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Reliability of Visual Diagnosis of Endometriosis
Original Article
Reliability of Visual Diagnosis of Endometriosis See Related Editorial, p. 733
Shavi Fernando, MBBS(hon), BMedSc(hon)*, Pei Qian Soh, MBBS(hon), Michael Cooper, MBBS, FRANZCOG, FRCOG, Susan Evans, MBBS, FRANZCOG, FFPMANZCA, Geoffrey Reid, MBBS, FRANZCOG, FRCOG, Jim Tsaltas, MBBS, FRANZCOG, FRCOG, and Luk Rombauts, MD, PhD, FRANZCOG, CREI From Monash Health, Melbourne (Drs. Fernando and Tsaltas; Dr. Rombauts), Goulburn Valley Health, Victoria (Dr. Soh), Department of Obstetrics and Gynecology, Sydney University, New South Wales (Dr. Cooper), Department of Obstetrics and Gynecology, University of Adelaide, South Australia (Dr. Evans), Department of Women’s and Child Health, Liverpool Hospital, New South Wales (Dr. Reid), and Department of Obstetrics and Gynecology, Monash University, Melbourne (Dr. Rombauts), Australia.
ABSTRACT Objective: To determine whether accuracy of visual diagnosis of endometriosis at laparoscopy is determined by stage of disease. Design: Prospective longitudinal cohort study (Canadian Task Force classification II-2). Setting: Tertiary referral centers in three Australian states. Patients: Of 1439 biopsy specimens, endometriosis was proved in at least one specimen in 431 patients. Interventions: Laparoscopy with visual diagnosis and staging of endometriosis followed by histopathologic analysis and confirmation. Operations were performed by five experienced laparoscopic gynecologists. Measurements and Main Results: Histopathologic confirmation of visual diagnosis of endometriosis adjusted for significant covariates. Endometriosis was accurately diagnosed in 49.7% of American Society for Reproductive Medicine (ASRM) stage I, which was significantly less accurate than for other stages of endometriosis. Deep endometriosis was more likely to be diagnosed accurately than superficial endometriosis (adjusted odds ratio, 2.51; 95% confidence interval, 1.50–4.18; p , .01). Lesion volume was also predictive, with larger lesions diagnosed more accurately than smaller lesions. In general, lesion site did not greatly influence accuracy except for superficial ovarian lesions, which were more likely to be incorrectly diagnosed visually as endometriosis (adjusted odds ratio, 0.16; 95% confidence interval, 0.06–0.41; p , .01). There was no statistically significant difference in accuracy between the gynecologic surgeons. Conclusion: The accuracy of visual diagnosis of endometriosis was substantially influenced by American Society of Reproductive Medicine stage, the depth and volume of the lesion, and to a lesser extent the location of the lesion. Journal of Minimally Invasive Gynecology (2013) 20, 783–789 Crown Copyright Ó 2013 Published by Elsevier Inc. All rights reserved. Keywords:
DISCUSS
Endometriosis; Histological diagnosis; Laparoscopy; Severity; Visual diagnosis
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Supported by an unconditional grant from the Australian Gynaecological Endoscopy & Surgery Society awarded to the AWARE group. The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding author: Dr. Shavi Fernando, MBBS(hon), BMedSc(hon), Monash Health, 246 Clayton Rd, Clayton, VIC 3144, Australia.
E-mail: [email protected] Submitted February 28, 2013. Accepted for publication April 22, 2013. Available at www.sciencedirect.com and www.jmig.org
1553-4650/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2013.04.017
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Although endometriosis is a common gynecologic condition, believed to occur in 10% of women of reproductive age [1], it remains challenging to diagnose accurately. One reason for this challenge is the poor correlation between the clinical symptoms and the severity of the disease [2–4]. The European Society of Human Reproduction and Embryology guidelines state that visual inspection of the pelvis is the criterion standard for diagnosis of endometriosis [5], and the most recent American Society for Reproductive Medicine (ASRM) guidelines state that ‘‘histologic evaluation is warranted whenever the diagnosis is not apparent on visual inspection at surgery’’ [6]. Although many specialists accept that visual recognition of lesions alone is usually sufficient [7], the accuracy of visual diagnosis alone has yielded mixed results in numerous studies [8–22]. This is important because classification of the disease on the basis of ASRM stage relies heavily on visual scoring [4]. A recent study, not specifically designed to ascertain the accuracy of visual diagnosis of endometriosis, incidentally found that only 410 of 565 patients (72.6%) with visually diagnosed endometriosis had histologically proved disease [23]. A systematic review conducted in 2004 showed that there is little agreement between studies assessing the value of visual diagnosis of endometriosis at laparoscopy, with positive predictive values ranging widely, from 25% to 100% [13]. These observed differences in positive predictive values were most likely due to a combination of factors, which were not controlled for in all studies. Differences in the appearance, depth, and location of endometriotic lesions and interobserver variability have previously been recognized as factors that influence the accuracy of visual diagnosis [8,17]. A study by Stratton et al [8] concluded that white or mixed color and larger endometriomas were more likely to be identified as endometriosis than were black or red and larger lesions. In another study that included 238 biopsy specimens, Kazanegra et al [17] assessed the accuracy of visual diagnosis of endometriosis as stratified according to ASRM stage, with scoring based on number, size, depth, and location of endometrial lesions. They found that endometriosis at higher stages was diagnosed more accurately than was minimal disease. Stegmann et al [22] agreed with this, finding that ASRM stage I endometriosis was diagnosed less accurately than was endometriosis of more advanced stages. More recently, however, a small retrospective analysis showed a diagnostic accuracy of visual diagnosis of endometriosis of 63.9%; however, the findings suggested that neither the stage nor the site of disease had any correlation with the histologic diagnosis [21]. Pardanani and Barbieri [24] investigated interobserver variability in the visual diagnosis of endometriosis. Their study of 91 patients included three gynecologists and found that individual visual diagnostic accuracy was 42%, 65%, and 76%, respectively. This wide variety in interobserver accuracy in the visual diagnosis of endometriosis is an impor-
tant finding and may reflect different experience and skill levels of the respective gynecologists or a different case mix. Thus, there is conflicting evidence insofar as the accuracy of visual diagnosis in relation to ASRM stage, potentially because other variables were not appropriately controlled for or sample sizes were not sufficient. Therefore, in the present large prospective study, we investigated whether the accuracy of visual diagnosis is affected by disease stage, accounting for other covariates. Material and Methods The present analysis was part of a larger prospective, longitudinal, cohort study, conducted across three states in Australia (South Australia, Victoria, and New South Wales) from September 2003 to July 2007, by five experienced gynecologists (M.C., S.E., G.R., J.T., L.R.), all accredited to perform level 6 laparoscopy as defined by the Royal Australian and New Zealand College of Obstetricians and Gynecologists [25]. The findings in this article focus on the accuracy of visual recognition of endometriotic lesions at laparoscopy. However, the primary objective of the longitudinal cohort study was to assess pain and fertility outcomes after laparoscopic surgery performed to treat endometriosis. Therefore, inclusion in the longitudinal cohort required patients to have at least one biopsy specimen with histologic confirmation of endometriosis. Five hundred thirty-three patients were identified as potentially eligible for enrollment on the basis of a presumed diagnosis of endometriosis because of pain or infertility before laparoscopy. Of these, 62 either did not have any visual features of endometriosis or, if biopsies were taken, none contained histologically proved endometriosis. In another 40 patients, surgery was performed by training registrars or fellows, and these patients were excluded because the number of procedures performed by each physician were too small to lead to meaningful conclusions. Thus, 102 patients were excluded from this analysis, leaving 431 women, from whom a total of 1439 biopsy specimens were obtained. Previous medical or surgical treatment of endometriosis was not a contraindication to study entry. Patients were excluded before laparoscopy if they had a suspected gynecologic malignancy, known current or chronic relapsing pelvic inflammatory disease, or current pregnancy or if they were unable to provide informed consent. Preoperatively, all subjects completed a questionnaire to collect demographic, biometric, and clinical data including age, body mass index, and gynecologic and medical history. Postoperatively, each gynecologist provided further clinical information for each patient regarding the operative findings. Gynecologists scored severity of disease using the revised ASRM classification [4]. Additional data included the total number, anatomical site, estimated size (small, ,100 mm3; medium, 100–1000 mm3; and large, .1000 mm3), and depth of the excised lesions. This
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Table 1 Accuracy of diagnosis by gynecologist and ASRM stage
Gynecologist
Patients treated, No. (%)
No. of biopsies per patient,a median (range)
Histologically proved disease according to ASRM stage, No. (%) Ib
IIb
IIIc
IVb
Biopsy specimens confirmed positive at histology,d No. (%)
1 2 3 4 5 Total
112 (26.0) 153 (35.5) 119 (27.6) 21 (4.9) 26 (6.0) 431 (100)
3 (1–13) 2 (1–9) 4 (1–11) 3 (1–9) 2 (1–8 ) 3 (1–13)
43/57 (75.4) 42/109 (38.5) 1/1 (100) 8/9 (88.9) 4/21 (19.0) 98/197 (49.7)
64/79 (81.0) 132/182 (72.5) 127/144 (88.2) 12/15 (80.0) 24/27 (88.9) 359/447 (80.3)
63/71 (88.7) 38/57 (66.7) 86/112 (76.8) 19/23 (82.6) 4/6 (66.7) 210/269 (78.1)
121/181 (66.9) 53/56 (94.6) 210/244 (86.1) 14/27 (51.9) 17/18 (94.4) 415/526 (78.9)
291/388 (75.0) 265/404 (65.6) 424/501 (84.6) 53/74 (71.6) 49/72 (68.0) 1082/1439 (75.2)
ASRM 5 American Society of Reproductive Medicine. a Analysis of variance, p , .01. b Fisher exact test, p , .01. c Fisher exact test, p 5 .02. d 2 c test, p , .01.
information was based on the gynecologist’s visual assessment of the disease and was collected before histologic analysis of samples. Only lesions thought to represent endometriosis were removed, via cold or diathermy excision. Gynecologists were instructed to excise every lesion in its entirety, with a margin of healthy tissue when possible. In patients with advanced disease, multiple biopsy specimens were obtained, with their size dependent on the size of the lesion. After each operation, all excised lesions were fixed in 10% formalin and sent for routine histologic examination by the standard local pathology service. All tissues were processed and embedded in paraffin blocks, sectioned, and stained with hematoxylin-eosin. Qualified gynecologic pathologists at each of the three sites analyzed the samples, and a diagnosis of endometriosis was made on the basis of presence of endometrial glands and stroma, consistent with previous research [13]. Reflective of routine practice, pathologists were not blinded to the presumed diagnosis for this study. Statistical analysis was performed using commercially available software (SPSS version 20; IBM Corp., Armonk, NY; 2011). The primary outcome measure was histologic confirmation of visually identified endometriotic lesions. Frequency was compared using the c2 test or the Fisher exact test. Continuous variables in multiple groups were compared using analysis of variance, with median and range used for non-normal distributions and mean and standard deviation used for normal data. The dataset contained two levels: the primary level, with the individual biopsy and its associated covariates including location, depth, and volume, and the secondary level, the patient, with multiple biopsy specimens from the same patient. These observations within the same patient may be correlated and therefore non-independent. To adjust for such within-patient correlations generalized estimating equation statistics were used, with an independent working correlation matrix and quasi-likelihood under
the independence model criterion and corrected quasilikelihood under the independence model criterion to select the most appropriate multilevel binary logistic regression model and covariates to be retained in the final regression model. Both main effects and two-way interactions were explored. Unadjusted and adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) are reported. A p value of .05 was assumed statistically significant. Subjects provided written informed consent. Ethics approval was obtained from the Southern Health Human Research Ethics Committee (project No. 04108C). Results A total of 1439 biopsy specimens were obtained from 431 patients by five gynecologic surgeons (Table 1). Patient mean (SD) age was 31.8 (7.2) years, and body mass index was 23.6 (4.5). The median number of previous laparoscopic and/or laparotomic procedures was 1 (range, 0–8), and median parity was 0 (range, 0–7). No adverse events were recorded. Table 1 gives for each specialist gynecologist the number of patients operated on, the median number of biopsy specimens excised per patient, and the percentage of histologically confirmed biopsy specimens, also stratified according to ASRM stage. For the entire cohort, a median number of three biopsy specimens (range, 1–13) was obtained from each patient. Of biopsy specimens from patients with ASRM stage I disease, 98 of 197 (49.7%) were accurately diagnosed via visual assessment alone. More severe forms of endometriosis were more accurately diagnosed, with ASRM stages II, III, and IV successfully diagnosed 80.3%, 78.1%, and 78.9% of the time, respectively. When stratified according to gynecologist, before adjustment for covariates, the mean positive predictive value was 75.2% (range, 65.6%–84.6%) (Table 1).
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Table 2
Table 3
Accuracy of diagnosis according to lesion location and characteristics
Unadjusted ORs for association of patient and lesion characteristics with histologically confirmed endometriosisa
Variable Site of lesiona Peritoneum in pouch of Douglas Other peritoneum Pelvic side wall Tubal serosa Vesical Uterosacral ligament Ovary Superficial Deep Bowel Rectal, full thickness Rectal serosa Other bowel, full thickness Other bowel serosa Other Uterus Cervix Fallopian tube Bladder full thickness Ureter Other Depth of lesiona Superficial Deep Volume of lesiona Small, ,100 mm3 Medium, 100–1000 mm3 Large, .1000 mm3 a
No. of biopsy specimens, No. (%)
Biopsy specimens histologically proved positive, No. (%)
170 (11.8)
128/170 (75.3)
442 (30.7) 325 (22.6) 16 (1.1) 101 (7.0) 376 (26.1)
319/442 (72.2) 234/325 (72.0) 10/16 (62.5) 75/101 (74.3) 301/376 (80.1)
39 (2.7) 171 (11.9) 105 (7.3) 25 (1.7) 46 (3.2) 17 (1.2) 17 (1.2) 136 (9.5) 12 (0.8) 84 (5.8) 16 (1.1) 8 (0.6) 2 (0.1) 14 (1.0)
12/39 (30.8) 134/171 (78.4) 79/105 (75.2) 23/25 (92.0) 33/46 (71.7) 12/17 (70.6) 11/17 (64.7) 109/136 (80.1) 9/12 (75.0) 69/84 (82.1) 13/16 (81.2) 7/8 (87.5) 1/2 (50.0) 10/14 (71.4)
460 (32.0) 979 (68.0)
271/460 (58.9) 811/979 (82.8)
440 (30.6) 573 (39.8) 426 (29.6)
279/440 (63.4) 465/573 (81.2) 338/426 (79.3)
c2 test, p , .01.
Biopsy specimens were obtained from multiple sites in the abdominal cavity, with most originating from the uterosacral ligament (26.1%), pelvic side wall peritoneum (22.6%), and deep ovary (11.9%). Specimens from the pouch of Douglas and bowel were also relatively common (Table 2). In keeping with previous studies [26], slightly more biopsy specimens were obtained from the left side of the pelvis than from the right side (36.8% vs 32.7%), and there was no significant difference in accuracy of diagnosis on the basis of laterality of lesion (data not shown). Univariate analysis of covariates potentially affecting the accuracy of diagnosis was performed (Table 3). At the lesion level, the strongest predictors of positive histologic findings were depth of the lesion, with deep lesions diagnosed more accurately than superficial lesions (OR, 3.35; 95% CI, 2.27– 4.93; p , .01) and estimated volume of the lesion, with me-
Variable
OR
95% CI
b
1.04 0.98 1.54 1.04 0.96
1.00–1.07 0.94–1.02 0.93–2.54 0.88–1.23 0.71–1.29
.03 .25 .09 .60 .77
1.00 0.57 1.64 0.71 0.65
0.29–1.14 0.82–3.30 0.21–2.43 0.21–2.04
Referent .11 .16 .59 .46
1.00 3.99 3.97 3.96
2.24–7.11 1.93–8.17 2.14–7.33
Referent ,.01 ,.01 ,.01
1.00 1.63 1.22
1.18–2.26 0.87–1.72
Referent ,.01 .25
0.17 1.47 1.13 1.45
0.07–0.41 0.92–2.35 0.64–1.98 0.87–2.41
,.01 .11 .67 .15
1.00 3.35
2.27–4.93
Referent ,.01
1.00 2.67 2.59
1.76–4.02 1.54–4.35
Referent ,.01 ,.01
Age Body mass indexb Age at menarcheb No. of previous operationsb,c Parityb Gynecologistd 1 2 3 4 5 ASRM staged I II III IV Site of lesiond Peritoneum Uterosacral Pouch of Douglas Ovary Superficial Deep Bowel Other Depth of lesiond Superficial Deep Volume of lesiond Small, ,100 mm3 Medium, 100–1000 mm3 Large, .1000 mm3
p value
ASRM 5 American Society of Reproductive Medicine; CI 5 confidence interval; OR 5 unadjusted odds ratio. a Univariate multilevel regression analysis was performed for all explanatory variables. b Continuous variables. c Previous procedures to treat endometriosis include laparoscopies and laparotomies. d Categorical variables.
dium and large lesions diagnosed more accurately (OR, 2.67; 95% CI, 1.76–4.02; p , .01), and (OR, 2.59; 95% CI, 1.54–4.35, respectively p , .01). At the patient level, age and ASRM stage were the strongest predictors. There seemed to be no difference in the ability of the different gynecologists to correctly recognize endometriotic lesions. All covariates were included in the multilevel logit regression model, and were deleted in stepwise fashion if they were not significant at the p 5 .20 level as assessed using the Wald c2 test. Lesion volume demonstrated a high level of collinearity with lesion depth and therefore was
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Table 4 Unadjusted and adjusted ORs for association of patient and lesion characteristics with histologically confirmed endometriosisa Variable ASRM stage I II III IV Superficial Deep Peritoneum Uterosacral ligament Pouch of Douglas Ovary Superficial Deep Bowel Other
OR
95% CI
p value
Adjusted OR 1.00 2.90 3.10 2.43 1.00 2.50 1.00 1.30 1.40
0.90–1.87 0.97–2.02
Referent ,.01 ,.01 .03 Referent ,.01 Referent .16 .07
0.16 0.83 0.77 1.05
0.06–0.41 0.50–1.38 0.45–1.32 0.63–1.75
,.01 .47 .35 .84
1.00 3.99 3.97 3.96 1.00 3.35 1.00 1.63 1.20
1.18–2.26 0.87–1.72
Referent ,.01 ,.01 ,.01 Referent ,.01 Referent ,.01 .25
0.17 1.47 1.13 1.45
0.07–0.41 0.92–2.35 0.64–1.98 0.87–2.41
,.01 .11 .67 .15
2.24–7.11 1.93–8.17 2.14–7.33 2.27–4.93
95% CI
1.56–5.39 1.37–7.03 1.09–5.39 1.50–4.18
p value
ASRM 5 American Society of Reproductive Medicine; CI 5 confidence interval; OR 5 odds ratio. a Multivariate multilevel logit regression model including only those explanatory variables that had a significant effect on accuracy of visual recognition as defined at histologic confirmation.
not included in the model. The final model included ASRM stage, depth of the lesion, and the categorized lesion site. Adjusted ORs for these covariates are given in Table 4. After multivariate analysis, deep endometriosis was more likely to be correctly diagnosed than superficial lesions were (adjusted OR, 2.50; 95% CI, 1.50–4.18; p , .01). Except for superficial ovarian endometriosis, which was diagnosed less successfully than endometriosis at other sites (adjusted OR, 0.16; 95% CI, 0.06–0.41; p , .01), lesion location did not significantly affect the accuracy of diagnosis. ASRM stage was a strong predictor, with stages II, III, and IV each diagnosed more accurately than stage I (Table 4).
Discussion The present study is the largest to date to confirm that severity of endometriosis determines a gynecologist’s ability to correctly identify endometriotic lesions via visual inspection alone, while adjusting for other covariates. Lesion depth and volume were also found to be positively correlated with a histologic diagnosis of endometriosis. However, volume was highly correlated with depth of the lesion (data not shown) and therefore was omitted from the final regression model. Laparoscopy remains the criterion standard for diagnosing endometriosis. However, the debate about the accuracy of visual diagnosis alone remains challenging. This is largely due to the various forms of clinical presentation and visual appearance of endometriosis, coupled with unclear pathophysiology [2–4]. Several investigators have endeavored to establish the accuracy of visual diagnosis at
laparoscopy against histologic confirmation, and results have varied significantly [13]. Among 1439 biopsy specimens included in the present study, one of the largest to date, the diagnosis of endometriosis was histologically confirmed in 1082 of 1439 (75.2%). This positive predictive value is consistent with previously reported results [9,16,17,27]. In our study, we analyzed the percentage of biopsy specimens confirmed rather than the number of patients with a diagnosis of the disease because per patient only one histologically confirmed biopsy specimen is required for a diagnosis of endometriosis even if all of the others are negative. Only one other study with a larger sample size has been performed, and reported a positive predictive value of visual diagnosis of endometriosis as high as 93.9% in a total of 2005 biopsy specimens [15]. However, that study primarily addressed the accuracy of diagnosis on the basis of lesion location and did not investigate the effect of interassessor variability or accuracy of ASRM staging. Our primary objective was to investigate whether the accuracy of visual diagnosis of endometriosis is influenced by severity of the disease. We found that lesions in more severe forms of endometriosis are diagnosed more accurately at visual inspection than are ASRM stage I lesions, even when correcting for other covariates. This is most likely because more severe disease is generally associated with more substantial anatomical distortion and more deep infiltrating endometriosis. Nevertheless, 25% of the biopsied lesions were not confirmed at histopathology, even in stages II, III, and IV. This finding strongly suggests that some patients may have had less severe disease than they were assigned, inasmuch as
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ASRM stage is determined immediately after surgery and relies only on visual assessment of the pelvis. Another explanation may be the use of excessive diathermy to remove lesions, resulting in thermal damage to endometriotic structures, in particular in smaller biopsy procedures. This might result in a false negative histologic result. However, the routine practice of all participating gynecologists was to leave a substantial margin of healthy tissue when excising lesions, reducing the risk of excessive thermal spread into the lesion itself. Despite this, we cannot exclude the possibility of diathermy-related artifacts. The difference in accuracy based on ASRM stage is in agreement with another study that was specifically designed to assess diagnostic accuracy stratified according to ASRM staging [17]. Kazanegra and associates retrospectively investigated 238 lesions from 104 patients and concluded that more severe stages of endometriosis are diagnosed more accurately, with stages I through IV correctly diagnosed 66.1%, 78.0%, 92.0%, and 81.1% of the time, respectively [17]. This result was supported by another study, performed by Stegmann et al [22] of 114 women with 487 biopsy specimens, designed to create a model to predict probability of endometriosis in suspect lesions to aid the gynecologist in selecting which tissue to biopsy. That study found that stage I endometriosis was diagnosed less accurately than were stages II, III, and IV combined (OR, 0.49; 95% CI, 0.31–0.79). In addition to accounting for lesion location, width, and stage, the authors accounted for lesion appearance (red, white, blue-black, brown, or mixed color). In contrast to other investigators [8,17], the authors found that lesions of any single color had a similar likelihood of being confirmed as endometriosis, whereas a mixed-color lesion marginally increased the probability of endometriosis from 66% to 78%. We did not collect data about appearance of the lesion; however, the large number of patients (431) and biopsy specimens (1439) in our study enabled us to look at each individual ASRM stage, and overall our findings are largely in agreement with the smaller studies of Kazanegra et al [17] and Stegmann et al [22]. Of the five experienced gynecologists included in the present study, samples were correctly diagnosed as endometriosis 65% to 85% of the time (mean, 75%). Despite this wide range in positive predictive value between gynecologists, when entered into multivariate analysis, these differences did not reach statistical significance, indicating that interobserver variability does not differ widely. Only two other studies have addressed the issue of interobserver variability of visual diagnosis of endometriosis at laparoscopy [24,28]. The study by Pardanani and Barbieri [24] included three gynecologists and reported the accuracy of visual diagnosis as 42%, 65%, and 76%, respectively, concluding that a substantial degree of interobserver variability exists in visual diagnosis of endometriosis. Their result may have differed from that in the present study because of different training levels of gynecologists and a much smaller number of cases (n 5 91), which also limited the ability to control for
covariates. A more recent study conducted by Schliep et al [28], which included eight gynecologists, examined the agreement of visual endometriosis diagnosis among gynecologic surgeons viewing operative digital images without histologic correlation. That study suggested that there was no significant interobserver or intraobserver variability and that agreement is not greatly affected by disease stage or location of lesions. However, that study was substantially different in that it assessed diagnoses only on the basis of retrospective interpretation of digital images. In the present study, location of the lesion did not affect accuracy much. The only types of lesions that were more likely to be incorrectly identified as endometriosis were superficial ovarian lesions. Diathermy artifacts to small superficial endometriotic lesions on the ovarian cortex is likely to have been a factor, although periovarian filmy adhesions are not uncommon and may also explain the result. Others have assessed the effect of lesion location on the accuracy of visual diagnosis of endometriosis and found that lesions on the uterus, ovaries, and fallopian tubes were less likely to be diagnosed correctly than those on the uterosacral ligaments or cul-de-sac (OR, 0.50; 95% CI, 0.26–0.97) [22]. While the present study is one of the largest to address this issue, it has some limitations. Operations were performed at different centers, and therefore different pathology laboratories were used to confirm the presence of endometriosis in the biopsy specimens. Nevertheless, histologic confirmation of endometriosis was clearly defined, histopathologists were equally trained in diagnosis of endometriosis, and reporting was consistent between analysts. In addition, only patients with at least one histologically proved biopsy specimen were enrolled in the study because women were recruited with the primary intention of assessing long-term clinical outcomes after surgery to treat endometriosis in a longitudinal cohort. Hence, if no lesions were observed or all biopsy specimens were negative for the disease, this patient would not have been retained in the database. Therefore, we are unable to comment on the total percentage of patients with a correct diagnosis of endometriosis. Similarly, because it is not standard clinical practice, random biopsy specimens were not obtained from normalappearing tissue. Hence, while we can comment on the percentage of correctly identified lesions (positive predictive value), we are unable to calculate the sensitivity, specificity, and negative predictive value of visual diagnosis of endometriosis. In conclusion, in this large prospective study involving 431 patients, 1439 biopsy specimens, and five experienced gynecologic surgeons, we found that specimens from women with ASRM stage I disease and from superficial lesions are more likely to be misdiagnosed as endometriosis at visual inspection. All five gynecologists performed similarly when diagnosing endometriosis visually, indicating that variability among experienced gynecologists is less than previously suggested. Nevertheless, visual diagnosis of endometriosis alone is generally unreliable as a primary diagnostic method
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because at least one in four biopsy specimens in our study did not meet the histologic diagnostic criteria. Acknowledgment We thank all of the patients who participated in the study. References 1. Missmer SA, Cramer DW. The epidemiology of endometriosis. Obstet Gynecol Clin N Am. 2003;30:1–19, vii. 2. Szendei G, Hernadi Z, Davanyi N, Csapo Z. Is there any correlation between stages of endometriosis and severity of chronic pelvic pain? possibilities of treatment. Gynaecol Endocrinol. 2005;21:93–100. 3. Porpora MG, Koninckx PR, Piazze J, Natili M, Colagrande S, Cosmi EV. Correlation between endometriosis and pelvic pain. J Am Assoc Gynecol Laparosc. 1999;6:429–434. 4. American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis:1996. Fertil Steril. 1997;67:817–821. 5. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698–2704. 6. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98:591–598. 7. Moses SH, Clark TJ. Current practice for the laparoscopic diagnosis and treatment of endometriosis: a national questionnaire survey of consultant gynaecologists in UK. BJOG. 2004;111:1269–1272. 8. Stratton P, Winkel CA, Sinaii N, Merino MJ, Zimmer C, Nieman LK. Location, color, size, depth, and volume may predict endometriosis in lesions resected at surgery. Fertil Steril. 2002;78:743–749. 9. Wood C, Kuhn R, Tsaltas J. Laparoscopic diagnosis of endometriosis. Aust N Z J Obstet Gynaecol. 2002;42:277–281. 10. Buchweitz O, Poel T, Diedrich K, Malik E. The diagnostic dilemma of minimal and mild endometriosis under routine conditions. J Am Assoc Gynecol Laparosc. 2003;10:85–89. 11. Stratton P, Winkel C, Premkumar A, et al. Diagnostic accuracy of laparoscopy, magnetic resonance imaging, and histopathologic examination for the detection of endometriosis. Fertil Steril. 2003;79:1078–1085. 12. Razzi S, Fava A, Sartini A, De Simone S, Cobellis L, Petraglia F. Treatment of severe recurrent endometriosis with an aromatase inhibitor in a young ovariectomised woman. BJOG. 2004;111:182–184. 13. Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: a systematic quantitative review. BJOG. 2004;111: 1204–1212. 14. Marchino GL, Gennarelli G, Enria R, Bongioanni F, Lipari G, Massobrio M. Diagnosis of pelvic endometriosis with use of macroscopic versus histologic findings. Fertil Steril. 2005;84:12–15.
789 15. Albee RB Jr, Sinervo K, Fisher DT. Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis. J Minim Invasive Gynecol. 2008;15:32–37. 16. El Bishry G, Tselos V, Pathi A. Correlation between laparoscopic and histological diagnosis in patients with endometriosis. J Obstet Gynaecol. 2008;28:511–515. 17. Kazanegra R, Zaritsky E, Lathi RB, Clopton P, Nezhat C. Diagnosis of stage I endometriosis: comparing visual inspection to histologic biopsy specimen. J Minim Invasive Gynecol. 2008;15:176–180. 18. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89:1632–1636. 19. Bazot M, Lafont C, Rouzier R, Roseau G, Thomassin-Naggara I, Darai E. Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis. Fertil Steril. 2009;92: 1825–1833. 20. Grasso RF, Di Giacomo V, Sedati P, et al. Diagnosis of deep infiltrating endometriosis: accuracy of magnetic resonance imaging and transvaginal 3D ultrasonography. Abdom Imaging. 2010;35:716–725. 21. Wanyonyi S, Sequeira E, Samuel G. Correlation between laparoscopic and histopathologic diagnosis of endometriosis. Int J Gynecol Obstet. 2011;115:273–276. 22. Stegmann B, Funk M, Sinaii N, et al. A logistic model for the prediction of endometriosis. Fertil Steril. 2009;91:51–55. 23. Chapron C, Souza C, Borghese B, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26:2028–2035. 24. Pardanani S, Barbieri RL. The gold standard for the surgical diagnosis of endometriosis: visual findings or biopsy results? J Gynecol Tech. 1998;4:121–124. 25. RANZCOG. Guidelines for performing advanced operative laparoscopy: consensus statement of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) and Australasian Gynaecological Endoscopy and Surgery Society (AGES). 2013; College Statement C-Trg2. 26. Chapron C, Fauconnier A, Dubuisson J, Vieira M, Bonte H, VacherLavenu M. Does deep endometriosis infiltrating the uterosacral ligaments present an asymmetric lateral distribution? BJOG. 2001;108: 1021–1024. 27. de Almeida Filho DP, de Oliveira LJ, do Amaral VF. Accuracy of laparoscopy for assessing patients with endometriosis. Sao Paulo Med J. 2008;126:305–308. 28. Schliep K, Stanford J, Chen Z, et al. Interrater and intrarater reliability in the diagnosis and staging of endometriosis. Obstet Gynecol. 2012; 120:104–112.
Reliability of Visual Diagnosis of Endometriosis See Related Editorial, p. 733
Shavi Fernando, MBBS(hon), BMedSc(hon)*, Pei Qian Soh, MBBS(hon), Michael Cooper, MBBS, FRANZCOG, FRCOG, Susan Evans, MBBS, FRANZCOG, FFPMANZCA, Geoffrey Reid, MBBS, FRANZCOG, FRCOG, Jim Tsaltas, MBBS, FRANZCOG, FRCOG, and Luk Rombauts, MD, PhD, FRANZCOG, CREI From Monash Health, Melbourne (Drs. Fernando and Tsaltas; Dr. Rombauts), Goulburn Valley Health, Victoria (Dr. Soh), Department of Obstetrics and Gynecology, Sydney University, New South Wales (Dr. Cooper), Department of Obstetrics and Gynecology, University of Adelaide, South Australia (Dr. Evans), Department of Women’s and Child Health, Liverpool Hospital, New South Wales (Dr. Reid), and Department of Obstetrics and Gynecology, Monash University, Melbourne (Dr. Rombauts), Australia.
ABSTRACT Objective: To determine whether accuracy of visual diagnosis of endometriosis at laparoscopy is determined by stage of disease. Design: Prospective longitudinal cohort study (Canadian Task Force classification II-2). Setting: Tertiary referral centers in three Australian states. Patients: Of 1439 biopsy specimens, endometriosis was proved in at least one specimen in 431 patients. Interventions: Laparoscopy with visual diagnosis and staging of endometriosis followed by histopathologic analysis and confirmation. Operations were performed by five experienced laparoscopic gynecologists. Measurements and Main Results: Histopathologic confirmation of visual diagnosis of endometriosis adjusted for significant covariates. Endometriosis was accurately diagnosed in 49.7% of American Society for Reproductive Medicine (ASRM) stage I, which was significantly less accurate than for other stages of endometriosis. Deep endometriosis was more likely to be diagnosed accurately than superficial endometriosis (adjusted odds ratio, 2.51; 95% confidence interval, 1.50–4.18; p , .01). Lesion volume was also predictive, with larger lesions diagnosed more accurately than smaller lesions. In general, lesion site did not greatly influence accuracy except for superficial ovarian lesions, which were more likely to be incorrectly diagnosed visually as endometriosis (adjusted odds ratio, 0.16; 95% confidence interval, 0.06–0.41; p , .01). There was no statistically significant difference in accuracy between the gynecologic surgeons. Conclusion: The accuracy of visual diagnosis of endometriosis was substantially influenced by American Society of Reproductive Medicine stage, the depth and volume of the lesion, and to a lesser extent the location of the lesion. Journal of Minimally Invasive Gynecology (2013) 20, 783–789 Crown Copyright Ó 2013 Published by Elsevier Inc. All rights reserved. Keywords:
DISCUSS
Endometriosis; Histological diagnosis; Laparoscopy; Severity; Visual diagnosis
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Supported by an unconditional grant from the Australian Gynaecological Endoscopy & Surgery Society awarded to the AWARE group. The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding author: Dr. Shavi Fernando, MBBS(hon), BMedSc(hon), Monash Health, 246 Clayton Rd, Clayton, VIC 3144, Australia.
E-mail: [email protected] Submitted February 28, 2013. Accepted for publication April 22, 2013. Available at www.sciencedirect.com and www.jmig.org
1553-4650/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2013.04.017
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Although endometriosis is a common gynecologic condition, believed to occur in 10% of women of reproductive age [1], it remains challenging to diagnose accurately. One reason for this challenge is the poor correlation between the clinical symptoms and the severity of the disease [2–4]. The European Society of Human Reproduction and Embryology guidelines state that visual inspection of the pelvis is the criterion standard for diagnosis of endometriosis [5], and the most recent American Society for Reproductive Medicine (ASRM) guidelines state that ‘‘histologic evaluation is warranted whenever the diagnosis is not apparent on visual inspection at surgery’’ [6]. Although many specialists accept that visual recognition of lesions alone is usually sufficient [7], the accuracy of visual diagnosis alone has yielded mixed results in numerous studies [8–22]. This is important because classification of the disease on the basis of ASRM stage relies heavily on visual scoring [4]. A recent study, not specifically designed to ascertain the accuracy of visual diagnosis of endometriosis, incidentally found that only 410 of 565 patients (72.6%) with visually diagnosed endometriosis had histologically proved disease [23]. A systematic review conducted in 2004 showed that there is little agreement between studies assessing the value of visual diagnosis of endometriosis at laparoscopy, with positive predictive values ranging widely, from 25% to 100% [13]. These observed differences in positive predictive values were most likely due to a combination of factors, which were not controlled for in all studies. Differences in the appearance, depth, and location of endometriotic lesions and interobserver variability have previously been recognized as factors that influence the accuracy of visual diagnosis [8,17]. A study by Stratton et al [8] concluded that white or mixed color and larger endometriomas were more likely to be identified as endometriosis than were black or red and larger lesions. In another study that included 238 biopsy specimens, Kazanegra et al [17] assessed the accuracy of visual diagnosis of endometriosis as stratified according to ASRM stage, with scoring based on number, size, depth, and location of endometrial lesions. They found that endometriosis at higher stages was diagnosed more accurately than was minimal disease. Stegmann et al [22] agreed with this, finding that ASRM stage I endometriosis was diagnosed less accurately than was endometriosis of more advanced stages. More recently, however, a small retrospective analysis showed a diagnostic accuracy of visual diagnosis of endometriosis of 63.9%; however, the findings suggested that neither the stage nor the site of disease had any correlation with the histologic diagnosis [21]. Pardanani and Barbieri [24] investigated interobserver variability in the visual diagnosis of endometriosis. Their study of 91 patients included three gynecologists and found that individual visual diagnostic accuracy was 42%, 65%, and 76%, respectively. This wide variety in interobserver accuracy in the visual diagnosis of endometriosis is an impor-
tant finding and may reflect different experience and skill levels of the respective gynecologists or a different case mix. Thus, there is conflicting evidence insofar as the accuracy of visual diagnosis in relation to ASRM stage, potentially because other variables were not appropriately controlled for or sample sizes were not sufficient. Therefore, in the present large prospective study, we investigated whether the accuracy of visual diagnosis is affected by disease stage, accounting for other covariates. Material and Methods The present analysis was part of a larger prospective, longitudinal, cohort study, conducted across three states in Australia (South Australia, Victoria, and New South Wales) from September 2003 to July 2007, by five experienced gynecologists (M.C., S.E., G.R., J.T., L.R.), all accredited to perform level 6 laparoscopy as defined by the Royal Australian and New Zealand College of Obstetricians and Gynecologists [25]. The findings in this article focus on the accuracy of visual recognition of endometriotic lesions at laparoscopy. However, the primary objective of the longitudinal cohort study was to assess pain and fertility outcomes after laparoscopic surgery performed to treat endometriosis. Therefore, inclusion in the longitudinal cohort required patients to have at least one biopsy specimen with histologic confirmation of endometriosis. Five hundred thirty-three patients were identified as potentially eligible for enrollment on the basis of a presumed diagnosis of endometriosis because of pain or infertility before laparoscopy. Of these, 62 either did not have any visual features of endometriosis or, if biopsies were taken, none contained histologically proved endometriosis. In another 40 patients, surgery was performed by training registrars or fellows, and these patients were excluded because the number of procedures performed by each physician were too small to lead to meaningful conclusions. Thus, 102 patients were excluded from this analysis, leaving 431 women, from whom a total of 1439 biopsy specimens were obtained. Previous medical or surgical treatment of endometriosis was not a contraindication to study entry. Patients were excluded before laparoscopy if they had a suspected gynecologic malignancy, known current or chronic relapsing pelvic inflammatory disease, or current pregnancy or if they were unable to provide informed consent. Preoperatively, all subjects completed a questionnaire to collect demographic, biometric, and clinical data including age, body mass index, and gynecologic and medical history. Postoperatively, each gynecologist provided further clinical information for each patient regarding the operative findings. Gynecologists scored severity of disease using the revised ASRM classification [4]. Additional data included the total number, anatomical site, estimated size (small, ,100 mm3; medium, 100–1000 mm3; and large, .1000 mm3), and depth of the excised lesions. This
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Table 1 Accuracy of diagnosis by gynecologist and ASRM stage
Gynecologist
Patients treated, No. (%)
No. of biopsies per patient,a median (range)
Histologically proved disease according to ASRM stage, No. (%) Ib
IIb
IIIc
IVb
Biopsy specimens confirmed positive at histology,d No. (%)
1 2 3 4 5 Total
112 (26.0) 153 (35.5) 119 (27.6) 21 (4.9) 26 (6.0) 431 (100)
3 (1–13) 2 (1–9) 4 (1–11) 3 (1–9) 2 (1–8 ) 3 (1–13)
43/57 (75.4) 42/109 (38.5) 1/1 (100) 8/9 (88.9) 4/21 (19.0) 98/197 (49.7)
64/79 (81.0) 132/182 (72.5) 127/144 (88.2) 12/15 (80.0) 24/27 (88.9) 359/447 (80.3)
63/71 (88.7) 38/57 (66.7) 86/112 (76.8) 19/23 (82.6) 4/6 (66.7) 210/269 (78.1)
121/181 (66.9) 53/56 (94.6) 210/244 (86.1) 14/27 (51.9) 17/18 (94.4) 415/526 (78.9)
291/388 (75.0) 265/404 (65.6) 424/501 (84.6) 53/74 (71.6) 49/72 (68.0) 1082/1439 (75.2)
ASRM 5 American Society of Reproductive Medicine. a Analysis of variance, p , .01. b Fisher exact test, p , .01. c Fisher exact test, p 5 .02. d 2 c test, p , .01.
information was based on the gynecologist’s visual assessment of the disease and was collected before histologic analysis of samples. Only lesions thought to represent endometriosis were removed, via cold or diathermy excision. Gynecologists were instructed to excise every lesion in its entirety, with a margin of healthy tissue when possible. In patients with advanced disease, multiple biopsy specimens were obtained, with their size dependent on the size of the lesion. After each operation, all excised lesions were fixed in 10% formalin and sent for routine histologic examination by the standard local pathology service. All tissues were processed and embedded in paraffin blocks, sectioned, and stained with hematoxylin-eosin. Qualified gynecologic pathologists at each of the three sites analyzed the samples, and a diagnosis of endometriosis was made on the basis of presence of endometrial glands and stroma, consistent with previous research [13]. Reflective of routine practice, pathologists were not blinded to the presumed diagnosis for this study. Statistical analysis was performed using commercially available software (SPSS version 20; IBM Corp., Armonk, NY; 2011). The primary outcome measure was histologic confirmation of visually identified endometriotic lesions. Frequency was compared using the c2 test or the Fisher exact test. Continuous variables in multiple groups were compared using analysis of variance, with median and range used for non-normal distributions and mean and standard deviation used for normal data. The dataset contained two levels: the primary level, with the individual biopsy and its associated covariates including location, depth, and volume, and the secondary level, the patient, with multiple biopsy specimens from the same patient. These observations within the same patient may be correlated and therefore non-independent. To adjust for such within-patient correlations generalized estimating equation statistics were used, with an independent working correlation matrix and quasi-likelihood under
the independence model criterion and corrected quasilikelihood under the independence model criterion to select the most appropriate multilevel binary logistic regression model and covariates to be retained in the final regression model. Both main effects and two-way interactions were explored. Unadjusted and adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) are reported. A p value of .05 was assumed statistically significant. Subjects provided written informed consent. Ethics approval was obtained from the Southern Health Human Research Ethics Committee (project No. 04108C). Results A total of 1439 biopsy specimens were obtained from 431 patients by five gynecologic surgeons (Table 1). Patient mean (SD) age was 31.8 (7.2) years, and body mass index was 23.6 (4.5). The median number of previous laparoscopic and/or laparotomic procedures was 1 (range, 0–8), and median parity was 0 (range, 0–7). No adverse events were recorded. Table 1 gives for each specialist gynecologist the number of patients operated on, the median number of biopsy specimens excised per patient, and the percentage of histologically confirmed biopsy specimens, also stratified according to ASRM stage. For the entire cohort, a median number of three biopsy specimens (range, 1–13) was obtained from each patient. Of biopsy specimens from patients with ASRM stage I disease, 98 of 197 (49.7%) were accurately diagnosed via visual assessment alone. More severe forms of endometriosis were more accurately diagnosed, with ASRM stages II, III, and IV successfully diagnosed 80.3%, 78.1%, and 78.9% of the time, respectively. When stratified according to gynecologist, before adjustment for covariates, the mean positive predictive value was 75.2% (range, 65.6%–84.6%) (Table 1).
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Table 2
Table 3
Accuracy of diagnosis according to lesion location and characteristics
Unadjusted ORs for association of patient and lesion characteristics with histologically confirmed endometriosisa
Variable Site of lesiona Peritoneum in pouch of Douglas Other peritoneum Pelvic side wall Tubal serosa Vesical Uterosacral ligament Ovary Superficial Deep Bowel Rectal, full thickness Rectal serosa Other bowel, full thickness Other bowel serosa Other Uterus Cervix Fallopian tube Bladder full thickness Ureter Other Depth of lesiona Superficial Deep Volume of lesiona Small, ,100 mm3 Medium, 100–1000 mm3 Large, .1000 mm3 a
No. of biopsy specimens, No. (%)
Biopsy specimens histologically proved positive, No. (%)
170 (11.8)
128/170 (75.3)
442 (30.7) 325 (22.6) 16 (1.1) 101 (7.0) 376 (26.1)
319/442 (72.2) 234/325 (72.0) 10/16 (62.5) 75/101 (74.3) 301/376 (80.1)
39 (2.7) 171 (11.9) 105 (7.3) 25 (1.7) 46 (3.2) 17 (1.2) 17 (1.2) 136 (9.5) 12 (0.8) 84 (5.8) 16 (1.1) 8 (0.6) 2 (0.1) 14 (1.0)
12/39 (30.8) 134/171 (78.4) 79/105 (75.2) 23/25 (92.0) 33/46 (71.7) 12/17 (70.6) 11/17 (64.7) 109/136 (80.1) 9/12 (75.0) 69/84 (82.1) 13/16 (81.2) 7/8 (87.5) 1/2 (50.0) 10/14 (71.4)
460 (32.0) 979 (68.0)
271/460 (58.9) 811/979 (82.8)
440 (30.6) 573 (39.8) 426 (29.6)
279/440 (63.4) 465/573 (81.2) 338/426 (79.3)
c2 test, p , .01.
Biopsy specimens were obtained from multiple sites in the abdominal cavity, with most originating from the uterosacral ligament (26.1%), pelvic side wall peritoneum (22.6%), and deep ovary (11.9%). Specimens from the pouch of Douglas and bowel were also relatively common (Table 2). In keeping with previous studies [26], slightly more biopsy specimens were obtained from the left side of the pelvis than from the right side (36.8% vs 32.7%), and there was no significant difference in accuracy of diagnosis on the basis of laterality of lesion (data not shown). Univariate analysis of covariates potentially affecting the accuracy of diagnosis was performed (Table 3). At the lesion level, the strongest predictors of positive histologic findings were depth of the lesion, with deep lesions diagnosed more accurately than superficial lesions (OR, 3.35; 95% CI, 2.27– 4.93; p , .01) and estimated volume of the lesion, with me-
Variable
OR
95% CI
b
1.04 0.98 1.54 1.04 0.96
1.00–1.07 0.94–1.02 0.93–2.54 0.88–1.23 0.71–1.29
.03 .25 .09 .60 .77
1.00 0.57 1.64 0.71 0.65
0.29–1.14 0.82–3.30 0.21–2.43 0.21–2.04
Referent .11 .16 .59 .46
1.00 3.99 3.97 3.96
2.24–7.11 1.93–8.17 2.14–7.33
Referent ,.01 ,.01 ,.01
1.00 1.63 1.22
1.18–2.26 0.87–1.72
Referent ,.01 .25
0.17 1.47 1.13 1.45
0.07–0.41 0.92–2.35 0.64–1.98 0.87–2.41
,.01 .11 .67 .15
1.00 3.35
2.27–4.93
Referent ,.01
1.00 2.67 2.59
1.76–4.02 1.54–4.35
Referent ,.01 ,.01
Age Body mass indexb Age at menarcheb No. of previous operationsb,c Parityb Gynecologistd 1 2 3 4 5 ASRM staged I II III IV Site of lesiond Peritoneum Uterosacral Pouch of Douglas Ovary Superficial Deep Bowel Other Depth of lesiond Superficial Deep Volume of lesiond Small, ,100 mm3 Medium, 100–1000 mm3 Large, .1000 mm3
p value
ASRM 5 American Society of Reproductive Medicine; CI 5 confidence interval; OR 5 unadjusted odds ratio. a Univariate multilevel regression analysis was performed for all explanatory variables. b Continuous variables. c Previous procedures to treat endometriosis include laparoscopies and laparotomies. d Categorical variables.
dium and large lesions diagnosed more accurately (OR, 2.67; 95% CI, 1.76–4.02; p , .01), and (OR, 2.59; 95% CI, 1.54–4.35, respectively p , .01). At the patient level, age and ASRM stage were the strongest predictors. There seemed to be no difference in the ability of the different gynecologists to correctly recognize endometriotic lesions. All covariates were included in the multilevel logit regression model, and were deleted in stepwise fashion if they were not significant at the p 5 .20 level as assessed using the Wald c2 test. Lesion volume demonstrated a high level of collinearity with lesion depth and therefore was
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Table 4 Unadjusted and adjusted ORs for association of patient and lesion characteristics with histologically confirmed endometriosisa Variable ASRM stage I II III IV Superficial Deep Peritoneum Uterosacral ligament Pouch of Douglas Ovary Superficial Deep Bowel Other
OR
95% CI
p value
Adjusted OR 1.00 2.90 3.10 2.43 1.00 2.50 1.00 1.30 1.40
0.90–1.87 0.97–2.02
Referent ,.01 ,.01 .03 Referent ,.01 Referent .16 .07
0.16 0.83 0.77 1.05
0.06–0.41 0.50–1.38 0.45–1.32 0.63–1.75
,.01 .47 .35 .84
1.00 3.99 3.97 3.96 1.00 3.35 1.00 1.63 1.20
1.18–2.26 0.87–1.72
Referent ,.01 ,.01 ,.01 Referent ,.01 Referent ,.01 .25
0.17 1.47 1.13 1.45
0.07–0.41 0.92–2.35 0.64–1.98 0.87–2.41
,.01 .11 .67 .15
2.24–7.11 1.93–8.17 2.14–7.33 2.27–4.93
95% CI
1.56–5.39 1.37–7.03 1.09–5.39 1.50–4.18
p value
ASRM 5 American Society of Reproductive Medicine; CI 5 confidence interval; OR 5 odds ratio. a Multivariate multilevel logit regression model including only those explanatory variables that had a significant effect on accuracy of visual recognition as defined at histologic confirmation.
not included in the model. The final model included ASRM stage, depth of the lesion, and the categorized lesion site. Adjusted ORs for these covariates are given in Table 4. After multivariate analysis, deep endometriosis was more likely to be correctly diagnosed than superficial lesions were (adjusted OR, 2.50; 95% CI, 1.50–4.18; p , .01). Except for superficial ovarian endometriosis, which was diagnosed less successfully than endometriosis at other sites (adjusted OR, 0.16; 95% CI, 0.06–0.41; p , .01), lesion location did not significantly affect the accuracy of diagnosis. ASRM stage was a strong predictor, with stages II, III, and IV each diagnosed more accurately than stage I (Table 4).
Discussion The present study is the largest to date to confirm that severity of endometriosis determines a gynecologist’s ability to correctly identify endometriotic lesions via visual inspection alone, while adjusting for other covariates. Lesion depth and volume were also found to be positively correlated with a histologic diagnosis of endometriosis. However, volume was highly correlated with depth of the lesion (data not shown) and therefore was omitted from the final regression model. Laparoscopy remains the criterion standard for diagnosing endometriosis. However, the debate about the accuracy of visual diagnosis alone remains challenging. This is largely due to the various forms of clinical presentation and visual appearance of endometriosis, coupled with unclear pathophysiology [2–4]. Several investigators have endeavored to establish the accuracy of visual diagnosis at
laparoscopy against histologic confirmation, and results have varied significantly [13]. Among 1439 biopsy specimens included in the present study, one of the largest to date, the diagnosis of endometriosis was histologically confirmed in 1082 of 1439 (75.2%). This positive predictive value is consistent with previously reported results [9,16,17,27]. In our study, we analyzed the percentage of biopsy specimens confirmed rather than the number of patients with a diagnosis of the disease because per patient only one histologically confirmed biopsy specimen is required for a diagnosis of endometriosis even if all of the others are negative. Only one other study with a larger sample size has been performed, and reported a positive predictive value of visual diagnosis of endometriosis as high as 93.9% in a total of 2005 biopsy specimens [15]. However, that study primarily addressed the accuracy of diagnosis on the basis of lesion location and did not investigate the effect of interassessor variability or accuracy of ASRM staging. Our primary objective was to investigate whether the accuracy of visual diagnosis of endometriosis is influenced by severity of the disease. We found that lesions in more severe forms of endometriosis are diagnosed more accurately at visual inspection than are ASRM stage I lesions, even when correcting for other covariates. This is most likely because more severe disease is generally associated with more substantial anatomical distortion and more deep infiltrating endometriosis. Nevertheless, 25% of the biopsied lesions were not confirmed at histopathology, even in stages II, III, and IV. This finding strongly suggests that some patients may have had less severe disease than they were assigned, inasmuch as
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Journal of Minimally Invasive Gynecology, Vol 20, No 6, November/December 2013
ASRM stage is determined immediately after surgery and relies only on visual assessment of the pelvis. Another explanation may be the use of excessive diathermy to remove lesions, resulting in thermal damage to endometriotic structures, in particular in smaller biopsy procedures. This might result in a false negative histologic result. However, the routine practice of all participating gynecologists was to leave a substantial margin of healthy tissue when excising lesions, reducing the risk of excessive thermal spread into the lesion itself. Despite this, we cannot exclude the possibility of diathermy-related artifacts. The difference in accuracy based on ASRM stage is in agreement with another study that was specifically designed to assess diagnostic accuracy stratified according to ASRM staging [17]. Kazanegra and associates retrospectively investigated 238 lesions from 104 patients and concluded that more severe stages of endometriosis are diagnosed more accurately, with stages I through IV correctly diagnosed 66.1%, 78.0%, 92.0%, and 81.1% of the time, respectively [17]. This result was supported by another study, performed by Stegmann et al [22] of 114 women with 487 biopsy specimens, designed to create a model to predict probability of endometriosis in suspect lesions to aid the gynecologist in selecting which tissue to biopsy. That study found that stage I endometriosis was diagnosed less accurately than were stages II, III, and IV combined (OR, 0.49; 95% CI, 0.31–0.79). In addition to accounting for lesion location, width, and stage, the authors accounted for lesion appearance (red, white, blue-black, brown, or mixed color). In contrast to other investigators [8,17], the authors found that lesions of any single color had a similar likelihood of being confirmed as endometriosis, whereas a mixed-color lesion marginally increased the probability of endometriosis from 66% to 78%. We did not collect data about appearance of the lesion; however, the large number of patients (431) and biopsy specimens (1439) in our study enabled us to look at each individual ASRM stage, and overall our findings are largely in agreement with the smaller studies of Kazanegra et al [17] and Stegmann et al [22]. Of the five experienced gynecologists included in the present study, samples were correctly diagnosed as endometriosis 65% to 85% of the time (mean, 75%). Despite this wide range in positive predictive value between gynecologists, when entered into multivariate analysis, these differences did not reach statistical significance, indicating that interobserver variability does not differ widely. Only two other studies have addressed the issue of interobserver variability of visual diagnosis of endometriosis at laparoscopy [24,28]. The study by Pardanani and Barbieri [24] included three gynecologists and reported the accuracy of visual diagnosis as 42%, 65%, and 76%, respectively, concluding that a substantial degree of interobserver variability exists in visual diagnosis of endometriosis. Their result may have differed from that in the present study because of different training levels of gynecologists and a much smaller number of cases (n 5 91), which also limited the ability to control for
covariates. A more recent study conducted by Schliep et al [28], which included eight gynecologists, examined the agreement of visual endometriosis diagnosis among gynecologic surgeons viewing operative digital images without histologic correlation. That study suggested that there was no significant interobserver or intraobserver variability and that agreement is not greatly affected by disease stage or location of lesions. However, that study was substantially different in that it assessed diagnoses only on the basis of retrospective interpretation of digital images. In the present study, location of the lesion did not affect accuracy much. The only types of lesions that were more likely to be incorrectly identified as endometriosis were superficial ovarian lesions. Diathermy artifacts to small superficial endometriotic lesions on the ovarian cortex is likely to have been a factor, although periovarian filmy adhesions are not uncommon and may also explain the result. Others have assessed the effect of lesion location on the accuracy of visual diagnosis of endometriosis and found that lesions on the uterus, ovaries, and fallopian tubes were less likely to be diagnosed correctly than those on the uterosacral ligaments or cul-de-sac (OR, 0.50; 95% CI, 0.26–0.97) [22]. While the present study is one of the largest to address this issue, it has some limitations. Operations were performed at different centers, and therefore different pathology laboratories were used to confirm the presence of endometriosis in the biopsy specimens. Nevertheless, histologic confirmation of endometriosis was clearly defined, histopathologists were equally trained in diagnosis of endometriosis, and reporting was consistent between analysts. In addition, only patients with at least one histologically proved biopsy specimen were enrolled in the study because women were recruited with the primary intention of assessing long-term clinical outcomes after surgery to treat endometriosis in a longitudinal cohort. Hence, if no lesions were observed or all biopsy specimens were negative for the disease, this patient would not have been retained in the database. Therefore, we are unable to comment on the total percentage of patients with a correct diagnosis of endometriosis. Similarly, because it is not standard clinical practice, random biopsy specimens were not obtained from normalappearing tissue. Hence, while we can comment on the percentage of correctly identified lesions (positive predictive value), we are unable to calculate the sensitivity, specificity, and negative predictive value of visual diagnosis of endometriosis. In conclusion, in this large prospective study involving 431 patients, 1439 biopsy specimens, and five experienced gynecologic surgeons, we found that specimens from women with ASRM stage I disease and from superficial lesions are more likely to be misdiagnosed as endometriosis at visual inspection. All five gynecologists performed similarly when diagnosing endometriosis visually, indicating that variability among experienced gynecologists is less than previously suggested. Nevertheless, visual diagnosis of endometriosis alone is generally unreliable as a primary diagnostic method
Fernando et al.
Reliability of Visual Diagnosis of Endometriosis
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