 (242)
43 (19) 36 (15) 21 (9) 35 (15) 39 (16) 48 (20) 17 (7) 43 (19) 45 (19) 36 (138)
11 (5) 17 (7) 5 (2) 16 (7) 15 (6) 14 (6) 5 (2) 24 (10) 24 (10) 15 (55)
Scarred lesion
Red vesicular lesion
Other vesicular lesion
9 (4) 10 (4) 12 (5) 5 (2) 5 (2) 17 (7) 5 (2) 7 (3) 7 (3) 9 (32)
9 (4) 0 (0) 0 (0) 2 (1) 5 (2) 7 (3) 2 (1) 7 (3) 10 (4) 5 (18)
5 (2) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (10)
Peritoneal defect Adhesion 2 (1) 0 (0) 0 (0) 0 (0) 2 (1) 2 (1) 0 (0) 0 (0) 0 (0) 0.7 (3)
7 (3) 5 (2) 2 (1) 9 (4) 10 (4) 5 (2) 2 (1) 2 (2) 0 (0) 5 (18)
Yellow lesion 0 (0) 2 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 0.4 (2)
*Mean of 9 sites.
from the Wilcoxon signed rank test). The distributions and agreement of AFS stages are illustrated in Table II. The visually determined stage was higher than the histologic stage for 36% (16) of the patients, including 12 patients whose diagnoses were downstaged from stage I, II, or III to 0. Visual findings for each site are summarized in Table III. The most common visually detected abnormality was a puckered pigmented lesion (40%, 55 of 138). Visually detected abnormalities were most common in the right posterior cul-de-sac and least common in the right psoas muscle. Histologic findings for each site are summarized in Table IV. The prevalence of endometriosis varied significantly among sites (χ2 = 20, P < .001 from the χ2 test of homogeneity), ranging from 31% for the posterior culde-sac to 2% for the right psoas muscle. Overall, 18% of the biopsy specimens provided a histologic diagnosis of endometriosis. PPV and sensitivity of abnormal visual findings for each biopsy site are summarized in Table V. Although sensitivities were high, the PPVs were not and varied considerably among the sites. Negative predictive value and specificity of normal visual findings for each site are summarized in Table VI. Specificity ranged from 66% for the anterior cul-de-sac to 85% for the right psoas muscle. Negative predictive values were high. Endometriosis was found in only 2 biopsy specimens (from 2 different patients), which had been described as normal on visual examination. Both patients had visual and histologic evidence of pelvic endometriosis elsewhere. PPV of each type of abnormal visual finding is summarized in Table VII. PPV was highest for lesions described as puckered pigmented (76%). Diagnostic characteristics for patients, rather than for individual biopsy specimens, are summarized in Table VIII. Eighty-four percent of the patients (37) had at least one site that was classified as abnormal on visual examination. However, the histologic findings indicated that only 52% (23) of the patients had
Table IV. Prevalence of histologic diagnoses of endometriosis for each biopsy site (with 95% CIs) Site
Mean (%)
No.
CI (%)
Anterior cul-de-sac Broad ligament, left Broad ligament, right Fossa ovarica, left Fossa ovarica, right Posterior cul-de-sac Psoas muscle, right Uterosacral ligament, left Uterosacral ligament, right All sites* Crude measure
14 21 7 19 17 31 2 26 26 18 18
6/44 9/42 3/42 8/43 7/41 13/42 1/42 11/42 11/42
5-27 10-37 2-19 8-33 7-32 18-47 0-13 14-42 14-42
69/380
*Mean of 9 sites.
Table V. PPV and sensitivity of abnormal visual findings versus histologic diagnosis of endometriosis (with 95% CIs) Site Anterior cul-de-sac Broad ligament, left Broad ligament, right Fossa ovarica, left Fossa ovarica, right Posterior cul-de-sac Psoas muscle, right Uterosacral ligament, left Uterosacral ligament, right All sites* Crude measure
PPV [% (No.)] CI (%)
Sensitivity [% (No.)]
CI (%)
32 (6/19) 53 (8/15) 33 (3/9)
13-57 100 (6/6) 27-79 89 (8/9) 7-70 100 (3/3)
54-100 52-100 29-100
47 (7/15) 44 (7/16) 65 (13/20) 14 (1/7) 61 (11/18)
21-73 20-70 41-85 0-58 36-83
47-100 59-100 75-100
88 (7/8) 100 (7/7) 100 (13/13) 100 (1/1) 100 (11/11)
72-100
58 (11/19) 34-80 100 (11/11) 72-100 45 49 (67/138)
97 97 (67/69)
*Mean of 9 sites.
at least one biopsy specimen with endometriosis. Among the patients with at least one abnormal site detected by visual examination, only 62% (23 of 37) had histologic confirmation of the abnormality. At least one puckered pig-
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Table VI. Negative predictive value and specificity of normal visual findings versus negative histologic diagnoses (with 95% CIs) NPV [% (No.)]
Site Anterior cul-de-sac Broad ligament, left Broad ligament, right Fossa ovarica, left Fossa ovarica, right Posterior cul-de-sac Psoas muscle, right Uterosacral ligament, left Uterosacral ligament, right All sites* Crude measure
CI (%)
Table VIII. Patient diagnostic characteristics for visual findings versus histologic diagnosis of endometriosis (with 95% CIs)
Specificity [% (No.)] CI (%)
Finding
100 (25/25) 86-100 66 (25/38) 96 (26/27) 81-100 79 (26/33)
49-80 61-91
100 (33/33) 89-100 85 (33/39)
69-94
96 (27/28) 100 (25/25) 100 (22/22) 100 (35/35) 100 (24/24)
77 (27/35) 74 (25/34) 76 (22/29) 85 (35/41) 77 (24/31)
60-90 56-87 56-90 71-94 59-90
Any visually detected abnormality PPV Sensitivity NPV Specificity Puckered pigmented lesions only PPV Sensitivity NPV Specificity
100 (23/23) 85-100 74 (23/31)
55-88
NPV, Negative predictive value.
82-100 86-100 85-100 90-100 86-100
99 99 (240/242)
77 77 (240/311)
NPV, Negative predictive value. *Mean of 9 sites.
Table VII. PPV of specific visual findings versus histologic diagnosis of endometriosis (with 95% CIs) Visual finding Puckered pigmented lesion All sites* Crude measure Scarred lesion All sites* Crude measure Red vesicular lesion All sites* Crude measure Other vesicular lesion All sites* Crude measure Peritoneal defect All sites* Crude measure Adhesion All sites* Crude measure Yellow lesion All sites* Crude measure
Positive predictive value (%)
76 76 (42/55) 22 25 (8/32)0 NA 61 (11/18) 00 00 (0/10)0 NA 00 (0/3)00 NA 28 (5/18)0 NA 50 (1/2)00
NA, Not available. *Mean of 9 sites.
mented lesion was noted in 45% (20) of the patients. Of those with puckered pigmented lesions, 85% (17 of 20) had the diagnosis of endometriosis confirmed histologically. All 7 patients with no visually detected abnormality had negative histologic diagnoses. Various pathologic diagnoses composed the falsepositive group. The most common was endosalpingiosis. The status of these patients will be the subject of a separate report.
Patients [% (No.)]
CI (%)
62 (23/37) 100 (23/23) 100 (7/7) 33 (7/21)
45-78 85-100 59-100 15-57
85 (17/20) 74 (17/23) 75 (18/24) 86 (18/21)
62-97 52-90 53-90 64-97
Comment Laparoscopic visualization of peritoneal lesions consistent with endometriosis has a low PPV for histologic confirmation of disease in our patient population with chronic pelvic pain. Use of histologic rather than visual criteria significantly decreases AFS scores, AFS stage, and frequency of diagnosis of endometriosis. Conversely, microscopic endometriosis is rare (2 of 380 biopsy specimens, both from patients with endometriosis in other pelvic sites), and therefore normal-appearing peritoneum is highly specific for the absence of endometriosis. The prevalence of histologically diagnosed endometriosis for our patients with chronic pelvic pain was 52%. Visual diagnosis of endometriosis on the basis of puckered pigmented lesions alone had higher PPV than visual diagnosis that included the other types of visually detected abnormalities. AFS scores and stages determined from the visual findings were substantially higher than those determined from histologic diagnosis. Of special concern are the 12 patients whose diagnoses were downstaged to 0 (3 of whom had visual AFS stage III), implying that these patients had single to multiple sites that were suggestive of endometriosis on visualization without any site being confirmed histologically. The prevalence of endometriosis and PPVs varied considerably among the 9 biopsy sites. For sites such as the posterior cul-de-sac, a visually detected abnormality was more likely to be endometriosis than a false-positive finding. However, for sites such as the right psoas muscle, a visually detected abnormality was more likely to be histologically negative for endometriosis. The highest PPV of any site was 65% for any visually detected abnormality in the posterior cul-de-sac, still insufficient to justify visual diagnosis alone. Others have studied peritoneal biopsy specimens from patients with histologically confirmed endometriosis. Although most studies confirmed moderate PPVs at best for histologic confirmation, serious methodologic flaws exist,
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including inconsistencies in definition of lesion types, patient populations, and biopsy specimen size and type.4-7 In an extensive study published in 1989, Martin et al8 noted findings similar to ours in terms of correlation between visually detected abnormalities and histologic confirmation. However, they concluded that lesions that were visually suggestive of endometriosis resulted in histologic confirmation in 97% to 99% of cases. The reason for the discrepancy between their results and conclusions is unclear, but they seem to suggest that visualization of classic and subtle lesions is adequate. Our data indicate otherwise. Various pathologic diagnoses are responsible for falsepositive visually detected abnormalities. In our study, the most common diagnosis was endosalpingiosis. Other diagnoses in our study and in other studies include normal peritoneum, mesothelial hyperplasia, fibrosis, hemosiderin deposition (not hemosiderin-laden macrophages), hemangiomas, suture granulomas, adrenal rests, malignancies (breast or ovarian), residual carbon from previous ablations, reaction to oil-based hysterosalpingogram dye, inflammatory changes, and splenosis. Laparoscopic excision of peritoneal lesions visually consistent with endometriosis provides histologic diagnosis, as well as removal of the diseased tissue. Some surgeons may be concerned that excisional biopsy will result in postoperative adhesion formation. However, from this case series, we are reassured: Of 3 patients who had complete excision of all lesions before inclusion in this study at our institution, none had any evidence of pelvic adhesive disease on subsequent laparoscopic exploration performed because of recurrent symptoms. All of these patients had histologically confirmed disease by findings on both laparoscopic procedures. Surgical complications in the 44 patients were limited to one retroperitoneal hematoma, which resolved with conservative management. Our recommendation is for histologic evaluation of visually detected abnormalities suggestive of endometriosis before a definitive diagnosis is made. The poor PPV on the basis of individual lesion type (0%-76% in our series) and per patient diagnosis (62%; overall 12 patients misdiagnosed) suggests that visual diagnosis alone is unreliable and should be abandoned, at least in patient populations with the primary complaint of chronic pelvic pain. The appearance of normal peritoneum is highly reliable for the absence of endometriosis, and it seems to be reasonable to omit biopsy to rule out microscopic endometriosis in these cases. However, we used only magnification to ×400 to confirm the presence or absence of microscopic endometriosis. Other authors have noted the incidence to be increased when normal-appearing peritoneum is subject to examination with electron microscopy.12 The clinical implications of endometriosis diagnosed in this manner and microscopic disease identified solely by light microscopic examination are unclear.
Recently, an algorithm has been espoused that eliminates laparoscopy (and thus histologic or visual confirmation of disease) in the diagnosis and management of chronic pelvic pain suspected of being caused by endometriosis.13 The advantages of this form of management when compared with excisional therapy with or without the use of postoperative GnRH agonists are unclear and will require further randomized prospective studies. At this point, when laparoscopic evaluation is performed in women with chronic pelvic pain for the specific purpose of ruling out endometriosis, we recommend that all visually detected abnormalities that are suggestive of endometriosis be excised or at least sampled before ablative therapy is initiated. This will significantly reduce the overdiagnosis of endometriosis. REFERENCES
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;53:984-8. 2. Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol 1990;162:568-9. 3. Williams TJ. Endometriosis. In: Thompson JD, Rock JA, editors. Te Linde’s operative gynecology. 7th ed. Philadelphia: JB Lippincott; 1992. p. 463-97. 4. Balasch J, Creus M, Fabregues F, Carmona F, Ordi J, MartinezRoman S, et al. Visible and non-visible endometriosis at laparoscopy in fertile and infertile women and in patients with chronic pelvic pain: a prospective study. Hum Reprod 1996;11:387-91. 5. Chatman DL, Zbella EA. Biopsy in laparoscopically diagnosed endometriosis. J Reprod Med 1987;32:855-7. 6. Ueki M, Saeki M, Tsurunaga T, Ueda M, Ushiroyama N, Sugimoto O. Visual findings and histologic diagnosis of pelvic endometriosis under laparoscopy and laparotomy. Int J Fertil Menopausal Stud 1995;40:248-53. 7. Jansen RP, Russell P. Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition. Am J Obstet Gynecol 1986;155:1154-9. 8. Martin DC, Hubert GD, Vander Zwaag R, el-Zeky FA. Laparoscopic appearances of peritoneal endometriosis. Fertil Steril 1989;51:63-7. 9. Redwine DB, Yocom LB. A serial section study of visually normal pelvic peritoneum in patients with endometriosis. Fertil Steril 1990;54:648-51. 10. Martin DC. Laparoscopic appearance of endometriosis: a color atlas. Philadelphia: Resurge Press; 1991. 11. Vercellini P, Vendola N, Bocciolone L, Rognoni MT, Carinelli SG, Candiani GB. Reliability of the visual diagnosis of ovarian endometriosis. Fertil Steril 1991;56:1198-2000. 12. Murphy AA, Green WR, Bobbie D, de la Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986;46: 522-4. 13. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999; 93:51-8.
Discussion DR FRANK LING, Memphis, Tennessee. First, I congratulate Dr Walter and his co-authors on a well-conceived clinical investigation and an excellent presentation. The Central Association has traditionally been a forum for papers of significant clinical relevance, and this paper certainly qualifies. The conclusion from the abstract reads:
1412 Walter et al
“A diagnosis of endometriosis should be established only after histologic confirmation.” With just today’s data, it is hard to argue with this conclusion. As we are told in the paper, publications of the past have already provided reports of marked discrepancies between visual diagnosis and histologic confirmation. I have no concerns with the study’s methodology, nor is there concern about data analyses. In fact, the statistical analysis of these findings should be complimented. The red flag for me is the potential clinical misapplication of these findings. Are the authors advocating that laparoscopy or some surgical procedure to access tissue be mandatory to diagnose endometriosis? For example, should the clinician’s judgment be relegated to a secondary role because only histologic examination can establish the diagnosis of endometriosis? What member of the audience has not performed a biopsy on what, on visual examination, was classic endometriosis, only to have the pathologist report that none was seen on the specimen? What clinician has not gone to the operating room suspecting endometriosis, only to see nothing abnormal? How many of us have been told by third-party carriers that we could not prescribe a GnRH agonist unless there was a tissue diagnosis of endometriosis? If we are limited in our ability to diagnose endometriosis, are we limiting our potential to successfully treat patients whose biopsy specimens fall short of the histologic gold standard? It is for situations such as these that the potential use of GnRH agonist on an empiric basis should be considered, before laparoscopy, or, in some cases, in spite of normal findings on laparoscopy. The authors have presented a comprehensive histologic view of patients that does not address the clinical dilemmas they face. These data do reaffirm our long-held suspicions that visual confirmation of endometriosis is not all that it is cracked up to be. Some, including myself, would argue that laparoscopy should not be mandatory to make the diagnosis but, instead, limited to those cases that do not respond to empiric medical treatment. As I reported in the January 1999 issue of Obstetrics and Gynecology, empiric use of GnRH agonist is an effective treatment before laparoscopy in cases of clinically suspected endometriosis.1 I bring the following 5 issues to the attention of the authors so that some of my cynicism about the limited applicability of their results might be addressed. Issue 1 concerns the study design. What evaluations were done to rule out other causes of chronic pelvic pain? Were patients with gastrointestinal, genitourinary, musculoskeletal, and/or psychiatric conditions included or excluded? Or were all patients scheduled for laparoscopy? What if patients who received GnRH agonist within the past 6 months had not been excluded? Why were subjects allowed if the medication had been received more than 6 months previously? Issue 2 concerns Table I, entitled “Prevalence of previous treatments for endometriosis,” although the text reads “Previous types of treatments for endometriosis or pelvic pain are summarized in Table I.” What, if any, non–endometriosis–related treatments were even sought? Issue 3 addresses the authors’ statement that patients
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were “downstaged” from stage I or higher to zero. In a practical sense, what does this mean from a clinical standpoint in a patient who still has pain? Issue 4 concerns the authors’ statement that “microscopic endometriosis is rare (2 of 380 biopsy specimens).” Does this mean that endometriosis is only a visible disease? Are these 2 biopsy specimens clinically therefore as the others that were grossly visible? How do the authors interpret their findings in light of the 1986 report of Murphy et al2 in which endometriosis was found in normalappearing biopsy specimens by means of electron microscopy? Issue 5 focuses on those patients who had complete excision of all endometriotic lesions at the authors’ institution before entry into the study. None had evidence of adhesive disease during laparoscopy in this series. What do the authors propose to be the cause of these patients’ pain? How do the authors recommend these patients be treated? In summary, this is an admirable addition to our knowledge about the limitations of the visual diagnosis of endometriosis. It does not, however, aid us very much in our ongoing struggle to better diagnose and treat chronic pelvic pain. I totally agree with the authors in saying patients who do not have endometriosis should not be labeled and treated as if they do. On the other hand, focusing too much on endometriosis alone might lead one to develop a case of “Gynevision,” in which the gynecologist gets too caught up in looking for and treating solely gynecologic abnormalities.3 Until more data are forthcoming, the practicing physician would be well advised to advocate the multidisciplinary approach to the diagnosis and management of chronic pelvic pain for which laparoscopy is used selectively, a management scheme that has been proven superior to the universal use of laparoscopy in all patients.1 I appreciate the opportunity to comment on this fine presentation. REFERENCES
1. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol 1999;93:51-8. 2. Murphy AA, Green WR, Bobbie D, de la Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986;46: 522-4. 3. Smith RP, Ling FW. Gynevision. Obstet Gynecol 1991;78:708-9.
DR WALTER (Closing). I would like to thank Dr Ling for his commentary. First, I have one general comment. This is not a treatment article. We are not recommending surgical excision as the only method of treatment for women who present with chronic pelvic pain. Clearly, pelvic pain is a multidimensional disease with gynecologic, urologic, gastrointestinal, psychiatric, neurologic, and musculoskeletal components that are well beyond the scope of this particular paper. The question we have attempted to answer is, if a gynecologic surgeon is performing a laparoscopy with the intention of diagnosing endometriosis, is visualization of peritoneal lesions
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adequate? The PPV of visualized peritoneal abnormalities for histologic confirmation, the gold standard of endometriosis, is insufficient. In regard to the specific questions, the first two issues from Dr Ling referred to our preoperative evaluation and the previous therapies the patients had received. We have a division of medical gynecology, and all preoperative workups were done by this division. This included the various workups that Dr Ling was suggesting. All patients who underwent surgery met the criteria that were outlined in Dr Ling’s article.1 The third issue was the significance of downstaging. Clearly, it is not significant when patients’ diagnoses are downstaged from stage III or II to stage I. That occurred in 4 of our patients. What is more significant are the 12 patients whose diagnoses were downstaged from visual stage I, stage II, and even stage III to stage 0. That is clearly significant because these patients did not have endometriosis according to accepted histologic criteria, despite visual evidence to the contrary. Issue 4, microscopic endometriosis, is very unclear. The incidence has been reported to be between 0% and 13% with light microscopy. I have not read the article on electron microscopy, so I cannot comment on that. The question clearly is, does microscopic endometriosis, if it is
a true ubiquitous phenomenon in patients who do not have visual evidence or histologic evidence of disease elsewhere, cause pain? Again, the last issue was in regard to the patients who underwent repeat laparoscopic evaluation because prior excisional therapy had failed. This was merely to address the potential for adhesions with aggressive excision of endometriosis, which we did not see in our patient population. All 3 of these patients had recurrent pain and recurrent histologic and visual evidence of endometriosis in the pelvis, and they benefitted from excision, followed by postoperative GnRH agonist therapy. We used only the sine qua non gold standard for the histologic diagnosis of endometriosis, that is, glands and stroma. There is some disagreement about whether hemosiderin in tissue does represent endometriosis. In the slide that I presented, that was probably a postsurgical change; also, incorporation of retrograde menstrual blood into the peritoneal lining may cause hemosiderin deposition only. REFERENCE
1. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999;93: 51-8.