Original Article
561
Importance of Transvaginal Ultrasound Applying Elastography for Identifying Deep Infiltrating Endometriosis – A Feasibility Study Stellenwert der transvaginalen Elastografie zur Diagnose tief infiltrierender Endometriose – eine Durchführbarkeitsstudie Authors
M. L. Schiffmann1, S. D. Schäfer1, A. N. Schüring1, L. Kiesel1, C. Sauerland2, M. Götte1, R. Schmitz1
Affiliations
1
Clinic of Obstetrics and Gynaecology, University Hospital Münster Institute of Biostatistics and Clinical Research, University of Münster
Key words
Abstract
Zusammenfassung
"
!
!
Purpose: To evaluate the presence of a lesion indicative of endometriosis with transvaginal elastography. Materials and Methods: Transvaginal ultrasound and clinical examination were carried out in 48 women with clinical symptoms indicative of endometriosis. In 31 cases strain values were measured at two regions of interest (ROIs) in the Douglas's cul-de-sac during a cycle of compression and decompression with a vaginal probe. Results: A significant difference was found for the ratio of the ROI measuring points in the Douglas' cul-de-sacs of women with a palpable nodule in examination compared to women without a palpable nodule (p = 0.002). Conclusion: The ratio of strain values between two ROIs in the Douglas' s cul-de-sac is associated with the presence of an endometriotic lesion. In the future, these findings could allow for a more detailed pre-surgical evaluation and possibly serve as a novel diagnostic tool for predicting deep infiltrating endometriosis.
Ziel: Beurteilung des Vorliegens eines Endometrioseherdes mithilfe transvaginaler Elastografie. Material und Methoden: Bei 48 Frauen mit typischer klinischer Symptomatik wurde ein transvaginaler Ultraschall und eine klinische Untersuchung durchgeführt. In 31 Fällen wurde die Verformbarkeit des Gewebes während abwechselnder Kompression und Dekompression gemessen. Diese Messungen fanden an zwei umschriebenen Bereichen des Douglas-Raums, so genannten “Regions of interest” (ROIs), statt. Ergebnisse: Im Vergleich von Frauen, bei denen in der klinischen Untersuchung ein Knoten getastet wurde, und Frauen, die keinen solchen Knoten aufwiesen, zeigte sich ein signifikanter Unterschied der Ratio der ROI-Messpunkte des Douglas-Raums (p = 0,002). Schlussfolgerung: Die Ratio der ROI-Messpunkte des Douglas-Raums ist mit dem Vorliegen eines Endometrioseherdes assoziiert. In der zukünftigen Anwendung können diese Erkenntnisse eine zusätzliche präoperative Einschätzung von Endometrioseherdbefunden ermöglichen. Die Elastografie kann als neue Methode in der Diagnostik der tief infiltrierenden Endometriose eingesetzt werden.
Introduction
endometriosis is not always correlated with the extent of symptoms a woman experiences and in some cases symptoms may be completely absent. With regard to an estimated number of unknown cases, the prevalence of endometriosis among premenopausal women is about 6 – 10 % [1]. In addition to pain symptoms, infertility is common in endometriosis. About 35 – 50 % of women with pelvic pain or infertility are estimated to suffer from endometriosis [3]. Several mechanisms are suspected to cause infertility, for instance the
● endometriosis ● ultrasound ● pelvic organs ● uterus " " "
received accepted
8.9.2013 28.5.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366747 Published online: July 11, 2014 Ultraschall in Med 2014; 35: 561–565 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0172-4614 Correspondence Marie-Luise Schiffmann Clinic of Obstetrics and Gynaecology, University Hospital Münster Albert-Schweitzer-Campus 1 Gebäude A1 48149 Münster Germany Tel.: ++ 49/2 51/8 34 82 61 Fax: ++ 49/2 51/8 34 82 10 [email protected]
!
Endometriosis is defined as the appearance of ectopic endometrial stroma and glands outside the uterine cavity [1]. As a consequence of cyclic hormonal changes, the ectopic endometrial tissue proliferates just like eutopic endometrium. This leads to a local inflammatory response, which is commonly associated with various clinical symptoms, for example dysmenorrhea, dysuria, dyschezia, bleeding disturbances and cycle-dependent or chronic pelvic pain [2]. The severity of
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2
Original Article
malfunction of the pelvic anatomy due to adhesions or impaired implantation potential [4]. At present, two classifications are used for endometriosis. The revised American Society of Reproductive Medicine classification of endometriosis (rASRM) was designed to classify the impact of endometriosis on infertility in the individual patient [5]. However, as a drawback, the rASRM classification cannot be used for deep infiltrating endometriosis (DIE). This gap is closed by the ENZIAN classification which specifically describes location and extent of DIE [6]. Transvaginal ultrasound (TVUS) is a time- and cost-efficient method for the diagnosis of endometriosis. Moreover, TVUS is well accepted by patients and it allows for dynamic examination of the pelvic anatomy. It is necessary to have preoperative information about adhesions, infiltration and the extent of endometriosis to be able to decide on the treatment strategy and take into consideration associated surgical risks. For these reasons TVUS should be used as an integral part of every gynecological exam [7]. Hudelist et al. [8] systematically reviewed 188 papers of which 10 fulfilled the inclusion criteria. They found that TVUS has a sensitivity of 90 % and a specificity of 98 % in the diagnosis of DIE of the bowel. However, the diagnosis of an endometriotic nodule in the Douglas’s cul-de-sac remains difficult. Fratelli et. al. [9] found that TVUS has a sensitivity of only 31 % and a specificity of 90 % in the diagnosis of the size of an endometriotic nodule located at the Douglas’s cul-de-sac. Elastography has been successfully utilized in the diagnosis of breast cancer [10, 11]. A significant number (21.2 %) of German ultrasound specialists are already using elastography to evaluate breast lesions. A further increase is expected [12]. Other areas of application are improvements in the diagnosis of prostate cancer, the evaluation of liver stiffness, and the differential diagnosis of benign and malignant cervical lymph nodes or thyroid nodules [11, 13 – 16]. Recently, Hernandez-Andrade et al. [17] evaluated the consistency of the uterine cervix during pregnancy by the use of ultrasound elastography. In order to gain more information about the endometriotic lesions delivered by B-mode TVUS, we used real-time Dopplerbased elastography. Ultrasound elastography can measure tissue elasticity. External compression is applied to the tissue with the ultrasound probe, which causes tissue deformation [18]. This is measured as strain. Strain is relative to the intensity of the applied compression and the modulus of elasticity of the intrinsic material [19]. A strain gradient between the posterior fornix and the Douglas’s cul-desac is known from clinical experience. It is possible to visualize the strain value by the use of superimposed coloring on the Bmode image. Moreover, it is possible to compare the strain of two regions of interest (ROI). The aim of our feasibility study was to correlate the presence of a lesion indicative of endometriosis located at the Douglas’s culde-sac with transvaginal elastography. Assuming that preoperative elastography can acquire further information about the position and infiltration depth of an endometriotic nodule, this information can be a useful tool for the surgeon for preoperative planning. Moreover, unnecessary operations could be prevented based on the gained information.
Methods !
Study population Between June 2011 and June 2012, we performed a prospective study. The study population consisted of 48 women with suspicion of endometriosis, who were transferred to the tertiary endometriosis referral center at the University Hospital Münster. We included women with suspicion of endometriosis due to dysmenorrhea, dyspareunia, dyschezia and dysuria. Detailed medical history was taken with regard to previous surgery, gravidity and previous treatment with gonadotropin-releasing hormone (GnRH) agonists. Patients with genital malformations and previous gynecologic surgery of the Douglas’s cul-de-sac were excluded. Informed consent was obtained from all patients. Our institutional ethics review board approved the study.
Clinical examination All women underwent a clinical examination conducted by an experienced gynecologist of the endometriosis center (S.S.) who included a vaginal and rectal examination prior to TVUS. The abdominal wall was palpated with regard to tenderness or a nodule. During a bimanual vaginal examination, special attention was paid to tenderness, areas of decreased elasticity or a nodule located in the Douglas’s cul-de-sac, the uterus, the vagina and the uterosacral ligaments. In the following digital rectal examination, we paid attention to any nodule involving the intestinal wall.
Raw dataset collection Transvaginal elastography was performed with an Aplio XG ultrasound system (Toshiba Medical Systems Europe, Zoetermeer, Netherlands) using the PVT-681MV 6-MHz transducer. The examining gynecologist was an experienced specialist of the gynecologic ultrasound department (R.S.). The uterus, the vagina and rectovaginal space, the uterosacral ligaments, both adnexa, the rectosigmoid and the urinary bladder were examined by B-mode ultrasound. The diagnosis of adenomyosis was made when the following criteria were met: heterogeneous structure or irregular shape of the myometrium, asymmetry of the anterior and the posterior uterine wall and thickening of the junctional zone. Subsequent to the B-mode scan, we performed the dual-mode scanning (twin-mode) for real-time Doppler elastography. The elasticity images are colored in a range from blue over green to red, according to the deformability of the tissue. They are superimposed on the B-mode images for better orientation. The ultrasound probe was pressed gently in the direction of the Douglas’s cul-de-sac. These movements could be traced on the screen by real-time B-mode. Alternating compression and decompression was performed several times to reduce image interference.
Offline analysis of the raw dataset The raw dataset was evaluated with TDI-Q software (Tissue Doppler Imaging Quantification, Toshiba Medical Systems Europe). A second investigator, who was not involved in any previous examination, reviewed the data. The perceived strain values for each raw dataset were blinded with respect to the previous results and to the first investigator. The preset for the strain measurements was “Tissue Tracking Natural” and angle correction was deactivated. In order to calculate the strain from the
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Surgical findings Surgery was performed in 26 cases by the first investigator (S. S.). The ENZIAN and rASRM [20] scores were determined on the basis of intraoperative findings.
Results !
Characteristics of the study population are summarized in ●" Table 1. The mean ± SD age of the population was 32.7 ± 8.0. A total of 33 (69 %) patients were nulliparous, 6 (12 %) had previous surgery and 10 (21 %) had been pre-treated with GnRH (gonadotropin-releasing hormone). The patients had a history of dysmenorrhea (33; 79 %), dyspareunia (18; 42 %), dyschezia (14; 30 %) and dysuria (12; 26 %). Surgery after elastography was conducted in 26 (54 %) cases. The rASRM and ENZIAN scores of the patients who " Table 2. underwent surgery are pictured in ● The findings of the clinical examinations are visualized in ●" Table 3. During the examination of the Douglas’s cul-de-sac, 9 (19 %) patients reported pain during palpation. The examination of the uterus/the uterosacral ligaments was associated with pain in 24 (50 %) and 6 (13 %) cases, respectively. Transvaginal sonography found the presence of a lesion indicative of endometriosis in the Douglas’s cul-de-sac in 7 (15 %) cases,
Statistical analysis Descriptive statistics were used to characterize the study population. The results are shown as mean ± standard deviation (SD) or the absolute number of patients is mentioned. Comparison of the ratio between the ROI measuring points in the Douglas’s cul-de-sac and the palpatory findings was assessed using the Mann-Whitney U-test for independent samples. Statistical analysis was performed by SPSS software (IBM Corporation, New York, NY, USA, version 21).
Table 1
Characteristics of the study population (n = 48).
age (years)
32.7 ± 8.0
missing
nulliparous
33 (69 %)
0
previous surgery
6 (12 %)
0
GnRH treatment 1
10 (21 %)
1
dysmenorrhea
33 (79 %)
6
values (n)
dyspareunia
18 (42 %)
5
dyschezia
14 (30 %)
2
dysuria
12 (26 %)
2
surgery after elastography
26 (54 %)
0
Data is given as mean ± SD or n (%). 1 GnRH, gonadotropin releasing hormone.
Fig. 1 Transvaginal elastography. a B-mode image. b Position of ROI pressure points in the Douglas’s cul-de-sac. The two ROIs were placed at an equal angle from the axis of the probe. c Strain curves derived from elastography during compression with the vaginal probe. Y-axis: Strain values. X-axis: Strain measurement over time in msec.
Abb. 1 Transvaginale Elastografie. a B-Mode Bild. b Position der ROIMesspunkte im Douglas-Raum. Die beiden Messpunkte wurden im gleichen Winkel zur Ultraschallsondenachse positioniert. c Verformbarkeitskurven (Strain-Kurven), die während der Kompression des Gewebes mit der Vaginalsonde mittels Elastografie ermittelt wurden. Y-Achse: Strain-Werte. X-Achse: Strain-Messung im Zeitverlauf in Millisekunden (ms).
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raw dataset, the presetting “natural strain” was used. We placed two ROIs in the tissue of the Douglas’ cul-de-sac. In order to analyze a representative and reproducible part of tissue, a circular ROI with a diameter of 2 mm was used. The first ROI was placed in close proximity to the cervix while the second ROI was positioned in the sacral direction at a distance of 6 mm. In order to allow for a comparable amount of applied pressure, the two ROIs were placed at an equal angle from the axis along the vaginal probe. Strain values were measured during a cycle of compression and decompression applied with the vaginal probe " Fig. 1). (● According to the strain gradient between the posterior fornix and the Douglas’s cul-de-sac, we calculated the ratio between the maximum strain value of the first and the second ROI (ROI1/ ROI2). This ratio was compared with the presence of a palpable nodule in the Douglas’s cul-de-sac.
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Table 2 rASRM and ENZIAN score of the patients who underwent surgery (n = 26).
patient
rASRM
A
4
ENZIAN A1 B3 FA
B
0
0
C
0
FA
D
2
0
E
4
A1 FB
F
4
A3 FA
G
4
0
H
3
A2 B1 FA FI
I
1
A1 B1
J
1
FA
K
0
0
L
4
C2 FA
M
1
FA
N
1
FA
O
1
FA
P
2
B3 FA
Q
0
A1
R
1
FA
S
3
B3 FB
T
4
B3
U
1
B2 FA
V
0
0
W
4
FA FI
X
3
A1 B1
Y
2
B3
Z
4
B3 FA
ENZIAN classification divides retropertitoneal structures into three compartments. A: rectovaginal septum and vagina, B: sacrouterine ligament to pelvic wall and C: rectum and sigmoid colon. The lesions are graded as 1: < 1 cm, 2: 1 – 3 cm or 3: > 3 cm. For retroperitoneal distant locations, the prefix F (“far“) is used (FA = adenomyosis, FB = involvement of the bladder, FU = intrinsic involvement of the ureter, FI = bowel disease cranial to the rectosigmoid junction, FO (“other”) = other locations). rASRM score distinguishes between four stages of severity Stage 1: 1 – 5 points, stage 2: 6 – 15 points, stage 3: 16 – 40 points, stage 4: > 40 points.
Table 3
Clinical examinations (n = 48).
location
pain during
palpable nodule
palpation Douglas uterus uterosacral ligaments
9 (19 %)
9 (19 %)
24 (50 %)
0 (0 %)
6 (13 %)
3 (6 %)
Data is given as n (%).
in the uterus in 31 (64 %) cases and in the uterosacral ligaments in 4 (8 %) cases. The data from elastography were compared with palpatory findings. The ratio between the ROI measuring points in the Douglas’s cul-de-sac was correlated with the presence of a palpable lesion indicative of endometriosis in the Douglas’s cul-de-sac. After offline analysis and applying the Mann-Whitney U-test, a significant correlation between the ROI1 / ROI2 ratio and a palpable lesion indicative of endometriosis was found (p = 0.002). The values of the ratio ranged from 0.28 to 7.60 with a median of 1.70. The comparison between the ratio and a palpable lesion indicative of endometriosis in the Douglas’s cul-de-sac is pictured with a box" Fig. 2). and-whisker plot (●
Fig. 2 Presence of a palpable lesion indicative of endometriosis correlated with the ratio (ROI1/ROI2) between two ROI measuring points in proximity of the uterus (ROI1) and 6 mm afar in sacral direction (ROI2) (p = 0.002). Abb. 2 Vorliegen eines tastbaren Endometrioseherdes in Korrelation mit der Ratio (ROI1/ROI2) zwischen zwei ROI Messpunkten in der Nähe des Uterus (ROI1) und in 6 mm Abstand in sakraler Richtung (ROI2) (p = 0.002).
Discussion !
DIE of Douglas’s cul-de-sac results in a generally reduced elasticity due to scarring and remodeling by connective tissue. Therefore, in our study, similar maximum strain values were observed at both ROI pressure points – at ROI2 in the immediate proximity of the uterus and at ROI2 at a distance of 6 mm in the sacral direction – leading to a smaller value of the respective ratio. In the case of a Douglas’s cul-de-sac without endometriosis, the maximum values became smaller with an increasing distance from the uterus. As a result, the ratio between the ROI pressure points increased. In order to prevent scar tissue from previous operations from impacting the distribution of strain during elastographic imaging, we excluded patients with previous gynecologic surgery of the Douglas’s cul-de-sac. In the diagnosis of breast tumors with elastography, it is possible to compare the surrounding normal tissue with the suspected malignant tumor. In contrast to a nodule in the breast, an endometriotic lesion in the pelvis cannot be visualized as easily and adjacent healthy – “reference” – tissue is not always present. As a consequence, it is more difficult to standardize the elasticity of endometriotic lesions versus normal elasticity. The results of our study support the hypothesis that the ratio between the applied ROI pressure points is an eligible parameter to identify patients with DIE. Strain can be calculated relatively to the initial length of an object (hereafter referred to as “Lagrangian strain”) or relative to a reference that changes during the process of deformation (“natural strain”). In the case of a small deformation, both the Lagrangian strain and the natural strain are comparable. However, in cases of large deformations, as occurred in this study, the natural strain should be preferred [21].
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As a possible limitation of our study, the force applied during transvaginal elastography could not be standardized. This could act as a possible confounder, because, apart from tissue stiffness itself, the applied force causes the extent of tissue deformation during compression [22]. However, to account for this potential source of bias, we calculated the ratio between the two ROIs, allowing for a force independent relative assessment of tissue elasticity. Alternatively, another way to standardize the applied force would have been by means of shear waves generated with shear wave sonoelastography. In this technique the ultrasound signal causes standardized shear deformation of the tissue [16, 23] which can be used in the case of an inhomogeneous nodule, for example endometriosis. Shear wave elastography requires no compression and thereby reduces inconsistencies caused by the operator [11]. Moreover, it is important to mention that the TDI-Q software, which was used for the offline analysis of the raw dataset, was not specifically developed for gynecological ultrasound. With elastography, the axial motion in the direction of the probe can be estimated very sensitively [24]. In conclusion, our study has confirmed that the calculation of the ROI ratio after the use of elastography is associated with the presence of a lesion indicative of endometriosis possibly allowing for a more detailed pre-surgical evaluation. We observed a significant correlation of the ratio between the two ROI measuring points in the Douglas’s cul-de-sac with the corresponding palpatory findings. Further studies with a larger number of patients are required to evaluate the diagnostic value of these novel findings. Furthermore, to overcome the limitations of Doppler-based strain measurements, a future aim could be to analyze the significance of shear waves and speckle tracking-based [25] deformation calculation.
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07 Piketty M, Chopin N, Dousset B et al. Preoperative work-up for patients with deeply infiltrating endometriosis: transvaginal ultrasonography must definitely be the first-line imaging examination. Hum Reprod 2009; 24: 602 – 607 08 Hudelist G, English J, Thomas AE et al. Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2011; 37: 257 – 263 09 Fratelli N, Scioscia M, Bassi E et al. Transvaginal sonography for preoperative assessment of deep endometriosis. J Clin Ultrasound 2013; 41: 69 – 75 10 Itoh A, Ueno E, Tohno E et al. Breast disease: clinical application of US elastography for diagnosis. Radiology 2006; 239: 341 – 350 11 Cosgrove D, Piscaglia F, Bamber J et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: Clinical applications. Ultraschall in Med 2013; 34: 238 – 253 12 Wojcinski S, Degenhardt F, Peisker U et al. Sonoelastography usage among German DEGUM-certified breast ultrasound specialists. Ultraschall in Med 2014; 35: 59 – 66 13 Pozzi E, Mantica G, Gastaldi C et al. The role of the elastography in the diagnosis of prostate cancer: a retrospective study on 460 patients. Arch Ital Urol Androl 2012; 84: 151 – 154 14 Sporea I, Sirli RL. Hepatic elastography for the assessment of liver fibrosis – present and future. Ultraschall in Med 2012; 33: 550 – 558 15 Teng DK, Wang H, Lin YQ et al. Value of ultrasound elastography in assessment of enlarged cervical lymph nodes. Asian Pac J Cancer Prev 2012; 13: 2081 – 2085 16 Sebag F, Vaillant-Lombard J, Berbis J et al. Shear wave elastography: a new ultrasound imaging mode for the differential diagnosis of benign and malignant thyroid nodules. J Clin Endocrinol Metab 2010; 95: 5281 – 5288 17 Hernandez-Andrade E, Hassan SS, Ahn H et al. Evaluation of cervical stiffness during pregnancy using semiquantitative ultrasound elastography. Ultrasound Obstet Gynecol 2013; 41: 152 – 161 18 Bamber J, Cosgrove D, Dietrich CF. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastrography. Part 1: Basic principles and technology. Ultraschall in Med 2013; 34: 169 – 184 19 Hall TJ. AAPM/RSNA physics tutorial for residents: topics in US: beyond the basics: elasticity imaging with US. Radiographics 2003; 23: 1657 – 1671 20 Haas D, Shebl O, Shamiyeh A et al. The rASRM score and the Enzian classification for endometriosis: their strengths and weaknesses. Acta Obstet Gynecol Scand 2012; 92: 3 – 7 21 D'hooge J, Heimdal A, Jamal F et al. Regional strain and strain rate measurements by cardiac ultrasound: principles, implementation and limitations. Eur J Echocardiogr 2000; 1: 154 – 170 22 Fruscalzo A, Schmitz R, Klockenbusch W et al. Reliability of cervix elastography in the late first and second trimester of pregnancy. Ultraschall in Med 2012; 33: 101 – 107 23 Parker KJ, Fu D, Graceswki SM et al. Vibration sonoelastography and the detectability of lesions. Ultrasound Med Biol 1998; 24: 1437 – 1447 24 Kyounghee K, Donghee P, Jingam P et al. A lateral speckle tracking algorithm for ultrasound elastography. Journal of the Korean Physical Society 2012; 60: 171 – 176 25 Geyer H, Caracciolo G, Abe H et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr 2010; 23: 351 – 369
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Original Article
561
Importance of Transvaginal Ultrasound Applying Elastography for Identifying Deep Infiltrating Endometriosis – A Feasibility Study Stellenwert der transvaginalen Elastografie zur Diagnose tief infiltrierender Endometriose – eine Durchführbarkeitsstudie Authors
M. L. Schiffmann1, S. D. Schäfer1, A. N. Schüring1, L. Kiesel1, C. Sauerland2, M. Götte1, R. Schmitz1
Affiliations
1
Clinic of Obstetrics and Gynaecology, University Hospital Münster Institute of Biostatistics and Clinical Research, University of Münster
Key words
Abstract
Zusammenfassung
"
!
!
Purpose: To evaluate the presence of a lesion indicative of endometriosis with transvaginal elastography. Materials and Methods: Transvaginal ultrasound and clinical examination were carried out in 48 women with clinical symptoms indicative of endometriosis. In 31 cases strain values were measured at two regions of interest (ROIs) in the Douglas's cul-de-sac during a cycle of compression and decompression with a vaginal probe. Results: A significant difference was found for the ratio of the ROI measuring points in the Douglas' cul-de-sacs of women with a palpable nodule in examination compared to women without a palpable nodule (p = 0.002). Conclusion: The ratio of strain values between two ROIs in the Douglas' s cul-de-sac is associated with the presence of an endometriotic lesion. In the future, these findings could allow for a more detailed pre-surgical evaluation and possibly serve as a novel diagnostic tool for predicting deep infiltrating endometriosis.
Ziel: Beurteilung des Vorliegens eines Endometrioseherdes mithilfe transvaginaler Elastografie. Material und Methoden: Bei 48 Frauen mit typischer klinischer Symptomatik wurde ein transvaginaler Ultraschall und eine klinische Untersuchung durchgeführt. In 31 Fällen wurde die Verformbarkeit des Gewebes während abwechselnder Kompression und Dekompression gemessen. Diese Messungen fanden an zwei umschriebenen Bereichen des Douglas-Raums, so genannten “Regions of interest” (ROIs), statt. Ergebnisse: Im Vergleich von Frauen, bei denen in der klinischen Untersuchung ein Knoten getastet wurde, und Frauen, die keinen solchen Knoten aufwiesen, zeigte sich ein signifikanter Unterschied der Ratio der ROI-Messpunkte des Douglas-Raums (p = 0,002). Schlussfolgerung: Die Ratio der ROI-Messpunkte des Douglas-Raums ist mit dem Vorliegen eines Endometrioseherdes assoziiert. In der zukünftigen Anwendung können diese Erkenntnisse eine zusätzliche präoperative Einschätzung von Endometrioseherdbefunden ermöglichen. Die Elastografie kann als neue Methode in der Diagnostik der tief infiltrierenden Endometriose eingesetzt werden.
Introduction
endometriosis is not always correlated with the extent of symptoms a woman experiences and in some cases symptoms may be completely absent. With regard to an estimated number of unknown cases, the prevalence of endometriosis among premenopausal women is about 6 – 10 % [1]. In addition to pain symptoms, infertility is common in endometriosis. About 35 – 50 % of women with pelvic pain or infertility are estimated to suffer from endometriosis [3]. Several mechanisms are suspected to cause infertility, for instance the
● endometriosis ● ultrasound ● pelvic organs ● uterus " " "
received accepted
8.9.2013 28.5.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366747 Published online: July 11, 2014 Ultraschall in Med 2014; 35: 561–565 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0172-4614 Correspondence Marie-Luise Schiffmann Clinic of Obstetrics and Gynaecology, University Hospital Münster Albert-Schweitzer-Campus 1 Gebäude A1 48149 Münster Germany Tel.: ++ 49/2 51/8 34 82 61 Fax: ++ 49/2 51/8 34 82 10 [email protected]
!
Endometriosis is defined as the appearance of ectopic endometrial stroma and glands outside the uterine cavity [1]. As a consequence of cyclic hormonal changes, the ectopic endometrial tissue proliferates just like eutopic endometrium. This leads to a local inflammatory response, which is commonly associated with various clinical symptoms, for example dysmenorrhea, dysuria, dyschezia, bleeding disturbances and cycle-dependent or chronic pelvic pain [2]. The severity of
Schiffmann ML et al. Importance of Transvaginal … Ultraschall in Med 2014; 35: 561–565
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Original Article
malfunction of the pelvic anatomy due to adhesions or impaired implantation potential [4]. At present, two classifications are used for endometriosis. The revised American Society of Reproductive Medicine classification of endometriosis (rASRM) was designed to classify the impact of endometriosis on infertility in the individual patient [5]. However, as a drawback, the rASRM classification cannot be used for deep infiltrating endometriosis (DIE). This gap is closed by the ENZIAN classification which specifically describes location and extent of DIE [6]. Transvaginal ultrasound (TVUS) is a time- and cost-efficient method for the diagnosis of endometriosis. Moreover, TVUS is well accepted by patients and it allows for dynamic examination of the pelvic anatomy. It is necessary to have preoperative information about adhesions, infiltration and the extent of endometriosis to be able to decide on the treatment strategy and take into consideration associated surgical risks. For these reasons TVUS should be used as an integral part of every gynecological exam [7]. Hudelist et al. [8] systematically reviewed 188 papers of which 10 fulfilled the inclusion criteria. They found that TVUS has a sensitivity of 90 % and a specificity of 98 % in the diagnosis of DIE of the bowel. However, the diagnosis of an endometriotic nodule in the Douglas’s cul-de-sac remains difficult. Fratelli et. al. [9] found that TVUS has a sensitivity of only 31 % and a specificity of 90 % in the diagnosis of the size of an endometriotic nodule located at the Douglas’s cul-de-sac. Elastography has been successfully utilized in the diagnosis of breast cancer [10, 11]. A significant number (21.2 %) of German ultrasound specialists are already using elastography to evaluate breast lesions. A further increase is expected [12]. Other areas of application are improvements in the diagnosis of prostate cancer, the evaluation of liver stiffness, and the differential diagnosis of benign and malignant cervical lymph nodes or thyroid nodules [11, 13 – 16]. Recently, Hernandez-Andrade et al. [17] evaluated the consistency of the uterine cervix during pregnancy by the use of ultrasound elastography. In order to gain more information about the endometriotic lesions delivered by B-mode TVUS, we used real-time Dopplerbased elastography. Ultrasound elastography can measure tissue elasticity. External compression is applied to the tissue with the ultrasound probe, which causes tissue deformation [18]. This is measured as strain. Strain is relative to the intensity of the applied compression and the modulus of elasticity of the intrinsic material [19]. A strain gradient between the posterior fornix and the Douglas’s cul-desac is known from clinical experience. It is possible to visualize the strain value by the use of superimposed coloring on the Bmode image. Moreover, it is possible to compare the strain of two regions of interest (ROI). The aim of our feasibility study was to correlate the presence of a lesion indicative of endometriosis located at the Douglas’s culde-sac with transvaginal elastography. Assuming that preoperative elastography can acquire further information about the position and infiltration depth of an endometriotic nodule, this information can be a useful tool for the surgeon for preoperative planning. Moreover, unnecessary operations could be prevented based on the gained information.
Methods !
Study population Between June 2011 and June 2012, we performed a prospective study. The study population consisted of 48 women with suspicion of endometriosis, who were transferred to the tertiary endometriosis referral center at the University Hospital Münster. We included women with suspicion of endometriosis due to dysmenorrhea, dyspareunia, dyschezia and dysuria. Detailed medical history was taken with regard to previous surgery, gravidity and previous treatment with gonadotropin-releasing hormone (GnRH) agonists. Patients with genital malformations and previous gynecologic surgery of the Douglas’s cul-de-sac were excluded. Informed consent was obtained from all patients. Our institutional ethics review board approved the study.
Clinical examination All women underwent a clinical examination conducted by an experienced gynecologist of the endometriosis center (S.S.) who included a vaginal and rectal examination prior to TVUS. The abdominal wall was palpated with regard to tenderness or a nodule. During a bimanual vaginal examination, special attention was paid to tenderness, areas of decreased elasticity or a nodule located in the Douglas’s cul-de-sac, the uterus, the vagina and the uterosacral ligaments. In the following digital rectal examination, we paid attention to any nodule involving the intestinal wall.
Raw dataset collection Transvaginal elastography was performed with an Aplio XG ultrasound system (Toshiba Medical Systems Europe, Zoetermeer, Netherlands) using the PVT-681MV 6-MHz transducer. The examining gynecologist was an experienced specialist of the gynecologic ultrasound department (R.S.). The uterus, the vagina and rectovaginal space, the uterosacral ligaments, both adnexa, the rectosigmoid and the urinary bladder were examined by B-mode ultrasound. The diagnosis of adenomyosis was made when the following criteria were met: heterogeneous structure or irregular shape of the myometrium, asymmetry of the anterior and the posterior uterine wall and thickening of the junctional zone. Subsequent to the B-mode scan, we performed the dual-mode scanning (twin-mode) for real-time Doppler elastography. The elasticity images are colored in a range from blue over green to red, according to the deformability of the tissue. They are superimposed on the B-mode images for better orientation. The ultrasound probe was pressed gently in the direction of the Douglas’s cul-de-sac. These movements could be traced on the screen by real-time B-mode. Alternating compression and decompression was performed several times to reduce image interference.
Offline analysis of the raw dataset The raw dataset was evaluated with TDI-Q software (Tissue Doppler Imaging Quantification, Toshiba Medical Systems Europe). A second investigator, who was not involved in any previous examination, reviewed the data. The perceived strain values for each raw dataset were blinded with respect to the previous results and to the first investigator. The preset for the strain measurements was “Tissue Tracking Natural” and angle correction was deactivated. In order to calculate the strain from the
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Surgical findings Surgery was performed in 26 cases by the first investigator (S. S.). The ENZIAN and rASRM [20] scores were determined on the basis of intraoperative findings.
Results !
Characteristics of the study population are summarized in ●" Table 1. The mean ± SD age of the population was 32.7 ± 8.0. A total of 33 (69 %) patients were nulliparous, 6 (12 %) had previous surgery and 10 (21 %) had been pre-treated with GnRH (gonadotropin-releasing hormone). The patients had a history of dysmenorrhea (33; 79 %), dyspareunia (18; 42 %), dyschezia (14; 30 %) and dysuria (12; 26 %). Surgery after elastography was conducted in 26 (54 %) cases. The rASRM and ENZIAN scores of the patients who " Table 2. underwent surgery are pictured in ● The findings of the clinical examinations are visualized in ●" Table 3. During the examination of the Douglas’s cul-de-sac, 9 (19 %) patients reported pain during palpation. The examination of the uterus/the uterosacral ligaments was associated with pain in 24 (50 %) and 6 (13 %) cases, respectively. Transvaginal sonography found the presence of a lesion indicative of endometriosis in the Douglas’s cul-de-sac in 7 (15 %) cases,
Statistical analysis Descriptive statistics were used to characterize the study population. The results are shown as mean ± standard deviation (SD) or the absolute number of patients is mentioned. Comparison of the ratio between the ROI measuring points in the Douglas’s cul-de-sac and the palpatory findings was assessed using the Mann-Whitney U-test for independent samples. Statistical analysis was performed by SPSS software (IBM Corporation, New York, NY, USA, version 21).
Table 1
Characteristics of the study population (n = 48).
age (years)
32.7 ± 8.0
missing
nulliparous
33 (69 %)
0
previous surgery
6 (12 %)
0
GnRH treatment 1
10 (21 %)
1
dysmenorrhea
33 (79 %)
6
values (n)
dyspareunia
18 (42 %)
5
dyschezia
14 (30 %)
2
dysuria
12 (26 %)
2
surgery after elastography
26 (54 %)
0
Data is given as mean ± SD or n (%). 1 GnRH, gonadotropin releasing hormone.
Fig. 1 Transvaginal elastography. a B-mode image. b Position of ROI pressure points in the Douglas’s cul-de-sac. The two ROIs were placed at an equal angle from the axis of the probe. c Strain curves derived from elastography during compression with the vaginal probe. Y-axis: Strain values. X-axis: Strain measurement over time in msec.
Abb. 1 Transvaginale Elastografie. a B-Mode Bild. b Position der ROIMesspunkte im Douglas-Raum. Die beiden Messpunkte wurden im gleichen Winkel zur Ultraschallsondenachse positioniert. c Verformbarkeitskurven (Strain-Kurven), die während der Kompression des Gewebes mit der Vaginalsonde mittels Elastografie ermittelt wurden. Y-Achse: Strain-Werte. X-Achse: Strain-Messung im Zeitverlauf in Millisekunden (ms).
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raw dataset, the presetting “natural strain” was used. We placed two ROIs in the tissue of the Douglas’ cul-de-sac. In order to analyze a representative and reproducible part of tissue, a circular ROI with a diameter of 2 mm was used. The first ROI was placed in close proximity to the cervix while the second ROI was positioned in the sacral direction at a distance of 6 mm. In order to allow for a comparable amount of applied pressure, the two ROIs were placed at an equal angle from the axis along the vaginal probe. Strain values were measured during a cycle of compression and decompression applied with the vaginal probe " Fig. 1). (● According to the strain gradient between the posterior fornix and the Douglas’s cul-de-sac, we calculated the ratio between the maximum strain value of the first and the second ROI (ROI1/ ROI2). This ratio was compared with the presence of a palpable nodule in the Douglas’s cul-de-sac.
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Table 2 rASRM and ENZIAN score of the patients who underwent surgery (n = 26).
patient
rASRM
A
4
ENZIAN A1 B3 FA
B
0
0
C
0
FA
D
2
0
E
4
A1 FB
F
4
A3 FA
G
4
0
H
3
A2 B1 FA FI
I
1
A1 B1
J
1
FA
K
0
0
L
4
C2 FA
M
1
FA
N
1
FA
O
1
FA
P
2
B3 FA
Q
0
A1
R
1
FA
S
3
B3 FB
T
4
B3
U
1
B2 FA
V
0
0
W
4
FA FI
X
3
A1 B1
Y
2
B3
Z
4
B3 FA
ENZIAN classification divides retropertitoneal structures into three compartments. A: rectovaginal septum and vagina, B: sacrouterine ligament to pelvic wall and C: rectum and sigmoid colon. The lesions are graded as 1: < 1 cm, 2: 1 – 3 cm or 3: > 3 cm. For retroperitoneal distant locations, the prefix F (“far“) is used (FA = adenomyosis, FB = involvement of the bladder, FU = intrinsic involvement of the ureter, FI = bowel disease cranial to the rectosigmoid junction, FO (“other”) = other locations). rASRM score distinguishes between four stages of severity Stage 1: 1 – 5 points, stage 2: 6 – 15 points, stage 3: 16 – 40 points, stage 4: > 40 points.
Table 3
Clinical examinations (n = 48).
location
pain during
palpable nodule
palpation Douglas uterus uterosacral ligaments
9 (19 %)
9 (19 %)
24 (50 %)
0 (0 %)
6 (13 %)
3 (6 %)
Data is given as n (%).
in the uterus in 31 (64 %) cases and in the uterosacral ligaments in 4 (8 %) cases. The data from elastography were compared with palpatory findings. The ratio between the ROI measuring points in the Douglas’s cul-de-sac was correlated with the presence of a palpable lesion indicative of endometriosis in the Douglas’s cul-de-sac. After offline analysis and applying the Mann-Whitney U-test, a significant correlation between the ROI1 / ROI2 ratio and a palpable lesion indicative of endometriosis was found (p = 0.002). The values of the ratio ranged from 0.28 to 7.60 with a median of 1.70. The comparison between the ratio and a palpable lesion indicative of endometriosis in the Douglas’s cul-de-sac is pictured with a box" Fig. 2). and-whisker plot (●
Fig. 2 Presence of a palpable lesion indicative of endometriosis correlated with the ratio (ROI1/ROI2) between two ROI measuring points in proximity of the uterus (ROI1) and 6 mm afar in sacral direction (ROI2) (p = 0.002). Abb. 2 Vorliegen eines tastbaren Endometrioseherdes in Korrelation mit der Ratio (ROI1/ROI2) zwischen zwei ROI Messpunkten in der Nähe des Uterus (ROI1) und in 6 mm Abstand in sakraler Richtung (ROI2) (p = 0.002).
Discussion !
DIE of Douglas’s cul-de-sac results in a generally reduced elasticity due to scarring and remodeling by connective tissue. Therefore, in our study, similar maximum strain values were observed at both ROI pressure points – at ROI2 in the immediate proximity of the uterus and at ROI2 at a distance of 6 mm in the sacral direction – leading to a smaller value of the respective ratio. In the case of a Douglas’s cul-de-sac without endometriosis, the maximum values became smaller with an increasing distance from the uterus. As a result, the ratio between the ROI pressure points increased. In order to prevent scar tissue from previous operations from impacting the distribution of strain during elastographic imaging, we excluded patients with previous gynecologic surgery of the Douglas’s cul-de-sac. In the diagnosis of breast tumors with elastography, it is possible to compare the surrounding normal tissue with the suspected malignant tumor. In contrast to a nodule in the breast, an endometriotic lesion in the pelvis cannot be visualized as easily and adjacent healthy – “reference” – tissue is not always present. As a consequence, it is more difficult to standardize the elasticity of endometriotic lesions versus normal elasticity. The results of our study support the hypothesis that the ratio between the applied ROI pressure points is an eligible parameter to identify patients with DIE. Strain can be calculated relatively to the initial length of an object (hereafter referred to as “Lagrangian strain”) or relative to a reference that changes during the process of deformation (“natural strain”). In the case of a small deformation, both the Lagrangian strain and the natural strain are comparable. However, in cases of large deformations, as occurred in this study, the natural strain should be preferred [21].
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As a possible limitation of our study, the force applied during transvaginal elastography could not be standardized. This could act as a possible confounder, because, apart from tissue stiffness itself, the applied force causes the extent of tissue deformation during compression [22]. However, to account for this potential source of bias, we calculated the ratio between the two ROIs, allowing for a force independent relative assessment of tissue elasticity. Alternatively, another way to standardize the applied force would have been by means of shear waves generated with shear wave sonoelastography. In this technique the ultrasound signal causes standardized shear deformation of the tissue [16, 23] which can be used in the case of an inhomogeneous nodule, for example endometriosis. Shear wave elastography requires no compression and thereby reduces inconsistencies caused by the operator [11]. Moreover, it is important to mention that the TDI-Q software, which was used for the offline analysis of the raw dataset, was not specifically developed for gynecological ultrasound. With elastography, the axial motion in the direction of the probe can be estimated very sensitively [24]. In conclusion, our study has confirmed that the calculation of the ROI ratio after the use of elastography is associated with the presence of a lesion indicative of endometriosis possibly allowing for a more detailed pre-surgical evaluation. We observed a significant correlation of the ratio between the two ROI measuring points in the Douglas’s cul-de-sac with the corresponding palpatory findings. Further studies with a larger number of patients are required to evaluate the diagnostic value of these novel findings. Furthermore, to overcome the limitations of Doppler-based strain measurements, a future aim could be to analyze the significance of shear waves and speckle tracking-based [25] deformation calculation.
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