CONFLICT OF INTEREST

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Lithuanian University of Health Sciences Faculty of Medicine Department of Gynecology and Obstetrics

Title of Master’s Thesis:

The value and applicability of hydrosonography for endometrial pathology differentiation Master of Medicine Lithuanian University of Health Sciences

Literature review Author: Ariadna Bernad Supervisor: Dr. Adrius Gaurilcikas

Kaunas 2018/2019

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2

SUMMARY

Author name: Ariadna Bernad

Research Title: The value and applicability of hydrosonography for endometrial pathology differentiation.

Aim: To assess the value and applicability of hydrosonography for endometrial pathology differentiation in different settings of patients compared to conventional transvaginal ultrasound and hysteroscopy.

Objectives:

1. To define the success rate of modified technique hydrosonography in premenopausal and postmenopausal patients.

2. To evaluate the accuracy of hydrosonography for the endometrial pathology in premenopausal and postmenopausal patients.

3. To evaluate the compliance of the patients to the method.

Methods: Literature research in Pubmed, Embase, Medline, using the search terms: “postmenopausal uterine bleeding”, “saline infusion sonohysterography”, “saline contrast sonohysterography”,”

hydrosonography”, “gel infusion sonohysterography”.

A total of 32 articles were used for this review and 12 articles were selected and analyzed.

Inclusion criteria: studies in populations of pre- and postmenopausal women presenting abnormal uterine bleeding, where all patients included underwent transvaginal ultrasound (TVS) and saline infusion sonohysterography (SIS), followed by hysteroscopy (HS) as a reference standard, were included into the analysis. To asses pain/discomfort of the saline infusion sonohysterography (SIS) procedure studies providing VAS score or questionnaire were selected for the analysis.

Results: SIS is more accurate to detect polyp lesions ranging from 37,04%-71,6% in 6 out of 7 studies and myoma lesions ranging from 13%-50% in 6 out of 7 studies than in TVS were polyps’ findings were

<30% detected in 6 out of 7 studies and myoma <27% detected in all studies. Overall sensitivity rates in all studies were >90% for SIS, ranging from 43,48%- 89,4% for TVS, while the overall specificity rates in all studies were 60-100% and 50-100% respectively. SIS overall PPV rates were >89% in 5 out of 7 studies, while TVS PPV rates were >80,90% in 4 out of 7 studies. SIS is well tolerated showing

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4 low-to-moderate discomfort according to VAS score (out of 10) mean 1,5 and 3 in 2 out of 5 studies and VAS score (out of 100) mean 43 and 22,9 in 2 out of 5 studies.

Conclusions: Saline infusion sonohysterography (SIS) procedure is highly accurate in the detection of focal endometrial pathologies, especially in polyp and myoma detection in pre- and postmenopausal women presenting abnormal uterine bleeding (AUB). SIS procedure was successful in the majority of patients irrespective of menopausal status. SIS procedure is uncomfortable, however, due to low- moderate pain/discomfort, it is sufficiently well-tolerated in different settings of patients.

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5

ACKNOWLEDGMENTS

The author wants to express her gratitude towards the supervisor of the work, doctor Adrius Gaurilcikas, for the opportunity to learn about this interesting topic, for all the help and for being so patient.

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6

CONFLICT OF INTEREST

The author reports no conflict of interest.

ABBREVIATION LIST

AUB: Abnormal uterine bleeding

FIGO: International Federation of Gynecology and Obstetrics

TUV/TVS: Transvaginal Ultrasound

SIS: Saline infusion sonohysterography

PMB: Post-menopausal Bleeding

HS: Hysteroscopy

GIS: Gel Instillation sonohysterography

PID: Pelvic inflammatory disease

HRT: Hormonal Replacement therapy

D&C: Dilation and curettage

VAS: Analogue visual scale

EB: Endometrial biopsy

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7

INTRODUCTION

Abnormal uterine bleeding (AUB) is a common complaint in reproductive age women.

Together with the bleeding in the postmenopausal period, they consist up 70 percent of all gynecological consultations (1,2).

The most important goal concerning postmenopausal bleeding (PMB) – is to exclude/confirm the diagnosis of endometrial cancer, which is diagnosed in 4–24 percent of women presenting postmenopausal bleeding (PMB) (3,4).

Traditional diagnostic methods such as cervical dilation and endometrial curettage no longer meet good clinical practice requirements and might be replaced by an assessment of the uterine mucosal pathology by ultrasound, hysteroscopy, and endometrial biopsy. (5)

Even though transvaginal ultrasound (TVS) is the first-line imaging technique in AUB, it has its limitations. Hydrosonography might be an alternative method that helps better visualization and differentiation between diffuse and local endometrial pathologies.

Hydrosonography is a minimally invasive method. This procedure consists of the installation of saline infusion into the uterine cavity through a catheter that is inserted into the cervix. Saline instillation produces uterine distension that allows a single endometrial layer view which provides better visualization of endometrial lesions, the imaging is performed with simultaneous TVS (8). However, sometimes there is an inappropriate filling of saline leading to improperly distension of the uterus due to the backflow of saline and the inability to discriminate endometrial pathology. Distension of the cervical canal or uterine cavity could also result in discomfort to the patient. In trying to overcome these disadvantages, saline infusion sonohysterography (SIS) technique can be modified by installation gel instead of saline (22), this procedure is called gel instillation sonohysterograpghy (GIS).

The aim of the study was to evaluate the value and applicability of hydrosnography for endometrial pathology differentiation compared to conventional transvaginal ultrasound and hysteroscopy.

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8

AIM AND OBJECTIVES

Aim: To assess the value and applicability of hydrosonography for endometrial pathology differentiation in different settings of patients compared to conventional transvaginal ultrasound and hysteroscopy.

Objectives:

1. To define the success rate of modified technique hydrosonography in premenopausal and postmenopausal patients.

2. To evaluate the accuracy of hydrosonography for the endometrial pathology in premenopausal and postmenopausal patients.

3. To evaluate the compliance of the patients to the method.

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9

LITERATURE REVIEW

ABNORMAL UTERINE BLEEDING

Abnormal uterine bleeding (AUB) is a common complaint among reproductive women also in pre- and postmenopausal women, which requires visits to the gynecological department and a sort of investigation. AUB is a significant clinical entity. AUB and its subgroup, heavy menstrual bleeding (HMB), are common conditions affecting 14–25% of women of reproductive age and may have a significant impact on their physical, social, emotional and material quality of life. (6)

In 2011 the International Federation of Gynecology and Obstetrics (FIGO) proposed a new classification system for AUB that was endorsed by the American Congress of Obstetrics and Gynecology accepted, PALM-COEIN, distinguishes AUB based upon suspected etiology: polyp; adenomyosis; leioma;

malignancy and hyperplasia; coagulopathy and ovulatory dysfunction (1) The ‘PALM’ is assessed visually and the ‘COEIN’ are non-structural. (6)

Bleeding occurs in 80-90% of women with endometrial cancer, and the prevalence of endometrial cancer among the women presenting PMB is reported being in the range of 1-60%. However, the majority of women presenting AUB have benign diseases (e.g., Endometrial atrophy, fibroids or polyps) (4)

To evaluate and determine the cause of AUB the following instrumental diagnosis is used; transvaginal ultrasound (TVU) and saline infusion sonohysterography (SIS). Also, other tests can be used like laboratory tests, cytology, hysteroscopy, and biopsy.

POSTMENOPAUSAL BLEEDING

Postmenopausal bleeding (PMB) refers to any uterine bleeding in a menopausal woman (other than the expected cyclic bleeding that occurs in women taking cyclic postmenopausal hormone therapy). It accounts for approximately 5 percent of office gynecology visits.

PMB is spontaneous uterine bleeding that occurs after at least one year after the last menstrual cycle. (8) This accounts for 5% of all gynecological visits and 70% gynecological counseling during perimenopause and postmenopausal (8). Bleeding from the uterus during the postmenopausal period should be considered a likely sign of endometrial cancer until another cause of bleeding has been

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10 confirmed. Therefore, the most important purpose of PMB diagnostics is to exclude endometrial cancer.

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Postmenopausal bleeding can begin due to various changes in the uterine mucosa: from normal eternal endometrial changes, atrophy, hyperplasia, inflammatory diseases of the uterine lining, various derivatives (myomas, polyps) until endometrial adenocarcinoma occurs. (9)

HYDROSONOGRAPHY PROCEDURE

Saline infusion sonohysterography (SIS) is a minimally invasive procedure that allows single endometrial layer examination and gives detailed information between local and diffuse lesions. This method is highly sensitive and specific in diagnosing the causes of abnormal uterine bleeding in pre and postmenopausal women. (3)

SIS procedure consists of the insertion of a flexible catheter containing saline infusion through the cervical canal until the uterine cavity. A 10-20 mL syringe containing sterile saline is attached to the catheter which is flushed before it is inserted through the cervical canal and advanced to the uterine fundus (2). Once the endometrium is seen on the screen, the saline infusion starts leading to distension of the uterine cavity providing a proper visualization of endometrial layers. Usually, 5-10 mL of saline solution are proved to be enough to distend the cavity (4). During saline infusion, the uterine cavity should be evaluated by TVS in longitudinal (or sagittal) and transverse planes. (2).

SIS allows evaluating the endometrium, myometrium and endometrial cavity, allows the identification of masses associated with AUB such polyps, submucous leiomyomas, and intra-cavitary blood cloths.

Compared with TVU, SIS permits the differentiation of endometrial, submucous or intramural lesions.

SIS allows directly taking a histological sample for diagnosis of AUB in pre and post-menopause women. Even though SIS has limitations, SIS is cycle-dependent and the best time to perform this procedure that allows a full clear image is during the proliferative-phase and this minimizes the false- negative, another issue is that it’s more uncomfortable than TVU and approx. 5% of examinations cannot be properly done and subsequently completed generally due to cervical stenosis or patient discomfort.

The thickening of the mucous membrane of the uterus is 5 mm and more shows increased the risk of malignant or another pathological process. (12) A thickened endometrium is a major indication (excluding bleeding) for invasive procedures. (10)

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11 SIS can also be performed adding three-dimensional, 3D SIS. The simultaneous display of 3 perpendicular planes offers a more comprehensive overview of the examined area. (27) 3D SIS is not routinely performed as conventional 2D SIS, however, 3D SIS is increasingly been used as an alternative diagnostic method if 2D SIS or TVS cannot define abnormal endometrial findings. Adding 3D to the SIS procedure helps in the distinction between endometrial and myometrial lesions. (27) It is advised to be used in clinical practice in cases with persistent abnormal uterine bleeding with normal routine vaginal sonography. (31)

HYDROSONOGRAPHY TECHNIQUE AND EQUIPMENT

As mentioned before, SIS is a cycle-dependent method, so SIS scheduling premenopausal women should be performed between 4 and 10 days of the patient’s menstrual cycle when the endometrium is the thinnest. (29) Postmenopausal women may undergo SIS at any time, except for those who are undergoing HRT, therefore, SIS should be performed at the end of the progesterone phase. (29)

The equipment required to perform SIS procedure consists of a speculum, catheter, saline infusion, transvaginal ultrasound and in some cases the use of tenaculum is also required. Speculum and saline are warmed up to prevent patient distension and cramping. Saline can be warmed up using a 1200W microwave oven, heating 500 ml of a bottle for 55 sec. (30)

Patients are placed in a semi-upright or dorsal lithotomy position with the buttocks slightly extended which allows speculum manipulation by the expertise. Obese women or those presenting knees or hip problems, they will not tolerate this position. Thus, it is recommended to bring the knees to the chest and support them manually. (29) Once the patient is placed in the correct lithotomy position, a speculum is inserted into the vagina. There is a variety of speculums accommodated to patient size, as an improper speculum selection can lead to unproperly visualization of the cervix. Graves and Pederson speculums are the most used, Graves has wider blades than Pederson, speculums are chosen according to parity, width and, length of the vagina.

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12 Figure 1. Graves and Pederson speculums

Before the catheter insertion, sterile saline is flushed through a catheter to rid of small amounts of air and the cervix is cleaned with a povidone-iodine solution (22). Foley balloon catheters 8-10 Fr. size are the most commonly used however different studies show a wide range of Foley’s catheter size used to perform SIS procedure from 6-18Fr. size, where 3Fr. is equal to 1 mm. Neonatal suction catheters 2mm in diameter can also be used. Balloon catheters achieve better filling than regular ones but are more likely to cause pain or discomfort to the patient during the procedure due to excessive increased intrauterine pressure (25). When catheter insertion is not possible due to cervical stenosis, some cervical dilators can be used to overcome this problem. The last option performed when difficult access to the cervix, is the tenaculum usage with local anesthesia into the cervix (exocervix) at 12 or 6 o’clock to avoid uterine arteries. (29)

Figure 2. Foley catheter Figure 3. Neonatal suction catheter

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13 The speculum is removed as soon as the catheter is inserted in the cervical canal till the uterine cavity, a continuous installation of saline (0,9% of sodium chloride) is infused causing uterine distension.

Mostly 10-20 ml of saline is used during the SIS procedure, even though there are studies using up till 50 ml of saline infusion. Chawla et al. used normal saline 40-50 ml/min, at 50-100 mm Hg pressure to distend uterus (15). As soon as endometrial images are seen on the screen, the balloon should be deflated (29).

Some examples of SIS endometrial pathologies findings are shown below:

Figure 4. Uterine Normal cavity Figure 5. Endometrial Polyps

Figure 6. Small scar defect Figure 7. Intracavitary fibroid

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14 Figure 8. Endometrial cancer

HYDROSONOGRAPHY LIMITATIONS

The most common cause for unsuccessful SIS procedure is when the uterus is not properly distended, so not clear visualization is obtained, it is due to air bubbles formed during the installation of saline causing a backflow which produce discomfort to the patient. To overcome this inconvenient, it can be used 60 mL of solution filled quickly, use balloon catheters or another technique called gel instillation sonohysterography (GIS) where saline is replaced by gel avoiding bubbles formation.

The gel is warmed up to 37C degrees to decrease viscosity and facilitate passage along the catheter (25).

Endosgel is a sterile gel preparation used during GIS composed of chlorhexidine gluconate, sodium lactate, methyl hydroxybenzonate, propyl hydroxybenzonate, hydroxybethylcellulose and purified water. (22) Instillagel is another gel preparation composed with the same products as Endosgel plus adding lidocaine hydrochloride 20mg/g. (25)

Another important limitation to successful SIS is the pain and the discomfort caused by patients’ anxiety to the procedure, to overcome this problem it is important to provide a calm and relaxing environment, minimal personal stuff and positioning patients away from the door and medical instruments (29).

It is recommended to take non-steroidal anti-inflammatory drugs 30-60 min before the procedure.

Topical xylocaine gel can be used along the vaginal wall and the cervix to avoid pain during the procedure (27).

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15 CONVENTIONAL PROCEDURES

- Transvaginal ultrasound (TVU) is the first line imaging technique for the evaluation of abnormal uterine bleeding in premenopausal and postmenopausal women. This diagnostic method is non-invasive, inexpensive and widely applied in modern clinical practice. Considering the cost-effectiveness ratio of the PMB research strategy, it is believed that TVU, as the primary diagnostic method for PMB, is more effective than endometrial biopsy. (5)

TVU is a non-invasive technique with high sensitivity to the assessment of endometrial pathologies and thickness, it allows full view of endometrium and myometrium so it is suitably used to detect pathologies such leiomyomas. The main purpose of this procedure is to measure the condition of the uterine cavity and to assess endometrium and to measure endometrial thickness in millimeters (10). During a TVU procedure, the endometrial thickness is measured as in postmenopausal women endometrial thickness is correlated with endometrial hyperplasia and cancer risk.

Performing 2D ultrasound sterile saline solution is injected into the uterine cavity - it helps to better evaluate endometrial layer and uterine cavity pathology. Compared to usual 2D transvaginal ultrasound, hydrosonography is more sensitive and more specific for endometrial pathology and has a lower frequency of positive-negative results. (11)

- Hysteroscopy (HS). A basic invasive procedure. This procedure is a minimally invasive surgical intervention that involves the diagnostics of uterus mucosal and therapeutic manipulations. (13) During this procedure, a good endometrium visualization and pathology identification is possible, as well as the removal of pathological derivatives. (13) HS enables to perform the uterine mucosal procedure safely and effectively. (14) Despite the fact that HS is widely used as a common minimally invasive procedure in clinical practice; there is a small debate around the world about the diagnostic value and subjectivity of the procedure compared to the histological uterine mucosa bioptat. (12) The results of this surgical intervention depending on the experience of the doctor, his or her knowledge and capacity. (12)

In the case of sufficient gynecologist qualification and technical capabilities, transvaginal ultrasound examination is a first choice simple and accurate diagnostic method. It helps to determine which women with postmenopausal bleeding have an increased risk of endometrial cancer. Measuring the endometrial thickness by ultrasound, it is possible to reliably differentiate women who have a high or low risk of endometrial cancer. An endometrium with a thickness greater than 5 mm should be considered as pathological, irrespective of hormone replacement therapy (HRT) use, but the frequency of false positive

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16 results for HRT users will be higher. Women whose endometrium cannot be measured are likely to have endometrial pathology and need further investigation. It is believed that those women who seek medical attention because of PMB and whose endometrial thickness does not exceed 4 mm, there is no need for endometrial biopsy, but further research is needed to measure outcomes so that such a surveillance strategy is completely justified.(5)

For women who are examined for PMB and with endometrium of 5 mm or more, endometrial pathology is diagnosed very often, which is almost always identified as focal endometrial pathology during hysteroscopy. If ultrasound diagnosis raises doubts, while performing hydrosonography focal changes in the uterine cavity should be excluded. If focal changes in the uterine cavity are detected, a hysteroscopy resection of these derivatives should be performed. (5)

- Endometrial biopsy (EB). This invasive procedure consists to take a small sample of uterine lining;

endometrium. The sample is later collected to perform a histological examination and establish a diagnosis. This procedure is performed in cases of AUB/PMB or non-uterine bleeding.

Endometrial biopsy sampling is directed taken during the HS procedure. EB is mandatory in order to exclude endometrial malignancies whereas TVS, SIS or HS alone cannot replace biopsy in cases of endometrial cancer suspicion. (20) Although EB is mostly performed in cases of endometrial cancer suspicion if only a small tissue sample is collected (less than 50% of the endometrium) cancer can be missed (28).

Most endometrial abnormalities, including carcinoma, appear as a focal mass during TVS/SIS, therefore women with multifocal or sessile lesions should undergo HS with directed EB (17). For providing accurate differentiation between focal and diffuse endometrial lesions, HS should be performed with directed EB. (17)

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17

RESEARCH METHODOLOGY AND METHODS

A systemic computer literature search for published English language studies was conducted in Pubmed, Embase and Medline databases from January 2009 to January 2019.

The following keywords were used: “saline infusion sonohysterography”, “saline contrast sonohysteropgraphy”, “hydrosonography”, “gel infusion sonohysterography”.

Inclusion criteria were:

- Population women presenting premenopausal and/or postmenopausal bleeding.

- All women included in the studies underwent TVS and SIS procedure followed by HS as a reference standard.

- Studies excluded women presenting: pelvic inflammatory disease (PID), genital tract injury/infections, pregnancy and use of tamoxifen or hormonal replacement therapy (HRT), all patients who didn’t undergo all three procedures also were excluded from the studies.

The following items were collected:

1. Authors and year of publication 2. Design of the study

3. Sample size

4. Pathological endometrial findings of TVS, SIS, and HS.

5. Sensitivity, specificity of TVS, SIS.

6. Positive predictive value (PPV) and Negative predictive value (NPV) of TVS and SIS 7. VAS score results after SIS/GIS/HS procedure.

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18

RESULTS

A total of 7 studies (15-21) (Table 1) met the inclusion criteria and were selected to answer the

question concerning the value, accuracy and success rate of hydrosnography compared to conventional TVS with the reference of HS and EB. The sample of the studies ranged from 60 (study 15) to 137 (study16).

Table 1: Summary of the studies reviewed for the assessment of value and accuracy of SIS compared to TVS with reference to HS and EB.

Nr. Study Year Design Method Reference

Standard

N women

1 Chawla I¹⁵ et al.

2014 Prospective TVS/SIS Hysteroscopy 60

2 Bingol¹⁶ et al.

2011 Prospective TVS/SIS Hysteroscopy with biopsy

137

3 Muhammad Aslam¹⁷et al.

4 Alborzi¹⁸ et al.

5 Mathew¹⁹et al.

2010 Retrospective TVS/SIS Hysteroscopy 70

6 Grimbizis G²⁰ et al.

7 Soguktas S²¹et al.

In order to evaluate the compliance of the patient for the discussed procedure 5 studies (22-26) (table 2) were selected for this review. Compliance was evaluated through a questionnaire of Vas scale of pain (during the introduction of catheter and installation of vaginal fluid) after and throughout SIS procedure.

The sample of the studies ranged from 65 (study 22) to 551 (study 25).

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19 Table 2: Summary of studies reviewed for the assessment of compliance of the patients to

hydrosonography

Nr. Study Year Design Method Method to asses

compliance

N women 8 Bij de

vaate A²²et al.

2010 Prospective GIS/SIS VAS score 65

9 Opolskiene G²³et al.

10 Van

Dongen²⁴ et al.

2010 Randomized controlled trial

SIS/HS VAS score 142

11 Van den Bosch²⁵ et al.

12 Rudra S²⁶ et al.

2009 Prospective SIS/HS VAS score 208

The data extracted from the studies were analyzed and the results are shown in the following tables.

Table 3 shows the endometrial pathological findings results and conclusions from 15-21 studies, where tables 4 and 5 show the comparison of the diagnostic performance of TVS and SIS and tables 6– 9 shows the diagnostic accuracy for each endometrial pathology. All data was taken in order to compare and determine the success rate and accuracy of SIS.

Table 3: Results and conclusions (15-21 studies)

Study Results Interpretation of the results

1.Chawla¹⁵ et

al. TVS: normal cavity 61,66%, endometrial hyperplasia 16,66%, endometrial polyp 15% and submucous myoma 6,66%.

SIS: normal cavity 31,7%, endometrial polyp 41,7%, submucous myoma 21,7%, endometrial hyperplasia 5%.

HS: normal cavity 23,33%, endometrial polyp 51,67%, submucous myoma 20%, endometrial hyperplasia 5%.

The application of SIS compared with TVS showed more accuracy for detecting focal endometrial pathologies. SIS showed overall sensitivity and specificity than TVS.

SIS can be used as an alternative procedure when HS is not available and HS can be reserved when SIS results are inconclusive.

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20 Bingol¹⁶ et al. TVS: endometrial hyperplasia 33,6%,

polyp 30,7%, submucosal myoma 16,1%, endometrial atrophy 14,6% and cancer 5,1%.

SIS: endometrial hyperplasia 27,7%, polyp 39,4%, submucosal myoma 14,6%, endometrial atrophy 14,6% and cancer 3,6%.

HS: endometrial hyperplasia 27,7%, polyp 39,4%, submucosal myoma 14,6%, endometrial atrophy 3,1% and cancer 5,1%.

Biopsy: endometrial hyperplasia 28,4%, polyp 38%, submucosal myoma 10,2%, endometrial atrophy 12,4% and cancer 5,8%.

SIS seems to be superior then TVS, more accurate to detect uterine abnormalities, especially at polyp detection in postmenopausal women presenting AUB.

SIS and HS findings are mostly identical, also superior to TVS.

The 3 methods were similar to detect cancer and atrophy although inferior then biopsy as the gold standard.

Muhammad¹⁷

Aslam et al. TVS: normal uterine cavity 53%, endometrial hyperplasia 28%, myoma 9%, polyp 10%.

SIS: normal uterine cavity 55%, endometrial hyperplasia 20%, myoma 13%, polyp 10%, other 2%.

HIS: normal uterine cavity 55%, endometrial hyperplasia 16%, myoma 13%, polyp 10, other 6%.

SIS seems to be a better tool than TVS detecting intrauterine lesions (polyp, hyperplasia and myoma) and it allows differentiation between focal and diffused endometrial lesions. HS can be used as an alternative method.

SIS should be used as a primary tool diagnosing AUB.

Alborzi¹⁸ et

al. TVS: myoma 27,16%, polyp 12,34%, adenomyosis 16%

SIS: myoma 29,63%, polyp 37,04%, adenomyosis 13,58%

HS: myoma 28,39%, polyp 39,50%, adenomyosis 11,11 %.

TVS has shown less overall

sensitivity, specificity, PPV and NPV than SIS.

SIS was more sensitive and specific in diagnosing polyp and myoma and adenomyosis compared to TVS.

SIS provided better visualization of uterine wall thickness and structures;

it is thought that it can be related to the cavity distension caused by the injection of contrast during SIS performance.

SIS results were more accurate than TVS and HS.

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21 Mathews¹⁹ et

al.

TVS: normal uterine cavity 45,7%, polyp/fibroid 27,1%, thick endometrium 27,1%.

SIS: normal uterine cavity 41,4%, polyp/fibroid 50%, other abnormalities 8,6%.

HS: normal uterine cavity 40%, polyp/fibroid 50%, other abnormalities 10%.

TVS has proved the value of being the first tool diagnosing AUB but it showed limitations evaluating the intrauterine cavity.

SIS has shown higher sensitivity and higher accuracy in polyp/fibroid detection as TVS.

SIS enhances the diagnostic accuracy of TVS at uterine cavity evaluation in women with AUB.

Grimbizi G²⁰

et al TVS: normal uterine cavity 22,4%, endometrial hyperplasia/cancer 35,7%, intracavitary masses 35,7% (myoma 22,8%/polyp 78,2%), others 6,1%.

SIS: normal uterine cavity 21,4%, endometrial hyperplasia/cancer 4,1%, intracavitary masses 68,4% (myoma 28,4%/ polyp 71,6%), other 6,1%.

HS: normal uterine cavity 24,5%, endometrial hyperplasia/cancer 5,1%, intracavitary masses 61,2% (myoma 26,7%/polyp 73,3%), other 8,2%.

SIS seems to be more valuable than TVS in the diagnosis of intracavitary masses (myoma, polyp), but HS was found to be a better technique than SIS and TVS.

SIS should be used when myoma or polyp are suspected and then proceed to HS performance.

Soguktas S²¹

et al. TVS: endometrial polyp 30,3%, submucosal myoma 3,4%, endometrial hyperplasia 19,1%, endometrial

carcinoma 7,9%, others 39,3%.

SIS: endometrial polyp 33,7%,

submucosal myoma 4,5%, endometrial hyperplasia 10,1%, endometrial

carcinoma 5,6% and other 46,1%.

HS: endometrial polyp 35,9%,

submucosal myoma 4,5%, endometrial hyperplasia 9,1%, endometrial carcinoma 5,6% and others 44,8%.

HS and SIS diagnostic accuracy detecting endometrial hyperplasia, cancer and submucous myoma findings were identical. TVS didn’t allow distinguishing them.

SIS seems to be superior detecting polyp then TVS, although HS is superior to SIS of diagnostic performance in the evaluation of AUB.

Table 4: Comparison of diagnostic performance of TVS and SIS: sensitivity and specificity (hysteroscopy as “gold standard”)

SIS TVS

Study Sensitivity (%) Specificity (%) Sensitivity (%) Specificity (%)

Chawla¹⁵et al. 89,1 100 43,48 78,57

Bingol¹⁶ et al. 89,6 77,30 70 50

Muhammad¹⁷ et al.

92,86 89,66 71,43 67,7

Alborzi¹⁸ et al. 94,1 95 72 92

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22 Table 5: Comparison of diagnostic performance of TVS and SIS: positive predictive value (PPV) and negative predictive value (NVP) (hysteroscopy as “gold standard”)

SIS TVS

Study PPV* NPV** PPV NPV

Chawla¹⁵ et al. 100% 73,7% 86,96% 29,73%

Bingo¹⁶ et al. 95,3% 58,3% 80,90% 35,4%

Muhammad¹⁷ et al.

92,86 89,66 54,35 81,48

Alborzi¹⁸ et al. 96% 90% 94% 90%

Mathew¹⁹ et al. 89,3% 94,1% 100% 100%

Grimbizi G²⁰ et al.

Not provided Soguktas S²¹ et

al.

Not provided

Table 6: Diagnostic accuracy of SIS for differential endometrial pathology: normal endometrial cavity

Study TVS SIS HS

Chawla¹⁵ at al. 61,66% 31,7% 23,3%

Bingo¹⁶ et al. - - -

Muhammad¹⁷ et al. 53% 55% 55%

Alborzi¹⁸ et al. - - -

Mathew¹⁹ et al. 45,7% 41,4% 40%

Grimbizi G²⁰ et al. 22,4% 21,4% 24,5%

Soguktas S²¹et al. - - -

Mathew¹⁹ et al. 91,4 92,6 72,4 100

Grimbizi G²⁰ et al

91,78 60 89,04 56

Soguktas S²¹ et al.

93,6 90,5 89,4 71,4

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23 Table 7: Diagnostic accuracy of SIS for differential endometrial pathology: Endometrial polyp

Chawla¹⁵ at al. 15% 41,7% 51,7%

Bingo¹⁶ et al. 30,7% 39,4% 39,4%

Alborzi¹⁸ et al. 12,34% 37,04% 39,5%

Mathew¹⁹ et al. 27,1% 50% 50%

Grimbizi G²⁰ et al. 78,2% 71,6% 73,3%

Soguktas S²¹et al. 30,3% 33,7% 35,9%

Table 8: Diagnostic accuracy of SIS for differential endometrial pathology: Myoma/fibroid

Chawla¹⁵ at al. 6,7% 21,7% 20%

Bingo¹⁶ et al. 16,1% 14,6% 10,2%

Alborzi¹⁸ et al. 27,16% 29,6% 28,4%

Mathew¹⁹ et al. 21,7% 50% 50%

Grimbizi G²⁰ et al. 22,8% 28,4% 26,7%

Soguktas S²¹et al. 3,4% 4,5% 4,5%

Table 9: Diagnostic accuracy of SIS for differential endometrial pathology: hyperplasia or cancer

Chawla¹⁵ at al. 16,66% 5% 5%

Bingo¹⁶ et al. 33,6% + 5,1% 27,7% + 3,6% 27,7% + 5,1%

Alborzi¹⁸ et al. - - -

Mathew¹⁹ et al. - - -

Grimbizi G²⁰ et al. 35,7% 4,1% 5,1%

Soguktas S²¹et al. 19,1% + 7,9% 10,1% +5,6% 9,1% + 5,6%

Table 10 summarizes findings of 22-26 studies, which were performed to evaluate the compliance of the patient for the SIS procedure.

Table 10: Results and conclusions (22-26 studies)

Study Results Interpretation of results

Bij de vaate A²² et al.

VAS (0=no pain – 10= worst pain) SIS: VAS score mean 1,5

(GIS: VAS score mean 1,6)

The mean of both procedures was low, meaning that processes were well tolerated.

Pain and discomfort were more associated during the insertion of the catheter than of

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24 installation than fluid, so for that, pain score can be influenced by the catheter insertion then by itself. Some patients experienced cramps during fluid installation; this could be avoided by reducing the amount.

Opolskiene G^23.et al.

VAS (0=no pain – 100= worst pain)

SIS: VAS score mean 43

Postmenopausal women (71%) experienced more pain (sharp pain) than premenopausal women (32%) (cramping pain) and 41%

didn’t experience pain. The pain experienced was moderate.

Postmenopausal women experienced pain one day after the SIS procedure.

Analgesia before performing SIS procedure in postmenopausal women should be recommended for further procedures.

Van Dongen²⁴et al.

VAS (0=no pain – 10= worst pain) SIS: VAS score mean 3

(HS: VAS score mean 4,9)

SIS procedure is less painful although more women prefer HS procedure.

Van den Bosch²⁵et al.

VAS (0=no pain – 100= worst pain)

SIS: VAS score mean 22,9 (GIS: VAS score mean 16,5)

The pain reported during GIS was less than in SIS procedure.

Rudra S²⁶et al. In this study, pain rating was used instead of VAS scale.

(1-minimal discomfort, 2-

acceptable discomfort, 3-tolerable pain, 4-sever intolerable pain) SIS: minimal discomfort 136 patients, acceptable 60, tolerable 4 and no patients experienced severe intolerable pain.

(HS: minimal discomfort 66 patients, acceptable discomfort 94, tolerable pain and severe

intolerable pain 14 patients)

The pain rating showed to be higher while performing HS than SIS.

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25

DISCUSSION

The variety of the studies analyzed in this systemic review provides a wide sight of the SIS procedure in order to evaluate and diagnose the cause of AUB in pre- and postmenopausal women.

According to data collected from the selected studies, SIS has shown to have high accuracy (high sensitivity and PPV) and diagnostic value diagnosing endometrial pathologies differentiation.

In order to detect focal endometrial pathology- endometrial polyp or myoma, SIS has demonstrated to be more accurate than TVS and mostly identical than HS used as the reference standard. It is shown that TVS misses the detection of polyps and myoma classifying as normal uterine cavity findings and fails to discriminate between them. This can be related due to TVS difficulties performing the procedure when women presenting endometrial thickness and are more remarkable when assessing postmenopausal women due to the endometrial changes after the menopause. Therefore, the addition of SIS to TVS increases its accuracy in order to examine postmenopausal women and women presenting a thickened endometrium.

In order to detect endometrial hyperplasia and endometrial cancer, according to the results, TVS has shown to be more accurate than SIS, this is an unexpected result as SIS procedure provides an endometrial layer visualization leading to be more accurate to diagnose focal and diffuse endometrial lesions with an overall high sensitivity and PPV. SIS procedure has shown to be highly sensitive to polyp and myoma detection, which might misdiagnosed polyps instead of hyperplasia or cancer detection. In contrast, Grimbizis et al. study, despite the results, determines that HS with direct EB is the most accurate way to detect endometrial cancer. (20) Although, this unexpected finding can be due to the narrow studies selected and maybe wider research is needed to determine which diagnostic procedure is more accurate to detect endometrial hyperplasia and cancer.

The accuracy of SIS and HS differs minimally. Bingo et al. and Muhammad et al. have shown that SIS and HS are not superior to each other although Soguktas et al. concludes that HS is superior to SIS in the evaluation of AUB (21). However, according to Chawla et al. study, considering the excellent correlation between SIS and HS, it can be used as an alternative procedure whenever HS is not available.

(20) Likewise, another study Epstein et al. has concluded an almost perfect agreement (96%) between SIS and HS in the diagnosis of focally growing lesions. (32)

(26)

26 Nevertheless, Muhammad et al. study (17) which shows higher SIS sensitivity than TVS, but results are shown to be less accurate detecting endometrial pathologies in both procedures, where the more normal endometrial cavity was found than endometrial pathologies, due to that fact the results cannot be trusted.

Regarding premenopausal women, TVS has shown to be successful in detecting intrauterine abnormalities although SIS may be performed because of higher diagnostic performance in premenopausal patients with no suspicious intracavitary abnormalities on TVS. (21) On the other hand, postmenopausal women due to endometrial changes in size and morphology, SIS procedure may be regarded as the primary method in the detection of uterine abnormalities (16).

Different catheters are used in SIS procedure, Foley balloon catheters are mostly used than neonatal suction catheters as they achieve better saline filling, however, balloon catheters are less tolerated and much more expensive than regular ones (32). Even though they are less tolerated, as they achieve a better filling of saline leading to great distension of uterine cavity to detect endometrial pathologies, it is better to use them instead of neonatal suction catheters while performing SIS procedure.

Patient compliance to SIS procedure shows that it is overall well moderated due to low-moderate pain/

discomfort according to VAS score results. Discomfort is mostly felt during the installation of the saline and is aggravated if air bubbles formation due to unproperly filling, although Bij de vaate A. et al study determines that pain and discomfort were more associated during catheter insertion than while installation of saline but, some patients experienced cramps during fluid installation (22). Due to this discrepancy, more studies should be done in order to determine if discomfort is much more felt during catheter insertion or saline instillation. It is also shown that postmenopausal women are more likely to feel pain/discomfort than premenopausal women this can be related to the endometrial changes after menopause.

Patient compliance to GIS procedure was also evaluated and compared to SIS. GIS procedure results had shown to be also overall well tolerated. GIS procedure seems to be better tolerated than SIS, this is related to the neonatal suction catheter used in GIS procedure, which is very thin and flexible compared to the Foley balloon catheter used in SIS. Gel infusion is usually warmed up to decrease viscosity leading to better passage through the catheter and no bubble formation as in saline infusion which causes the discomfort, this could be also a reason for GIS to be well tolerated. Van den Bosch et al. concluded that pain reported by GIS was less than SIS and that lidocaine used during GIS could lower the pain. (24)

(27)

27 Patient compliance to SIS procedure could be improved by providing a relaxed and calm environment, with decreased personal stuff. Also, the intake of anti-inflammatory drugs since half an hour, to one hour before the procedure and using regional anaesthesia as it is shown to decrease discomfort/pain during saline infusion, especially in postmenopausal women.

Studies used in this review have all shown that SIS allowed the detection of intracavitary abnormalities in most of the patients with an overall high sensitivity, specificity, and PPV over TVS, consequently SIS procedure has shown to be successful. SIS accuracy is greater detecting endometrial focal pathologies;

polyp and myoma than detecting hyperplasia and cancer.

(28)

28

CONCLUSIONS

1. SIS procedure is successful for the majority of patients irrespective of menopausal status.

2. SIS procedure is highly accurate in the detection of endometrial pathologies, especially in detection of focal endometrial pathology exceeding the accuracy of TVS. However, SIS is not that accurate in comparison to TVS to detect endometrial hyperplasia and cancer.

3. SIS procedure is uncomfortable, but rather tolerable due to low-moderate pain/discomfort during the procedure, especially in postmenopausal women.

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29

PRACTICAL RECOMMENDATIONS

1. SIS could be used as a primary diagnostic tool in women presenting AUB, due to the high accuracy in detecting endometrial lesions, high sensitivity and specificity of the procedure and due to that is simple and well tolerated, so great compliance, in the majority of cases.

2. SIS should be always applied additionally to TVS, then conventional TVS fails to discriminate endometrium in pre- and postmenopausal women presenting AUB.

3. It would be convenient to create a confident and comfortable environment for the patients while performing the procedure to avoid any uncomfortable situation that wouldn’t allow them to undergo the procedure or do not obtain satisfactory findings to establish a diagnosis.

4. Regional anesthesia can be used before SIS procedure in order to avoid pain or discomfort feeling of patients while procedure performance.

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30

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CONFLICT OF INTEREST

TABLE OF CONTENTS

SUMMARY

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

ABBREVIATION LIST

INTRODUCTION

AIM AND OBJECTIVES

LITERATURE REVIEW

RESEARCH METHODOLOGY AND METHODS

RESULTS

DISCUSSION

CONCLUSIONS

PRACTICAL RECOMMENDATIONS

REFERENCES