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Combination of the non-invasive tests for the diagnosis of endometriosis

  • Review
  • Diagnostic

Authors

  • Vicki Nisenblat,

    Corresponding author
    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, Adelaide, SA, Australia
    • Vicki Nisenblat, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Level 6, Medical School North,, Frome Rd, Adelaide, SA, 5005, Australia. vnisenblat@gmail.com.

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  • Lucy Prentice,

    1. Tauranga Hospital, Bay of Plenty DHB, Obstetrics and Gynaecology, Tauranga, New Zealand
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  • Patrick MM Bossuyt,

    1. Academic Medical Center, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam, Netherlands
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  • Cindy Farquhar,

    1. University of Auckland, Department of Obstetrics and Gynaecology, Auckland, New Zealand
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  • M Louise Hull,

    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, Adelaide, SA, Australia
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  • Neil Johnson

    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, Adelaide, SA, Australia
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Abstract

Background

About 10% of women of reproductive age suffer from endometriosis, a costly chronic disease causing pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but is expensive and carries surgical risks. Currently, there are no non-invasive tests available in clinical practice to accurately diagnose endometriosis. This review assessed the diagnostic accuracy of combinations of different non-invasive testing modalities for endometriosis and provided a summary of all the reviews in the non-invasive tests for endometriosis series.

Objectives

To estimate the diagnostic accuracy of any combination of non-invasive tests for the diagnosis of pelvic endometriosis (peritoneal and/or ovarian or deep infiltrating) compared to surgical diagnosis as a reference standard. The combined tests were evaluated as replacement tests for diagnostic surgery and triage tests to assist decision-making to undertake diagnostic surgery for endometriosis.

Search methods

We did not restrict the searches to particular study designs, language or publication dates. We searched CENTRAL to July 2015, MEDLINE and EMBASE to May 2015, as well as the following databases to April 2015: CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP, ClinicalTrials.gov, DARE and PubMed.

Selection criteria

We considered published, peer-reviewed, randomised controlled or cross-sectional studies of any size, including prospectively collected samples from any population of women of reproductive age suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). We included studies comparing the diagnostic test accuracy of a combination of several testing modalities with the findings of surgical visualisation of endometriotic lesions.

Data collection and analysis

Three review authors independently collected and performed a quality assessment of the data from each study by using the QUADAS-2 tool. For each test, the data were classified as positive or negative for the surgical detection of endometriosis and sensitivity and specificity estimates were calculated. The bivariate model was planned to obtain pooled estimates of sensitivity and specificity whenever sufficient data were available. The predetermined criteria for a clinically useful test to replace diagnostic surgery were a sensitivity of 0.94 and a specificity of 0.79 to detect endometriosis. We set the criteria for triage tests at a sensitivity of 0.95 and above and a specificity of 0.50 and above, which 'rules out' the diagnosis with high accuracy if there is a negative test result (SnOUT test), or a sensitivity of 0.50 and above and a specificity of 0.95 and above, which 'rules in' the diagnosis with high accuracy if there is a positive result (SpIN test).

Main results

Eleven eligible studies included 1339 participants. All the studies were of poor methodological quality. Seven studies evaluated pelvic endometriosis, one study considered DIE and/or ovarian endometrioma, two studies differentiated endometrioma from other ovarian cysts and one study addressed mapping DIE at specific anatomical sites. Fifteen different diagnostic combinations were assessed, including blood, urinary or endometrial biomarkers, transvaginal ultrasound (TVUS) and clinical history or examination. We did not pool estimates of sensitivity and specificity, as each study analysed independent combinations of the non-invasive tests.

Tests that met the criteria for a replacement test were: a combination of serum IL-6 (cut-off >15.4 pg/ml) and endometrial PGP 9.5 for pelvic endometriosis (sensitivity 1.00 (95% confidence interval (CI) 0.91 to 1.00), specificity 0.93 (95% CI, 0.80, 0.98) and the combination of vaginal examination and transvaginal ultrasound (TVUS) for rectal endometriosis (sensitivity 0.96 (95% CI 0.86 to 0.99), specificity 0.98 (95% CI 0.94 to 1.00)). Tests that met the criteria for SpIN triage tests for pelvic endometriosis were: 1. a multiplication of urine vitamin-D-binding protein (VDBP) and serum CA-125 (cut-off >2755) (sensitivity 0.74 (95% CI 0.60 to 0.84), specificity 0.97 (95% CI 0.86 to 1.00)) and 2. a combination of history (length of menses), serum CA-125 (cut-off >35 U/ml) and endometrial leukocytes (sensitivity 0.61 (95% CI 0.54 to 0.69), specificity 0.95 (95% CI 0.91 to 0.98)). For endometrioma, the following combinations qualified as SpIN test: 1. TVUS and either serum CA-125 (cut-off ≥25 U/ml) or CA 19.9 (cut-off ≥12 U/ml) (sensitivity 0.79 (95% CI 0.64 to 0.91), specificity 0.97 (95% CI 0.91 to 1.00)); 2. TVUS and serum CA 19.9 (cut-off ≥12 U/ml) (sensitivity 0.54 (95% CI 0.37 to 0.70), specificity 0.97 (95% CI 0.91 to 1.0)); 3-4. TVUS and serum CA-125 (cut-off ≥20 U/ml or cut-off ≥25 U/ml) (sensitivity 0.69 (95% CI 0.49 to 0.85), specificity 0.96 (95% CI 0.88 to 0.99)); 5. TVUS and serum CA-125 (cut-off ≥35 U/ml) (sensitivity 0.52 (95% CI 0.33 to 0.71), specificity 0.97 (95% CI 0.90 to 1.00)). A combination of vaginal examination and TVUS reached the threshold for a SpIN test for obliterated pouch of Douglas (sensitivity 0.87 (95% CI 0.69 to 0.96), specificity 0.98 (95% CI 0.95 to 1.00)), vaginal wall endometriosis (sensitivity 0.82 (95% CI 0.60 to 0.95), specificity 0.99 (95% CI 0.97 to 1.0)) and rectovaginal septum endometriosis (sensitivity 0.88 (95% CI 0.47 to 1.00), specificity 0.99 (95% CI 0.96 to 1.00)).

All the tests were evaluated in individual studies and displayed wide CIs. Due to the heterogeneity and high risk of bias of the included studies, the clinical utility of the studied combination diagnostic tests for endometriosis remains unclear.

Authors' conclusions

None of the biomarkers evaluated in this review could be evaluated in a meaningful way and there was insufficient or poor-quality evidence. Laparoscopy remains the gold standard for the diagnosis of endometriosis and using any non-invasive tests should only be undertaken in a research setting.

Plain language summary

Combination of different types of tests for the non-invasive diagnosis of endometriosis

Review Question

Can any combination of non-invasive tests be accurate enough to replace or reduce the need for surgery in the diagnosis of endometriosis?

Background

Women with endometriosis have endometrial tissue (the tissue that lines the womb and is shed during menstruation) growing outside the womb within the pelvic cavity. This tissue responds to reproductive hormones, causing painful periods, chronic lower abdominal pain and difficulty conceiving. Currently, the only reliable way of diagnosing endometriosis is to perform keyhole surgery and visualise the endometrial deposits inside the abdomen. Because surgery is risky and expensive, combinations of various tests have been evaluated for their ability to detect endometriosis non-invasively. An accurate test could lead to the diagnosis of endometriosis without the need for surgery or it could reduce the need for diagnostic surgery so only women who were most likely to have endometriosis would require it.

Study characteristics

The evidence included in this review is current to April 2015. We included 11 studies on combinations of several testing methods involving 1339 participants. All studies evaluated women of reproductive age who were undertaking diagnostic surgery to investigate symptoms of endometriosis or for other indications. Fifteen combinations of different blood, endometrial and urinary biomarkers were studied, incorporating ultrasound, clinical history and examination. Each combination of tests was assessed in small individual studies.

Key results and quality of evidence

Several studies identified the combined tests that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit.

The reports were of low methodological quality, which is why these results cannot be considered reliable unless confirmed in large high-quality studies. Overall, there is not enough evidence to demonstrate benefit of any combined non-invasive test for use in clinical practice for the diagnosis of endometriosis over the current ‘gold standard’ of diagnostic laparoscopy.

Future research

More high-quality research studies are needed to accurately assess the diagnostic potential of any type of non-invasive tests or their combinations that were identified in only a few studies as possibly having value in the detection of endometriosis.

Laienverständliche Zusammenfassung

Kombination verschiedener Arten von Tests zur nicht-invasive Diagnose von Endometriose

Fragestellung

Kann eine beliebige Kombination von nicht-invasiven Tests genau genug sein, um die Notwendigkeit einer Operation zur Diagnose der Endometriose zu reduzieren oder sie zu ersetzen?

Hintergrund

Bei Frauen mit Endometriose wächst Endometriumgewebe (das Gewebe, das die Gebärmutter auskleidet und während der Menstruation abgestoßen wird) außerhalb der Gebärmutter in der Beckenhöhle. Dieses Gewebe reagiert auf Fortpflanzungshormone, was zu Regelschmerzen, chronischen Unterbauchschmerzen und Schwierigkeiten bei der Empfängnis führt. Derzeit kann Endometriose zuverlässig nur durch einen minimalinvasiven Eingriff („Schlüssellochchirurgie“) diagnostiziert werden, bei dem die Endometrioseherde im Bauchraum sichtbar gemacht werden. Da eine Operation immer mit Risiken verbunden und teuer ist, hat man die Kombination von bildgebenden Verfahren auf ihr Potential untersucht, Endometriose auf nicht-invasive Art zu erkennen. Ein genauer Test könnte die Diagnose von Endometriose ohne die Notwendigkeit eines chirurgischen Eingriffs ermöglichen oder die Notwendigkeit eines solchen Eingriffs derart verringern, dass er nur bei Frauen mit der höchsten Wahrscheinlichkeit für Endometriose nötig wäre.

Studienmerkmale

Die Evidenz in diesem Review ist auf dem Stand von April 2015. Wir schlossen 11 Studien über Kombinationen von mehreren Testverfahren ein, die 1339 Teilnehmer untersuchten. Alle Studien wurden an Frauen im gebärfähigen Alter durchgeführt, die sich einem diagnostischen Eingriff unterzogen, entweder um Endometriose-Symptome abzuklären oder aufgrund anderer Indikationen. Fünfzehn Kombinationen verschiedener Blut, Endometrium und Urin-Biomarker wurden untersucht, unter Verwendung von Ultraschall, klinischer Anamnese und Untersuchungen. Jede Kombination der Tests wurde in kleinen einzelnen Studien untersucht.

Hauptergebnisse und Qualität der Evidenz

Mehrere Studien mit kombinierten Testverfahren, die möglicherweise zu der Diagnose einer Endometriose verwendet werden können, wurden identifiziert. Dennoch gibt es zu wenige Berichte, um ihren diagnostischen Nutzen sicher zu belegen.

Die Berichte waren von niedriger methodischer Qualität, weshalb die Ergebnisse nicht als zuverlässig angesehen werden können. Deswegen sollten sie in großen, hochwertigen Studien bestätigt werden. Insgesamt ist nicht genügend Evidenz bezüglich kombinierter nicht-invasiver Tests für die Diagnose von Endometriose in der klinischen Praxis vorhanden, die gegenüber dem aktuellen "Goldstandard", der diagnostischen Laparoskopie, Vorteile aufweist.

Zukünftige Forschungsarbeiten

Mehr hochwertige Studien werden benötigt, um das diagnostische Potential jeder Art von nicht-invasiver Tests oder deren Kombinationen genauer zu bewerten. Nur wenige der gefundenen Studien eigneten sich für die Erkennung von Endometriose.

Anmerkungen zur Übersetzung

R. Binder, freigegeben durch Cochrane Deutschland.