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Preoperative and Postoperative Clinical and Transvaginal Ultrasound Findings of Adenomyosis in Patients With Deep Infiltrating Endometriosis Lucia Lazzeri, Alessandra Di Giovanni, Caterina Exacoustos, Claudia Tosti, Serena Pinzauti, Mario Malzoni, Felice Petraglia and Errico Zupi Reproductive Sciences published online 14 February 2014 DOI: 10.1177/1933719114522520 The online version of this article can be found at: http://rsx.sagepub.com/content/early/2014/02/14/1933719114522520
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Original Article
Preoperative and Postoperative Clinical and Transvaginal Ultrasound Findings of Adenomyosis in Patients With Deep Infiltrating Endometriosis
Reproductive Sciences 1-7 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719114522520 rs.sagepub.com
Lucia Lazzeri, MD1, Alessandra Di Giovanni, MD2, Caterina Exacoustos, MD, PhD3, Claudia Tosti, MD1, Serena Pinzauti, MD1, Mario Malzoni, MD2, Felice Petraglia, MD, PhD1, and Errico Zupi, MD1
Abstract Objectives: Deep infiltrating endometriosis (DIE) represents the most complex form of endometriosis and its treatment is still challenging. The coexistence of DIE with other appearances of endometriosis stimulates new studies to improve the preoperative diagnosis. Adenomyosis is a clinical form that shares several symptoms with DIE. The present study investigated the possible presence of adenomyosis in a group of women with DIE and its impact on pre- and postoperative symptoms. Materials and Methods: A group of women (n ¼ 121) undergoing laparoscopic treatment for DIE were enrolled. Clinical and ultrasound evaluations were performed as preoperative assessment. The ultrasonographical appearances of DIE and of adenomyosis were recorded by 2-dimensional ultrasound. The following symptoms were considered: dysmenorrhea, dyspareunia, abnormal uterine bleeding, bowel, and urinary symptoms. Pain was evaluated by the visual analog scale system and menstrual bleeding was assessed by the use of the pictorial blood assessment chart. In a subgroup of women (n ¼ 55), a follow-up evaluation (3-6 months after surgery) was done. Results: A relevant number of patients with DIE showed adenomyosis (n ¼ 59; 48.7%); in this group, dysmenorrhea (P ¼ .0019), dyspareunia (P ¼ .0004), and abnormal uterine bleeding (P < .001) were statistically higher than that in the group with only DIE. After surgery, painful symptoms improved in the whole group but remained significantly higher (P < .001) in the group with adenomyosis. Conclusions: Deep infiltrating endometriosis is frequently associated with adenomyosis, significantly affecting pre- and postoperative symptoms and thus influencing the follow-up management. Keywords deep infiltrating endometriosis, adenomyosis, transvaginal ultrasound, dysmenorrhea, heavy menstrual bleeding
Introduction Deep infiltrating endometriosis (DIE) is the most severe form of endometriosis, associated with infertility or pain symptoms, including chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia.1 A wide spectrum of symptom severity is described, and the stage of endometriosis at laparoscopy is poorly correlated with the extent and severity of pain, often causing misdiagnosis or delayed diagnosis.2,3 A growing interest on adenomyosis derives from the observation that it is often associated with peritoneal endometriosis, particularly in infertile patients.4 Therefore, the presence of DIE should alert physicians to evaluate the possible presence of adenomyosis. Adenomyosis is known as an histological diagnosis but it has a clinical dignity showing symptoms (dysmenorrhea, dyspareunia, abnormal uterine bleeding, and infertility) and sharing some pathogenic mechanisms with endometriosis.5
Established imaging criteria may support an accurate diagnosis of adenomyosis. Magnetic resonance imaging (MRI) is still considered the gold standard in imaging for the diagnosis of adenomyosis but the use of transvaginal sonography (TVS) in diagnosing adenomyosis is comparable to MRI. The
1 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy 2 Advanced Gynecological Endoscopy Center, Malzoni Medical Center, Avellino, Italy 3 Department of Obstetrics and Gynecology, University of Rome ‘‘Tor Vergata’’, Roma, Italy
Corresponding Author: Lucia Lazzeri, Department of Molecular and Developmental Medicine, University of Siena, Viale Bracci, 53100, Siena, Italy. Email: [email protected]; [email protected]
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2-dimensional (2D) sonographic criteria of adenomyosis involve alterations in myometrium, such as presence of myometrial hypoechoic striations, myometrial cysts or heterogeneous areas, asymmetry of the myometrial walls, diffuse vascularity, and globular uterine configuration.6-9 The subjective impression of a poorly defined junctional zone by 2D is also referred as a diagnostic criterion for adenomyosis but with low sensitivity.10 In some patients pain is not responsive to surgical excision of DIE11 and recurrence of symptoms is present despite the radicality of the procedure.12,13 Transvaginal sonography is highly accurate for a correct presurgical diagnosis of DIE in order to localize the lesions and other possible abnormalities and to establish the best therapeutical management.14-18 The present study aimed to investigate the possible presence of adenomyosis by TVS in a group of women with DIE and its impact on pre- and postoperative symptoms.
Materials and Methods A total of 121 women aged 20 to 48 years (mean + standard deviation [SD] ¼ 34.3 + 5.1 years) were included in this prospective clinical trial from January 1, 2012, through March 30, 2013, in 3 Endometriosis centers in Italy (Siena, Roma, and Avellino). The study was approved by the institutional review board of the University of Siena. Women with ovarian endometrioma were excluded. Presurgical assessment included completion of TVS, transabdominal, and transrectal scans when needed 3 months before surgery and 3 or 6 months after surgical treatment. All ultrasonographic examinations were performed by the same 3 examiners (CE, ADG, and LL). The ultrasound scan was always performed with either a GE E8 or E6 (GE Healthcare, Zipf, Austria) ultrasound machine, using a wideband 5- to 9-MHz transducer without bowel preparation. The examination was performed at any phase of the menstrual cycle regardless of hormonal therapy. The diagnosis of DIE was made if at least 1 structure in the anterior or posterior compartment showed the presence of retroperitoneal abnormal hypoechoic linear or nodular thickening with irregular contours and no vascular Doppler signals, as described previously and validated ultrasonographic criteria.19,20 Locations for DIE in the anterior (bladder) or posterolateral compartment (vagina, rectovaginal septum, torus and uterosacral ligaments, parametria and ureteral involvement, rectum, and rectosigmoid junction) were examined. The presence of ovarian endometriomas and adnexal adhesions was also recorded. For the diagnosis of adenomyosis, uterus and endometrium were evaluated for any abnormality. The presence of TVS features associated with adenomyosis was determined:
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increased myometrial echogenicity or linear hyperechoic bands extending deep into the myometrium, which indicates the presence of islets of ectopic endometrial tissue; hypoechoic areas in the myometrium compatible with hyperplasia of the muscle tissue surrounding the ectopic tissue;
anechoic areas due to glandular dilatation or myometrial cysts; enlargement of the uterus with asymmetrical myometrial thickening of the walls unrelated to leiomyoma; presence of straight vessels into the hypertrophic myometrium at the color Doppler examination; focal adenomyosis was defined by the presence of adenomyotic lesions with elliptical appearance and ill-defined margins; no calcifications and hypervascularity at color Power Doppler evaluation. Diagnosis of adenomyosis was made when all of the recognized features of the disease were observed on the examination.6-9 These morphological features have been accepted with a wide consensus as reliable morphological markers of adenomyosis.6-9,21-23
The following signs and symptoms were recorded: dysmenorrhea, dyspareunia, functional bowel signs (constipation, diarrhea, painful defecation during menses, and rectal bleeding), functional urinary tract signs (dysuria, urgency, and hematuria), and abnormal uterine bleeding. The level of patient’s discomfort and pain was evaluated by the visual analog scale (VAS) system, utilizing a 10-cm line with the extreme points 0 and 10 corresponding to ‘‘no pain’’ and ‘‘maximum pain,’’ respectively. Menstrual bleeding was assessed with the use of the pictorial blood loss assessment chart (PBAC),24 a validated method used to objectively estimate blood loss; monthly scores range from 0 to more than 500, with higher numbers indicating more bleeding, and menorrhagia was defined as a PBAC >100 during 1 menstrual period, which corresponds to a blood loss of more than 80 mL. The same evaluations were performed before surgery and, in a subgroup who had desire of pregnancy (n ¼ 55), were also repeated after surgery (3-6 months) without receiving any other treatment. Patients not looking for pregnancy were recommended to take hormonal therapies (progestins, oral contraceptives, and levonorgestrel-intrauterine device) in order to prevent symptoms relapse and/or recurrences of the disease. The surgical strategy consisted of the laparoscopic excision of all visually suspected endometriotic lesions, after extensive adhesiolysis when adhesions were present (about 85% of cases), performed by either of the 2 surgeons (MM and EZ) with extensive experience in DIE laparoscopic radical resection and histological confirmation of DIE.
Statistical Analysis For population characteristics, all continuous variables are expressed in terms of mean + SD while categorical variables are expressed in terms of frequency and percentage. The accuracy of ultrasound was assessed by calculating the sensitivity and specificity for each site of possible endometriotic lesion. Positive predictive values (PPVs), negative predictive values (NPVs), and positive and negative likelihood ratios were calculated to determine the ability of the tests to predict the presence or absence of disease. For each of the test
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Table 1. Study Population Characteristics. Mean + SD or N (%) Group A, n ¼ 62
Patient Characteristics Age, years Height, cm Weight, kg Body mass index, kg/m2 Parity (n, %) 0 1 2 Previous medical treatment for endometriosis (n, %) Types of medical treatment (n, %) GnRH analogs Estroprogestins Danazol Progestins Previous surgery for endometriosis (n, %) 0 1 2
34.6 + 166.7 + 58.5 + 21.1 +
5.2 (range 5.9 (range 7.4 (range 1.3 (range
21-48) 150-180) 42-91) 16.02-29.07)
Mean + SD or N (%) Group B, n ¼ 59 34.1 + 5.0 165.4 + 6.2 59.2 + 7.1 21.3 + 1.4
(range (range (range (range
20-48) 152-181) 45-89) 16.05-29.5)
P Value .5911 .2396 .5968 .4168
45 13 4 43
(72.5) (20.9) (6.4) (69.3)
47 7 5 40
(79.6) (11.8) (8.4) (67.7)
.4001 .2239 .7393 1.0000
18 38 3 20
(29) (61.2) (4.8) (32.2)
17 36 1 20
(28.8) (61.0) (1.6) (33.8)
1.0000 1.0000 .6191 1.0000
8 (13.5) 37 (62.7) 14 (23.7)
.8003 1.0000 .8278
10 (16.1) 39 (62.9) 13 (20.9)
Abbreviations: GnRH, gonadotropin-releasing hormone; SD, standard deviation.
results, 95% confidence intervals were calculated to determine the precision of the results. Statistical analysis was performed using the Fisher exact test to detect differences in percentages while the Student t-test was used to compare means. Statistical significance was set at P < .05.
Results According to the presurgical, ultrasonographic evaluation, patients were subdivided in 2 groups:
group A (n ¼ 62) women with only DIE; group B (n ¼ 59) women with DIE and adenomyosis.
The clinical characteristics of all patients are shown in Table 1. No statistically significant difference was found in age, weight, and body mass index between the 2 groups. The majority of our patients had previous hormonal therapies and/ or previous surgery for endometriosis but no statistically significant difference was found in the groups. Surgical and histologic confirmation of DIE lesions showed that 56 (46.2%) of 121 women had right uterosacral ligament involvement while the infiltration of left uterosacral ligament was found in 67 (55.3%) of 121 patients. In all, 29 (23.9%) women had vaginal endometriosis, 78 (64.4%) had pouch of Douglas obliteration, and 40 (33%) had rectosigmoidal junction involvement while the caudal rectum nodules was found as the most frequent site of DIE in 83 (68.5%) patients. In all, 45 (37.1%) women had rectovaginal space infiltration and 7 (5.7%) had urinary bladder involvement. The sensitivity, specificity, PPV and NPV, and accuracy of TVS for the diagnosis of the different locations of pelvic endometriosis are shown in Table 2.
The 2 groups were homogeneous for the distribution of different sites of DIE lesions confirmed at surgery and was similar as shown in Table 3. Features of adenomyosis were found in 59 of 121 patients by TVS. The total association of adenomyosis in patients with DIE was 48.7%, resulting focal in 13.5% (n ¼ 8) patients and diffuse in 86.4% (n ¼ 51) patients (Figure 1). There was no significant correlation with the location of DIE. The most common symptoms of both the groups were dysmenorrhea, dyspareunia, infertility, and bowel functional symptoms (dyschezia, constipation, diarrhea, and rectal bleeding). The frequency of painful symptoms was higher in patients with adenomyosis. Before surgery, dysmenorrhea was found in 40 (64.5%) of 62 patients in group A while in group B it was detected in 52 (88.1%) of 59 patients (P ¼ .0028). Similarly, dyspareunia was present in 45 (72.5%) of 62 patients of group A and in the 54 (91.5%) of 59 patients in group B (P ¼ .0090). The pain intensity of dysmenorrhea (P ¼ .0019) and dyspareunia (P ¼ .0004) was significantly higher in patients of group B than that in group A (Figure 2A). There was no statistically significant difference between the 2 groups regarding the other pain symptoms such as dyschezia and dysuria and no statistically significant difference was found for bowel and urinary dysfunctional signs (data not shown). Before surgery, heavy menstrual bleeding was found more frequently in group B (40 of 59; 67.7%) than that in group A (20 of 62; 32.2%; P < .0001), resulting also quantitatively higher (PBAC ¼ 141.1 + 48; P < .0001). Transvaginal sonography examination, painful symptoms, and PBAC score assessment were performed at 3or 6 months after surgery in a subgroup of women (n ¼ 55). Transvaginal sonography evaluation showed no evidence of persistence of DIE lesions after surgical treatment while in women with
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Table 2. Accuracy of TVS in Diagnosis of Deep Infiltrating Endometriosis.a Surgical Distribution of DIE; Prevalence (%, n)
Patients, n ¼ 121 DIE location Bladder infiltration Right uterosacral ligament Left uterosacral ligament Rectovaginal septum Vagina Rectosigmoid junction Caudal rectum Obliteration of the Douglas pouch
5.7 (7) 46.2 (56) 55.3 (67) 37.1 (45) 23.9 (29) 33.0 (40) 68.5 (83) 64.4 (78)
Sensitivity, Specificity, PPV, NPV, LRþ LR– Accuracy, % % % % (95% CI) (95% CI) % 100 81.2 87.9 73.5 61.1 79.2 94.1 98.7
96.4 80.7 83.6 85.2 81.2 84.9 86.1 93.0
63.6 100 82.5 79.3 86.6 85.2 79.5 80.5 57.9 83.1 77.6 86.1 94.1 86.1 96.2 97.5
28.5 4.2 5.37 5.00 3.24 5.25 6.77 14.1
0 0.23 0.14 0.31 0.47 0.24 0.06 0.01
97 81 86 80 75 83 92 97
Abbreviations: CI, confidence interval; DIE, deep infiltrating endometriosis; LR, negative likelihood ratio; LRþ, positive likelihood ratio; TVS, transvaginal sonography; PPV, positive predictive value; NPV, negative predictive value. a Data for sensitivity, specificity, PPV and NPV are given as n and % (95% CI).
Table 3. Distribution of Deep Infiltrating Endometriosis.
Distribution of DIE Sites Location Bladder infiltration Right uterosacral ligament Left uterosacral ligament Torus Rectovaginal septum Vagina Rectosigmoid junction Caudal rectum Obliteration of the Douglas pouch
Group A (n ¼ 62); Prevalence (%)
Group B (n ¼ 59); Prevalence (%)
P Value
6.4 (4) 46.7 (29) 56.4 (35) 48.3 (30) 35.4 (22) 24.1 (15) 33.8 (21) 67.7 (42) 64.5 (40)
5.8 (3) 45.7 (27) 54.2 (32) 49.1 (29) 38.9 (23) 23.7 (14) 32.2 (19) 69.4 (41) 64.4 (38)
1.0000 1.0000 .8560 .8564 .7107 1.0000 1.0000 .7024 .5694 Figure 1. Ultrasound assessment: diffuse uterine adenomyosis and rectal sigmoid endometriotic nodules (*) that was visualized as an irregular hypoechoic mass penetrating into the intestinal wall replacing its normal structure, attached to the posterior uterine wall.
Abbreviation: DIE, deep infiltrating endometriosis.
previous diagnosis of adenomyosis (n ¼ 30) the persistence of adenomyosis signs was confirmed. Dysmenorrhea and dyspareunia were improved (both frequency and intensity) compared with preoperative value but in the subgroup with adenomyosis, the VAS score remained significantly higher (P < .001; Figure 2B). Also, dyschezia and dysuria ameliorated after surgery without statistical significant differences between the 2 groups (P ¼ .8). The postsurgical assessment of PBAC score showed a persistence of heavy menstrual bleeding was higher in patients with adenomyosis than in patients only with DIE (P < .0001; Figure 3).
Discussion The present study for the first time showed that in high percentage of patients with DIE, a pre- and postoperative evaluation of clinical symptoms and the use of TVS allows to detect adenomyosis, which persisted after surgery. 4
Until relatively recently, the diagnosis of adenomyosis was only accepted by histological examination following an hysterectomy but improvements in the resolution of imaging techniques have enabled a more detailed assessment of uterine architecture. Magnetic resonance imaging was the first imaging technique used to detect adenomyosis,25 and by T2-weighted MRI, it appears as an ill-demarcated low-signal-intensity lesion with uterine enlargement. The recognition of the various MRI signs of adenomyosis (including the junctional zone evaluation) allows a precise and accurate diagnosis with a sensitivity ranging between 78% and 88% and a specificity between 67% and 100%.26,27 Following a series of comparison with MRI, in experienced hands TVS has a similar diagnostic value with a sensitivity ranging between 53% and 89% and the specificity between 50% and 99%.16,28-31 A recent systematic review and metaanalysis concluded that TVS appears to be an accurate diagnostic tool for adenomyosis.32 Since the agreement between preoperative TVS diagnosis of adenomyosis and
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Figure 2. Visual analog scale score for dysmenorrhea and dyspareunia before surgery (A) and 3 to 6 months after surgical treatment (B) in groups A and B; P < .05 was considered statistically significant.
histological findings, the use of TVS examination is part of clinical practice for a noninvasive diagnosis of adenomyosis.8,32-34 Therefore, TVS is low cost and high accurate method for the diagnosis of adenomyosis, using MRI when transvaginal ultrasound is inconclusive.8 We found in the present study that the incidence of adenomyosis in DIE is in the same order with Naftalin et al showing by TVS a strong association (40%) between adenomyosis and endometriosis35 and underlying the crucial role of the transvaginal examination in the pretherapeutical assessment. In our study, the TVS diagnosis of adenomyosis was also well correlated with pain and abnormal uterine bleeding, thus supporting the hypothesis of a possible common pathogenesis and clinics of the 2 diseases. The most common hypothesis for the pathogenesis of adenomyosis includes that endometrial stroma, in direct contact with the underlying myometrium, invaginates or invades a structurally weakened myometrium during periods of regeneration, healing, and/or reepithelization.36-38 Mechanical damage to and/or physical disruption of the endometrial– myometrial interface may be due to dysfunctional uterine hyperperistalsis and/or dysfunctional contractility of the subendometrial myometrium. Dislocation of basal endometrium also results in endometriosis through retrograde menstruation.39
Figure 3. Pictorial blood loss assessment chart score (mean + SD) before surgery and 3 or 6 months after treatment in groups A and B; P < .05 was considered statistically significant.
The common symptoms and signs associated with adenomyosis are dysmenorrhea and dyspareunia.38,40 In our study, dysmenorrhea and dyspareunia were found significantly higher
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in DIE women also having adenomyosis both before and after surgery. Dysmenorrhea increases with greater depth of penetration of the adenomyotic process and to the density of deep endometrial glands into myometrium.40 Although dyspareunia is not considered a constant symptom in patients with adenomyosis, erratic or chronic pain in patients with adenomyosis is not considered typical.41 Our study showed a persistence of dyspareunia in women after surgery for DIE when adenomyosis was present. Other studies showed a pain recurrence in DIE, despite the radicality of the surgery42 and the present study confirmed that painful symptoms more likely persist in patients with adenomyosis. Heavy bleeding may be positively related to the depth of penetration of individual adenomyotic glands into the myometrium and to the density of deep endometrial glands within the myometrium.43 Our data showed a significative prevalence of abnormal uterine bleeding in the group of patients with adenomyosis associated to DIE and surgery did not affect the menstrual cycle characteristics, showing a crucial role of adenomyosis in determining heavy menstrual bleeding. This information allows the chance of a correct counseling before surgery, a subsequent medical approach is suggested to avoid the persistence of metrorrhagia after surgery. The association between DIE and adenomyosis detected in our series strongly suggests an accurate pretherapeutical evaluation of signs and symptoms, and transvaginal ultrasound represents the primary accurate diagnostic tool for the diagnosis. This information should help to develop more effective treatment strategies in women affected by DIE and adenomyosis. In addition, our data also confirm that TVS represents the first-line investigation to assess DIE and support that a modern and more comprehensive management for women with DIE has to consider all clinical signs and imaging features.
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Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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21. Reinhold C, McCarthy S, Bret PM, et al. Diffuse adenomyosis: comparison of endovaginal US and MR imaging with histopathologic correlation. Radiology. 1996;199(1):151-158. 22. Bazot M, Cortez A, Darai E, et al. Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology. Hum Reprod. 2001;16(11): 2427-2433. 23. Kepkep K, Tuncay YA, Go¨ynu¨mer G, Tutal E. Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate? Ultrasound Obstet Gynecol. 2007;30(3):341-345. 24. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990; 97(8):734-739. 25. Brosens JJ, de Souza NM, Barker FG. Uterine junctional zone: function and disease. Lancet. 1995;346(8974):558-560. 26. Tamai K, Togashy K, Ito T, Morisawa N, Fujiwara T, Koyama T. MR imaging findings of adenomyosis: correlation with histopathologic features and diagnostic pitfalls. Radiographics. 2005;25(1): 21-40. 27. Reinhold C, Tafazoli F, Mehio A, et al. Uterine adenomyosis: endovaginal US and MR imaging features with histopathologic correlation. Radiographics. 1999;19:S147-S160. 28. Fedele L, Bianchi S, Dorta M, Zanotti F, Brioschi D, Carinelli S. Transvaginal ultrasonography in the differential diagnosis of adenomyoma versus leiomyoma. Am J Obstet Gynecol. 1992;167(3): 603-606. 29. Brosens JJ, De Souza NM, Barker FG, Paraschos T, Winston RM. Endovaginal ultrasonography in the diagnosis of adenomyosis uteri: identifying the predictive characteristics. Br J Obstet Gynaecol. 1995;102(6):471-474. 30. Atzori E, Tronci C, Sionis L. Transvaginal ultrasound in the diagnosis of diffuse adenomyosis. Gynecol Obstet Invest. 1996;42(1): 39-41. 31. Exacoustos C, Brienza L, Di Giovanni A, et al. Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet Gynecol. 2011;37(4):471-479.
32. Meredith SM, Sanchez-Ramos L, Kaunitz AM. Diagnostic accuracy of transvaginal sonography for the diagnosis of adenomyosis: systematic review and metaanalysis. Am J Obstet Gynecol. 2009;201(1):107.e1-e6. 33. Levy G, Dehaene A, Laurent N, et al. An update on adenomyosis. Diagn Interv Imaging. 2013;94(1):3-25. 34. Bromley B, Shipp TD, Benacerraf B. Adenomyosis: sonographic findings and diagnostic accuracy. J Ultrasound Med. 2000;19(8): 529-534. 35. Naftalin J, Hoo W, Pateman K, Mavrelos D, Holland T, Jurkovic D. How common is adenomyosis? a prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Hum Reprod. 2012;27(12):3432-3439. 36. Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod. 2002;17(10):2725-2736. 37. Leyendecker G, Kunz G, Wildt L, Beil D, Deininger H. Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility. Hum Reprod. 1996;11(7):1542-1551. 38. Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update. 1998;4(4):312-322. 39. Leyendecker G, Kunz G, Herbertz M, et al. Uterine peristaltic activity and the development of endometriosis. Ann N Y Acad Sci. 2004;1034:338-355. 40. Bird C, McElin T, Manalo-Estrella P. The elusive adenomyosis of the uterus - revisited. Am J Obstet Gynecol. 1972;112(5):583-593 41. Peric H, Fraser IS. The symptomatology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):547-555. 42. Ferrero S, Camerini G, Menada MV, Biscaldi E, Ragni N, Remorgida V. Uterine adenomyosis in persistence of dysmenorrhea after surgical excision of pelvic endometriosis and colorectal resection. J Reprod Med. 2009;54(6):366-372. 43. Munro MG, Critchley HO, Fraser IS; FIGO Menstrual Disorders Working Group. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril. 2011; 95(7):2204-2208.
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Preoperative and Postoperative Clinical and Transvaginal Ultrasound Findings of Adenomyosis in Patients With Deep Infiltrating Endometriosis Lucia Lazzeri, Alessandra Di Giovanni, Caterina Exacoustos, Claudia Tosti, Serena Pinzauti, Mario Malzoni, Felice Petraglia and Errico Zupi Reproductive Sciences published online 14 February 2014 DOI: 10.1177/1933719114522520 The online version of this article can be found at: http://rsx.sagepub.com/content/early/2014/02/14/1933719114522520
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Original Article
Preoperative and Postoperative Clinical and Transvaginal Ultrasound Findings of Adenomyosis in Patients With Deep Infiltrating Endometriosis
Reproductive Sciences 1-7 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719114522520 rs.sagepub.com
Lucia Lazzeri, MD1, Alessandra Di Giovanni, MD2, Caterina Exacoustos, MD, PhD3, Claudia Tosti, MD1, Serena Pinzauti, MD1, Mario Malzoni, MD2, Felice Petraglia, MD, PhD1, and Errico Zupi, MD1
Abstract Objectives: Deep infiltrating endometriosis (DIE) represents the most complex form of endometriosis and its treatment is still challenging. The coexistence of DIE with other appearances of endometriosis stimulates new studies to improve the preoperative diagnosis. Adenomyosis is a clinical form that shares several symptoms with DIE. The present study investigated the possible presence of adenomyosis in a group of women with DIE and its impact on pre- and postoperative symptoms. Materials and Methods: A group of women (n ¼ 121) undergoing laparoscopic treatment for DIE were enrolled. Clinical and ultrasound evaluations were performed as preoperative assessment. The ultrasonographical appearances of DIE and of adenomyosis were recorded by 2-dimensional ultrasound. The following symptoms were considered: dysmenorrhea, dyspareunia, abnormal uterine bleeding, bowel, and urinary symptoms. Pain was evaluated by the visual analog scale system and menstrual bleeding was assessed by the use of the pictorial blood assessment chart. In a subgroup of women (n ¼ 55), a follow-up evaluation (3-6 months after surgery) was done. Results: A relevant number of patients with DIE showed adenomyosis (n ¼ 59; 48.7%); in this group, dysmenorrhea (P ¼ .0019), dyspareunia (P ¼ .0004), and abnormal uterine bleeding (P < .001) were statistically higher than that in the group with only DIE. After surgery, painful symptoms improved in the whole group but remained significantly higher (P < .001) in the group with adenomyosis. Conclusions: Deep infiltrating endometriosis is frequently associated with adenomyosis, significantly affecting pre- and postoperative symptoms and thus influencing the follow-up management. Keywords deep infiltrating endometriosis, adenomyosis, transvaginal ultrasound, dysmenorrhea, heavy menstrual bleeding
Introduction Deep infiltrating endometriosis (DIE) is the most severe form of endometriosis, associated with infertility or pain symptoms, including chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia.1 A wide spectrum of symptom severity is described, and the stage of endometriosis at laparoscopy is poorly correlated with the extent and severity of pain, often causing misdiagnosis or delayed diagnosis.2,3 A growing interest on adenomyosis derives from the observation that it is often associated with peritoneal endometriosis, particularly in infertile patients.4 Therefore, the presence of DIE should alert physicians to evaluate the possible presence of adenomyosis. Adenomyosis is known as an histological diagnosis but it has a clinical dignity showing symptoms (dysmenorrhea, dyspareunia, abnormal uterine bleeding, and infertility) and sharing some pathogenic mechanisms with endometriosis.5
Established imaging criteria may support an accurate diagnosis of adenomyosis. Magnetic resonance imaging (MRI) is still considered the gold standard in imaging for the diagnosis of adenomyosis but the use of transvaginal sonography (TVS) in diagnosing adenomyosis is comparable to MRI. The
1 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy 2 Advanced Gynecological Endoscopy Center, Malzoni Medical Center, Avellino, Italy 3 Department of Obstetrics and Gynecology, University of Rome ‘‘Tor Vergata’’, Roma, Italy
Corresponding Author: Lucia Lazzeri, Department of Molecular and Developmental Medicine, University of Siena, Viale Bracci, 53100, Siena, Italy. Email: [email protected]; [email protected]
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2-dimensional (2D) sonographic criteria of adenomyosis involve alterations in myometrium, such as presence of myometrial hypoechoic striations, myometrial cysts or heterogeneous areas, asymmetry of the myometrial walls, diffuse vascularity, and globular uterine configuration.6-9 The subjective impression of a poorly defined junctional zone by 2D is also referred as a diagnostic criterion for adenomyosis but with low sensitivity.10 In some patients pain is not responsive to surgical excision of DIE11 and recurrence of symptoms is present despite the radicality of the procedure.12,13 Transvaginal sonography is highly accurate for a correct presurgical diagnosis of DIE in order to localize the lesions and other possible abnormalities and to establish the best therapeutical management.14-18 The present study aimed to investigate the possible presence of adenomyosis by TVS in a group of women with DIE and its impact on pre- and postoperative symptoms.
Materials and Methods A total of 121 women aged 20 to 48 years (mean + standard deviation [SD] ¼ 34.3 + 5.1 years) were included in this prospective clinical trial from January 1, 2012, through March 30, 2013, in 3 Endometriosis centers in Italy (Siena, Roma, and Avellino). The study was approved by the institutional review board of the University of Siena. Women with ovarian endometrioma were excluded. Presurgical assessment included completion of TVS, transabdominal, and transrectal scans when needed 3 months before surgery and 3 or 6 months after surgical treatment. All ultrasonographic examinations were performed by the same 3 examiners (CE, ADG, and LL). The ultrasound scan was always performed with either a GE E8 or E6 (GE Healthcare, Zipf, Austria) ultrasound machine, using a wideband 5- to 9-MHz transducer without bowel preparation. The examination was performed at any phase of the menstrual cycle regardless of hormonal therapy. The diagnosis of DIE was made if at least 1 structure in the anterior or posterior compartment showed the presence of retroperitoneal abnormal hypoechoic linear or nodular thickening with irregular contours and no vascular Doppler signals, as described previously and validated ultrasonographic criteria.19,20 Locations for DIE in the anterior (bladder) or posterolateral compartment (vagina, rectovaginal septum, torus and uterosacral ligaments, parametria and ureteral involvement, rectum, and rectosigmoid junction) were examined. The presence of ovarian endometriomas and adnexal adhesions was also recorded. For the diagnosis of adenomyosis, uterus and endometrium were evaluated for any abnormality. The presence of TVS features associated with adenomyosis was determined:
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increased myometrial echogenicity or linear hyperechoic bands extending deep into the myometrium, which indicates the presence of islets of ectopic endometrial tissue; hypoechoic areas in the myometrium compatible with hyperplasia of the muscle tissue surrounding the ectopic tissue;
anechoic areas due to glandular dilatation or myometrial cysts; enlargement of the uterus with asymmetrical myometrial thickening of the walls unrelated to leiomyoma; presence of straight vessels into the hypertrophic myometrium at the color Doppler examination; focal adenomyosis was defined by the presence of adenomyotic lesions with elliptical appearance and ill-defined margins; no calcifications and hypervascularity at color Power Doppler evaluation. Diagnosis of adenomyosis was made when all of the recognized features of the disease were observed on the examination.6-9 These morphological features have been accepted with a wide consensus as reliable morphological markers of adenomyosis.6-9,21-23
The following signs and symptoms were recorded: dysmenorrhea, dyspareunia, functional bowel signs (constipation, diarrhea, painful defecation during menses, and rectal bleeding), functional urinary tract signs (dysuria, urgency, and hematuria), and abnormal uterine bleeding. The level of patient’s discomfort and pain was evaluated by the visual analog scale (VAS) system, utilizing a 10-cm line with the extreme points 0 and 10 corresponding to ‘‘no pain’’ and ‘‘maximum pain,’’ respectively. Menstrual bleeding was assessed with the use of the pictorial blood loss assessment chart (PBAC),24 a validated method used to objectively estimate blood loss; monthly scores range from 0 to more than 500, with higher numbers indicating more bleeding, and menorrhagia was defined as a PBAC >100 during 1 menstrual period, which corresponds to a blood loss of more than 80 mL. The same evaluations were performed before surgery and, in a subgroup who had desire of pregnancy (n ¼ 55), were also repeated after surgery (3-6 months) without receiving any other treatment. Patients not looking for pregnancy were recommended to take hormonal therapies (progestins, oral contraceptives, and levonorgestrel-intrauterine device) in order to prevent symptoms relapse and/or recurrences of the disease. The surgical strategy consisted of the laparoscopic excision of all visually suspected endometriotic lesions, after extensive adhesiolysis when adhesions were present (about 85% of cases), performed by either of the 2 surgeons (MM and EZ) with extensive experience in DIE laparoscopic radical resection and histological confirmation of DIE.
Statistical Analysis For population characteristics, all continuous variables are expressed in terms of mean + SD while categorical variables are expressed in terms of frequency and percentage. The accuracy of ultrasound was assessed by calculating the sensitivity and specificity for each site of possible endometriotic lesion. Positive predictive values (PPVs), negative predictive values (NPVs), and positive and negative likelihood ratios were calculated to determine the ability of the tests to predict the presence or absence of disease. For each of the test
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Table 1. Study Population Characteristics. Mean + SD or N (%) Group A, n ¼ 62
Patient Characteristics Age, years Height, cm Weight, kg Body mass index, kg/m2 Parity (n, %) 0 1 2 Previous medical treatment for endometriosis (n, %) Types of medical treatment (n, %) GnRH analogs Estroprogestins Danazol Progestins Previous surgery for endometriosis (n, %) 0 1 2
34.6 + 166.7 + 58.5 + 21.1 +
5.2 (range 5.9 (range 7.4 (range 1.3 (range
21-48) 150-180) 42-91) 16.02-29.07)
Mean + SD or N (%) Group B, n ¼ 59 34.1 + 5.0 165.4 + 6.2 59.2 + 7.1 21.3 + 1.4
(range (range (range (range
20-48) 152-181) 45-89) 16.05-29.5)
P Value .5911 .2396 .5968 .4168
45 13 4 43
(72.5) (20.9) (6.4) (69.3)
47 7 5 40
(79.6) (11.8) (8.4) (67.7)
.4001 .2239 .7393 1.0000
18 38 3 20
(29) (61.2) (4.8) (32.2)
17 36 1 20
(28.8) (61.0) (1.6) (33.8)
1.0000 1.0000 .6191 1.0000
8 (13.5) 37 (62.7) 14 (23.7)
.8003 1.0000 .8278
10 (16.1) 39 (62.9) 13 (20.9)
Abbreviations: GnRH, gonadotropin-releasing hormone; SD, standard deviation.
results, 95% confidence intervals were calculated to determine the precision of the results. Statistical analysis was performed using the Fisher exact test to detect differences in percentages while the Student t-test was used to compare means. Statistical significance was set at P < .05.
Results According to the presurgical, ultrasonographic evaluation, patients were subdivided in 2 groups:
group A (n ¼ 62) women with only DIE; group B (n ¼ 59) women with DIE and adenomyosis.
The clinical characteristics of all patients are shown in Table 1. No statistically significant difference was found in age, weight, and body mass index between the 2 groups. The majority of our patients had previous hormonal therapies and/ or previous surgery for endometriosis but no statistically significant difference was found in the groups. Surgical and histologic confirmation of DIE lesions showed that 56 (46.2%) of 121 women had right uterosacral ligament involvement while the infiltration of left uterosacral ligament was found in 67 (55.3%) of 121 patients. In all, 29 (23.9%) women had vaginal endometriosis, 78 (64.4%) had pouch of Douglas obliteration, and 40 (33%) had rectosigmoidal junction involvement while the caudal rectum nodules was found as the most frequent site of DIE in 83 (68.5%) patients. In all, 45 (37.1%) women had rectovaginal space infiltration and 7 (5.7%) had urinary bladder involvement. The sensitivity, specificity, PPV and NPV, and accuracy of TVS for the diagnosis of the different locations of pelvic endometriosis are shown in Table 2.
The 2 groups were homogeneous for the distribution of different sites of DIE lesions confirmed at surgery and was similar as shown in Table 3. Features of adenomyosis were found in 59 of 121 patients by TVS. The total association of adenomyosis in patients with DIE was 48.7%, resulting focal in 13.5% (n ¼ 8) patients and diffuse in 86.4% (n ¼ 51) patients (Figure 1). There was no significant correlation with the location of DIE. The most common symptoms of both the groups were dysmenorrhea, dyspareunia, infertility, and bowel functional symptoms (dyschezia, constipation, diarrhea, and rectal bleeding). The frequency of painful symptoms was higher in patients with adenomyosis. Before surgery, dysmenorrhea was found in 40 (64.5%) of 62 patients in group A while in group B it was detected in 52 (88.1%) of 59 patients (P ¼ .0028). Similarly, dyspareunia was present in 45 (72.5%) of 62 patients of group A and in the 54 (91.5%) of 59 patients in group B (P ¼ .0090). The pain intensity of dysmenorrhea (P ¼ .0019) and dyspareunia (P ¼ .0004) was significantly higher in patients of group B than that in group A (Figure 2A). There was no statistically significant difference between the 2 groups regarding the other pain symptoms such as dyschezia and dysuria and no statistically significant difference was found for bowel and urinary dysfunctional signs (data not shown). Before surgery, heavy menstrual bleeding was found more frequently in group B (40 of 59; 67.7%) than that in group A (20 of 62; 32.2%; P < .0001), resulting also quantitatively higher (PBAC ¼ 141.1 + 48; P < .0001). Transvaginal sonography examination, painful symptoms, and PBAC score assessment were performed at 3or 6 months after surgery in a subgroup of women (n ¼ 55). Transvaginal sonography evaluation showed no evidence of persistence of DIE lesions after surgical treatment while in women with
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Table 2. Accuracy of TVS in Diagnosis of Deep Infiltrating Endometriosis.a Surgical Distribution of DIE; Prevalence (%, n)
Patients, n ¼ 121 DIE location Bladder infiltration Right uterosacral ligament Left uterosacral ligament Rectovaginal septum Vagina Rectosigmoid junction Caudal rectum Obliteration of the Douglas pouch
5.7 (7) 46.2 (56) 55.3 (67) 37.1 (45) 23.9 (29) 33.0 (40) 68.5 (83) 64.4 (78)
Sensitivity, Specificity, PPV, NPV, LRþ LR– Accuracy, % % % % (95% CI) (95% CI) % 100 81.2 87.9 73.5 61.1 79.2 94.1 98.7
96.4 80.7 83.6 85.2 81.2 84.9 86.1 93.0
63.6 100 82.5 79.3 86.6 85.2 79.5 80.5 57.9 83.1 77.6 86.1 94.1 86.1 96.2 97.5
28.5 4.2 5.37 5.00 3.24 5.25 6.77 14.1
0 0.23 0.14 0.31 0.47 0.24 0.06 0.01
97 81 86 80 75 83 92 97
Abbreviations: CI, confidence interval; DIE, deep infiltrating endometriosis; LR, negative likelihood ratio; LRþ, positive likelihood ratio; TVS, transvaginal sonography; PPV, positive predictive value; NPV, negative predictive value. a Data for sensitivity, specificity, PPV and NPV are given as n and % (95% CI).
Table 3. Distribution of Deep Infiltrating Endometriosis.
Distribution of DIE Sites Location Bladder infiltration Right uterosacral ligament Left uterosacral ligament Torus Rectovaginal septum Vagina Rectosigmoid junction Caudal rectum Obliteration of the Douglas pouch
Group A (n ¼ 62); Prevalence (%)
Group B (n ¼ 59); Prevalence (%)
P Value
6.4 (4) 46.7 (29) 56.4 (35) 48.3 (30) 35.4 (22) 24.1 (15) 33.8 (21) 67.7 (42) 64.5 (40)
5.8 (3) 45.7 (27) 54.2 (32) 49.1 (29) 38.9 (23) 23.7 (14) 32.2 (19) 69.4 (41) 64.4 (38)
1.0000 1.0000 .8560 .8564 .7107 1.0000 1.0000 .7024 .5694 Figure 1. Ultrasound assessment: diffuse uterine adenomyosis and rectal sigmoid endometriotic nodules (*) that was visualized as an irregular hypoechoic mass penetrating into the intestinal wall replacing its normal structure, attached to the posterior uterine wall.
Abbreviation: DIE, deep infiltrating endometriosis.
previous diagnosis of adenomyosis (n ¼ 30) the persistence of adenomyosis signs was confirmed. Dysmenorrhea and dyspareunia were improved (both frequency and intensity) compared with preoperative value but in the subgroup with adenomyosis, the VAS score remained significantly higher (P < .001; Figure 2B). Also, dyschezia and dysuria ameliorated after surgery without statistical significant differences between the 2 groups (P ¼ .8). The postsurgical assessment of PBAC score showed a persistence of heavy menstrual bleeding was higher in patients with adenomyosis than in patients only with DIE (P < .0001; Figure 3).
Discussion The present study for the first time showed that in high percentage of patients with DIE, a pre- and postoperative evaluation of clinical symptoms and the use of TVS allows to detect adenomyosis, which persisted after surgery. 4
Until relatively recently, the diagnosis of adenomyosis was only accepted by histological examination following an hysterectomy but improvements in the resolution of imaging techniques have enabled a more detailed assessment of uterine architecture. Magnetic resonance imaging was the first imaging technique used to detect adenomyosis,25 and by T2-weighted MRI, it appears as an ill-demarcated low-signal-intensity lesion with uterine enlargement. The recognition of the various MRI signs of adenomyosis (including the junctional zone evaluation) allows a precise and accurate diagnosis with a sensitivity ranging between 78% and 88% and a specificity between 67% and 100%.26,27 Following a series of comparison with MRI, in experienced hands TVS has a similar diagnostic value with a sensitivity ranging between 53% and 89% and the specificity between 50% and 99%.16,28-31 A recent systematic review and metaanalysis concluded that TVS appears to be an accurate diagnostic tool for adenomyosis.32 Since the agreement between preoperative TVS diagnosis of adenomyosis and
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Figure 2. Visual analog scale score for dysmenorrhea and dyspareunia before surgery (A) and 3 to 6 months after surgical treatment (B) in groups A and B; P < .05 was considered statistically significant.
histological findings, the use of TVS examination is part of clinical practice for a noninvasive diagnosis of adenomyosis.8,32-34 Therefore, TVS is low cost and high accurate method for the diagnosis of adenomyosis, using MRI when transvaginal ultrasound is inconclusive.8 We found in the present study that the incidence of adenomyosis in DIE is in the same order with Naftalin et al showing by TVS a strong association (40%) between adenomyosis and endometriosis35 and underlying the crucial role of the transvaginal examination in the pretherapeutical assessment. In our study, the TVS diagnosis of adenomyosis was also well correlated with pain and abnormal uterine bleeding, thus supporting the hypothesis of a possible common pathogenesis and clinics of the 2 diseases. The most common hypothesis for the pathogenesis of adenomyosis includes that endometrial stroma, in direct contact with the underlying myometrium, invaginates or invades a structurally weakened myometrium during periods of regeneration, healing, and/or reepithelization.36-38 Mechanical damage to and/or physical disruption of the endometrial– myometrial interface may be due to dysfunctional uterine hyperperistalsis and/or dysfunctional contractility of the subendometrial myometrium. Dislocation of basal endometrium also results in endometriosis through retrograde menstruation.39
Figure 3. Pictorial blood loss assessment chart score (mean + SD) before surgery and 3 or 6 months after treatment in groups A and B; P < .05 was considered statistically significant.
The common symptoms and signs associated with adenomyosis are dysmenorrhea and dyspareunia.38,40 In our study, dysmenorrhea and dyspareunia were found significantly higher
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in DIE women also having adenomyosis both before and after surgery. Dysmenorrhea increases with greater depth of penetration of the adenomyotic process and to the density of deep endometrial glands into myometrium.40 Although dyspareunia is not considered a constant symptom in patients with adenomyosis, erratic or chronic pain in patients with adenomyosis is not considered typical.41 Our study showed a persistence of dyspareunia in women after surgery for DIE when adenomyosis was present. Other studies showed a pain recurrence in DIE, despite the radicality of the surgery42 and the present study confirmed that painful symptoms more likely persist in patients with adenomyosis. Heavy bleeding may be positively related to the depth of penetration of individual adenomyotic glands into the myometrium and to the density of deep endometrial glands within the myometrium.43 Our data showed a significative prevalence of abnormal uterine bleeding in the group of patients with adenomyosis associated to DIE and surgery did not affect the menstrual cycle characteristics, showing a crucial role of adenomyosis in determining heavy menstrual bleeding. This information allows the chance of a correct counseling before surgery, a subsequent medical approach is suggested to avoid the persistence of metrorrhagia after surgery. The association between DIE and adenomyosis detected in our series strongly suggests an accurate pretherapeutical evaluation of signs and symptoms, and transvaginal ultrasound represents the primary accurate diagnostic tool for the diagnosis. This information should help to develop more effective treatment strategies in women affected by DIE and adenomyosis. In addition, our data also confirm that TVS represents the first-line investigation to assess DIE and support that a modern and more comprehensive management for women with DIE has to consider all clinical signs and imaging features.
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Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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