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Treatment of the benign inverted nipple: A systematic review and recommendations for future therapy
The Breast 29 (2016) 82e89
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Review
Treatment of the benign inverted nipple: A systematic review and recommendations for future therapy Q.M. Hernandez Yenty a, W.J.F.M. Jurgens a, P.P.M. van Zuijlen a, b, c, H.C.W. de Vet d, e, P.D.H.M. Verhaegen a, * a
Department of Plastic, Reconstructive and Hand Surgery, VU Medical Center, Amsterdam, The Netherlands Department of Plastic, Reconstructive and Hand Surgery, Red Cross Hospital, Beverwijk, The Netherlands MOVE Research Institute, VU, Amsterdam, The Netherlands d Department of Epidemiology and Biostatistics, VU Medical Center, Amsterdam, The Netherlands e EMGO Institute for Health and Care Research, VU Medical Center, Amsterdam, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 February 2016 Received in revised form 8 June 2016 Accepted 9 July 2016
The inverted nipple is a frequently encountered problem which can cause difficulties with breastfeeding, sexuality, and aesthetic dissatisfaction. Up to now, no consensus exists on a preferred treatment method. We performed a systematic review to identify the best treatment method for correction of benign inverted nipples. Treatment techniques were subdivided in the categories lactiferous duct preserving and lactiferous duct damaging. A systematic review was performed using the PRISMA statement. Inclusion criteria were: female patients with congenital or acquired inverted nipples, a minimum sample size of 10 nipples, and studies reporting recurrence of inversion with a minimum follow-up of six months. Exclusion criteria were nipple inversion caused by malignancy. Thirteen studies met the inclusion criteria which all had a level of evidence IV. No non-invasive treatment techniques were identified. In the duct preserving category eight studies were included with a recurrence rate of 0.6% (2/350) versus 9.9% (16/161) in the duct damaging category (n ¼ 5). Other outcome parameters were not systematically reported in all studies. Because of a small number of low quality studies with heterogeneous interventions and outcomes a meta-analysis could not be performed and no preferred treatment method was identified. Based on the available data there is no statistical evidence that duct damaging treatment is superior to duct preserving treatment. We recommend that the first method of choice should be a duct preserving treatment method. In the future, more studies of better methodological quality are required and recommendations were made on how these could be conducted. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Inverted nipple Retracted nipple Depressed nipple Systematic review
Introduction The benign inverted nipple is a common phenomenon with a prevalence amongst women ranging from 1.7 to 3.5% [1e3]. The pathogenesis of the inverted nipple remains controversial: authors reported that inverted nipples may result from a failure of the underlying mesenchym to proliferate and to push the nipple out of its normal depressed position [3,4]. However, Han and Hong did not structurally find this soft tissue deficiency in the nipples that they
* Corresponding author. VU Medical Centre, Department of Plastic, Reconstructive, and Hand Surgery, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. E-mail address: [email protected] (P.D.H.M. Verhaegen). http://dx.doi.org/10.1016/j.breast.2016.07.011 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
histologically investigated [5]. Others currently agree that the major basis for inverted nipples is shortened, undeveloped breast ducts, combined with resistant collagen fibers [6,7]. The average projection of the nipple was measured to be 0.9 cm based on a study of 600 nipple measurements in adult women [2]. The manifestation of inverted nipples is classified based upon appearance and the ability of manually pulling out the nipple. The grading system according to Han and Hong is most often used in literature and classifies three degrees of nipple inversion (Table 1) [5]. Inverted nipples can cause functional problems such as difficulty or inability to breastfeed, problems with respect to sexuality, and aesthetic dissatisfaction [6,8e10]. For this reason patients often wish to undergo treatment for the correction of their nipple inversion.
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Table 1 Grading system of nipple inversion developed by Han and Hong. Lactiferous ducts are indicated by vertical lines, fibrosis is indicated by small x [5]. Grade of nipple inversion
Preoperative
After traction
Clinical findings
I
The nipple can be easily pulled out manually and maintains its projection quite well. There is minimal or no fibrosis.
II
The nipple can be pulled out manually, but not as easily as in grade I. The nipple has difficulty maintaining its position and tends to retract. There is a moderate degree of fibrosis and mildly retracted lactiferous ducts.
III
The nipple is severely inverted and retracted. It is very difficult to pull out the nipple manually. Despite application of pressure on the nipple to force it to protrude, it promptly retracts. The fibrosis is remarkable and there are short and severely retracted lactiferous ducts with insufficient soft tissue.
According to Long et al. an ideal method of correcting inverted nipples should meet the following requirements: 1) regain normal shape; 2) keep visible scars at a minimum; 3) maintain normal sensation; 4) maintain an intact ductal system (enabling breastfeeding); 5) low recurrence rate; and 6) easy to perform [11]. Besides these six requirements, the patients' wishes are relevant in the decision-making process, e.g: 1) is there a preference for an invasive or non-invasive treatment method? 2) is there a wish to breastfeed (in the future)? 3) does the patient object to a treatment which may take several months? Since the first surgical correction of the inverted nipple by Kehrer in 1879 [12] a great variety of invasive and non-invasive treatment methods have been described. However, up to now no consensus exists on the preferred treatment method. There is no information available which treatment method has the lowest recurrence with the least complications. Therefore, the aim of this study was to assess the available literature on treatment methods of the benign inverted nipple and to identify a superior treatment method with respect to the recurrence and complication rates. Treatment methods were subdivided into two categories based on technical characteristics: lactiferous duct preserving and lactiferous duct damaging treatment techniques. Duct preserving treatment can be either a non-invasive treatment method (such as rubber bands or an external suction device) [8,9,13,14] or an invasive technique in which the lactiferous ducts are not damaged and fibrosis is not removed. Duct damaging treatment is characterized by an invasive technique in which the lactiferous ducts are damaged and fibrotic strands are transected. This categorization was performed: 1) to provide more evidence whether a duct preserving or a duct damaging treatment method is superior with respect to the recurrence rate; and 2) to provide a superior treatment method for women wishing to breastfeed, whereby a duct preserving therapy is preferred. Materials and methods To assure a systematic method of procedure the PRISMA statement (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) was used [15,16]. Search strategy Electronic searches were performed until August 29th 2015 in Pubmed, Embase, and Cochrane databases. Search terms included
were “inverted nipple”, “retracted nipple”, and “depressed nipple”. The included MeSH terms were “Nipple/Surgery” and “Nipple/Deformities”. In addition, all references of the included articles were checked to identify additional relevant studies. Inclusion and exclusion criteria Studies investigating treatment methods of patients with congenital, acquired, bilateral, or unilateral nipple inversion were considered for inclusion. Both non-invasive and invasive treatment methods were considered. The minimum sample size was set at 10 nipples. Although the authors consider a sample size of 10 still relatively low, we anticipated that otherwise the eligible amount of studies would be too low for a systematic analysis. Inclusion and exclusion criteria are summarized in Table 2. The one outcome parameter that was obligatory for inclusion of the study was registration of the recurrence of nipple inversion. In addition the following outcome parameters were systematically scored: nipple projection, nipple necrosis, nipple sensibility, ability to breastfeed after treatment, infection, hematoma, other complications, and patient satisfaction. Aforementioned clinical outcomes were selected based on requirements for an ideal method of correcting inverted nipples [11]. Data collection and extraction Studies were collected and de-duplicated using Reference Manager 12 (Thomson Reuters, New York, USA). The selection process comprised three stages: selection by title, review by abstract, and review by full text. One author (QH) assessed all titles and abstracts identified by the literature search. The same titles and abstracts were assessed by one of the two other authors (PV and WJ) who each assessed half of the titles and abstracts. Potentially relevant studies were identified and full text articles were retrieved for final selection. Full text screening took place in the same fashion. If there was any disagreement between the reviewers, the final decision was reached by consensus, and when agreement could not be reached a fourth author (PvZ) decided upon inclusion. Three authors (PV, QH, and WJ) independently extracted the following data from all included full text articles: study design, year of data collection, sample size, mean age, gradation of nipple inversion, nipple projection, and the type of treatment method. Complications such as nipple necrosis, loss of nipple sensibility,
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Q.M. Hernandez Yenty et al. / The Breast 29 (2016) 82e89 Table 2 Inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
1. 2. 3. 4. 5.
1. 2. 3. 4.
Studies presenting a treatment of the inverted nipple Female Minimum sample size of 10 Minimum follow-up period of six months Registration of the outcome parameter recurrence
infection, and hematoma were scored. The ability to breastfeed after treatment and patient satisfaction was registered. In addition, the level of evidence was assessed according to the Oxford Centre for Evidence-based Medicine [17].
No English abstract available Breastfeeding during treatment Nipple inversion caused by malignancy Previously treated nipples for nipple inversion
inversion was calculated for each treatment category and per grade of nipple inversion (grade I to III). Statistical pooling of the data would only be undertaken if this was sensible. This decision depended on the judgment of the degree of clinical homogeneity [19,20].
Analysis To appraise the risk of bias for all included studies, the “summary assessments” approach of The Cochrane Collaboration's tool for assessing risk of bias was used [18]. The level of evidence of the included studies was assessed and data were summarized. Each included study was fit in the duct preserving or duct damaging treatment category. Subsequently, the recurrence rate of nipple
Results Selection and characteristics of studies A total of 2045 records were screened based on title and abstract of which 1847 were excluded. Of the remaining 198 manuscripts,
Fig. 1. Flowchart of the search.
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Table 3 Overview of the included studies. X ¼ Unknown, * ¼ Seven patients were lost to follow-up. ** ¼ knowing the mean follow-up and the maximum follow-up period it was assumed that the minimum follow-up was at least 6 months. Number Reference
Year of publication Patients treated Nipples treated Mean age in years (range) Mean follow-up in months (range) Treatment category
1 2 3 4 5 6 7 8 9 10 11 12 13
2008 2014 2015 2006 2009 1998 2003 2011 2012 2011 1980 2005 2011
Caviggioli Durgun Jeong Kim Kolker Lee (Hoon-Bum) Lee (Michael) Long Paraskevas Persichetti Rayner Ritz Zhou Total
16 26 15 31 18 17 53 13 28 9 11 36*
28 28 47 29 58 35 17 95 24 52 16 18 64 511
27 (17e35) 34 (16e64) 26 (21e55) 27 (20e33) 26 (20e31)
(23e37) 31 26 (17e35)
(12-X) 17 (8e24) 14** 14 (X-60)** 22 (8e69) 24 (12e48) (12-X) 12 (8e18) (12e36) (12e72) (15e36) 28 (X-48)** (6e36)
Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct
preserving preserving preserving preserving damaging preserving damaging preserving preserving damaging damaging damaging preserving
Fig. 2. Example of a lactiferous duct preserving technique by Long et al. using stainless wires through a nipple retractor. A: a 10 ml or 5 ml syringe is used to make the retractor, B: piercing procedure for inverted nipple using a crossed wire, C: fixation of the nipple retractor using the wire [11].
185 full text manuscripts could be retrieved and assessed for eligibility. Thirteen studies were included (Fig. 1). Although no strict inclusion criteria were applied, still 49 studies had to be excluded because of an unclear sample size or a sample size lower than 10 nipples. Thirteen studies were excluded because the outcome parameter recurrence of nipple inversion was not measured during follow-up: one randomized controlled trial (RCT) conducted by Alexander et al. with a sample size of n ¼ 96 comparing two non-invasive (duct preserving) treatment techniques was excluded for this reason [8]. Besides this RCT, no relevant studies
with a high methodological quality have been excluded unintentionally. A total of 511 nipples were analyzed whereby the follow-up period ranged from six to 69 months. Patient age ranged from 17 to 55 years. An overview of the basic study characteristics is summarized in Table 3. No non-invasive treatment methods were included. Eight studies presented a treatment method with the preservation of the lactiferous ducts of which an example of the surgical technique is presented in Fig. 2 [11,21e23]. These techniques varied from minimal invasive fixating stainless wires through a nipple retractor for six months [11] to more invasive
Fig. 3. Example of a lactiferous duct damaging flap transposition technique creating projection of the nipple by Ritz et al. A: nipple is elevated to its maximal length, B: blunt dissection and creation of two tunnels for the two dermofibrous deepithelialized skin flaps, C: the two dermofibrous flaps are inserted into the tunnels, D: postoperative image [32].
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techniques releasing the fibrous tissue between the ducts followed by splinting [21] or a purse string suture combined with splinting [24]. The majority of these studies presented a technique using (deepithelialized) flaps to provide bulk under the nipple [22,23,25e27]. Five studies reported a treatment method whereby the lactiferous ducts were damaged of which an example of a surgical technique is presented in Fig. 3 [28e32]. The common technique used for these studies is extensive release (surgical or with needle) beneath the nipple to release the fibrous tissue, thereby damaging the lactiferous ducts. Projection of the nipple was created through various (flap) transposition techniques [30e32], a purse string suture [28], or by suturing the internal sidewalls of the nipple [29]. Recurrence rate of nipple inversion Recurrence rate per treatment category Recurrence was described using different terms: recurrence of nipple inversion, relapse, loss of projection, and flattening. The total recurrence rate of all 13 studies measured 3.5% (18/511 nipples). Recurrence in the duct preserving category was 0.6% (2/350) versus 9.9% (16/161) in the duct damaging category. The recurrence rate specified per study and treatment category is summarized in Table 4. Only two studies quantified the nipple projection: one study measured a decrease in nipple projection from 10.8 ± 0.8 mm (immediately postoperatively) to 9.0 ± 1.0 mm at 14 months postoperatively [23]. Long et al. only reported a decrease of nipple height of 4.7 mm (range 3e7 mm) six months postoperatively [11]. Statistical pooling of the data was not possible due to the small number of studies and the heterogeneity of the data presented (different treatment techniques, heterogeneous outcome description, and lack of statistical analysis). Recurrence rate per grade of nipple inversion Four studies specified the recurrence rate based on the Han and Hong classification [11,21,28,29] (Table 5). In summary, the data of these four studies report no recurrence (0/18) for grade I nipple inversion, a recurrence rate of 10.3% (8/78) for grade II, and a recurrence rate of 4.9% (5/102) for grade III nipple inversion. Statistical pooling the data was not possible due to the small number of studies which specified the recurrence rate per grade of nipple inversion. In addition, pooling would not be sensible because the average recurrence rate of these four studies lies very far apart from the actual recurrence rates that are reported in the individual studies (grade II average ¼ 10.3% versus Kolker et al. ¼ 27% and Caviggioli, Lee, Long et al. reported no recurrence, grade III average ¼ 4.9% versus Kolker et al. ¼ 50% and Caviggioli, Lee, Long et al. reported no recurrence).
Table 5 Recurrence of nipple inversion per Han and Hong classification. The recurrence rate is calculated based on the amount of nipples treated. Reference
Grade 1 (%)
Caviggioli Lee (Michael) Long Kolker Total
Grade 2 (%)
Grade 3 (%)
0.0 (0/28)
0.0 (0/18) 0.0 (0/26)
0.0 (0/20) 27.0 (8/30) 10.3 (8/78)
0.0 (0/17) 0.0 (0/75) 50.0 (5/10) 4.9 (5/102)
Complications In the majority of studies, registration of complications such as nipple necrosis, loss of nipple sensibility, infection, and hematoma was part of the protocol. No nipple necrosis (0/356, 9 studies) [11,21e24,26e28,32], infection (0/351, 8 studies) [11,22e24,26,28,30,32], or hematoma (0/241, 6 studies) [11,22e24,26,32] was registered postoperatively. In 3.4% (11/322, 9 studies) of the nipples a loss of sensibility was described [11,22e24,26,27,30,32]. In six studies the patient satisfaction was described by the authors, which ranged from satisfied to highly satisfied [22,25,27,29,30,32]. For this purpose, no reliable or validated questionnaires were used. Four studies reported sufficient data on the ability to breastfeed after treatment [22,23,26,32]: out of 23 patients who tried breastfeeding after treatment in 96% (22/ 23) of the cases breastfeeding succeeded. Two studies reported data on breastfeeding, which were insufficient for calculating the percentage of successful breastfeeding [25,27]. Assessment of the risk of bias All included studies were case series with a level of evidence of IV. Consecutive inclusion of patients was not described in any of the included studies. Based on the Cochrane Handbook for Systematic Reviews of Interventions we conclude that a high risk of bias is applicable for all studies. Discussion In this systematic review for the first time an overview was provided with a critical appraisal of the available treatment methods for the benign inverted nipple. It was not possible to perform a meta-analysis due to clinical heterogeneity of the included studies, insufficient data available, and the low level of evidence. A wide range of inclusion criteria was applied to allow studies with various level of evidence to be included, as it appeared very little has been published on this topic. Nonetheless this
Table 4 Recurrence of nipple inversion per study and treatment category. The recurrence rate is calculated based on the amount of nipples treated. Reference
Recurrence of nipple inversion for duct preserving treatment (%)
Caviggioli Durgun Jeong Kim Kolker Lee (Hoon-Bum) Lee (Michael) Long Paraskevas Persichetti Rayner Ritz Zhou Total
0.0 3.6 0.0 0.0
Recurrence of nipple inversion for duct damaging treatment (%)
(0/28) (1/28) (0/47) (0/29) 22.0 (13/58)
0.0 (0/35) 0.0 (0/17) 0.0 (0/95) 4.2 (1/24) 1.9 (1/52) 0.0 (0/16) 11.0 (2/18) 0.0 (0/64) 0.6 (2/350)
9.9 (16/161)
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resulted in the inclusion of only 13 studies which all had a level of evidence of IV. The average calculated recurrence rate of nipple inversion of these studies was 3.5%. No studies investigating noninvasive treatment methods could be included. Eight studies presented a treatment method preserving the lactiferous ducts, with an average recurrence rate of 0.6% (0.0e4.2%) [11,21e27]. Five studies reported a treatment method damaging the lactiferous ducts with an average recurrence rate of 9.9% (0.0e22.0%) [28e32]. Because of the small number and heterogeneity of included studies per treatment category (duct preserving versus duct damaging) no statistically supported conclusions can be drawn whether preserving or damaging the lactiferous ducts influences the recurrence rate of nipple inversion. Since, at this moment no superior treatment can be identified the authors would choose the least damaging technique, i.e. a duct preserving treatment method as the first method of choice. With respect to women wishing to breastfeed there was no specific duct preserving treatment method that provided convincing superior results. Thus, based on the evidence available at this moment any duct preserving treatment method can be applied for this patient category dependent on the patients' wishes and the surgeons preference. Even though no studies on non-invasive and minimal-invasive treatment techniques met the inclusion criteria of our search, we feel that in this review the following treatment techniques deserve mentioning: an RCT conducted by Alexander et al. presents the use of breast shells versus Hoffman's exercises (stretching the nipples by manipulation) [8]. They focused on the ability to breastfeed and no recurrence rates were investigated. Various non-surgical suction devices aiming to stretch the lactiferous ducts, showed promising results, such as the “Niplette” [7] and a cheaper suction system described by Ozcan et al. using two syringes [33]. Lastly, various piercing systems have been investigated: these studies could not be included because of unclear follow-up data [34,35] or a small sample size [36]. More research into non-invasive treatment techniques should first be performed before evidence-based recommendations can be made. The authors realize that the majority of the included studies has a relatively small sample size ranging from 16 to 95 included nipples. We hypothesize that this could be explained because a low percentage of women with inverted nipples seek medical help and therefore collection of a large amount of patient data takes many years. The authors excluded one well conducted study by Gould et al. with an exceptional high sample size of 191 nipples, because the minimum follow-up was less than six months [37]. However, the study had a mean follow-up of eight months (range 3 weekse9 years) and therefore we find the data worth presenting: this lactiferous duct preserving technique using a combination of sutures and traction (for two to five days) showed a recurrence rate of 13% with 3% eschar/redness and 3% infection. This recurrence rate of 13% is relatively high compared to our calculated average recurrence rate of 0.6% for duct preserving techniques. Gould et al. explain this relatively high recurrence rate because of differences in
patient demographics and the short duration of the application of the nipple retractor. It has often been suggested that a higher degree of nipple inversion according to the Han and Hong classification would require a more invasive (and duct damaging) treatment method. Based on the results of this review there is no evidence that for a higher degree of nipple inversion a more invasive operation technique would be required. Although the authors realize data are limited, analysis of the four studies which scored the recurrence per grade of nipple inversion did not show more recurrence for a higher grade of inverted nipples that were treated with a duct preserving treatment method. On the contrary, the only treatment (out of these four studies) that had a recurrence rate higher than 0% (27% for grade II, 50% for grade III), concerned a duct damaging operation technique [28]. The strength of this review is that based on the shortcomings of the included studies a well-advised proposal can be done for to the set-up of future research on this topic: the authors would like to provide recommendations for the minimal requirements of investigating a treatment method for the inverted nipple: since there is a large clinical variety in the degree of nipple inversion, reliable classification of the degree of nipple inversion is of paramount importance. The Han and Hong classification is the latest and most accepted grading system, which is based on the amount of effort needed to pull out the nipple manually. This is a subjective classification system of which the intra- and inter-observer reliability is unknown. We therefore would like to suggest performing a clinimetric assessment of their classification system before widely applying the grading system in clinical research. Another option to acquire more uniformity in grading of nipple inversion would be the use of an objective measurement tool which measures the pressure needed to evert the nipple. A vacuum-manometer, which has been used for increasing the length of the nipple-areola complex in lactating women, could be suitable for this purpose [38]. However, again a clinimetric assessment of this measurement device for the purpose of grading nipple inversion would be the first step towards clinical application. The study design should at least include a prospective cohort study whereby consecutive patient inclusion is mandatory. When breastfeeding is of importance a randomized controlled trial comparing a non-invasive to an invasive duct preserving technique would be clinically relevant. However, the authors realize that inclusion of sufficient patients to be able to draw powerful conclusions may be challenging. Basic patient characteristics that need to be described should at least include age, amount of nipples involved/treated per patient, smoking, relevant comorbidity, and whether the nipple(s) have been treated previously. In addition wish for breastfeeding, previous breastfeeding, and inability to breastfeed at the moment of inclusion should be systematically registered. We suggest a minimum follow-up period of six months: this advice is based on evidence that maturation of both burn scars and surgical scars at the least takes six months [39e41] and thus a surgical end result
Table 6 Outcome parameters and suggested measurement method for evaluating treated inverted nipples at follow-up. * reliable and valid for measuring patient satisfaction after total hip arthroplasty. Outcome parameters
Measurement method
Nipple projection Nipple sensibility
1-mm unit micrometer caliper, patient in supine position Semmes Weinstein Test [43] Pressure-Specified Sensory Device [42,43] Brush test [23] Breast Q - Reconstruction questionnaire, item 10 [44] Visual Analogue Scale for patient satisfaction* [45] Patient and Observer Scar Assessment Scale [46] Hematoma, nipple necrosis, infection, inability to breastfeed
Patient satisfaction Scar appearance Complications Recurrence of nipple inversion
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cannot be expected earlier than this time period. The minimum outcome parameters that we suggest to measure at follow-up are summarized in Table 6. The authors would like to stress that the use of reliable and valid measurement methods are mandatory for measuring outcome parameters of any study. For measuring nipple sensation three different measurement methods (Semmes Weinstein Test, Pressure-Specified Sensory Device, and brush test) have been used most frequently in recent literature [23,42,43]. However, no clinimetric assessment has been performed for the application for measuring nipple sensibility. The BREAST-Q questionnaire is reliable and valid for patient satisfaction which is specified per item of the nipple appearance [44]. The authors suggest to use an additional VAS score to quantify the general patient satisfaction. It should be noted that the use of the VAS score for registering patient satisfaction has only been found reliable and valid for scoring after total hip arthroplasty [45]. For the outcome parameter scar appearance we advocate using the Patient and Observer Scar Assessment Scale. The authors agree that sufficient clinimetric appraisal has been performed for the use of this measurement method. Conclusions Because only studies with a low level of evidence could be included and mostly insufficient data were provided on the outcome parameters and complications, it was not possible to identify a superior treatment for nipple inversion. Based on the evidence available at this moment both duct preserving and duct damaging treatment techniques can be applied. However, the authors advocate to use the least damaging technique, i.e. a duct preserving treatment. There were no manuscripts on non-invasive treatment methods that met our inclusion criteria, therefore at this moment no conclusions on the application of non-invasive treatment techniques can be drawn. Regarding the currently available lack of high quality literature on this topic, future research is strongly recommended. The authors have suggested minimal requirements in the set-up of studies on nipple inversion to be able to provide more powerful evidence in the future. Conflict of interest statement None declared. Acknowledgements We would like to acknowledge C.F.W. Peeters from the department of Epidemiology and Biostatistics of the VU Medical Center for advice concerning the statistical analysis of the acquired data. References [1] Park HS, Yoon CH, Kim HJ. The prevalence of congenital inverted nipple. Aesthet Plast Surg 1999;23(2):144e6. [2] Sanuki J, Fukuma E, Uchida Y. Morphologic study of nipple-areola complex in 600 breasts. Aesthet Plast Surg 2009;33(3):295e7. [3] Schwager RG, Smith JW, Gray GF, Goulian Jr D. Inversion of the human female nipple, with a simple method of treatment. Plast Reconstr Surg 1974;54(5): 564e9. [4] Ramakrishnan KM, Rao DK. Congenital inversion of the human nipple. Aesthet Plast Surg 1980;4(1):65e72. [5] Han S, Hong YG. The inverted nipple: its grading and surgical correction. Plast Reconstr Surg 1999;104(2):389e95. discussion 96e7. [6] Crestinu JM. The correction of inverted nipples without scars: 17 years' experience, 452 operations. Aesthet Plast Surg 2000;24(1):52e7. [7] McGeorge DD. The “Niplette”: an instrument for the non-surgical correction of inverted nipples. Br J Plast Surg 1994;47(1):46e9. [8] Alexander JM, Grant AM, Campbell MJ. Randomised controlled trial of breast shells and Hoffman's exercises for inverted and non-protractile nipples. BMJ 1992;304(6833):1030e2.
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Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. [17] OCEBM Levels of Evidence Working Pool*. “The Oxford Levels of Evidence 2”. Oxford Centre for Evidence-Based Medicine. Available from http://www. cebm.net/index.aspx?o¼5653. Consulted October 2015. [18] Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Consulted October 2015. 1999;143(16):843-8. [19] Scholten RJ, Assendelft WJ, Kostense PJ, Bouter LM. [The practice of systematic reviews. V. 17. OCEBM Levels of Evidence Working Pool*. “The Oxford Levels of Evidence 2”. Oxford Centre for Evidence-Based Medicine. Available from http://www.cebm.net/index.aspx?o¼5653. Consulted October 2015. [20] Scholten RJ, Kostense PJ, Assendelft WJ, Bouter LM. The practice of systematic reviews. IV. 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[26] Zhou H, Tan Q, Wu J, Zheng DF, Zhou HR, Xu P, et al. Correction of inverted nipple with bilateral areolar rhomboid dermal flaps. J Plast Reconstr Aesthet Surg JPRAS 2011;64(6). e159e61. [27] Kim JT, Lim YS, Oh JG. Correction of inverted nipples with twisting and locking principles. Plast Reconstr Surg 2006;118(7):1526e31. [28] Kolker AR, Torina PJ. Minimally invasive correction of inverted nipples: a safe and simple technique for reliable, sustainable projection. Ann Plast Surg 2009;62(5):549e53. [29] Lee MJ, Depoli PA, Casas LA. Aesthetic and predictable correction of the inverted nipple. Aesthet Surg J/Am Soc Aesthet Plast Surg 2003;23(5):353e6. [30] Persichetti P, Poccia I, Pallara T, Delle Femmine PF, Marangi GF. A new simple technique to correct nipple inversion using 2 V-Y advancement flaps. Ann Plast Surg 2011;67(4):343e5. [31] Rayner CR. The correction of permanently inverted nipples. Br J Plast Surg 1980;33(4):413e7. [32] Ritz M, Silfen R, Morgan D, Southwick G. Simple technique for inverted nipple correction. Aesthet Plast Surg 2005;29(1):24e7. [33] Ozcan M, Kahveci R. The 'Niplette' for the non-surgical correction of inverted nipples. Br J Plast Surg 1995;48(2):115. [34] Hyakusoku H, Chin T. Usefulness of the nipple-suspension piercing device after correction of inverted nipples. Aesthet Plast Surg 2006;30(4):396e8. [35] Scholten E. A contemporary correction of inverted nipples. Plast Reconstr Surg 2001;107(2):511e3. [36] Tal MG. Correction of inverted nipple using piercing. Plast Reconstr Surg 2003;112(4):1178e9. [37] Gould DJ, Nadeau MH, Macias LH, Stevens WG. Inverted nipple repair revisited: a 7-year experience. Aesthet Surg J/Am Soc Aesthet Plast Surg 2015;35(2):156e64. [38] Il'in VI, Alekseev NP. Effect of the vacuum stimuli on length nipple-areola complex of the woman lactation mammary gland. Ross Fiziol zh Im I M Sechenova 2014;100(2):232e7. [39] Bond JS, Duncan JA, Mason T, Sattar A, Boanas A, O'Kane S, et al. Scar redness in humans: how long does it persist after incisional and excisional wounding? Plast Reconstr Surg 2008;121(2):487e96. [40] Bond JS, Duncan JA, Sattar A, Boanas A, Mason T, O'Kane S, et al. Maturation of the human scar: an observational study. Plast Reconstr Surg 2008;121(5): 1650e8. [41] van der Wal MB, Vloemans JF, Tuinebreijer WE, van de Ven P, van Unen E, van Zuijlen PP, et al. Outcome after burns: an observational study on burn scar
Q.M. Hernandez Yenty et al. / The Breast 29 (2016) 82e89 maturation and predictors for severe scarring. Wound Repair Regen Off Publ Wound Heal Soc Eur Tissue Repair Soc 2012;20(5):676e87. [42] Ferreira MC, Costa MP, Cunha MS, Sakae E, Fels KW. Sensibility of the breast after reduction mammaplasty. Ann Plast Surg 2003;51(1):1e5. [43] Mofid MM, Dellon AL, Elias JJ, Nahabedian MY. Quantitation of breast sensibility following reduction mammaplasty: a comparison of inferior and medial pedicle techniques. Plast Reconstr Surg 2002;109(7):2283e8. [44] Pusic AL, Klassen AF, Scott AM, Klok JA, Cordeiro PG, Cano SJ. Development of a new patient-reported outcome measure for breast surgery: the BREAST-Q. Plast Reconstr Surg 2009;124(2):345e53.
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[45] Brokelman RB, Haverkamp D, van Loon C, Hol A, van Kampen A, Veth R. The validation of the visual analogue scale for patient satisfaction after total hip arthroplasty. Eur Orthop Traumatol 2012;3(2):101e5. [46] van de Kar AL, Corion LU, Smeulders MJ, Draaijers LJ, van der Horst CM, van Zuijlen PP. Reliable and feasible evaluation of linear scars by the patient and observer scar assessment scale. Plast Reconstr Surg 2005;116(2):514e22.
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Review
Treatment of the benign inverted nipple: A systematic review and recommendations for future therapy Q.M. Hernandez Yenty a, W.J.F.M. Jurgens a, P.P.M. van Zuijlen a, b, c, H.C.W. de Vet d, e, P.D.H.M. Verhaegen a, * a
Department of Plastic, Reconstructive and Hand Surgery, VU Medical Center, Amsterdam, The Netherlands Department of Plastic, Reconstructive and Hand Surgery, Red Cross Hospital, Beverwijk, The Netherlands MOVE Research Institute, VU, Amsterdam, The Netherlands d Department of Epidemiology and Biostatistics, VU Medical Center, Amsterdam, The Netherlands e EMGO Institute for Health and Care Research, VU Medical Center, Amsterdam, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 February 2016 Received in revised form 8 June 2016 Accepted 9 July 2016
The inverted nipple is a frequently encountered problem which can cause difficulties with breastfeeding, sexuality, and aesthetic dissatisfaction. Up to now, no consensus exists on a preferred treatment method. We performed a systematic review to identify the best treatment method for correction of benign inverted nipples. Treatment techniques were subdivided in the categories lactiferous duct preserving and lactiferous duct damaging. A systematic review was performed using the PRISMA statement. Inclusion criteria were: female patients with congenital or acquired inverted nipples, a minimum sample size of 10 nipples, and studies reporting recurrence of inversion with a minimum follow-up of six months. Exclusion criteria were nipple inversion caused by malignancy. Thirteen studies met the inclusion criteria which all had a level of evidence IV. No non-invasive treatment techniques were identified. In the duct preserving category eight studies were included with a recurrence rate of 0.6% (2/350) versus 9.9% (16/161) in the duct damaging category (n ¼ 5). Other outcome parameters were not systematically reported in all studies. Because of a small number of low quality studies with heterogeneous interventions and outcomes a meta-analysis could not be performed and no preferred treatment method was identified. Based on the available data there is no statistical evidence that duct damaging treatment is superior to duct preserving treatment. We recommend that the first method of choice should be a duct preserving treatment method. In the future, more studies of better methodological quality are required and recommendations were made on how these could be conducted. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Inverted nipple Retracted nipple Depressed nipple Systematic review
Introduction The benign inverted nipple is a common phenomenon with a prevalence amongst women ranging from 1.7 to 3.5% [1e3]. The pathogenesis of the inverted nipple remains controversial: authors reported that inverted nipples may result from a failure of the underlying mesenchym to proliferate and to push the nipple out of its normal depressed position [3,4]. However, Han and Hong did not structurally find this soft tissue deficiency in the nipples that they
* Corresponding author. VU Medical Centre, Department of Plastic, Reconstructive, and Hand Surgery, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. E-mail address: [email protected] (P.D.H.M. Verhaegen). http://dx.doi.org/10.1016/j.breast.2016.07.011 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
histologically investigated [5]. Others currently agree that the major basis for inverted nipples is shortened, undeveloped breast ducts, combined with resistant collagen fibers [6,7]. The average projection of the nipple was measured to be 0.9 cm based on a study of 600 nipple measurements in adult women [2]. The manifestation of inverted nipples is classified based upon appearance and the ability of manually pulling out the nipple. The grading system according to Han and Hong is most often used in literature and classifies three degrees of nipple inversion (Table 1) [5]. Inverted nipples can cause functional problems such as difficulty or inability to breastfeed, problems with respect to sexuality, and aesthetic dissatisfaction [6,8e10]. For this reason patients often wish to undergo treatment for the correction of their nipple inversion.
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Table 1 Grading system of nipple inversion developed by Han and Hong. Lactiferous ducts are indicated by vertical lines, fibrosis is indicated by small x [5]. Grade of nipple inversion
Preoperative
After traction
Clinical findings
I
The nipple can be easily pulled out manually and maintains its projection quite well. There is minimal or no fibrosis.
II
The nipple can be pulled out manually, but not as easily as in grade I. The nipple has difficulty maintaining its position and tends to retract. There is a moderate degree of fibrosis and mildly retracted lactiferous ducts.
III
The nipple is severely inverted and retracted. It is very difficult to pull out the nipple manually. Despite application of pressure on the nipple to force it to protrude, it promptly retracts. The fibrosis is remarkable and there are short and severely retracted lactiferous ducts with insufficient soft tissue.
According to Long et al. an ideal method of correcting inverted nipples should meet the following requirements: 1) regain normal shape; 2) keep visible scars at a minimum; 3) maintain normal sensation; 4) maintain an intact ductal system (enabling breastfeeding); 5) low recurrence rate; and 6) easy to perform [11]. Besides these six requirements, the patients' wishes are relevant in the decision-making process, e.g: 1) is there a preference for an invasive or non-invasive treatment method? 2) is there a wish to breastfeed (in the future)? 3) does the patient object to a treatment which may take several months? Since the first surgical correction of the inverted nipple by Kehrer in 1879 [12] a great variety of invasive and non-invasive treatment methods have been described. However, up to now no consensus exists on the preferred treatment method. There is no information available which treatment method has the lowest recurrence with the least complications. Therefore, the aim of this study was to assess the available literature on treatment methods of the benign inverted nipple and to identify a superior treatment method with respect to the recurrence and complication rates. Treatment methods were subdivided into two categories based on technical characteristics: lactiferous duct preserving and lactiferous duct damaging treatment techniques. Duct preserving treatment can be either a non-invasive treatment method (such as rubber bands or an external suction device) [8,9,13,14] or an invasive technique in which the lactiferous ducts are not damaged and fibrosis is not removed. Duct damaging treatment is characterized by an invasive technique in which the lactiferous ducts are damaged and fibrotic strands are transected. This categorization was performed: 1) to provide more evidence whether a duct preserving or a duct damaging treatment method is superior with respect to the recurrence rate; and 2) to provide a superior treatment method for women wishing to breastfeed, whereby a duct preserving therapy is preferred. Materials and methods To assure a systematic method of procedure the PRISMA statement (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) was used [15,16]. Search strategy Electronic searches were performed until August 29th 2015 in Pubmed, Embase, and Cochrane databases. Search terms included
were “inverted nipple”, “retracted nipple”, and “depressed nipple”. The included MeSH terms were “Nipple/Surgery” and “Nipple/Deformities”. In addition, all references of the included articles were checked to identify additional relevant studies. Inclusion and exclusion criteria Studies investigating treatment methods of patients with congenital, acquired, bilateral, or unilateral nipple inversion were considered for inclusion. Both non-invasive and invasive treatment methods were considered. The minimum sample size was set at 10 nipples. Although the authors consider a sample size of 10 still relatively low, we anticipated that otherwise the eligible amount of studies would be too low for a systematic analysis. Inclusion and exclusion criteria are summarized in Table 2. The one outcome parameter that was obligatory for inclusion of the study was registration of the recurrence of nipple inversion. In addition the following outcome parameters were systematically scored: nipple projection, nipple necrosis, nipple sensibility, ability to breastfeed after treatment, infection, hematoma, other complications, and patient satisfaction. Aforementioned clinical outcomes were selected based on requirements for an ideal method of correcting inverted nipples [11]. Data collection and extraction Studies were collected and de-duplicated using Reference Manager 12 (Thomson Reuters, New York, USA). The selection process comprised three stages: selection by title, review by abstract, and review by full text. One author (QH) assessed all titles and abstracts identified by the literature search. The same titles and abstracts were assessed by one of the two other authors (PV and WJ) who each assessed half of the titles and abstracts. Potentially relevant studies were identified and full text articles were retrieved for final selection. Full text screening took place in the same fashion. If there was any disagreement between the reviewers, the final decision was reached by consensus, and when agreement could not be reached a fourth author (PvZ) decided upon inclusion. Three authors (PV, QH, and WJ) independently extracted the following data from all included full text articles: study design, year of data collection, sample size, mean age, gradation of nipple inversion, nipple projection, and the type of treatment method. Complications such as nipple necrosis, loss of nipple sensibility,
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Q.M. Hernandez Yenty et al. / The Breast 29 (2016) 82e89 Table 2 Inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
1. 2. 3. 4. 5.
1. 2. 3. 4.
Studies presenting a treatment of the inverted nipple Female Minimum sample size of 10 Minimum follow-up period of six months Registration of the outcome parameter recurrence
infection, and hematoma were scored. The ability to breastfeed after treatment and patient satisfaction was registered. In addition, the level of evidence was assessed according to the Oxford Centre for Evidence-based Medicine [17].
No English abstract available Breastfeeding during treatment Nipple inversion caused by malignancy Previously treated nipples for nipple inversion
inversion was calculated for each treatment category and per grade of nipple inversion (grade I to III). Statistical pooling of the data would only be undertaken if this was sensible. This decision depended on the judgment of the degree of clinical homogeneity [19,20].
Analysis To appraise the risk of bias for all included studies, the “summary assessments” approach of The Cochrane Collaboration's tool for assessing risk of bias was used [18]. The level of evidence of the included studies was assessed and data were summarized. Each included study was fit in the duct preserving or duct damaging treatment category. Subsequently, the recurrence rate of nipple
Results Selection and characteristics of studies A total of 2045 records were screened based on title and abstract of which 1847 were excluded. Of the remaining 198 manuscripts,
Fig. 1. Flowchart of the search.
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Table 3 Overview of the included studies. X ¼ Unknown, * ¼ Seven patients were lost to follow-up. ** ¼ knowing the mean follow-up and the maximum follow-up period it was assumed that the minimum follow-up was at least 6 months. Number Reference
Year of publication Patients treated Nipples treated Mean age in years (range) Mean follow-up in months (range) Treatment category
1 2 3 4 5 6 7 8 9 10 11 12 13
2008 2014 2015 2006 2009 1998 2003 2011 2012 2011 1980 2005 2011
Caviggioli Durgun Jeong Kim Kolker Lee (Hoon-Bum) Lee (Michael) Long Paraskevas Persichetti Rayner Ritz Zhou Total
16 26 15 31 18 17 53 13 28 9 11 36*
28 28 47 29 58 35 17 95 24 52 16 18 64 511
27 (17e35) 34 (16e64) 26 (21e55) 27 (20e33) 26 (20e31)
(23e37) 31 26 (17e35)
(12-X) 17 (8e24) 14** 14 (X-60)** 22 (8e69) 24 (12e48) (12-X) 12 (8e18) (12e36) (12e72) (15e36) 28 (X-48)** (6e36)
Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct Duct
preserving preserving preserving preserving damaging preserving damaging preserving preserving damaging damaging damaging preserving
Fig. 2. Example of a lactiferous duct preserving technique by Long et al. using stainless wires through a nipple retractor. A: a 10 ml or 5 ml syringe is used to make the retractor, B: piercing procedure for inverted nipple using a crossed wire, C: fixation of the nipple retractor using the wire [11].
185 full text manuscripts could be retrieved and assessed for eligibility. Thirteen studies were included (Fig. 1). Although no strict inclusion criteria were applied, still 49 studies had to be excluded because of an unclear sample size or a sample size lower than 10 nipples. Thirteen studies were excluded because the outcome parameter recurrence of nipple inversion was not measured during follow-up: one randomized controlled trial (RCT) conducted by Alexander et al. with a sample size of n ¼ 96 comparing two non-invasive (duct preserving) treatment techniques was excluded for this reason [8]. Besides this RCT, no relevant studies
with a high methodological quality have been excluded unintentionally. A total of 511 nipples were analyzed whereby the follow-up period ranged from six to 69 months. Patient age ranged from 17 to 55 years. An overview of the basic study characteristics is summarized in Table 3. No non-invasive treatment methods were included. Eight studies presented a treatment method with the preservation of the lactiferous ducts of which an example of the surgical technique is presented in Fig. 2 [11,21e23]. These techniques varied from minimal invasive fixating stainless wires through a nipple retractor for six months [11] to more invasive
Fig. 3. Example of a lactiferous duct damaging flap transposition technique creating projection of the nipple by Ritz et al. A: nipple is elevated to its maximal length, B: blunt dissection and creation of two tunnels for the two dermofibrous deepithelialized skin flaps, C: the two dermofibrous flaps are inserted into the tunnels, D: postoperative image [32].
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techniques releasing the fibrous tissue between the ducts followed by splinting [21] or a purse string suture combined with splinting [24]. The majority of these studies presented a technique using (deepithelialized) flaps to provide bulk under the nipple [22,23,25e27]. Five studies reported a treatment method whereby the lactiferous ducts were damaged of which an example of a surgical technique is presented in Fig. 3 [28e32]. The common technique used for these studies is extensive release (surgical or with needle) beneath the nipple to release the fibrous tissue, thereby damaging the lactiferous ducts. Projection of the nipple was created through various (flap) transposition techniques [30e32], a purse string suture [28], or by suturing the internal sidewalls of the nipple [29]. Recurrence rate of nipple inversion Recurrence rate per treatment category Recurrence was described using different terms: recurrence of nipple inversion, relapse, loss of projection, and flattening. The total recurrence rate of all 13 studies measured 3.5% (18/511 nipples). Recurrence in the duct preserving category was 0.6% (2/350) versus 9.9% (16/161) in the duct damaging category. The recurrence rate specified per study and treatment category is summarized in Table 4. Only two studies quantified the nipple projection: one study measured a decrease in nipple projection from 10.8 ± 0.8 mm (immediately postoperatively) to 9.0 ± 1.0 mm at 14 months postoperatively [23]. Long et al. only reported a decrease of nipple height of 4.7 mm (range 3e7 mm) six months postoperatively [11]. Statistical pooling of the data was not possible due to the small number of studies and the heterogeneity of the data presented (different treatment techniques, heterogeneous outcome description, and lack of statistical analysis). Recurrence rate per grade of nipple inversion Four studies specified the recurrence rate based on the Han and Hong classification [11,21,28,29] (Table 5). In summary, the data of these four studies report no recurrence (0/18) for grade I nipple inversion, a recurrence rate of 10.3% (8/78) for grade II, and a recurrence rate of 4.9% (5/102) for grade III nipple inversion. Statistical pooling the data was not possible due to the small number of studies which specified the recurrence rate per grade of nipple inversion. In addition, pooling would not be sensible because the average recurrence rate of these four studies lies very far apart from the actual recurrence rates that are reported in the individual studies (grade II average ¼ 10.3% versus Kolker et al. ¼ 27% and Caviggioli, Lee, Long et al. reported no recurrence, grade III average ¼ 4.9% versus Kolker et al. ¼ 50% and Caviggioli, Lee, Long et al. reported no recurrence).
Table 5 Recurrence of nipple inversion per Han and Hong classification. The recurrence rate is calculated based on the amount of nipples treated. Reference
Grade 1 (%)
Caviggioli Lee (Michael) Long Kolker Total
Grade 2 (%)
Grade 3 (%)
0.0 (0/28)
0.0 (0/18) 0.0 (0/26)
0.0 (0/20) 27.0 (8/30) 10.3 (8/78)
0.0 (0/17) 0.0 (0/75) 50.0 (5/10) 4.9 (5/102)
Complications In the majority of studies, registration of complications such as nipple necrosis, loss of nipple sensibility, infection, and hematoma was part of the protocol. No nipple necrosis (0/356, 9 studies) [11,21e24,26e28,32], infection (0/351, 8 studies) [11,22e24,26,28,30,32], or hematoma (0/241, 6 studies) [11,22e24,26,32] was registered postoperatively. In 3.4% (11/322, 9 studies) of the nipples a loss of sensibility was described [11,22e24,26,27,30,32]. In six studies the patient satisfaction was described by the authors, which ranged from satisfied to highly satisfied [22,25,27,29,30,32]. For this purpose, no reliable or validated questionnaires were used. Four studies reported sufficient data on the ability to breastfeed after treatment [22,23,26,32]: out of 23 patients who tried breastfeeding after treatment in 96% (22/ 23) of the cases breastfeeding succeeded. Two studies reported data on breastfeeding, which were insufficient for calculating the percentage of successful breastfeeding [25,27]. Assessment of the risk of bias All included studies were case series with a level of evidence of IV. Consecutive inclusion of patients was not described in any of the included studies. Based on the Cochrane Handbook for Systematic Reviews of Interventions we conclude that a high risk of bias is applicable for all studies. Discussion In this systematic review for the first time an overview was provided with a critical appraisal of the available treatment methods for the benign inverted nipple. It was not possible to perform a meta-analysis due to clinical heterogeneity of the included studies, insufficient data available, and the low level of evidence. A wide range of inclusion criteria was applied to allow studies with various level of evidence to be included, as it appeared very little has been published on this topic. Nonetheless this
Table 4 Recurrence of nipple inversion per study and treatment category. The recurrence rate is calculated based on the amount of nipples treated. Reference
Recurrence of nipple inversion for duct preserving treatment (%)
Caviggioli Durgun Jeong Kim Kolker Lee (Hoon-Bum) Lee (Michael) Long Paraskevas Persichetti Rayner Ritz Zhou Total
0.0 3.6 0.0 0.0
Recurrence of nipple inversion for duct damaging treatment (%)
(0/28) (1/28) (0/47) (0/29) 22.0 (13/58)
0.0 (0/35) 0.0 (0/17) 0.0 (0/95) 4.2 (1/24) 1.9 (1/52) 0.0 (0/16) 11.0 (2/18) 0.0 (0/64) 0.6 (2/350)
9.9 (16/161)
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resulted in the inclusion of only 13 studies which all had a level of evidence of IV. The average calculated recurrence rate of nipple inversion of these studies was 3.5%. No studies investigating noninvasive treatment methods could be included. Eight studies presented a treatment method preserving the lactiferous ducts, with an average recurrence rate of 0.6% (0.0e4.2%) [11,21e27]. Five studies reported a treatment method damaging the lactiferous ducts with an average recurrence rate of 9.9% (0.0e22.0%) [28e32]. Because of the small number and heterogeneity of included studies per treatment category (duct preserving versus duct damaging) no statistically supported conclusions can be drawn whether preserving or damaging the lactiferous ducts influences the recurrence rate of nipple inversion. Since, at this moment no superior treatment can be identified the authors would choose the least damaging technique, i.e. a duct preserving treatment method as the first method of choice. With respect to women wishing to breastfeed there was no specific duct preserving treatment method that provided convincing superior results. Thus, based on the evidence available at this moment any duct preserving treatment method can be applied for this patient category dependent on the patients' wishes and the surgeons preference. Even though no studies on non-invasive and minimal-invasive treatment techniques met the inclusion criteria of our search, we feel that in this review the following treatment techniques deserve mentioning: an RCT conducted by Alexander et al. presents the use of breast shells versus Hoffman's exercises (stretching the nipples by manipulation) [8]. They focused on the ability to breastfeed and no recurrence rates were investigated. Various non-surgical suction devices aiming to stretch the lactiferous ducts, showed promising results, such as the “Niplette” [7] and a cheaper suction system described by Ozcan et al. using two syringes [33]. Lastly, various piercing systems have been investigated: these studies could not be included because of unclear follow-up data [34,35] or a small sample size [36]. More research into non-invasive treatment techniques should first be performed before evidence-based recommendations can be made. The authors realize that the majority of the included studies has a relatively small sample size ranging from 16 to 95 included nipples. We hypothesize that this could be explained because a low percentage of women with inverted nipples seek medical help and therefore collection of a large amount of patient data takes many years. The authors excluded one well conducted study by Gould et al. with an exceptional high sample size of 191 nipples, because the minimum follow-up was less than six months [37]. However, the study had a mean follow-up of eight months (range 3 weekse9 years) and therefore we find the data worth presenting: this lactiferous duct preserving technique using a combination of sutures and traction (for two to five days) showed a recurrence rate of 13% with 3% eschar/redness and 3% infection. This recurrence rate of 13% is relatively high compared to our calculated average recurrence rate of 0.6% for duct preserving techniques. Gould et al. explain this relatively high recurrence rate because of differences in
patient demographics and the short duration of the application of the nipple retractor. It has often been suggested that a higher degree of nipple inversion according to the Han and Hong classification would require a more invasive (and duct damaging) treatment method. Based on the results of this review there is no evidence that for a higher degree of nipple inversion a more invasive operation technique would be required. Although the authors realize data are limited, analysis of the four studies which scored the recurrence per grade of nipple inversion did not show more recurrence for a higher grade of inverted nipples that were treated with a duct preserving treatment method. On the contrary, the only treatment (out of these four studies) that had a recurrence rate higher than 0% (27% for grade II, 50% for grade III), concerned a duct damaging operation technique [28]. The strength of this review is that based on the shortcomings of the included studies a well-advised proposal can be done for to the set-up of future research on this topic: the authors would like to provide recommendations for the minimal requirements of investigating a treatment method for the inverted nipple: since there is a large clinical variety in the degree of nipple inversion, reliable classification of the degree of nipple inversion is of paramount importance. The Han and Hong classification is the latest and most accepted grading system, which is based on the amount of effort needed to pull out the nipple manually. This is a subjective classification system of which the intra- and inter-observer reliability is unknown. We therefore would like to suggest performing a clinimetric assessment of their classification system before widely applying the grading system in clinical research. Another option to acquire more uniformity in grading of nipple inversion would be the use of an objective measurement tool which measures the pressure needed to evert the nipple. A vacuum-manometer, which has been used for increasing the length of the nipple-areola complex in lactating women, could be suitable for this purpose [38]. However, again a clinimetric assessment of this measurement device for the purpose of grading nipple inversion would be the first step towards clinical application. The study design should at least include a prospective cohort study whereby consecutive patient inclusion is mandatory. When breastfeeding is of importance a randomized controlled trial comparing a non-invasive to an invasive duct preserving technique would be clinically relevant. However, the authors realize that inclusion of sufficient patients to be able to draw powerful conclusions may be challenging. Basic patient characteristics that need to be described should at least include age, amount of nipples involved/treated per patient, smoking, relevant comorbidity, and whether the nipple(s) have been treated previously. In addition wish for breastfeeding, previous breastfeeding, and inability to breastfeed at the moment of inclusion should be systematically registered. We suggest a minimum follow-up period of six months: this advice is based on evidence that maturation of both burn scars and surgical scars at the least takes six months [39e41] and thus a surgical end result
Table 6 Outcome parameters and suggested measurement method for evaluating treated inverted nipples at follow-up. * reliable and valid for measuring patient satisfaction after total hip arthroplasty. Outcome parameters
Measurement method
Nipple projection Nipple sensibility
1-mm unit micrometer caliper, patient in supine position Semmes Weinstein Test [43] Pressure-Specified Sensory Device [42,43] Brush test [23] Breast Q - Reconstruction questionnaire, item 10 [44] Visual Analogue Scale for patient satisfaction* [45] Patient and Observer Scar Assessment Scale [46] Hematoma, nipple necrosis, infection, inability to breastfeed
Patient satisfaction Scar appearance Complications Recurrence of nipple inversion
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cannot be expected earlier than this time period. The minimum outcome parameters that we suggest to measure at follow-up are summarized in Table 6. The authors would like to stress that the use of reliable and valid measurement methods are mandatory for measuring outcome parameters of any study. For measuring nipple sensation three different measurement methods (Semmes Weinstein Test, Pressure-Specified Sensory Device, and brush test) have been used most frequently in recent literature [23,42,43]. However, no clinimetric assessment has been performed for the application for measuring nipple sensibility. The BREAST-Q questionnaire is reliable and valid for patient satisfaction which is specified per item of the nipple appearance [44]. The authors suggest to use an additional VAS score to quantify the general patient satisfaction. It should be noted that the use of the VAS score for registering patient satisfaction has only been found reliable and valid for scoring after total hip arthroplasty [45]. For the outcome parameter scar appearance we advocate using the Patient and Observer Scar Assessment Scale. The authors agree that sufficient clinimetric appraisal has been performed for the use of this measurement method. Conclusions Because only studies with a low level of evidence could be included and mostly insufficient data were provided on the outcome parameters and complications, it was not possible to identify a superior treatment for nipple inversion. Based on the evidence available at this moment both duct preserving and duct damaging treatment techniques can be applied. However, the authors advocate to use the least damaging technique, i.e. a duct preserving treatment. There were no manuscripts on non-invasive treatment methods that met our inclusion criteria, therefore at this moment no conclusions on the application of non-invasive treatment techniques can be drawn. Regarding the currently available lack of high quality literature on this topic, future research is strongly recommended. The authors have suggested minimal requirements in the set-up of studies on nipple inversion to be able to provide more powerful evidence in the future. Conflict of interest statement None declared. Acknowledgements We would like to acknowledge C.F.W. Peeters from the department of Epidemiology and Biostatistics of the VU Medical Center for advice concerning the statistical analysis of the acquired data. References [1] Park HS, Yoon CH, Kim HJ. The prevalence of congenital inverted nipple. Aesthet Plast Surg 1999;23(2):144e6. [2] Sanuki J, Fukuma E, Uchida Y. Morphologic study of nipple-areola complex in 600 breasts. Aesthet Plast Surg 2009;33(3):295e7. [3] Schwager RG, Smith JW, Gray GF, Goulian Jr D. Inversion of the human female nipple, with a simple method of treatment. Plast Reconstr Surg 1974;54(5): 564e9. [4] Ramakrishnan KM, Rao DK. Congenital inversion of the human nipple. Aesthet Plast Surg 1980;4(1):65e72. [5] Han S, Hong YG. The inverted nipple: its grading and surgical correction. Plast Reconstr Surg 1999;104(2):389e95. discussion 96e7. [6] Crestinu JM. The correction of inverted nipples without scars: 17 years' experience, 452 operations. Aesthet Plast Surg 2000;24(1):52e7. [7] McGeorge DD. The “Niplette”: an instrument for the non-surgical correction of inverted nipples. Br J Plast Surg 1994;47(1):46e9. [8] Alexander JM, Grant AM, Campbell MJ. Randomised controlled trial of breast shells and Hoffman's exercises for inverted and non-protractile nipples. BMJ 1992;304(6833):1030e2.
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