Surgical outcomes of total duct excision in the diagnosis and management of nipple discharge

Introduction Total duct excision (TDE) is performed for the diagnosis and management of nipple discharge. The Association of Breast Surgery’s recent guidelines recommend considering diagnostic surgery for single-duct, blood-stained or clear nipple discharge, and for symptomatic management. Methods We retrospectively reviewed the diagnostic and surgical outcomes of all cases of TDE between January 2013 and November 2019. Results In total, 259 TDEs were carried out: 219 for nipple discharge, 29 for recurrent mastitis, 3 for screening abnormalities and 8 for breast lumps. Of the nipple discharge group, 121 had blood-stained discharge. Mean patient age was 52 years (range 19–81). Median follow-up time was 45 months (interquartile range 24–63). The following cases were identified on histopathology: 236 benign breast changes, 10 atypical ductal hyperplasia, 4 lobular carcinoma in situ, 2 low-grade ductal carcinoma in situ (DCIS), 3 intermediate-grade DCIS, 2 high-grade DCIS and 2 invasive ductal carcinomas. In total, 3.5% of patients who underwent TDE had a diagnosis of DCIS or invasive carcinoma. Blood-stained discharge was associated with a significant increase in risk of DCIS or carcinoma compared with other nipple discharge colours (p = 0.043). The most common complications of TDE were infection, poor wound healing and haematoma. Nipple discharge recurred in 14.2% of cases. Conclusions TDE can be considered for the diagnostics and management of nipple discharge. Blood-stained nipple discharge increases the risk of DCIS or malignancy, but the majority of the time TDE reveals benign breast pathology.


Introduction
Nipple discharge is a frequent cause for presentation to breast clinic, 1 and affects up to 80% of women of reproductive age. 2 There are both physiological and pathological causes of nipple discharge including: pregnancy, hyperprolactinaemia, duct ectasia and recurrent mastitis. 1Because nipple discharge has traditionally been considered a possible sign of breast cancer, further assessment is routinely required for persistent and unexpected symptoms. 3otal duct excision (TDE) has traditionally been used in the diagnostics and management of suspicious and troublesome nipple discharge.5][6][7][8] TDE also has a therapeutic advantage, stopping or reducing the nipple discharge. 8,9An alternative option is microdochectomy for single-duct discharge, but this study focuses on TDE, which has traditionally been our multidisciplinary team's (MDT) recommendation (if the patient is not considering breastfeeding in the future).5][6][7][8] Discharge colour may have predictive value.In a study of 925 cases of surgical duct exploration for persistent nipple discharge, 30.3% of those with blood-stained discharge and 17.6% of those with clear discharge had a diagnosis of carcinoma. 8ytology, galactography and mammary ductoscopy have been suggested as alternatives for the assessment of suspicious nipple discharge.These tests are often unavailable, are poorly validated and are neither sensitive nor specific. 10,11n January 2019, the Association of Breast Surgery (ABS) introduced new guidelines on the management of nipple discharge. 1These guidelines emphasise that single-duct nipple discharge is concerning, and requires thorough clinical assessment.If clinical assessment and imaging are normal, the incidence of malignancy is estimated at below 3%.If single-duct nipple discharge is blood-stained or clear in colour, TDE or microdochectomy should be considered for further diagnostics.Within this study, we assess the diagnostic and surgical outcomes of TDE at a single, UK-based breast surgery department.

Methods
This is a retrospective study, conducted in the breast department of a busy university teaching hospital.All patients who underwent TDE or microdochectomy between January 2013 and November 2019 were included.The study was conducted in accordance with local research and ethics policies, and was approved locally by the research and development team (Project Reference/GF0289).
All patients underwent a standardised work-up in the breast clinic consisting of history-taking, examination and breast imaging with ultrasound scan, plus mammography if aged 40 years or over (Figure 1).If a breast lesion was identified and accessible, radiologically guided biopsy was performed.Patients underwent TDE using a standard Hadfield's technique.During this method, the major duct system is excised, leaving the nipple intact. 12All surgical specimens were sent to histopathology for diagnostics.
All histology was discussed in a local MDT meeting.Patients with benign disease were reviewed postoperatively and discharged from the breast service.Patients with ADH or LCIS were followed-up with annual mammograms for 5 years.Patients with DCIS or invasive carcinoma underwent further treatment according to MDT recommendation, such as further surgery or adjuvant treatment, and surveillance mammography.

Statistical analysis
Statistical analysis was carried out using Microsoft Excel and SPSS Statistics.The rate of malignant disease was compared between imaging findings and nipple discharge colour groups, using a two-tailed Fisher's exact test.A logistic regression model was used to assess the association between age and breast malignancy on TDE.The level of significance for all statistical tests was taken as p < 0.05.

Population
In total, 259 cases of TDE were performed, 257 in female patients, and 2 in male patients.Mean patient age was 52 years (range 19-81).Median follow-up time was 45 months (interquartile range 24-63).

Surgical indication
In total, 219 patients (84.6%) underwent TDE for nipple discharge.Of these, 208 were TDE operations alone and 11 were done simultaneously with local excision biopsy, owing to abnormal findings on imaging or clinical examination.Twenty-nine patients (11.2%) underwent TDE for recurrent mastitis.Eleven patients (4.2%) underwent TDE for further diagnosis of a suspicious breast lump or thickening identified in breast clinic or on routine breast screening; two of which were performed with an additional excision biopsy.Twenty-six patients in this series had undergone previous ipsilateral TDE surgery, and underwent a repeat procedure.

Nipple discharge colour
Nipple discharge colour was recorded for 207 cases.Nipple discharge was blood-stained in 124 cases (59.9%), clear in 41 cases (19.8%) and other colours (black, brown, cream, green, yellow or white) in 42 cases (20.3%).All cases of intermediate-grade DCIS, high-grade DCIS or invasive carcinomas were associated with blood-stained nipple discharge (Table 1).

Histopathology results of TDE
In total, 236 (91.1%) patients who underwent TDE were diagnosed with benign disease: 91 cases were benign papillomas, 83 were duct ectasia, 61 were benign breast changes and there was 1 myofibroblastoma.Fourteen patients (5.4%) had atypical changes including ten cases of ADH and four cases of LCIS.Nine patients (3.5%) were diagnosed with malignant disease including two cases of low-grade DCIS, three cases of intermediate-grade DCIS, two cases of high-grade DCIS and two invasive ductal carcinomas.

Imaging
In total, 256 cases (98.8%) underwent preoperative imaging, and 65.6% of cases had an abnormality on imaging.All imaging abnormalities were associated with an increased chance of atypical changes or malignant disease on TDE, in comparison with the normal imaging group (Table 2).Any imaging abnormality, dilated ducts or the presence of a discrete lesion did not significantly increase the risk of atypical changes or malignant disease.
Breast asymmetric density significantly increased the risk of atypical changes or malignant disease on TDE compared with normal imaging (p = 0.044).All cases of DCIS had abnormalities on imaging (n = 7): three were associated with dilated ducts,

Patients with atypical cells, preinvasive disease or malignancy
Ten patients were diagnosed with ADH and four with LCIS.This group were followed-up with annual mammography for 5 years.Two patients were diagnosed with low-grade DCIS on TDE.Three patients were diagnosed with intermediate-grade DCIS on TDE (Table 1).High-grade DCIS was diagnosed in two patients (Table 1).Invasive ductal carcinoma was identified for two patients (Table 1).Patients with a diagnosis of DCIS or carcinoma were treated with further treatment as per our breast oncology MDT recommendation.

Risk factors for DCIS and breast carcinoma
Univariate analysis found that blood-stained nipple discharge was associated with a significant increase in the risk of intermediate-to high-grade DCIS or breast carcinoma compared with all other nipple discharge colours (p = 0.043), whereas clear nipple discharge was not (p = 0.36).The mean age of patients with DCIS or carcinoma was 67 years (range 43-81).On logistic regression, increasing age was associated with a significantly increased risk of intermediate-to high-grade DCIS or carcinoma on TDE (p = 0.007, R 2 = 0.173).

Procedure failure and complications
In total, 14.2% of patients who underwent TDE for nipple discharge experienced a recurrence of symptoms.This figure rose to 30.8% for those undergoing a repeat TDE procedure.The most common complications following TDE were infection (11.2%), poor wound healing (7.0%), haematoma (4.6%) and cosmetic dissatisfaction (4.2%).

Histopathology results of TDE
Most patients who underwent TDE within this series were found to have benign histopathology.Papilloma and duct ectasia were the most frequent diagnoses and are already a well-established benign cause of nipple discharge. 13,143][4][5][6][7][8] Within this study, 3.5% of patients had a diagnosis of DCIS or carcinoma.
In a large series of 915 cases of selective duct excision, Montroni et al reported a much higher malignancy rate of 23%. 7During this study, all patients were investigated pre-operatively with nipple discharge cytology and galactography, which may have led to more careful selection of surgical candidates, increasing the rate of malignancy detection.It is expected that TDE without additional pre-operative nipple discharge studies yields a much lower malignancy rate, which is predicted to be around 3% in the ABS nipple discharge guidelines. 1 Supporting this, a prospective study looking at 10,000 breast service referrals in New Jersey, USA, found that only 3.77% of patients who presented with nipple discharge had an underlying diagnosis of breast carcinoma. 4Furthermore, a UK study of 86 patients by Richards et al, found a malignancy rate of 2.3%.Only two patients who underwent TDE had a diagnosis of DCIS, and there were no cases of established breast carcinoma. 14here are several retrospective studies within the literature looking at the rate of breast malignancy following TDE.Variations in the incidence may depend on surgical criteria, nipple discharge colour, age and preoperative investigations.Risk factors for malignancy should be stratified by clinicians to decide when TDE is performed for patients with nipple discharge.
Blood-stained nipple discharge as a marker of malignancy ABS guidelines advise that cases of single-duct, blood-stained or clear nipple discharge should be considered for TDE owing to the risk of breast malignancy. 1 Interestingly, all cases of intermediate-to high-grade DCIS or malignancy in this series were associated with blood-stained nipple discharge, and none with clear nipple discharge (Table 1).Foulkes et al found when reviewing 194 duct excision operations that all malignancies presented with blood-stained nipple discharge. 15Furthermore, a meta-analysis of 3,110 cases of breast cancer found that patients with blood-stained nipple discharge are at significantly greater risk of breast malignancy than those with clear discharge (p = 0.011) or without discharge (p < 0.001). 16lood-stained nipple discharge may be more likely to be associated with DCIS or malignancy than other nipple discharge colours.Nipple discharge colour should always be considered in patients who may undergo TDE.

Age as a risk factor for malignancy
It is well-established that age is an independent risk factor for breast malignancy. 17Here, we found that age also increases the risk of DCIS and breast carcinoma in patients with nipple discharge (p = 0.007).Furthermore, all patients with a diagnosis of DCIS and breast malignancy were above the age of 40.
Given that TDE can effect a patient's future ability to breastfeed, age should be considered prior to surgical investigation of nipple discharge.It would not be unreasonable to consider a higher threshold for surgical intervention in young women with nipple discharge, in the absence of breast imaging abnormalities, and considering a microdochectomy rather than TDE.

Imaging in nipple discharge
All imaging abnormalities increased the odds of atypical changes or malignant disease on TDE and breast asymmetric density increased the odds by 11-fold.The sensitivity of conventional ultrasound scanning and mammography breast imaging is reduced for patients presenting with nipple discharge, because causative lesions are often small and non-calcified. 18,19In this study, one patient with normal ultrasound scanning and mammography was later found to have invasive ductal carcinoma on TDE.One of the limitations of this study is that we have not directly compared the site of imaging abnormalities (for example the site of a lesion) with pathological outcome following TDE.Further work is required within this field to assess if the location of a breast lesion is correlated with the risk of breast malignancy in a patient group with persistent nipple discharge.
Although not routinely used, there is increasing evidence that breast magnetic resonance imaging (MRI) may be a useful adjuvant in the investigation of suspicious nipple discharge.MRI may detect DCIS in some cases that are undetectable on mammogram.In one UK-based study, bilateral breast MRI was carried out in 82 patients with persistent nipple discharge prior to diagnostic microdochectomy.Microdochectomy led to the detection of malignancy in 14 patients who had a normal mammogram and ultrasound scan.The sensitivity and specificity of MRI was 85.7% and 98.5%, respectively. 20

Complications of TDE and recurrence of symptoms
The most frequent complications after TDE were infection and pain, which are reported elsewhere within the literature; 21 however, very few studies objectively quantify complication risk following TDE.A retrospective study of 915 patients who received selective duct excision for single-duct nipple discharge, reported exceptionally low complication rates of infection (n = 2), haematoma (n = 2) and nipple necrosis (n = 0). 7It is important to note that this study was performed retrospectively from a 'breast database', and the completeness of this analysis is unknown.In our study, all clinic letters, microbiology results and emergency department admission documentation were reviewed for each patient, to ensure that most complications were recorded.Furthermore, this study only reviews patients who underwent selective duct excision for single-duct nipple discharge; whereas we have reviewed patients who underwent TDE for any form of persistent nipple discharge.Clearly more research is needed to further quantify complication risks after nipple surgery.Further studies comparing complication rates following selective and total duct excision would also be beneficial.
Smoking history was not routinely recorded as part of this study; however, smoking is a known risk factor for breast sepsis and periductal mastitis, 22,23 hence higher complication rates are expected within this group.
High rates of discharge recurrence were seen within this study (14%), especially for those undergoing repeat TDE (31%).In comparison, a retrospective study of 152 patients who underwent surgical treatment of periductal mastitis, found that 7.2% of patients developed recurrent mastitis at a median follow-up time of 3 years.This centre used a range of surgical techniques including a wide surgical excision, fistulectomy and extended excision with transfer of a random breast dermo-glandular flap. 8

Conclusions
Benign breast pathology is the most common cause for persistent nipple discharge, and papilloma is the commonest histological finding on TDE followed by duct ectasia.In this study, DCIS or malignancy was diagnosed in 3.5% of cases of TDE, and blood-stained nipple discharge was found to be significantly associated with DCIS or malignancy on TDE (p = 0.043).Despite this, the majority of blood-stained nipple discharge was due to benign disease, no patients with clear discharge were found to have DCIS or malignancy, and no cases of DCIS or malignancy were diagnosed on TDE in patients under 40 years of age within this series.Nipple discharge reoccurs in 14% of patients undergoing TDE and 31% of those undergoing repeat TDE.

Figure 1
Figure 1 Local treatment algorithm for management of patients with suspicious nipple discharge.The flow diagram shows the local treatment pathway that patients with suspicious nipple discharge followed.

Table 1
Demographics and outcomes of patients with intermediate to high-grade DCIS or carcinoma Of the invasive carcinomas, one had normal imaging and the other had dilated ducts on ultrasound imaging.Thirty-nine patients (23.2%) with an imaging abnormality had a pre-operative biopsy result of abnormal or uncertain potential on histology (B3).No B4 or B5 lesions were detected pre-operatively.
There were seven cases of intermediate to high-grade DCIS or carcinoma following TDE.DCIS = ductal carcinoma in situ; TDE = total duct excision.three had a focal lesion and one was associated with breast asymmetric density.

Table 2
Rates of atypical changes/malignant pathology on TDE in patients with imaging abnormalitiesThe table shows the number of cases of TDE that had imaging abnormalities.The odds ratio shows the chance of atypical changes/malignant disease on TDE in each imaging abnormality group in comparison with those with normal imaging.The level of significance shows the p-value on Fisher's exact test when comparing the rate of atypical changes/malignant disease in each imaging abnormality group with those with normal imaging.The number of patients who had an abnormal pre-operative biopsy is also shown for each group.All abnormal biopsies were B3 lesions of abnormal or uncertain potential.