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Correlation between laparoscopic and histopathologic diagnosis of endometriosis
International Journal of Gynecology and Obstetrics 115 (2011) 272–275
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Correlation between laparoscopic and histopathologic diagnosis of endometriosis Sikolia Z. Wanyonyi a,⁎, Evan Sequeira a, Samuel G. Mukono b a b
Department of Obstetrics and Gynecology, Aga Khan University Hospital, Nairobi, Kenya Department of Pathology, Aga Khan University Hospital, Nairobi, Kenya
a r t i c l e
i n f o
Article history: Received 15 April 2011 Received in revised form 13 July 2011 Accepted 29 August 2011 Keywords: Diagnosis Endometriosis Histology Histopathology Laparoscopy
a b s t r a c t Objective: To review the histopathologic diagnosis of biopsies taken following visualization of endometriosis at laparoscopy and to correlate visual with microscopic diagnoses. Methods: A retrospective review was undertaken of medical charts with a diagnosis of endometriosis at Aga Khan University Hospital, Nairobi, Kenya, between January 2001 and October 2010. Eligibility included visual diagnosis of endometriosis at laparoscopy, with a clear record of site, size, morphology, and number of lesions. The histopathologic diagnosis of the biopsies sampled was sought. Correlation was undertaken using κ statistics for diagnostic variability. Results: Of the 204 relevant records, 152 (74.5%) met the eligibility criteria; from these cases, 239 specimens were submitted for histology. The most common symptom was chronic pelvic pain (108 [71.1%]). Most biopsies were obtained from the ovary and posterior cul-de-sac. Histopathologic diagnosis was confirmed in (152 [63.8%]) specimens and correlated with Asian race, multiparity, and chronic pelvic pain. Neither the site of the lesion nor the stage of disease influenced the histopathologic diagnosis. Conclusion: Laparoscopic visualization of endometriosis does not always correlate with histopathologic diagnosis; several other lesions may mimic endometriosis on histopathologic examination. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Endometriosis is a common gynecologic condition affecting women of reproductive age. It is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and menstrual disorders [1,2]. The diagnosis of endometriosis is commonly made following laparoscopic visualization of “typical” or “atypical” lesions in the pelvic organs and peritoneum. Laparoscopy is, however, a costly procedure with substantial anesthetic risks, as well as potential for visceral and vascular injury. Accurate diagnosis is, therefore, essential for optimally targeting women likely to benefit from this diagnostic and treatment modality. This will reduce unnecessary operative morbidity and efficiently use health service resources. Some authorities recommend only visual inspection at laparoscopy to make a diagnosis of endometriosis, although they do acknowledge that histopathologic confirmation of the condition remains ideal [3]. Consensus is lacking to inform clinical practice because there is a paucity of data on the relevance of histopathologic diagnosis of endometriosis [4]. This may be because of a lack of alternate tests with a diagnostic power similar to that of laparoscopy, thus rendering confirmation of diagnosis difficult. The diagnostic accuracy of endometriosis at laparoscopy is also affected by the level of experience of the surgeon; furthermore, even when the surgeon is experienced, the
⁎ Corresponding author at: 3rd Parklands Avenue, PO Box 16963–00100, Nairobi, Kenya. Tel.: + 254 723250061; fax: + 254 203743935. E-mail address: [email protected] (S.Z. Wanyonyi).
quality of the laparoscopic equipment may influence the accuracy of visual diagnosis. Endometriosis seems to undergo a “lifecycle,” and the appearance of the lesions may vary depending on the stage at which the diagnosis is made. Active “red” lesions, endometriomas, and typical “powder-burn” lesions may be easier to visualize than older “white” lesions, which may present only as scar tissue or fibrosis [2]. Consequently, histopathologic confirmation may be required to complement visual diagnosis. The histopathologic accuracy of biopsies of peritoneal lesions indicative of endometriosis varies from 3% to 100%, depending on the type and location of the lesions [5,6]. According to Walter et al. [7], the mean prevalence of abnormalities visually consistent with endometriosis is 36%, with only 18% being confirmed on histopathology. These figures are low and may bring into doubt the value of diagnostic laparoscopy, which is considered to be the “gold standard.” Nevertheless, in the absence of an alternate test, laparoscopy remains the only diagnostic tool [3,4]. Some clinicians will, therefore, be content with optical visualization of endometriosis and may not see the need to obtain biopsies for histopathologic evaluation. Because endometriosis may be present without obvious lesions at laparoscopy or laparoscopy may incorrectly indicate abnormalities consistent with endometriosis [2], patients may receive either suboptimal or unnecessary treatment. The aim of the present study was to correlate the visual and histopathologic diagnoses of biopsies obtained following visualization of endometriosis at laparoscopy in a typical clinical setting.
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.07.022
274
S.Z. Wanyonyi et al. / International Journal of Gynecology and Obstetrics 115 (2011) 272–275
2. Materials and methods The present study was a retrospective review of patients’ charts at Aga Khan University Hospital, Nairobi, Kenya. Diagnoses were filed according to the International Disease Classification, Tenth Revision, Clinical Modification (ICD-10-CM code) [8]. All records with a diagnosis of endometriosis between January 2001 and October 2010 were reviewed, and only those reporting either diagnostic or operative laparoscopy were selected for the study. Laparoscopic surgery at the study hospital is undertaken only by consultants with appropriate credentials. For cases to be eligible for inclusion, a visual diagnosis of endometriosis must have been made at laparoscopy, with clear documentation of the site, size, and morphology of lesions recorded either diagrammatically or in writing. The site and number of biopsies obtained and submitted for histopathologic examination also had to be stated. All procedures for which a biopsy was not obtained at surgery were excluded from the study, regardless of the size, site, and morphologic appearance of the lesion. Diagnoses of endometriosis made during or after an open surgical procedure were also excluded, unless there was conversion from laparoscopy to open surgery. In the event that a patient had to undergo subsequent laparoscopy within the study period, the repeat procedures were excluded from the review and only the initial surgery considered. This was done to avoid duplication because it would have over-represented the burden of the disease. All biopsies were processed at the Aga Khan University Hospital Laboratory. Briefly, the standard operating procedure for handling all biopsies for histopathology at the study hospital involves fixing the tissue in 10% buffered formalin; the specimen is then processed using an automated system (Shandon Citadel 2000; Rankin Biomed, Holly, MI, USA) and embedded in paraffin blocks, after which 5-μmthick sections are made and stained using hematoxylin-and-eosin stain. For the present study, the blocks for patients fulfilling the inclusion criteria were retrieved, and new sections made and stained. Two pathologists independently reviewed the slides and made the diagnosis. The pathologists were not blinded to the laparoscopic diagnosis. Histopathologic diagnosis of endometriosis was defined as the presence of endometrial-like glands, endometrial stroma, or hemosiderin-laden histiocytes. In cases in which the pathologists’ diagnoses differed, the slides were jointly reviewed and a consensus diagnosis was made. Patient charts were reviewed for demographic characteristics, presenting symptoms, and prior medication. The present definition of chronic pelvic pain included all women with longstanding (at least 6 months) pain in the lower abdomen or pelvis, and women with dysmenorrhea, dyspareunia, cyclic pelvic pain, or dyspareunia. Infertility was considered to be the main indication for diagnostic laparoscopy if the woman was considered for the procedure as part of her fertility work-up. The investigators relied on the information provided in the operation notes to assess the size, site, and morphology of the lesions. This was dependent on surgeon preference because the standards for laparoscopic surgery at the institution varied over the study period. Video and DVD recordings were reviewed if necessary. All lesions regarded as endometriosis were considered for further evaluation so long as a biopsy had been obtained intraoperatively, regardless of state of maturity (i.e. whether active red, mature powder-burn, old white, endometrioma, or pseudocyst). To ensure standardization and enable comparison, staging for the severity of endometriosis was undertaken in all cases using the American Society for Reproductive Medicine (ASRM) criteria [9]. Scores were determined in retrospect from lesion size, status of posterior cul-de-sac, presence and size of ovarian endometriomas, and presence and nature of tubo-ovarian adhesions. According to the study center's research and ethics regulations, ethics approval was not required, but necessary institutional policies
regarding the review of medical charts for research purposes were adhered to. Data were analyzed using SPSS version 15.0 (SPSS, Chicago, IL, USA). Descriptive statistics were used for demographic characteristics and diagnostic characteristics. κ statistics were used to determine variations in visual and histologic diagnosis of endometriosis. Comparison between those with and those without histopathologic diagnosis of endometriosis was undertaken using differences in proportion plus 95% confidence intervals (CIs). P b 0.05 was considered to be statistically significant.
3. Results In total, 204 laparoscopic procedures with documented visualization of endometriosis were undertaken during the period investigated. Of these cases, 152 (74.5%) met the inclusion criteria, and 239 specimens were obtained and submitted for histopathology. The mean age of the patients was 34.3 ± 6.7 years; other demographic characteristics of patients included in the study are presented in Table 1. The main presenting symptoms in the 152 cases were chronic pelvic pain (108 [71.1%]), primary subfertility (25 [16.4%]), menstrual abnormalities (12 [7.9%]), and secondary subfertility (5 [3.3%]). In 2 cases, the diagnosis of endometriosis was made incidentally when the patients were undergoing laparoscopic procedures for an indication not related to the condition. Symptoms varied according to site of lesion (Table 2). Sixty-eight (44.7%) women received only nonsteroidal antiinflammatory drugs prior to the index laparoscopy; 50 (32.9%) were not receiving any form of treatment; and 10 (6.6%) and 16 (10.5%) were taking gonadotropin-releasing hormone analogs and combined oral contraceptive pills, respectively.
Table 1 Demographic characteristics of patients with endometriosis (n= 152). Characteristic Age, yrs b 19 19–24 25–30 31–36 37–42 43–48 Parity Nulliparous Multiparous Marital status Single Married Race African Asian Caucasian Other Occupation Student Formal employment Informal employment Unemployed Contraceptive use None COCP Sterilization DMPA Barrier methods Other
No. (%) 8 (5.3) 39 (25.7) 52 (34.2) 30 (19.7) 20 (13.2) 3 (2.0) 76 (50.0) 76 (50.0) 26 (17.1) 126 (82.9) 81 (53.3) 44 (28.9) 26 (17.1) 1 (0.7) 10 111 16 15
(6.6) (73.0) (10.5) (9.9)
121 (79.6) 16 (10.5) 7 (4.6) 4 (2.6) 2 (1.3) 2 (1.3)
Abbreviations: COCP, combined oral contraceptive pill; DMPA, depot medroxyprogesterone acetate.
S.Z. Wanyonyi et al. / International Journal of Gynecology and Obstetrics 115 (2011) 272–275
275
Table 2 Distribution of symptoms according to site of lesion.a Pouch of Douglas Chronic pain Primary infertility Secondary infertility Menorrhagia Incidental a b
b
36 (21.1) 10 (24.4) 3 (42.9) 2 (12.5) 0 (0.0)
Uterus
Uterosacral ligament
Peritoneum
Ovarian fossa
Anterior cul-de-sac
Rectum
Ovary
12 (7.0) 1 (2.4) 1 (14.3) 4 (25.0) 0 (0.0)
18 (10.5) 8 (19.5) 0 (0.0) 1 (6.3) 2 (50.0)
11 (6.4) 1 (2.4) 1 (14.3) 1 (6.3) 0 (0.0)
5 (2.9) 1 (2.4) 0 (0.0) 1 (6.3) 1 (25.0)
8 (4.7) 1 (2.4) 1 (14.3) 0 (0.0) 0 (0.0)
4 (2.3) 1 (2.4) 0 (0.0) 1 (6.3) 0 (0.0)
77 (45.0) 18 (43.9) 1 (14.3) 6 (37.5) 1 (25.0)
Values are given as number (percentage). Posterior cul-de-sac.
At laparoscopy, 42 (27.6%) women were diagnosed with minimal disease, 48 (31.6%) with mild disease, 47 (30.9%) with moderate disease, and 15 (9.9%) with severe disease. Of the 152 women with a diagnosis of endometriosis at laparoscopy, only 97 (63.8%) had a histopathology-confirmed diagnosis. The characteristics of patients with a histopathologic diagnosis of endometriosis were compared with those of women with negative histology (Table 3); 239 biopsies were submitted for histology, of which 162 (67.8%) were diagnostic of endometriosis. The site and histopathologic diagnosis of endometriosis are shown in Table 4. Histopathologic features of non-endometriotic lesions are presented in Table 5, according to site. Further analysis revealed no significant association between previous treatment and ASRM stage of disease (P = 0.447). 4. Discussion In the present study, a positive histopathologic diagnosis of endometriosis was more likely among women who were multiparous (odds ratio [OR] 0.49; 95% CI, 0.25–0.95), of Asian origin (OR 0.29; 95% CI, 0.12–0.74), and experiencing chronic pelvic pain (OR 0.54; 95% CI, 0.31–0.94). The prevalence of positive histopathology among patients presenting with primary infertility was, however, higher (18 [72.0%]) than among those who presented with chronic pelvic pain (70 [64.8%]). The racial and parity differences observed in the present study could not be explained. Infertility was the main presenting symptom associated with a positive histopathologic diagnosis of endometriosis, consistent with findings from other studies [1,3,10]. Chronic pelvic pain is a common symptom with multiple etiologies, and it may have similar presentation regardless of cause. Thirty-eight (35.2%) biopsies obtained from patients with chronic pelvic pain and a positive diagnosis of endometriosis at laparoscopy
Table 3 Comparison of histopathologic findings according to patient characteristics, clinical symptoms, and stage of disease.a Endometriosis Non-endometriosis Odds ratio (95% confidence interval) Parity Nulliparous Multiparous Race African Asian Caucasian Other Symptom Chronic pain Primary infertility Secondary infertility Menorrhagia Incidental Stage of disease Minimal Mild Moderate Severe a
46 (60.5) 51 (67.1)
30 (39.5) 25 (32.9)
0.65 (0.34–1.24) 0.49 (0.25–0.95)
49 (60.5) 34 (77.3) 13 (50.0) 1 (100.0)
32 (39.5) 10 (22.7) 13 (50.0) 0 (0.0)
0.67 (0.36–1.25) 0.29 (0.12–0.74) 1.00 (0.34–2.96) —
70 (64.8) 18 (72.0) 2 (40.0) 7 (58.3) 0 (0.0)
38 (35.2) 7 (28.0) 3 (60.0) 5 (41.7) 2 (100.0)
0.54 0.42 1.00 1.71 —
16 26 40 15
26 (61.9) 22 (45.8) 7 (14.9) 0 (0.0)
1.63 (0.68–3.87) 9.31 (1.09–30.00) 2.57 (1.62–10.00) —
(38.1) (54.2) (85.1) (100.0)
(0.31–0.94) (0.13–1.36) (0.08–12.56) (0.14–3.58)
Values are given as number (percentage) unless otherwise indicated.
had no histopathologic confirmation. With chronic pelvic pain being one of the main indications for diagnostic laparoscopy [10] for endometriosis, this may imply that a significant proportion of women undergoing the procedure are unlikely to benefit from it. Overall, the prevalence of positive histology—regardless of presenting complaint—was 63.8%, and 67.8% of all specimens were confirmed as endometriosis at histology. The prevalence varied according to the site from which the biopsy was taken, being higher in rectal (6 [100.0%]), uterosacral (19 [65.5%]), and ovarian (66 [64.1%]) biopsies. The positivity of the histology depended on the stage of the disease, with mild (OR 9.31; 95% CI, 1.09–30.00) and moderate (OR 2.57; 95% CI, 1.62–10.00) disease tending to be more positive than minimal disease (OR 1.63; 95% CI, 0.68–3.87). Because the present study was retrospective, the number of biopsies taken per patient was limited and down to surgeon discretion, so it is possible that failure to sample more lesions may have resulted in a skewed yield for histopathologic diagnosis. It was observed that surgeons were more likely to obtain biopsies from endometriomas and active red lesions or mature powderburn lesions. White lesions were rarely sampled. Small lesions were also more likely to be missed. Furthermore, the ability to obtain samples from lesions located near structures such as the ureter, intestines, or bladder depends on the level of experience and comfort of the surgeon. This may explain the high yield from biopsies obtained from the rectum—because such biopsies were likely to have been taken by very experienced surgeons. Inadequate sampling may also occur for deeply infiltrating endometriosis, resulting in false-negative results [11]. Histopathologic diagnosis of endometriosis is made based on the presence of endometrial-like glands, endometrial stroma, and hemosiderin deposit, either within histiocytes or in the stroma [11]. This classic triad may, however, not be present or may be obscured by hemorrhage, thus resulting in false-negatives. This is a result of secondary changes occurring in the lesions owing to bleeding and fibrosis, which may later transform the areas of endometriosis—including the lining of large cysts—into granulation tissue with numerous histiocytes (pseudoxanthoma cells) and fibrosis. In such circumstances, the pathologist can reach a sole diagnosis of “consistent with endometriosis” [12]. Therefore, negative histology results do not necessarily exclude endometriosis. False-positives identified for endometriosis in the study population included fibrosis, inflammatory changes, normal ovarian stroma, ovarian hyperthecosis, hemorrhage into adjacent
Table 4 Distribution of positive histopathologic diagnosis according to site.a Site
Endometriosis-positive
95% confidence interval
Uterosacral ligaments (n = 29) Ovary (n = 103) Rectum (n = 6) Posterior cul-de-sac (n = 51) Peritoneum (n = 14) Uterus (n = 18) Ovarian fossa (n = 8) Anterior cul-de-sac (n = 10)
19 (65.5) 66 (64.1) 6 (100.0) 36 (70.6) 8 (57.1) 16 (88.9) 4 (50.0) 7 (70.0)
56.2–74.8 54.6–73.5 98.2–100.0 61.7–79.5 47.4–66.8 81.6–94.4 40.2–59.8 61.0–78.9
a
Values are given as number (percentage) unless otherwise indicated.
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Table 5 Histopathologic findings of non-endometriotic lesions according to site. Site
Histologic diagnosis
No. of lesions
Fibrosis Hyperthecosis Normal ovarian stroma Serous cystadenoma Follicular cysts Corpus luteum cyst Hemorrhage into adjacent tissues Inflammatory cysts Other
5 3 8 2 4 6 11 4 1
Ovary
Posterior cul de sac Fibrosis Hemorrhagic changes Inflammatory cells Charred tissue
1 4 6 1
Fibrosis
8
Inflammatory changes Normal peritoneum
5 8
Uterosacral ligament Peritoneum
tissue without hemosiderin-laden macrophages, follicular cysts, hemorrhagic cysts, corpus luteum cysts, and normal peritoneum. The present study was limited by the fact that the histopathologists were aware of the suspected diagnosis, which may have led to bias in their search for evidence of endometriosis in the biopsies submitted. Although all surgeries were performed either by a consultant or under their direct supervision, the quality of the operations cannot be assumed to have been standard. However, we believe that the present results represent the true clinical picture because it is a uniform requirement to provide such details to histopathologists to guide them in interpreting their findings. We believe that, by using retrospective data, we avoided the possibility of the Hawthorne effect among surgeons. This is difficult to control for in prospective studies of this nature because there is a high probability of surgeon performance being influenced. We can strongly assert that, despite its limitation, the present study was reflective of a true clinical picture. There is a clear lack of correlation between laparoscopy and histopathology in the diagnosis of endometriosis. However, it is difficult to
recommend strongly or dismiss routine histopathologic diagnosis for confirming visual laparoscopic findings based on the present findings alone. Clinicians need to be aware of lesions that may mimic endometriosis at laparoscopy. Without accurate histopathologic diagnosis, there may be overtreatment of patients, resulting in morbidity and psychologic sequelae associated with failed therapy. Further studies are needed to evaluate whether sampling more sites would result in better yield of endometriosis on histopathology. Conflict of interest The authors have no conflicts of interest. References [1] Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol 1990;162(2):568–9. [2] Shaw RW. Endometriosis. In: Shaw RW, Soutter WP, Stanton SL, editors. Gynaecology. 3rd edition. Edinburgh: Churchill Livingstone; 2003. p. 493–510. [3] Royal College of Obstetricians and Gynaecologists. Endometriosis, Investigation and Management (Green-top 24). www.rcog.org.uk. http://www.rcog.org.uk/womenshealth/clinical-guidance/investigation-and-management-endometriosis-green-top-24. Published 2006. [4] Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: a systematic quantitative review. BJOG 2004;111(11):1204–12. [5] Balasch J, Creus M, Fábregues F, Carmona F, Ordi J, Martinez-Román 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(2): 387–91. [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(5):248–53. [7] Walter AJ, Hentz JG, Magtibay PM, Cornella JL, Magrina JF. Endometriosis: correlation between histologic and visual findings at laparoscopy. Am J Obstet Gynecol 2001;184(7):1407–11. [8] International Disease Classification, Tenth Revision, Clinical Modification (ICD-10CM code). www.cdc.gov/nchs/icd/icd10cm.htm. Published 2010. [9] Revised American Society for Reproductive Medicine: 1996. Fertil Steril 1997;67(5): 817–21. [10] Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005;11(6): 595–606. [11] Crum CP, Lee KR. Diagnostic Gynecologic and Obstetric Pathology. Philadelphia: Elsevier Saunders; 2006. [12] Fox H, Wells M. Haines and Taylor Obstetrical and Gynaecological Pathology. 5th edition. Edinburgh: Churchill Livingstone; 2003.
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Correlation between laparoscopic and histopathologic diagnosis of endometriosis Sikolia Z. Wanyonyi a,⁎, Evan Sequeira a, Samuel G. Mukono b a b
Department of Obstetrics and Gynecology, Aga Khan University Hospital, Nairobi, Kenya Department of Pathology, Aga Khan University Hospital, Nairobi, Kenya
a r t i c l e
i n f o
Article history: Received 15 April 2011 Received in revised form 13 July 2011 Accepted 29 August 2011 Keywords: Diagnosis Endometriosis Histology Histopathology Laparoscopy
a b s t r a c t Objective: To review the histopathologic diagnosis of biopsies taken following visualization of endometriosis at laparoscopy and to correlate visual with microscopic diagnoses. Methods: A retrospective review was undertaken of medical charts with a diagnosis of endometriosis at Aga Khan University Hospital, Nairobi, Kenya, between January 2001 and October 2010. Eligibility included visual diagnosis of endometriosis at laparoscopy, with a clear record of site, size, morphology, and number of lesions. The histopathologic diagnosis of the biopsies sampled was sought. Correlation was undertaken using κ statistics for diagnostic variability. Results: Of the 204 relevant records, 152 (74.5%) met the eligibility criteria; from these cases, 239 specimens were submitted for histology. The most common symptom was chronic pelvic pain (108 [71.1%]). Most biopsies were obtained from the ovary and posterior cul-de-sac. Histopathologic diagnosis was confirmed in (152 [63.8%]) specimens and correlated with Asian race, multiparity, and chronic pelvic pain. Neither the site of the lesion nor the stage of disease influenced the histopathologic diagnosis. Conclusion: Laparoscopic visualization of endometriosis does not always correlate with histopathologic diagnosis; several other lesions may mimic endometriosis on histopathologic examination. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Endometriosis is a common gynecologic condition affecting women of reproductive age. It is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and menstrual disorders [1,2]. The diagnosis of endometriosis is commonly made following laparoscopic visualization of “typical” or “atypical” lesions in the pelvic organs and peritoneum. Laparoscopy is, however, a costly procedure with substantial anesthetic risks, as well as potential for visceral and vascular injury. Accurate diagnosis is, therefore, essential for optimally targeting women likely to benefit from this diagnostic and treatment modality. This will reduce unnecessary operative morbidity and efficiently use health service resources. Some authorities recommend only visual inspection at laparoscopy to make a diagnosis of endometriosis, although they do acknowledge that histopathologic confirmation of the condition remains ideal [3]. Consensus is lacking to inform clinical practice because there is a paucity of data on the relevance of histopathologic diagnosis of endometriosis [4]. This may be because of a lack of alternate tests with a diagnostic power similar to that of laparoscopy, thus rendering confirmation of diagnosis difficult. The diagnostic accuracy of endometriosis at laparoscopy is also affected by the level of experience of the surgeon; furthermore, even when the surgeon is experienced, the
⁎ Corresponding author at: 3rd Parklands Avenue, PO Box 16963–00100, Nairobi, Kenya. Tel.: + 254 723250061; fax: + 254 203743935. E-mail address: [email protected] (S.Z. Wanyonyi).
quality of the laparoscopic equipment may influence the accuracy of visual diagnosis. Endometriosis seems to undergo a “lifecycle,” and the appearance of the lesions may vary depending on the stage at which the diagnosis is made. Active “red” lesions, endometriomas, and typical “powder-burn” lesions may be easier to visualize than older “white” lesions, which may present only as scar tissue or fibrosis [2]. Consequently, histopathologic confirmation may be required to complement visual diagnosis. The histopathologic accuracy of biopsies of peritoneal lesions indicative of endometriosis varies from 3% to 100%, depending on the type and location of the lesions [5,6]. According to Walter et al. [7], the mean prevalence of abnormalities visually consistent with endometriosis is 36%, with only 18% being confirmed on histopathology. These figures are low and may bring into doubt the value of diagnostic laparoscopy, which is considered to be the “gold standard.” Nevertheless, in the absence of an alternate test, laparoscopy remains the only diagnostic tool [3,4]. Some clinicians will, therefore, be content with optical visualization of endometriosis and may not see the need to obtain biopsies for histopathologic evaluation. Because endometriosis may be present without obvious lesions at laparoscopy or laparoscopy may incorrectly indicate abnormalities consistent with endometriosis [2], patients may receive either suboptimal or unnecessary treatment. The aim of the present study was to correlate the visual and histopathologic diagnoses of biopsies obtained following visualization of endometriosis at laparoscopy in a typical clinical setting.
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.07.022
274
S.Z. Wanyonyi et al. / International Journal of Gynecology and Obstetrics 115 (2011) 272–275
2. Materials and methods The present study was a retrospective review of patients’ charts at Aga Khan University Hospital, Nairobi, Kenya. Diagnoses were filed according to the International Disease Classification, Tenth Revision, Clinical Modification (ICD-10-CM code) [8]. All records with a diagnosis of endometriosis between January 2001 and October 2010 were reviewed, and only those reporting either diagnostic or operative laparoscopy were selected for the study. Laparoscopic surgery at the study hospital is undertaken only by consultants with appropriate credentials. For cases to be eligible for inclusion, a visual diagnosis of endometriosis must have been made at laparoscopy, with clear documentation of the site, size, and morphology of lesions recorded either diagrammatically or in writing. The site and number of biopsies obtained and submitted for histopathologic examination also had to be stated. All procedures for which a biopsy was not obtained at surgery were excluded from the study, regardless of the size, site, and morphologic appearance of the lesion. Diagnoses of endometriosis made during or after an open surgical procedure were also excluded, unless there was conversion from laparoscopy to open surgery. In the event that a patient had to undergo subsequent laparoscopy within the study period, the repeat procedures were excluded from the review and only the initial surgery considered. This was done to avoid duplication because it would have over-represented the burden of the disease. All biopsies were processed at the Aga Khan University Hospital Laboratory. Briefly, the standard operating procedure for handling all biopsies for histopathology at the study hospital involves fixing the tissue in 10% buffered formalin; the specimen is then processed using an automated system (Shandon Citadel 2000; Rankin Biomed, Holly, MI, USA) and embedded in paraffin blocks, after which 5-μmthick sections are made and stained using hematoxylin-and-eosin stain. For the present study, the blocks for patients fulfilling the inclusion criteria were retrieved, and new sections made and stained. Two pathologists independently reviewed the slides and made the diagnosis. The pathologists were not blinded to the laparoscopic diagnosis. Histopathologic diagnosis of endometriosis was defined as the presence of endometrial-like glands, endometrial stroma, or hemosiderin-laden histiocytes. In cases in which the pathologists’ diagnoses differed, the slides were jointly reviewed and a consensus diagnosis was made. Patient charts were reviewed for demographic characteristics, presenting symptoms, and prior medication. The present definition of chronic pelvic pain included all women with longstanding (at least 6 months) pain in the lower abdomen or pelvis, and women with dysmenorrhea, dyspareunia, cyclic pelvic pain, or dyspareunia. Infertility was considered to be the main indication for diagnostic laparoscopy if the woman was considered for the procedure as part of her fertility work-up. The investigators relied on the information provided in the operation notes to assess the size, site, and morphology of the lesions. This was dependent on surgeon preference because the standards for laparoscopic surgery at the institution varied over the study period. Video and DVD recordings were reviewed if necessary. All lesions regarded as endometriosis were considered for further evaluation so long as a biopsy had been obtained intraoperatively, regardless of state of maturity (i.e. whether active red, mature powder-burn, old white, endometrioma, or pseudocyst). To ensure standardization and enable comparison, staging for the severity of endometriosis was undertaken in all cases using the American Society for Reproductive Medicine (ASRM) criteria [9]. Scores were determined in retrospect from lesion size, status of posterior cul-de-sac, presence and size of ovarian endometriomas, and presence and nature of tubo-ovarian adhesions. According to the study center's research and ethics regulations, ethics approval was not required, but necessary institutional policies
regarding the review of medical charts for research purposes were adhered to. Data were analyzed using SPSS version 15.0 (SPSS, Chicago, IL, USA). Descriptive statistics were used for demographic characteristics and diagnostic characteristics. κ statistics were used to determine variations in visual and histologic diagnosis of endometriosis. Comparison between those with and those without histopathologic diagnosis of endometriosis was undertaken using differences in proportion plus 95% confidence intervals (CIs). P b 0.05 was considered to be statistically significant.
3. Results In total, 204 laparoscopic procedures with documented visualization of endometriosis were undertaken during the period investigated. Of these cases, 152 (74.5%) met the inclusion criteria, and 239 specimens were obtained and submitted for histopathology. The mean age of the patients was 34.3 ± 6.7 years; other demographic characteristics of patients included in the study are presented in Table 1. The main presenting symptoms in the 152 cases were chronic pelvic pain (108 [71.1%]), primary subfertility (25 [16.4%]), menstrual abnormalities (12 [7.9%]), and secondary subfertility (5 [3.3%]). In 2 cases, the diagnosis of endometriosis was made incidentally when the patients were undergoing laparoscopic procedures for an indication not related to the condition. Symptoms varied according to site of lesion (Table 2). Sixty-eight (44.7%) women received only nonsteroidal antiinflammatory drugs prior to the index laparoscopy; 50 (32.9%) were not receiving any form of treatment; and 10 (6.6%) and 16 (10.5%) were taking gonadotropin-releasing hormone analogs and combined oral contraceptive pills, respectively.
Table 1 Demographic characteristics of patients with endometriosis (n= 152). Characteristic Age, yrs b 19 19–24 25–30 31–36 37–42 43–48 Parity Nulliparous Multiparous Marital status Single Married Race African Asian Caucasian Other Occupation Student Formal employment Informal employment Unemployed Contraceptive use None COCP Sterilization DMPA Barrier methods Other
No. (%) 8 (5.3) 39 (25.7) 52 (34.2) 30 (19.7) 20 (13.2) 3 (2.0) 76 (50.0) 76 (50.0) 26 (17.1) 126 (82.9) 81 (53.3) 44 (28.9) 26 (17.1) 1 (0.7) 10 111 16 15
(6.6) (73.0) (10.5) (9.9)
121 (79.6) 16 (10.5) 7 (4.6) 4 (2.6) 2 (1.3) 2 (1.3)
Abbreviations: COCP, combined oral contraceptive pill; DMPA, depot medroxyprogesterone acetate.
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Table 2 Distribution of symptoms according to site of lesion.a Pouch of Douglas Chronic pain Primary infertility Secondary infertility Menorrhagia Incidental a b
b
36 (21.1) 10 (24.4) 3 (42.9) 2 (12.5) 0 (0.0)
Uterus
Uterosacral ligament
Peritoneum
Ovarian fossa
Anterior cul-de-sac
Rectum
Ovary
12 (7.0) 1 (2.4) 1 (14.3) 4 (25.0) 0 (0.0)
18 (10.5) 8 (19.5) 0 (0.0) 1 (6.3) 2 (50.0)
11 (6.4) 1 (2.4) 1 (14.3) 1 (6.3) 0 (0.0)
5 (2.9) 1 (2.4) 0 (0.0) 1 (6.3) 1 (25.0)
8 (4.7) 1 (2.4) 1 (14.3) 0 (0.0) 0 (0.0)
4 (2.3) 1 (2.4) 0 (0.0) 1 (6.3) 0 (0.0)
77 (45.0) 18 (43.9) 1 (14.3) 6 (37.5) 1 (25.0)
Values are given as number (percentage). Posterior cul-de-sac.
At laparoscopy, 42 (27.6%) women were diagnosed with minimal disease, 48 (31.6%) with mild disease, 47 (30.9%) with moderate disease, and 15 (9.9%) with severe disease. Of the 152 women with a diagnosis of endometriosis at laparoscopy, only 97 (63.8%) had a histopathology-confirmed diagnosis. The characteristics of patients with a histopathologic diagnosis of endometriosis were compared with those of women with negative histology (Table 3); 239 biopsies were submitted for histology, of which 162 (67.8%) were diagnostic of endometriosis. The site and histopathologic diagnosis of endometriosis are shown in Table 4. Histopathologic features of non-endometriotic lesions are presented in Table 5, according to site. Further analysis revealed no significant association between previous treatment and ASRM stage of disease (P = 0.447). 4. Discussion In the present study, a positive histopathologic diagnosis of endometriosis was more likely among women who were multiparous (odds ratio [OR] 0.49; 95% CI, 0.25–0.95), of Asian origin (OR 0.29; 95% CI, 0.12–0.74), and experiencing chronic pelvic pain (OR 0.54; 95% CI, 0.31–0.94). The prevalence of positive histopathology among patients presenting with primary infertility was, however, higher (18 [72.0%]) than among those who presented with chronic pelvic pain (70 [64.8%]). The racial and parity differences observed in the present study could not be explained. Infertility was the main presenting symptom associated with a positive histopathologic diagnosis of endometriosis, consistent with findings from other studies [1,3,10]. Chronic pelvic pain is a common symptom with multiple etiologies, and it may have similar presentation regardless of cause. Thirty-eight (35.2%) biopsies obtained from patients with chronic pelvic pain and a positive diagnosis of endometriosis at laparoscopy
Table 3 Comparison of histopathologic findings according to patient characteristics, clinical symptoms, and stage of disease.a Endometriosis Non-endometriosis Odds ratio (95% confidence interval) Parity Nulliparous Multiparous Race African Asian Caucasian Other Symptom Chronic pain Primary infertility Secondary infertility Menorrhagia Incidental Stage of disease Minimal Mild Moderate Severe a
46 (60.5) 51 (67.1)
30 (39.5) 25 (32.9)
0.65 (0.34–1.24) 0.49 (0.25–0.95)
49 (60.5) 34 (77.3) 13 (50.0) 1 (100.0)
32 (39.5) 10 (22.7) 13 (50.0) 0 (0.0)
0.67 (0.36–1.25) 0.29 (0.12–0.74) 1.00 (0.34–2.96) —
70 (64.8) 18 (72.0) 2 (40.0) 7 (58.3) 0 (0.0)
38 (35.2) 7 (28.0) 3 (60.0) 5 (41.7) 2 (100.0)
0.54 0.42 1.00 1.71 —
16 26 40 15
26 (61.9) 22 (45.8) 7 (14.9) 0 (0.0)
1.63 (0.68–3.87) 9.31 (1.09–30.00) 2.57 (1.62–10.00) —
(38.1) (54.2) (85.1) (100.0)
(0.31–0.94) (0.13–1.36) (0.08–12.56) (0.14–3.58)
Values are given as number (percentage) unless otherwise indicated.
had no histopathologic confirmation. With chronic pelvic pain being one of the main indications for diagnostic laparoscopy [10] for endometriosis, this may imply that a significant proportion of women undergoing the procedure are unlikely to benefit from it. Overall, the prevalence of positive histology—regardless of presenting complaint—was 63.8%, and 67.8% of all specimens were confirmed as endometriosis at histology. The prevalence varied according to the site from which the biopsy was taken, being higher in rectal (6 [100.0%]), uterosacral (19 [65.5%]), and ovarian (66 [64.1%]) biopsies. The positivity of the histology depended on the stage of the disease, with mild (OR 9.31; 95% CI, 1.09–30.00) and moderate (OR 2.57; 95% CI, 1.62–10.00) disease tending to be more positive than minimal disease (OR 1.63; 95% CI, 0.68–3.87). Because the present study was retrospective, the number of biopsies taken per patient was limited and down to surgeon discretion, so it is possible that failure to sample more lesions may have resulted in a skewed yield for histopathologic diagnosis. It was observed that surgeons were more likely to obtain biopsies from endometriomas and active red lesions or mature powderburn lesions. White lesions were rarely sampled. Small lesions were also more likely to be missed. Furthermore, the ability to obtain samples from lesions located near structures such as the ureter, intestines, or bladder depends on the level of experience and comfort of the surgeon. This may explain the high yield from biopsies obtained from the rectum—because such biopsies were likely to have been taken by very experienced surgeons. Inadequate sampling may also occur for deeply infiltrating endometriosis, resulting in false-negative results [11]. Histopathologic diagnosis of endometriosis is made based on the presence of endometrial-like glands, endometrial stroma, and hemosiderin deposit, either within histiocytes or in the stroma [11]. This classic triad may, however, not be present or may be obscured by hemorrhage, thus resulting in false-negatives. This is a result of secondary changes occurring in the lesions owing to bleeding and fibrosis, which may later transform the areas of endometriosis—including the lining of large cysts—into granulation tissue with numerous histiocytes (pseudoxanthoma cells) and fibrosis. In such circumstances, the pathologist can reach a sole diagnosis of “consistent with endometriosis” [12]. Therefore, negative histology results do not necessarily exclude endometriosis. False-positives identified for endometriosis in the study population included fibrosis, inflammatory changes, normal ovarian stroma, ovarian hyperthecosis, hemorrhage into adjacent
Table 4 Distribution of positive histopathologic diagnosis according to site.a Site
Endometriosis-positive
95% confidence interval
Uterosacral ligaments (n = 29) Ovary (n = 103) Rectum (n = 6) Posterior cul-de-sac (n = 51) Peritoneum (n = 14) Uterus (n = 18) Ovarian fossa (n = 8) Anterior cul-de-sac (n = 10)
19 (65.5) 66 (64.1) 6 (100.0) 36 (70.6) 8 (57.1) 16 (88.9) 4 (50.0) 7 (70.0)
56.2–74.8 54.6–73.5 98.2–100.0 61.7–79.5 47.4–66.8 81.6–94.4 40.2–59.8 61.0–78.9
a
Values are given as number (percentage) unless otherwise indicated.
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Table 5 Histopathologic findings of non-endometriotic lesions according to site. Site
Histologic diagnosis
No. of lesions
Fibrosis Hyperthecosis Normal ovarian stroma Serous cystadenoma Follicular cysts Corpus luteum cyst Hemorrhage into adjacent tissues Inflammatory cysts Other
5 3 8 2 4 6 11 4 1
Ovary
Posterior cul de sac Fibrosis Hemorrhagic changes Inflammatory cells Charred tissue
1 4 6 1
Fibrosis
8
Inflammatory changes Normal peritoneum
5 8
Uterosacral ligament Peritoneum
tissue without hemosiderin-laden macrophages, follicular cysts, hemorrhagic cysts, corpus luteum cysts, and normal peritoneum. The present study was limited by the fact that the histopathologists were aware of the suspected diagnosis, which may have led to bias in their search for evidence of endometriosis in the biopsies submitted. Although all surgeries were performed either by a consultant or under their direct supervision, the quality of the operations cannot be assumed to have been standard. However, we believe that the present results represent the true clinical picture because it is a uniform requirement to provide such details to histopathologists to guide them in interpreting their findings. We believe that, by using retrospective data, we avoided the possibility of the Hawthorne effect among surgeons. This is difficult to control for in prospective studies of this nature because there is a high probability of surgeon performance being influenced. We can strongly assert that, despite its limitation, the present study was reflective of a true clinical picture. There is a clear lack of correlation between laparoscopy and histopathology in the diagnosis of endometriosis. However, it is difficult to
recommend strongly or dismiss routine histopathologic diagnosis for confirming visual laparoscopic findings based on the present findings alone. Clinicians need to be aware of lesions that may mimic endometriosis at laparoscopy. Without accurate histopathologic diagnosis, there may be overtreatment of patients, resulting in morbidity and psychologic sequelae associated with failed therapy. Further studies are needed to evaluate whether sampling more sites would result in better yield of endometriosis on histopathology. Conflict of interest The authors have no conflicts of interest. References [1] Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol 1990;162(2):568–9. [2] Shaw RW. Endometriosis. In: Shaw RW, Soutter WP, Stanton SL, editors. Gynaecology. 3rd edition. Edinburgh: Churchill Livingstone; 2003. p. 493–510. [3] Royal College of Obstetricians and Gynaecologists. Endometriosis, Investigation and Management (Green-top 24). www.rcog.org.uk. http://www.rcog.org.uk/womenshealth/clinical-guidance/investigation-and-management-endometriosis-green-top-24. Published 2006. [4] Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: a systematic quantitative review. BJOG 2004;111(11):1204–12. [5] Balasch J, Creus M, Fábregues F, Carmona F, Ordi J, Martinez-Román 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(2): 387–91. [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(5):248–53. [7] Walter AJ, Hentz JG, Magtibay PM, Cornella JL, Magrina JF. Endometriosis: correlation between histologic and visual findings at laparoscopy. Am J Obstet Gynecol 2001;184(7):1407–11. [8] International Disease Classification, Tenth Revision, Clinical Modification (ICD-10CM code). www.cdc.gov/nchs/icd/icd10cm.htm. Published 2010. [9] Revised American Society for Reproductive Medicine: 1996. Fertil Steril 1997;67(5): 817–21. [10] Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005;11(6): 595–606. [11] Crum CP, Lee KR. Diagnostic Gynecologic and Obstetric Pathology. Philadelphia: Elsevier Saunders; 2006. [12] Fox H, Wells M. Haines and Taylor Obstetrical and Gynaecological Pathology. 5th edition. Edinburgh: Churchill Livingstone; 2003.