Sonohysterographic endometrial sampling and hysteroscopic endometrial biopsy: a comparative study

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1 Ultrasound Obstet Gynecol 2007; 29: Published online in Wiley InterScience ( DOI: /uog.3981 Sonohysterographic endometrial sampling and hysteroscopic endometrial biopsy: a comparative study F. P. G. LEONE*, L. CARSANA, C. LANZANI*, G. VAGO, and E. FERRAZZI* *Department of Obstetrics and Gynaecology and Department of Pathology, Clinical Sciences Institute L. Sacco, University of Milan, Milan, Italy KEYWORDS: abnormal uterine bleeding; curettage; endometrial sampling; hysteroscopy; morphometry; sonohysterography ABSTRACT Objectives To compare the quantity and quality of endometrial tissue sampled at saline contrast sonohysterography (SCSH) with that obtained by directed endometrial biopsy by operative hysteroscopy in patients with diffusely thickened and/or inhomogeneous endometrium at SCSH. A secondary aim was a comparison of the extent of procedure-related pain. Methods One hundred and twenty-eight patients with diffusely thickened (> 4 mm) and/or inhomogeneous endometrium at SCSH were prospectively recruited. Endometrial sampling was performed at the end of SCSH using the same 4.7-mm intrauterine catheter that had been used for saline instillation. These samples were compared to directed endometrial biopsies obtained with the guidance of an office 5-mm hysteroscope. After hysteroscopy, an extended guided curettage was performed under general anesthesia, providing specimens that were considered the gold standard for histological diagnosis. Endometrial specimen area (mm 2 ), histologic concordance and procedure related pain (10-cm VAS) were compared for the two techniques. Results The median age of 88 pre- and of 40 postmenopausal patients was 41 (interquartile range, 34 48) years and 57 (interquartile range, 52 67) years, respectively. The median area of endometrial specimen obtained by SCSH was 25.1 (interquartile range, ) mm 2 and was not significantly different from that obtained by hysteroscopy (16.9 (interquartile range, ) mm 2 ). The K values of the two different techniques for typical (n = 61) and for premalignant and malignant lesions (n = 26) were 0.91 and 0.94, respectively. Procedure-related pain was not significantly different between pre- and postmenopausal patients for both sampling techniques. Conclusions SCSH with sampling proved to be as good as and as tolerable as hysteroscopic biopsy in cases with diffusely thickened and/or inhomogeneous endometrium. Both these imaging and biopsy techniques should be considered a reliable outpatient procedure in the management of patients with abnormal uterine bleeding. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Transvaginal sonography (TVS) is the imaging technique of choice for first-line investigation of endometrial abnormalities as a possible cause of abnormal uterine bleeding (AUB). This technique has been shown to be an effective and efficacious screening test in postmenopausal women for evaluating AUB caused by endometrial atrophy 1 3. When thickened and inhomogeneous endometrium is present, this procedure, when used as a screening test, is associated with a low specificity and diagnostic limitations which can be overcome by saline contrast sonohysterography (SCSH) 4,5. This can be easily and rapidly performed at minimal cost, is well tolerated by patients and is virtually devoid of complications 6. SCSH has been shown to accurately differentiate focal lesions such as polyps and submucous myomas 7 9 from diffuse lesions such as and cancer 10,11.Inthe case of diffuse lesions, analysis of endometrial histology provides the most relevant information for appropriate treatment. Traditional cytological analysis of the fluid retrieved from the endometrial cavity during SCSH does not contribute to histological diagnosis 12. Hysteroscopically guided curettage has long been the diagnostic gold standard in cases of AUB. Hysteroscopy itself is an effective but expensive screening test for investigating the uterine cavity in both pre- and postmenopausal patients with AUB 13,14. However, both SCSH and hysteroscopy may require histological confirmation of Correspondence to: Dr F. P. G. Leone, Clinical Sciences Institute L. Sacco, University of Milan, Via G.B. Grassi 74, 20157, Milan, Italy ( f.leone@hsacco.it) Accepted: 18 October 2006 Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 444 Leone et al. observed intrauterine lesions 15. Office 5-mm operative hysteroscopy can obtain direct endometrial biopsies using miniaturized forceps in an outpatient setting 16.Thecombined use of SCSH followed by endometrial biopsy has been proposed. A shortcut to this two-step procedure, however, might be achieved by using the same catheter used for saline instillation. Among the few studies focusing on the character of intrauterine catheters 17 20,Bernard et al. 20 reported inadequate specimens at biopsy during SCSH, which were directly correlated with the size and shape of the catheters. In 2001 our group reported preliminary experience of sonographically guided endometrial sampling during SCSH using a 4.7-mm (14-F) intrauterine catheter, obtaining an adequate specimen for one-step sonobioptic (sonographic and histological) diagnosis 21. The objective of this study was to compare the quantity and quality of endometrial tissue sampled at SCSH with that obtained by directed biopsies by office 5-mm operative hysteroscopy in a prospective cohort of patients with diffusely thickened (> 4 mm) and/or inhomogeneous endometrium at SCSH. The secondary aim of the study was a comparison of procedure-related pain. PATIENTS AND METHODS Patients The patients in this study were part of a consecutive series of pre- and postmenopausal women referred for AUB to our outpatient ultrasound clinic. In 510 patients SCSH was performed because of a thickened postmenopausal endometrium (> 4 mm) or inconclusive findings on TVS, or for an inhomogeneous or asynchronous endometrium thicker than 4 mm in premenopausal women. A 4.7- mm (14-F) female urinary catheter (Nelaton ) was used for saline instillation during SCSH (Figure 1). The overall need for cervical dilatation was 17%, with a failure rate in positioning the intrauterine catheter of 8%. At the end of the sonohysterographic examination, these patients underwent endometrial sampling with the same catheter. In 262 patients diffuse endometrial thickening was diagnosed, with a co-existing focal lesion in 33 cases. One hundred and twenty-eight patients with diffuse thickening agreed to undergo a traditional extended curettage under general anesthesia, after hysteroscopic examination and biopsy with a 5-mm operative hysteroscope with miniaturized operative forceps. These 128 patients constituted the study group. Demographic and clinical data were recorded. Ethics committee approval was obtained for the clinical protocol and its informed consent form, which was then signed by each patient. Figure 1 The 4.7-mm (14-F) adapted intrauterine, flexible, oriented, catheter used for sonobiopsy. pattern in premenopausal patients or a thickened endometrial bilayer (> 4 mm) in postmenopausal patients was diagnosed at TVS, they underwent SCSH. SCSH was also performed when endometrial findings on transvaginal imaging were inconclusive. A diagnosis of a diffuse lesion was made when a diffusely thickened endometrial stripe, without focal abnormality, was observed. Figures 2 and 3 show a regular polypoid thickened diffuse endometrial lesion and a focal hyperechoic asynchronous thickened endometrial lesion, both suggestive of endometrial. Figure 4 shows an irregular polypoid thickened diffuse endometrial lesion suggestive of endometrial cancer. As mentioned above, SCSH was performed with a female urinary catheter. This adapted intrauterine, flexible, oriented, catheter has two distal opposed ellipsoid openings of mm at its tip, an inner catheter diameter of 4 mm, and a proximal end capable of being orientated with a round opening of 5.8 mm (Figure 1). This was connected to the 2.7-mm round opening of a 50-mL syringe. After positioning the speculum, the cervix was cleansed with a povidone-iodine solution Imaging and sampling techniques All the patients were assessed using high-resolution TVS with a 3 9-MHz vaginal microconvex probe (Technos MP, Esaote, Genova, Italy) and by SCSH. When an inhomogeneous or asynchronous thickened endometrial Figure 2 Endometrium at saline contrast sonohysterography suggesting diffuse endometrial.

3 Sonohysterographic endometrial sampling 445 Figure 3 Endometrium at saline contrast sonohysterography suggesting focal endometrial. allow for subsequent general anesthesia. The vaginoscopic approach was used, with intrauterine pressure set to 50 mmhg. The uterine cervix and cavity, and tubal ostia were adequately investigated, and three consecutive targeted directed endometrial biopsies (hysteroscopic biopsy) were performed using crocodile forceps with the grasping technique 22. All procedures were digitally recorded. Neither analgesic drugs nor prophylactic antibiotics were administered. After hysteroscopy, a guided extended curettage of the uterine cavity was performed in all patients under general anesthesia, to obtain a standard endometrial sample. Procedure-related pain on a 10-cm visual analog scale (VAS) was assessed for both these imaging and biopsy techniques as follows: no/mild pain (0 4); moderate pain (5 7); severe/intolerable pain (8 10). Histological evaluation Figure 4 Endometrium diffusely thickened and irregular at saline contrast sonohysterography suggesting cancer. and this 14-F catheter was carefully introduced into the uterine cavity. Dilatation of the cervix with a 4-mm dilator was performed in cases of cervical stenosis. At this point, the speculum was gently withdrawn, and the ultrasound probe reintroduced. A 50-mL plastic syringe, filled with 20 ml of sterile isotonic saline solution, was used to slowly inject the fluid into the uterine cavity, which was directly visualized sonographically on sagittal and transverse planes. In doubtful cases injection and withdrawal was performed for a second or third time. Distension of the endometrial cavity was achieved with 5 to 20 ml of fluid. Sonohysterographic sampling was performed at the end of the imaging examination by repeated, combined delicate vacuum aspiration using the 50-mL syringe piston, and fluid injection, with the sampling instrument rotated and moved up and down before its withdrawal. Neither analgesic drugs nor prophylactic antibiotics were administered. All patients underwent hysteroscopy, within 1 month, performed by using the Bettocchi Storz continuous-flow 5-mm ( mm) office hysteroscope with a 5-F operative channel (Karl Storz GmbH & Co., Tuttlingen, Germany). This outpatient procedure was performed without anesthesia, although in an operating theater, to All the samples were immediately fixed in buffered formalin and then wholly embedded in paraffin, cut into 4-µm sections, mounted on slides and stained with H&E. All the histological slices were coded and archived. Microscopic evaluation was then performed on all the slides by a pathologist and reviewed by a senior pathologist in doubtful cases without disclosing the type of biopsy (sonohysterographic sampling, hysteroscopically directed biopsy and guided curettage). An adequate sample was defined as at least one or more pieces of endometrium large enough to determine the gland to stroma ratio and endometrial morphologic features. Histological diagnoses were made according to the current World Health Organization classification 23 and then grouped into five categories, as follows: not adequate; functional endometrium; without atypia; with atypia; cancer. Histological slides were scanned into 300 dpi-definition JPEG-format files using a digital scanner (AGFA, Studio Scan II). Endometrial specimen areas (mm 2 ) were measured by semi-automatic digital color-pattern recognition (Figure 5) 24 using the Kontron Zeiss software. Statistics Demographic data were analyzed by descriptive statistics. Baseline characteristics were summarized as mean and SD for normally distributed variables and by median, 25 th and 75 th percentiles (interquartile range) for non-normally distributed variables. Parametric descriptive statistics were used after demographic data and parameters related to the diagnostic procedure had been tested for normality distribution. The Baily test and the K-test were used to assess diagnostic accuracy of the two tests and compare their perfomances. Sample areas obtained by sonohysterographically guided endometrial sampling, by directed hysteroscopic biopsies and by extended curettage after hysteroscopy were compared after log 10 transformation, using the ANOVA test.

4 446 Leone et al. Table 1 Pathological results according to menopausal status Pathological result Premenopausal women (n = 88) Postmenopausal women (n = 40) Benign lesions Functional/atrophy 37 4 Typical Malignant lesions Atypical 2 2 Cancer 22 Figure 5 Specimen area at sonohysterographic sampling. RESULTS Eighty-eight (69%) patients were premenopausal with a median age of 41 (interquartile range, 34 48) years, and 40 (31%) patients were postmenopausal with a median age of 57 (interquartile range, 52 67) years. Mean body mass index (± SD) was 27 ± 7kg/m 2 and 24 ± 5kg/m 2 in the two groups, respectively. Hysteroscopy was performed in all patients. In six cases (5%) this required the use of hysteroscopic forceps for overcoming cervical stenosis/synechiae. Sonohysterographic sampling and hysteroscopic biopsy were inadequate for histological examination in four (3%) and in three (2%) cases, respectively (a non-statistically significant difference). Twenty-two cases of malignant and two premalignant endometrial lesions were found in the postmenopausal women and only two premalignant lesions were found among the premenopausal women. Typical was more commonly found in premenopausal (49/88) than in postmenopausal women (11/40) (Table 1). Endometrial thickness according to final pathological diagnosis is shown in Table 2. Endometrial thickness in women with atypical /cancer was significantly higher than in women with functional endometrium in postmenopausal but not in premenopausal patients (P = 0.01). Median specimen areas obtained by SCSH, hysteroscopy and extended curettage were 25.1 (interquartile range, ), 16.9 (interquartile range, ) and 25.1 (interquartile range, ) mm 2, respectively. Specimen areas obtained by SCSH and hysteroscopy were not significantly different (ANOVA test, P = 0.18). Table 3 shows the diagnostic concordance of sonohysterographically guided endometrial sampling compared with extended curettage after hysteroscopy. Two premalignant lesions (5 mm and 17 mm at TVS) and six cases of typical endometrial were not diagnosed by sonohysterographically guided endometrial sampling. Table 4 shows the diagnostic concordance of hysteroscopically directed endometrial biopsy compared with extended curettage after hysteroscopy. Premalignant and malignant lesions (26 cases) were correctly diagnosed in Table 2 Endometrial thickness at transvaginal sonography according to pathological report and menopausal status Pathological diagnosis Median thickness (mm (interquartile range)) Premenopausal women (n = 88) Postmenopausal women (n = 40) Functional/atrophy 8 (6 13) 5 (4 6) Typical 12 (7 15) 9 (6 12) Atypical /cancer 11 (7 14) 16 (8 21) Table 3 Diagnostic concordance of sonohysterographically guided endometrial sampling compared with extended curettage after hysteroscopy Histological findings at sonohysterographic sampling Benign lesions (n = 102) Functional (n = 45) Typical (n = 57) Premalignant or malignant lesions (n = 26) Atypical (n = 4) Cancer (n = 22) Functional 40 5 Typical 3* 51 1 Atypical 2 2 Cancer 20 Inadequate *In three patients focal was diagnosed only at saline contrast sonohysterography. Endometrial thickness 17 mm. Endometrial thickness 3 and 6 mm. Endometrial thickness 4 mm. Endometrial thickness 5 mm. all cases. Within benign conditions (102 cases), five cases of simple endometrial were not diagnosed by hysteroscopically directed endometrial biopsy. The percent of agreement (K value) of the two different techniques compared to the gold standard for typical (n = 61) and for pre- and malignant lesions (n = 26) was 0.91 and 0.94, respectively. Mean procedure-related pain scores (± SD) for SCSH with guided endometrial sampling, and for hysteroscopy with directed endometrial biopsy, were 3.8 ± 2.3 and 3.9 ± 2.0, in premenopausal, and 3.7 ± 2.2and3.7 ± 2.0 in postmenopausal women, respectively. No significant differences were observed between the two methods nor between pre- and postmenopausal patients. Patients

5 Sonohysterographic endometrial sampling 447 Table 4 Diagnostic concordance of hysteroscopically directed endometrial biopsy compared with guided curettage after hysteroscopy Hysteroscopic biopsy findings Benign lesions (n = 102) Functional (n = 45) Typical (n = 57) Premalignant or malignant lesions (n = 26) Atypical (n = 4) Cancer (n = 22) Functional 43 3 Typical 1* 52 Atypical 4 1 Cancer 21 Inadequate 1 2 *In one patient focal was diagnosed only at hysteroscopic biopsy. Endometrial thickness 5 mm. Endometrial thickness 3 and 4 mm. reported no/mild, moderate and severe/intolerable pain at SCSH with guided endometrial sampling and at hysteroscopy with directed endometrial biopsy in 73%, 19% and 8%, and in 75%, 16% and 9% of cases, respectively. One clinical vasovagal reaction occurred at the end of sonohysterographic sampling with mild lipothymia, which spontaneously resolved. DISCUSSION In previous decades different diagnostic approaches have been advocated in the management of AUB. A common consensus is that dilatation and curettage (introduced in 1834), and vacuum aspiration (introduced in 1971), performed prior to the availability of direct or indirect imaging techniques, should no longer be recommended because of their limited accuracy The unavailability of endometrial histology in cases of thickened and/or inhomogeneous endometrium could be a major limitation for a complete diagnostic work-up in sonographically based triage for AUB, but this limitation can be overcome by operative office hysteroscopy, which assists directed biopsies. This prospective consecutive case series proved that the diagnostic accuracy achieved by endometrial sampling at SCSH in patients with diffusely thickened and/or inhomogeneous endometrium is comparable to that of directed endometrial biopsy at office hysteroscopy. The percentage of agreement was excellent, both for typical (n = 61) and for pre- and malignant lesions (n = 26), with K values of 0.91 and 0.94, respectively. Specimen areas obtained both at SCSH by delicate vacuum aspiration and at office hysteroscopy by crocodile forceps were not significantly different. In one case only, endometrial sampling at SCSH could have led to temporary clinical under-treatment because a pathological diagnosis of typical eventually proved to be an atypical premalignant lesion. On the other hand, both techniques yielded four tissue samples with a pathologic assessment of typical that was not confirmed by extended curettage. This margin of noncorrespondence does not differ from that for hysteroscopy proved by a large meta-analysis 15 and could be attributed to either different pathological interpretations of tissue samples, or to different samples as obtained by guided or directed biopsies and the final extended curettage. In 2001 we reported preliminary data on one-step sonographic imaging and biopsy, or sonobiopsy, with a 4.7 mm (14-F) intrauterine catheter for saline instillation during SCSH 21. Those findings were not replicated by Metzger et al. 28, who used a smaller (3.1-mm) catheter connected to a standard 10-mL syringe. In our opinion the validity of the sampling technique described in this study is based on the technical aspects of the catheter syringe system we adopted. The catheter used had a 4-mm inner diameter with two distal opposed ellipsoidal openings of 2.3 mm mean diameter at its tip, connected to the 2.7-mm round opening of a 50-mL vesical syringe. This progressively enlarging system is probably of major importance in avoiding tissue disruption during aspiration, as well as the fact that tissue is moved into the syringe by a fluid vector and not by air. The aspiration technique should be performed with repeated rotation and up-and-down movements. Orientated aspirations could be performed in case of diffuse lesions predominantly located in one quadrant of the uterine cavity. Obviously, directed biopsy on focal lesions can be achieved only by forceps under visual direct guidance either by hysteroscopy or ultrasound 29. These data are in agreement with those obtained by a complex three-step procedure in different sequences (vaginal sonography, SCSH, 5-mm Pipelle or vacuum aspiration) reported by other authors 30,31. The overall need for cervical dilatation with a 4-mm dilator was 17%, thus cervical stenosis can be considered a mechanical limit in the feasibility of the technique. Another limitation of this sonobiopsy technique is the procedure-related pain, which is greater than that of standard SCSH, albeit it does not differ between preand postmenopausal women or from hysteroscopy with directed biopsy as observed in the present series. Severe pain was reported by approximately one patient for every ten procedures. Similar results were obtained by several studies comparing standard SCSH to standard diagnostic hysteroscopy 28,32. This is related to the diameter of the catheter, to patient anxiety and to the sampling procedure. Continuously improving catheter characteristics, as occurred with the shift from hysteroscopes to minihysteroscopes, could reduce procedure-related pain. Sonohysterographic endometrial sampling was well tolerated and provided adequate tissue samples in excellent agreement with the results of extended curettage of the endometrium after hysteroscopy, and was as good as office hysteroscopic endometrial biopsies. These results indicate that sonohysterographic endometrial sampling could complete the one-step ultrasound based triage in the majority of patients with thickened and inhomogeneous endometrium.

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