Probe-Guided Microdochectomy for Bloody Nipple Discharge with Normal Breast Imaging

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1 台灣癌症醫誌 (J. Cancer Res. Pract.) 28(4), , 2012 Original Article journal homepage: Probe-Guided Microdochectomy for Bloody Nipple Discharge with Normal Breast Imaging Chia-Chi Tsai 1, Shih-Ping Cheng 1, Chien-Liang Liu 1,2, Tsen-Long Yang 1,2, Hou-Keng Liu 3, William C. Dooley 4, Yuan-Ching Chang 1,2 * 1 Department of General Surgery, Mackay Memorial Hospital, Taipei, Taiwan 2 Mackay Medicine, Nursing and Management College, Taipei, Taiwan 3 Department of Plastic Surgery, Mackay Memorial Hospital, Taipei, Taiwan 4 The University of Oklahoma Breast Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Abstract. Purpose: Bloody nipple discharge (BND) has been associated with breast cancer in women with normal mammograms. Surgical intervention is the only reliable tool for definitive diagnosis of the cause and treatment of BND. However, in patients with BND with normal imaging and without palpable lesions, an accurate biopsy is challenging to perform. This study evaluated a combination of methylene blue and probe-guided microdochectomy as a means of diagnosing and treating patients with BND, who also had benign or normal imaging results. Materials and Methods: From August 2006 to July 2010, 26 patients with BND and occult breast lesion which were apparent on routine imaging were studied by a single breast surgeon at Mackay Memorial Hospital. All patients in this study underwent microdochectomy under sedation and local anesthesia, assisted by intra-operative use of methylene blue injected intraductally in order to trace the affected duct and its side branches. All patients in our study received nipple aspirate fluid (NAF ) and ductal lavage before proceeding to microdochectomy. Results: A total of 27 microdochectomy procedures were performed in 26 patients, with a mean age of 52 years. All the patients presented with BND, with normal or benign mammography and ultrasound findings (BIRADS 1,2) in 26 cases (100%). The histopathological results in the 27 lesions biopsied demonstrated fibrocystic change and nonspecific results in 2 cases, intraductal papilloma with ductal hyperplasia in 9 cases, dilated duct with papillomatosis in 4 cases, papilloma with atypical hyperplasia in 3 cases, intraductal carcinoma in 5 cases, and invasive carcinoma in 4 cases. Clinical signs of BND were resolved in 24 patients (96%), and no complications occurred. Patients were followed for a mean period of 2.5 years. No recurrence was found in the cancer group and no subsequent breast cancer developed in the benign group. Conclusions: Microdochectomy with a combination of probe insertion and methylene blue injection is a safe procedure with high diagnostic and therapeutic value for the management of BND. Keywords : breast cancer, bloody nipple discharge, lacrimalduct probe, microdochectomy

2 162 C. C. Tsai et al./jcrp 28(2012) 原著論文 鼻淚管通條應用於乳頭血色分泌但乳房影像檢查正常患者之微乳管切片手術 蔡家騏 1 鄭世平 1 劉建良 1,2 楊圳隆 1,2 劉厚耕 3 William C. Dooley 4 張源清 1,2 * 1 馬偕紀念醫院一般外科 2 馬偕醫護管理專科學校 3 馬偕紀念醫院整形外科 4 The University of Oklahoma Breast Institute, Oklahoma City, OK, USA 中文摘要乳房門診的病人中, 有 5% 的病人主訴乳頭有分泌物 婦女一旦有乳頭分泌物常造成患者的恐慌 雖然大部份的分泌物病人都是良性變化, 其中以乳突瘤為主, 約佔 40% 至 70% 的患者 但是仍有相當比例潛伏乳癌的可能性 ( 約 1~23%) 傳統影像檢查 ( 乳房攝影或超音波 ), 卻常無法得到令人放心的診斷 乳管攝影對乳癌偵測敏感性高, 但專一性低, 施作上有一定難度且常造成病人疼痛 核磁共振影像 (MRI) 雖然被認為比傳統乳房攝影或超音波都來得準確 但是應用核磁共振於乳頭血色分泌患者仍需克服一些障礙, 包括較高假陽性率, 高成本而且不易以核磁共振影像導引切片 鼻淚管通條可作為術中可疑乳管內病灶切除的導引切片, 使得外科醫師只要在適當的局部麻醉下就能很容易找到乳管內病灶, 更準確而有效率取得組織診斷, 減少不必要的手術及醫療成本, 避免醫療糾紛 乳癌被認為是來自正常乳腺細胞連串的突變, 約 85% 的乳癌起源於乳腺管或乳小葉上皮細胞 (TDLU), 從正常乳腺上皮細胞經過增生 (hyperplasia) 異化增生 (atypical hyperplasia) 原位癌 (carcinoma in situ) 然後逐漸進展成侵犯性癌 (invasive carcinoma) 這種細胞惡性轉型進展常以乳頭血色分泌物表現 身為腫瘤外科醫師, 我們總會希望早期診斷及適當的介入, 阻止這種細胞惡性轉型的進展 本研究的延伸將可提供安全 準確的乳頭血色分泌病人切片手術模式 關鍵字 : 乳癌 乳頭血色分泌 鼻淚管通條 微乳管切片手術 INTRODUCTION Bloody nipple discharge (BND) has been associated with breast cancer in women with normal mammograms[1]. Consequently, bloody nipple discharge causes a high degree of anxiety in women, who frequently have substantial fears and concerns about *Corresponding author: Yuan-Ching Chang M.D. * 通訊作者 : 張源清醫師 Tel: Fax: yuanching.chang@gmail.com breast cancer. Commonly, the absence of palpable or mammographic abnormalities gives a false sense of security, causing delays in breast cancer diagnosis. Treatment of BND often entails surgical duct excision for symptomatic relief and histopathological examination. Intraepithelial neoplasia may spread through a breast, which giving the potential for diagnostic and therapeutic access to breast parenchyma via the nipple. Ductal segments, each of which ultimately drains to a single major lactiferous sinus at the nipple, vary in size and depth in the breast. Accordingly, accurate knowledge of breast duct anatomy in three dimensions

3 C. C. Tsai et al./jcrp 28(2012) Table 1. Baseline demographic and clinical characteristics of study population Patient Age Pathology NAF Ductal lavage 0 = normal, 1 = atypia 1 45 microinvasive papillary carcinoma papillomas with ADH DCIS papillary carcinoma in situ IDC pailloma with ADH papilloma with DH papilloma with DH papilloma with DH papilloma with DH fibrocystic disease papilloma with DH papillomatosis atypical papillary hyperplasia ADH papilloma with ADH fibrocystic disease IDC ADH fibrocystic disease Invasive papillary carcinoma papilloma with DH DCIS fibrocystic disease DCIS papilloma with DH DCIS 0 1 is needed when confronted with bloody nipple discharge. The mastectomy nipples contain central ducts (median 27, inter-quartile range 21-30). Major variations in duct morphology and extent define highly variable territories in which intraepithelial neoplasia could grow [2]. In our study, image occult breast malignancy wasfound in one-third of patients with single duct BND. Incomplete excisions are more probable if the standard breast imaging does not correspond to the entire extent of the lesion. There is headway being made in the efficacy of breast MRI in detecting the

4 164 C. C. Tsai et al./jcrp 28(2012) Figure 1. Basic steps of the probe-assisted microdochectomy: (a) probing of the affected duct with 2-0 prolene. (b) guiding the placement of 24-gauge intravenous catheter extent of disease and mammographically occult le- when MRI-guided biopsy is available. Additionally, sions within the breast. Although preliminary data MRI does not always accurately predict the extent of regarding MRI is encouraging, an important limitation non-invasive cancer, especially when low-grade DCIS of MRI is its high rate of false-positive results. About is present (55% of occult malignancy in our series). 75% of MRI studies will show some area of enhance- Furthermore, the high cost of MRI is prohibitive in ment that needs further assessment, but ultimately many healthcare settings. proves to be dense but histologically benign breast Breast surgeons should carefully evaluate the can- tissue [3]. The use of MRI in the absence of MRI- cer distribution and extent in the breast prior to sur- guided sampling or clip placement is not recom- gery. A combination of imaging methods (mammog- mended, because in many cases the questions raised raphy with magnification views, ultrasonography, by studies cannot be resolved before lumpectomy. The MRI, or all) may yield the best estimates of overall use of MRI off-trial should be restricted to centers tumor extent. However, in patients with BND with with substantial experience in MRI interpretation, and normal imaging and without palpable lesions it is a

5 C. C. Tsai et al./jcrp 28(2012) Figure 2. (a) injection of the dye, (b) palpation of the probe,(c) ultrasound detection and (d) circumareolar incision great challenge to have mammogram and breast ultra- traluminal defects? We determined the distribution, sound imaging to direct our surgical procedures. Most and pathologic territory of the BND using methylene breast surgery today is performed with the same blue and lacrimal duct probe approaches, all of which longstanding tools that Halsted used: the surgeon s were based on the successful identification of and palpation and the eye alone. Attempts to access the gaining of access to the nipple ductal orifices. There- ductal systems of the breast have made it imperative fore, these lesions can be localized preoperatively un- to obtain a more accurate description of the ductal der lacrimal probe and methylene blue guidance to anatomy than presently exists. Those tumors with in- plan an accurate resection. It should be offered as an traductal spreading are best excised by resections ac- option to all patients with BND. cording to their distribution. Can we perform a more accurate lumpectomy by actually mapping out the MATERIALS AND METHODS extent of the involved ductal system and either excis- This pilot study was a prospective correlative ing it all or excising the lesion and all associated in- analysis of female patients requiring a biopsy exami-

6 166 C. C. Tsai et al./jcrp 28(2012) Figure 3. (a) dissection of the affected duct free from the surrounding healthy gland, and dissection of the affected duct territory, (b) specimen nation according to the current standard of care, iden- derwent the procedure were given adequate sedation tified in the Mackay Memorial Hospital Breast Care with propofol, and a local anesthetic was given by Center. Inclusion criteria were as follows: women age dermal infiltration of the incision site. 18 years or older, bloody nipple discharge with both a After nipple aspiration, ducts were identified for Breast Imaging Reporting and Data System (BIRADS) cannulation based on the presence of bloody nipple 1 or 2 mammogram and breast ultrasound. discharge. The orifice of the discharging duct was Pregnant or lactating patients, women with palpa- identified by gentle pressure on the nipple to express a ble tumors by physical examination or mammogram, drop of discharge. The duct was then probed with a or prior areolar surgery within 2 cm of the nipple- 2-0 prolene, gently passed peripherally as far as possi- areolar complex were excluded. The breast surgeon ble, which then guided the placement of a 24-gauge collected nipple aspirate fluid (NAF), and performed intravenous catheter (Figure 1). These steps represent ductal lavage (DL) immediately before the scheduled passage of the catheter through the nipple sphincter breast biopsy. All such patients with microdochecto- and successful navigation through the lactiferous sinus my were operated on at Mackay Memorial Hospital into a duct without piercing the wall of the duct. In from August 2006-July All subjects who un- this procedure local anesthetic (lidocaine) was infused,

7 C. C. Tsai et al./jcrp 28(2012) the breast was massaged and then ductal lavage occurred, where the 24 G intravenous cannula was kept in place to inject 0.2~2 ml of methylene blue dye. The cannula was removed and the lacrimal probe was reinserted to mark the position of the affected duct. A limited circum-areolar incision was made to raise the areola skin flap (Figure 2d). We then identified the probed duct close to its attachment to the underside of the nipple, and carefully dissected it free from the surrounding tissues and the unaffected ducts (Figure 3a). The duct was then removed by transecting it close to the skin, and was marked with a single suture to orientate the specimen (Figure 3b). The specimens were inked and examined histologically. All patients were discharged the same day after recovering from anesthesia. RESULTS A total of 27 microdochectomy (Table 1) procedures were performed in 26 patients with a mean age of 49 years (26~70 years). Additionally, 48% of the 27 eligible subjects had atypia by NAF compared with 52% by ductal lavage. Concordance between NAF and ductal-lavage cytomorphology was poor. 30% of the women with atypia in their NAF specimens had ductal-lavage specimens interpreted as benign, 37% of atypical lavage specimens were associated with benign or NAF specimens, and 67% of the specimens were interpreted as inconsistent results by a different cell collection method. Subsequent microdochectomy showed papillomas with atypical ductal hyperplasia (ADH) in 13 excisions (25.9%). Five patients had ductal carcinoma in situ (18.5%), and 4 had invasive carcinoma (14.8%). Other benign causes (7 papillomas or 4 fibrocystic change) occurred in 11 (40.7%) patients. There were no surgical complications recorded. With a mean follow-up of 27.5 months (4~41) among the patients with benign disease, there was one recurrence of BND. A 58-year-old woman had ipsilateral breast recurrence of papilloms with ADH during 6 months of follow-up. Nine (33.3%) patients with image occult malignant histology enjoyed a cancer-free life during a mean follow-up period of 25 months (3~43). The mean age of the patients found to have cancer was 50.8 years (37~70). All of the five patients with invasive carcinoma had no metastasis in the sentinel lymph node. The age of the patients with cancer was not statistically different from those with benign disease. DISCUSSION The work-up of the patients presenting with BND should follow the same principles as with any other breast complaint. Subsequent to obtaining patient history and complete clinical and breast examination, imaging and cytology should be performed. Irrespective of age, all women with BND should undergo a mammogram to assess the subareolar area for microcalcifications or other abnormalities, and also to examine the other breast to rule out synchronous contralateral lesions (SCL). In the presence of a palpable abnormality, the possibility of SCL should be assessed and followed-up as usual. The sensitivity of smear cytology in the evaluation of the discharge for malignancy is very low (26.7%) [4]. This is particularly true in the absence of blood, with 2.7% false positive and 20% to 35% false negative rate. Nevertheless, the specificity for cancer is reported to be high (81.1%). Despite the fact that it does not represent an appropriate diagnostic tool for identification of occult breast cancer, this test should be performed because if positive, it can add valuable information to the operation plan [4,5]. Ductal aspiration (lavage), galactography (ductography) and ductoscopy have been used to evaluate bloody nipple discharge. Ductography is helpful especially for detecting distally and/or multiple located intraductal lesions, but the procedural process is uncomfortable for the patient [6,7]. Despite its high sensitivity for detecting cancer

8 168 C. C. Tsai et al./jcrp 28(2012) (100%), ductography is not sufficiently specific[5,7], while in cases with duct ectasia it is unreliable[4,7], and has not become standard medical procedure in many parts of the world [8]. Fiberoptic ductoscopy (FD) is a promising alternative, which was introduced in the 1990s. However, there are limitations in its use; FD is expensive and time consuming, requires special skills and training and cannot currently be used alone for diagnostic purposes since it is not sufficiently accurate to reliably verify malignancy [9,10]. With the introduction of magnetic resonance imaging (MRI), there is increasingly more interest in using this modality for patients with normal mammograms. The reported sensitivity of MRI in identifying invasive cancer ranges between 68% and 100% and for non-invasive cancers between 40% and 100% [6]. The use of MRI should be restricted to centers with medical personnel experienced in MRI interpretation, and with available MRI-guided biopsy. Accurate surgical biopsy is the only reliable tool for definite diagnosis of the cause and treatment of BND. However, in patients with BND with normal imaging and cytology and without palpable lesions, an alternative approach is close follow-up until the discharge resolves, and only after discussion with the patients about the benefits and consequences of both approaches. It is worth noting that observation may put the patient at risk for progression of intraductal malignancy. Microdochectomy is the conventional treatment for patients with BND. Provided that the correct origin of the discharge is identified, it can be both diagnostic and therapeutic, alleviating a persistent and sometimes troublesome symptom without major interference with the breast [11]. It is less invasive than the radical subareolar duct excision (Hadfield s operation), with lower morbidity. Microdochectomy may also be superior to major duct excision as a diagnostic procedure. The reason for this could be related to the fact that up to 20% of lesions are distal to the limits of major duct excision, but are usually excised with microdochectomy [4,11]. The use of methylene blue dye to delineate the diseased duct and the distal side branches increases the likelihood that a specific pathology will be found [12]. Our findings suggest that normal mammography and benign epithelial cells on cytology should not be a green light for observation since 8 of 14 such patients had cancer in our series. It is difficult to extrapolate on the precise incidence of this phenomenon because of the modest patient numbers in our study. Patients with cancer presenting with BND are reported to have a high incidence of local recurrence following breast conserving surgery. Moreover, the extent of the DCIS with PND has been reported to be much higher than that of other presentations. This precludes breast conservation, leading to higher mastectomy rates (66% vs 33%) [13]. More accurately located ductal excision by guided probe may play a role in our higher diagnostic rate, as well as lower recurrent symptomatic discharge and even cancer recurrence. In addition, our results seem to have lower recurrence in comparison with these previous publications. Overall, our study does have limitations, arising from both the small number of study patients, and shorter follow-up time period. CONCLUSIONS Cytology workup and breast imaging may not cause suspicion of underlying malignancy in patients with BND. Therefore, probe-guided microdochectomy combined with methylene blue injection is a safe and accurate approach for patients with BND, and should be offered as an option to all patients with this condition. REFERENCES 1. King TA, Carter KM, Bolton JS, et al. A simple approach to nipple discharge. Am Surg 66(10):

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