Systematic review Systematic review and meta-analysis of the diagnostic accuracy of ductoscopy in patients with pathological nipple discharge L. Waaijer1,J.M.Simons1,I.H.M.BorelRinkes1,P.J.vanDiest2,H.M.Verkooijen3 and A. J. Witkamp1 Departments of 1Surgery and 2Pathology and 3Imaging Division, University Medical Centre Utrecht, Utrecht, The Netherlands Correspondence to: Ms L. Waaijer, Department of Surgery, University Medical Centre Utrecht, PO Box 85500, G04.228, 3508 GA Utrecht, The Netherlands (e-mail: [email protected]) Background: Invasive surgery remains the standard for diagnosis of pathological nipple discharge (PND). Only a minority of patients with nipple discharge and an unsuspicious finding on conventional breast imaging have cancer. Ductoscopy is a minimally invasive alternative for evaluation of PND. This systematic review and meta-analysis was designed to evaluate the diagnostic accuracy of ductoscopy in patients with PND. Methods: A systematic search of electronic databases for studies addressing ductoscopy in patients with PND was conducted. Two classification systems were assessed. Forany DS , all visualized ductoscopic abnormalities were classified as positive, whereas forsusp DS , only suspicious findings were considered positive. After checking heterogeneity, pooled sensitivity and specificity of DSany and DSsusp were calculated. Results: The search yielded 4642 original citations, of which 20 studies were included in the review. Malignancy rates varied from 0 to 27 per cent. Twelve studies, including 1994 patients, were eligible for meta-analysis. Pooled sensitivity and specificity of DSany were 94 (95 per cent c.i. 88 to 97) per cent and 47 (44 to 49) per cent respectively. Pooled sensitivity and specificity ofsusp DS were 50 (36 to 64) and 83 (81 to 86) per cent respectively. Heterogeneity between studies was moderate to large for sensitivity 2 = ⋅ 2 = ⋅ 2 = ⋅ (DSany: I 17 5 per cent; DSsusp: I 37 9 per cent) and very large for specificity (DSany: I 96 8per 2 = ⋅ cent; DSsusp: I 92 6 per cent). Conclusion: Ductoscopy detects about 94 per cent of all underlying malignancies in patients with PND, but does not permit reliable discrimination between malignant and benign findings. Paper accepted 6 January 2016 Published online 23 March 2016 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.10125 Background with MRI, as well as galactography and/or cytology of nipple aspiration fluid (NAF) or ductal lavage. In patients Pathological nipple discharge (PND), defined as spon- with PND with no signs of malignancy on conventional taneous, unilateral, haemorrhagic or serous discharge, is diagnostic examination by mammography and ultrasono- responsible for approximately 5 per cent of surgical refer- graphy, the added value of breast MRI is limited4,12. rals to the breast clinic1. Malignancy rates of up to 23⋅9 per cent have been reported in patients with PND2, Investigations by galactography and cytological analysis but these studies are outdated, contained only surgically of NAF or ductal lavage lack sensitivity and usually do 2,4,13–15 treated patients or included patients with suspect findings not reveal the underlying pathology .Useofthese on imaging2–7. Modern studies on patients with PND diagnostic modalities therefore often results in a series of and negative conventional imaging by mammography and negative results. ultrasound imaging have shown considerably lower malig- There is no consensus on the diagnostic approach nancy rates of 3–7 per cent3,8–11. to PND, but surgery, by either selective duct excision Toevaluate the nature of PND, mammography and ultra- (microdochectomy) or major duct excision, is considered sonography are commonly used, sometimes supplemented the standard16. These procedures are invasive with a © 2016 BJS Society Ltd BJS 2016; 103: 632–643 Published by John Wiley & Sons Ltd Ductoscopy in pathological nipple discharge 633 concomitant risk of complications17, and possible effects Original studies performing ductoscopy were eligible for on cosmesis, breastfeeding potential and sensitivity of the inclusion in the systematic review. Studies had to report nipple. ductoscopic outcome in patients with PND or a hetero- Ductoscopy is a minimally invasive procedure that visu- genic cohort in which test performance was documented alizes the ductal epithelium of the breast via the nipple14,18. separately for each group, and use histological assessment It can be performed under local anaesthesia in the out- (following surgical excision or endoscopic tissue collection) patient clinic. Although ductoscopy is frequently used for and/or follow-up as a reference test. evaluating PND19, its accuracy in patients with symp- Studies reporting small series (fewer than 25 patients), toms of PND remains a matter of debate. Several studies studies including patients with preoperative diagnosis of have reported promising results, but included hetero- breast cancer, overlapping studies (only the most recent geneous patient populations, rating systems and previous article or the article reporting the data of interest was diagnostics20. Although some studies21,22 reported a sig- included) and studies other than original clinical trials nificant correlation between intraductal morphological (for instance congress abstracts, reviews, editorials, case findings and histological diagnosis, others23–26 found this reports, ex vivo studies, protocols) were excluded. only for papillomas. A cross-reference check was performed to assess the The aim of the present study was to carry out a sys- quality of the search and to identify eligible additional tematic review of the literature, and if possible to per- studies not identified by the primary search. form a meta-analysis to determine the diagnostic accuracy Two authors performed study selection, quality assess- of ductoscopy in the diagnosis of malignancy in patients ment and data extraction independently. Any differences with PND. were resolved by mutual agreement. Any disagreement was resolved through re-evaluation by a third author, blinded to the outcome of previous assessment. Methods Search strategy Quality assessment A systematic search of the PubMed, Embase and Cochrane The quality of eligible studies was assessed using the Qual- Library databases was performed according to the Pre- ity Assessment of Diagnostic Accuracy Studies (QUADAS) ferred Reporting Items for Systematic Reviews and 2 questionnaire28. The QUADAS-2 was tailored to the Meta-Analyses (PRISMA) guidelines27. The search query present analysis, as described in the guideline (Appendix S2, was limited to 2 February 2015 and included synonym supporting information)28, and applied to a random terms within the index test (ductoscopy) (Appendix S1, sample from the available studies to evaluate inter-rater supporting information). To minimize the risk of miss- agreement. Finally, all included studies were evaluated ing relevant studies, synonyms for the target condition (Table S1, supporting information). or reference standard were not included in the search strategy. Data extraction and management The following data were extracted for each study: study Selection of studies period, inclusion criteria and sample size, together with After removal of duplicates, all identified studies were patients’ ages, and technical and procedural characteristics. screened by title and abstract. Full-text papers were For meta-analysis, two different definitions were used retrieved when studies evaluated ductoscopy, reported to classify ductoscopic findings. For DSany,anyvisu- original data, and were written in English, German, alized finding at ductoscopy was classified as positive, French or Dutch. and normal ducts in ductoscopy were classified as nega- Studies reporting ductoscopic findings in patients pre- tive. For DSsusp, ductoscopically suspicious findings were senting with PND were included. Studies that reported classified as positive29–31. Suspicious ductoscopic findings on ductoscopic findings combined with histopathological were defined as duct wall irregularities, epithelial thick- outcome after surgery were classified as ‘surgical refer- ening, inflammatory changes, web, stricture, red patches ence studies’. In some studies, negative or non-suspect or fronds. Normal ducts, intraductal debris or polypoid ductoscopic findings were not followed by surgery. In lesions were defined as non-suspicious/negative. these patients, clinical follow-up was used as a surrogate Malignancy at histopathology or during follow-up was reference standard and these studies were classified as considered a positive outcome of the reference test. Malig- ‘selective follow-up studies’. nancy was defined as ductal carcinoma in situ (DCIS) © 2016 BJS Society Ltd www.bjs.co.uk BJS 2016; 103: 632–643 Published by John Wiley & Sons Ltd 634 L. Waaijer, J. M. Simons, I. H. M. Borel Rinkes, P. J. van Diest, H. M. Verkooijen and A. J. Witkamp Records identified through database searching n = 4811 PubMed n = 2893 Embase n = 1350 Cochrane Library n = 568 Duplicates removed n = 169 Title/abstract screened n = 4642 Records excluded n = 4484 Full-text articles assessed n = 158 Papers excluded based on study type n = 90 Review n = 31 Unpublished study n = 1 Language n = 25 Not about ductoscopy n = 4 Not original research n = 30 n Articles included in systematic review = 20 Original articles excluded n = 49< n Surgical reference = 13 Inclusion criteria n = 24 n Selective follow-up = 7 No results of ductoscopy n = 3 Overlapping data n