Prevalence of Terminal Duct Lobular Units and Frequency of Neoplastic Involvement of the Nipple in Mastectomy

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1 Prevalence of Terminal Duct Lobular Units and Frequency of Neoplastic Involvement of the Nipple in Mastectomy Oleksandr N. Kryvenko, MD; Ji Yoon Yoon, MD; Dhananjay A. Chitale, MD; Min W. Lee, MD Context. Breast cancer treatment has greatly evolved from radical mastectomy to more cosmetically acceptable and less-debilitating surgeries. Nipple-sparing mastectomy is increasingly done for both cancer treatment and risk reduction. The frequency of terminal duct lobular units (TDLUs) and occult neoplastic epithelial proliferation in grossly/clinically unremarkable nipples (GUNs) is not well investigated. Objective. To describe frequency of TDLUs and occult and overt neoplastic nipple involvement. Design. Nipples from 105 consecutive specimens (90 therapeutic, 15 prophylactic) were studied. Sixty-five nipples were entirely submitted to evaluate frequency of TDLUs; the rest had 1 vertical section submitted. Results. Terminal duct lobular unit was seen in 17 GUNs (26%). Six had TDLU in the base, 6 had it in the papilla, and 5 in both. Four GUNs showed lobular carcinoma in situ (1), Paget disease (1), and pagetoid extension of underlying malignancy (2). Grossly/clinically abnormal nipples had Paget disease (2), lymphovascular Improved general awareness and relatively easy accessibility of screening modalities (ie, mammography) to detect early breast cancer have led to significant changes of breast cancer seen in contemporary clinical practice. The detected cancers are smaller in size and thus have lower pathologic T stage, the frequency of regional lymph node metastases is lower, and more cancers are detected at preinvasive stage. 1,2 These changes triggered a cascade evolution of breast cancer treatment from radical mastectomy with radiation therapy and lymph node dissection to less debilitating and more cosmetically acceptable procedures of breast-conserving therapy. 3,4 Nipple-sparing mastectomy (NSM) is a variant of breast-sparing mastectomy performed in patients with minimal risk of nipple involvement by carcinoma to preserve this important anatomic structure for consecutive breast reconstruction. 5 In younger patients nipple preservation may be a decisive factor in invasion (2), invasive carcinoma (4), and pagetoid extension (5). Involved nipples were closer to tumor (mean, 1.1 versus 3.2 cm, P,.001), had larger underlying tumors (mean, 4.3 versus 2.6 cm, P ¼.03) and of higher grade (P ¼.04), and more often had lymph node metastases (91% versus 44%, P ¼.007). No pathologic abnormalities were found in prophylactic mastectomy nipples. Conclusions. Terminal duct lobular units were seen in 26% of nipples. They were frequently seen in the nipple papilla. Occult neoplastic epithelial proliferation was seen in 5% of grossly/clinically unremarkable therapeutic mastectomy nipples. Pagetoid extension was the dominant spread of underlying malignancy. Overall, the nipple was more often involved by larger and higher-grade tumors located closer to the nipple. All prophylactic mastectomies had unremarkable nipples. These findings should be considered while selecting patients for nipple-sparing mastectomy. (Arch Pathol Lab Med. 2013;137: ; doi: / arpa oa) treatment selection. 6 Nipple-sparing mastectomy is an increasingly used procedure for patients undergoing riskreduction (prophylactic) mastectomy with cancer in contralateral breast or those with high cancer risk due to some germline mutations in BRCA1/2 genes. 7,8 However, despite total removal of glandular breast tissue, the patients still have some oncologic risk associated with occult nippleareolar complex involvement. 9 Literature related to histologic evaluation of terminal duct lobular units (TDLUs) in the entire nipple is limited. It has been reported that the occurrence of TDLU in the nipple is infrequent and that this finding supports the safe use of NSM, including for those women carrying BRCA1/2 mutations. The goals of our study were to investigate the frequency of TDLUs in the nipple and assess frequency of involvement of grossly unremarkable nipple by occult neoplastic epithelial proliferation. Also, we have analyzed the tumor factors that influence nipple involvement (both overt and occult). Accepted for publication August 20, MATERIALS AND METHODS From the Department of Pathology, Henry Ford Hospital, Detroit, We prospectively collected all nipples from consecutive female Michigan. Dr Kryvenko is now with the Department of Pathology, mastectomy specimens obtained at Henry Ford Hospital, Detroit, The Johns Hopkins Hospital, in Baltimore, Maryland. The authors have no relevant financial interest in the products or Michigan, in the year To assess the prevalence of TDLU in companies described in this article. the nipple we modified our grossing protocol, which consisted of Reprints: Oleksandr N. Kryvenko, MD, Department of Pathology, submission of 1 sagittal section including entire cross-section of the The Johns Hopkins Hospital, Weinberg 2242, 401 N Broadway, Baltimore, MD ( okryven2@jhmi.edu). nipple, underlying lactiferous ducts, and proximal-to-the nipple areolar skin. The study protocol included amputation of the nipple Arch Pathol Lab Med Vol 137, July 2013 TDLU and Neoplasia in the Nipple Kryvenko et al 955

2 Figure 1. A diagram of the grossing technique for entire submission of the nipple (left) and macrophotography of the corresponding sections (right). at the level of the areolar skin and submission of the nipple base as en face section and papilla (top portion elevating above the areolar skin) as serial sections parallel to the lactiferous ducts (Figure 1). This allowed adequate evaluation of the entire nipple to assess the presence or absence of TDLU. Low or retracted nipples, which could not be grossed according to the modified study protocol, had submission of 1 vertical section per institutional protocol. The demographic information and pathologic data, including tumor type and grade (defined according to a Nottingham modification of Bloom-Richardson-Elston grading system 10 ), tumor size, its distance from the nipple, and lymph node status, were retrieved from the pathologic reports. Clinical assessment of the nipples was obtained from the surgical notes. All nipples were reviewed by 4 participating pathologists. Presence of TDLU and any pathologic changes were recorded. We defined TDLU as a terminal duct surrounded by a lobule containing acini. 11 Contingency table analysis of categorical data was performed with v 2 analysis. Differences in means of age, tumor size, and its distance to the nipple were compared with the 2-tailed t test. In patients with bilateral mastectomy, each breast was considered as a separate statistical event. Analytic results were considered significant when P value was.05. RESULTS One hundred five mastectomies with removal of the nipple were performed in 92 patients (13 women had bilateral mastectomies) over the study period. Among these, there were 90 therapeutic and 15 prophylactic mastectomies. The therapeutic mastectomies were performed for ductal carcinoma in situ (16 cases), invasive ductal carcinoma (55 cases), and invasive lobular carcinoma (19 cases). Regional lymph nodes were dissected in 63 therapeutic mastectomies with invasive cancer, and lymph node metastases were seen in 33 cases. Overall, average patients age was 59.9 years (range, years). Candidates of prophylactic mastectomies were younger (mean, 49 years; range, years) than those of therapeutic mastectomies (mean, 62 years; range, years) (P,.001). Patients with nipples involved by neoplastic proliferation were on average 5 years older (69.9 years) than patients with unremarkable nipples (61.3 years), but this difference did not reach statistical significance (P ¼.15). Thirteen nipples were grossly/clinically abnormal. Anatomic structure of 27 grossly/clinically unremarkable nipples precluded us from submitting them according to the study protocol and 1 sagittal section was submitted. Nipples from 65 mastectomy specimens from 58 patients ranging in age from 33 to 92 years (mean, 58.6 years) were grossly/clinically unremarkable and were submitted entirely according to the study protocol. These included 56 therapeutic and 9 prophylactic mastectomies. Terminal duct lobular unit was seen in 26% (17 of 65) of cases. Two prophylactic mastectomies (22%) had unremarkable TDLU in the nipple. In 6 cases TDLU was seen in the section of base, while 6 cases had TDLU in the sections of papilla and 5 nipples had TDLU present in both separately submitted nipple compartments. Thus, frequency of TDLU in the nipple papilla was 17% (11 of 65). The TDLUs were composed of a terminal duct surrounded by a lobule supported by dense fibromuscular stroma (Figure 2, A). There was no statistically significant difference in age between the patients with and without TDLU in the nipple (56 and 59 years, respectively; P ¼.41). Seventeen nipples, all from therapeutic mastectomies, were involved by neoplastic epithelial proliferations. Four of these nipples were grossly and clinically unremarkable. Occult neoplastic epithelial proliferations identified in 4 nipples (Table 1) included primary disease with 1 case of lobular carcinoma in situ involving TDLU in the nipple (Figure 2, A) and 1 case of Paget disease with lesion measuring 0.1 cm (Figure 2, B); and extension of underlying malignancy with 2 cases of pagetoid spread of spatially remote invasive ductal carcinoma (IDC) along lactiferous ducts (Figure 2, C and D). The other 13 nipples were grossly/ clinically abnormal and included 2 cases of Paget disease, 2 lymphovascular invasions, 4 invasive carcinomas (3 IDCs and 1 invasive lobular carcinoma), and 5 pagetoid extensions (4 IDCs and 1 ductal carcinoma in situ). Comparison of pathologic characteristics of the underlying malignancies in cases with and without extension to the nipple is provided in Table 2. Cases with nipple involvement were more often subject to operation because of higher-grade tumor as shown in Figure 3. One nipple had columnar cell change seen in TDLU of the nipple. Intraductal papilloma measuring 0.1 cm without atypical epithelial proliferation was seen in a lactiferous duct in 1 case. Another case demonstrated usual ductal hyperplasia in the lactiferous duct. No neoplastic epithelial proliferations were found in the nipples submitted from prophylactic mastectomies. All participating pathologists were consistent in microscopic interpretation of the above findings. COMMENT Nipple-sparing mastectomy is increasingly becoming an often-performed procedure that was made possible owing to detection of breast cancer at lower stages and lessadvanced local spread. 1,2 The other need for this procedure is for patients with prophylactic mastectomy performed for cancer risk reduction with germline mutations (eg, BRCA1 and BRCA2) and cancer identified in contralateral breast. 7 As expected, the cosmetic demand for nipple preservation is higher in younger patients. 6 However, the procedure poses 2 oncologic risks: involvement of the nipple-areola complex by a cancer at time of mastectomy or recurrence of breast cancer in the nipple. In this study we analyzed the presence of TDLU as the potential grounds for development of a new malignancy in the preserved nipple, and the frequency of nipple involvement by overt and occult neoplastic epithelial proliferation. The weakness of the study is that, while the number of the entirely submitted nipples may be sufficient to reflect the prevalence of TDLU in the nipple, the number 956 Arch Pathol Lab Med Vol 137, July 2013 TDLU and Neoplasia in the Nipple Kryvenko et al

3 Figure 2. A, A lactiferous duct with surrounding terminal duct lobular unit involved by lobular carcinoma in situ. B, Paget disease of the nipple. Note presence of neoplastic cells infiltrating the epidermis. C, One of 4 lactiferous ducts involved by pagetoid extension of carcinoma. D, Lactiferous duct demonstrating atypical ductal hyperplasia and pagetoid extension of carcinoma. Note in contrast to C that the neoplastic cells extend at the periphery of the duct (hematoxylin-eosin, original magnifications 3100 [A, B, and C] and 3400 [D, inset B]). of grossly unremarkable nipples with occult neoplastic proliferation is less than sufficient to come to powerful conclusions applicable to the entire cohort of patients with breast cancer. Moreover, this study, like other studies involving mastectomy specimens, is subject to selection bias because tumors requiring such a debilitating procedure could be more advanced than average contemporary breast cancer seen in American women. Multiple correlations have been described to predict the nipple-areola complex involvement by cancer. Among those are distance of tumor from the nipple-areola complex, tumor size, tumor location, multicentricity, type of tumor, and lymph node status. 9,12 14 Our data support the above observations indicating that the nipple is more likely to be involved in larger and higher-grade tumors located closer to the nipples and having regional lymph node metastases. In one older study, 15 the investigators found no correlation between the above factors and nipple involvement. However, the limiting factors in the older study were the small number of analyzed specimens (19 involved and 14 uninvolved) and, most probably, the more aggressive characteristics of breast cancer seen more than 2 decades ago. In a recent report, Paepke et al 16 described their successful experience with NSM in patients with retroareolar tumors by performing careful dissection of lactiferous ducts proximal to the nipple. This work demonstrates that Table 1. Demographic and Pathologic Data of 4 Patients With Occult Nipple Involvement Age, y Diagnosis Tumor Size, cm Distance to Nipple, cm Associated DCIS/LCIS Nipple Lesion 60 IDC, md DCIS and LCIS LCIS 51 DCIS, hg DCIS Paget disease 72 IDC, md DCIS Pagetoid extension 61 IDC, wd DCIS Pagetoid extension Abbreviations: DCIS, ductal carcinoma in situ; hg, high grade; IDC, invasive ductal carcinoma; LCIS, lobular carcinoma in situ; md, moderately differentiated; wd, well-differentiated. Arch Pathol Lab Med Vol 137, July 2013 TDLU and Neoplasia in the Nipple Kryvenko et al 957

4 Table 2. Comparison of Invasive Tumor Characteristics in Cases With and Without Nipple Involvement Distance to Nipple, mean (range), cm Tumor Size, mean (range), cm Positive Lymph Nodes, % a Involved nipples 1.1 (0 8.5) 4.3 (1.1 15) 91 (10/11) Unremarkable nipples 3.2 (0 8) 2.6 (0.2-10) 44 (23/52) P value, a Number with lymph node metastases/number with lymph node dissection is given in parentheses. contemporary surgical techniques may overcome some of the earlier-discovered risk factors of occult nipple involvement by performing more thorough tissue dissection and leaving more superficial tissue of the nipple not yet involved by cancer. The reported frequency of occult involvement of grossly unremarkable nipple in therapeutic mastectomy specimens varies significantly. The data range 10-fold from 5.9% (2 of 34) 17 to 58% (19 of 33), 15 with a number of reports indicating the frequency between these 2 extremes (Table 3). 9,13,14 Such high variation may be because the cited references span a 20-year period, with higher frequency in older reports and noticeably lower frequency in recent publications. The overall prevalence of occult nipple involvement in our series was 4% (4 of 92) or 5% (4 of 77) if considered for therapeutic mastectomies only. However, if further stratified, two (lobular carcinoma in situ and Paget disease) of the occult neoplastic epithelial proliferations were primarily in the nipple and not related to the underlying malignancy. Thus, microscopic extension of the malignancy for which mastectomy was directed occurred in 3% (2 of 77) of cases. We believe that such data are more in keeping with currently diagnosed breast cancer, and this frequency should be considered for patients contemplating therapeutic nipplesparing mastectomy. Moreover, the only mode of occult extension of underlying malignancy was a pagetoid spread of carcinoma. It would be difficult to determine this type of spread preoperatively, as tumor just extends along lactiferous duct without mass-forming effect or induration. Brachtel et al 9 recommended a retroareolar en face margin to test for occult nipple involvement. The procedure had a high sensitivity and negative predictive value (0.8 and 0.96, respectively) and could probably be performed intraoperatively to avoid a re-excision. If we had applied this approach to our cases, we would have potentially missed 2 incidents of neoplastic proliferations limited to the nipple without involvement of the subareolar lactiferous ducts. These retained preinvasive malignant processes would have increased the risk of subsequent development of invasive cancer in patients undergoing NSM, compared to the general population. Such risk may be less significant for older individuals. But in younger women seeking NSM, the expected residual life period is long and these low-grade malignant processes have a higher chance of progression into clinically significant invasive cancer. One of the breast carcinogenesis hypotheses states that, other than intraductal papilloma, all other neoplastic epithelial proliferations, including in situ and invasive carcinoma, develop from terminal duct lobular unit epithelium. 18 In this view, a high frequency of TDLU in the nipple is of importance in patients undergoing NSM as it serves as a potential source of de novo cancer development in the preserved nipple. Histologically, we observed a difference in the TDLU seen in the nipple compared to the glandular mammary tissue. In contrast to the TDLU in the peripheral glandular mammary tissue, where a specialized lobular stroma is represented by loose connective tissue, the TDLU seen in the nipple is supported by dense stroma similar to surrounding fibromuscular nipple tissue. Such difference in the anatomic structure is rather of academic interest and it is not clear how this rigid stroma may affect the risk of invasive breast cancer developing in the nipple. It also appears that prevalence of TDLU in the nipple is not affected by hormonal status, as there was no age difference in patients with and without this finding in the nipple. Similar to occult neoplastic involvement, the reported frequency of TDLU in the nipple varies significantly. The reported frequencies range from 10% to 24%. 7,8,19 This difference to some extent may be explained by different methods of nipple submission for histologic examination, as in some studies only a single vertical section was examined. Ninety-four nipples in the reviewed literature targeting Figure 3. Distribution of the grade of invasive cancer in cases with uninvolved nipple and cases with extension of underlying malignancy into the nipple. Abbreviations: G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated. 958 Arch Pathol Lab Med Vol 137, July 2013 TDLU and Neoplasia in the Nipple Kryvenko et al

5 Source, y a 1 Brachtel et al, Gülben et al, Luttges et al, Menon and van Geel, Reynolds et al, Rosen and Tench, Stolier and Wang, Voltura et al, Table 3. Summary of Selected Studies Describing Occult Nipple Involvement and Frequency of Terminal Duct Lobular Units (TDLUs) in the Nipple No. of Mastectomies Prophylactic Therapeutic Cases With TDLU, No. (%) TDLU Location Occult Nipple Involvement, No. (%) b Age, mean (range), y Nipple Submission NA NA 49 (15.5) Prophylactic, 47 Therapeutic, 56 Entirely submitted None 397 NA NA 58 (14.6) 47 (22 79) Single vertical section c None 166 NA NA 64 (38.6) 63 (NA) Three vertical sections None 33 NA NA 19 (58) 53.9 (30 88) Entirely submitted (24) Papilla and retroareolar (5) Retroareolar (10) 3 (5) 42.3 (27 79) Entirely submitted None (17) NA 13 (13) 56 (33 80) Single vertical section (9) Base (3) None 52.5 (37 75) Entirely submitted NA NA 2 (4) 48 (35 72) Single retroareolar section Abbreviation: NA, not available. a Publications are provided in alphabetic order. b None of the nipples examined in prophylactic mastectomies had occult neoplastic involvement. The studies involved temporarily and possibly clinically heterogeneous groups of patients, and incidence of occult nipple involvement cannot be compared. c Personal communication with authors. evaluation of TDLU frequency were submitted entirely and 101 had 1 vertical section submitted for histologic evaluation. We have found TDLU in 26% of the nipples, which is consistent with a recent report by Reynolds et al, 8 demonstrating TDLU in 24% (15 of 62) of entirely submitted nipples. In contrast to other studies demonstrating a dominant TDLU location in the base of the nipple, 7,8 we demonstrated a high frequency of TDLU in the nipple papilla, which should be considered in surgical procedures dissecting the base and leaving the superficial portion of the nipple. 16 This is more important and relevant when surgeons attempt to remove tissue from within the nipple papilla during NSM, although how thoroughly ductal tissue is removed from the nipple by using current techniques is not known. The earliest mention of the term coring appears to be by Randall et al 20 in They referred to the process as apple coring, in which the entire tip of the nipple was removed with nipple contents, thereby assuring removal of all ducts. Because of such a wide range of data regarding the frequency of TDLU in the nipple, there are controversial opinions regarding the risk of NSM in patients with BRCA germline mutations. 7,8,21 To reduce the risk of recurrence, intraoperative radiotherapy of the spared nipple-areola complex is recommended by some authors in Europe, with favorable results. 22,23 We have identified 1 low-grade primary neoplastic proliferation arising in TDLU in the nipple unrelated to underlying malignancy. Such observation is underreported in the literature and demonstrates that malignant processes other than Paget disease may start in the nipple. However, this finding was in the breast removed because of malignancy and no neoplastic proliferation has been found in 15 nipples from prophylactic mastectomies. In a PubMed search (US National Library of Medicine) from 2005 to 2011 we identified a total of 156 nipples examined in prophylactic mastectomies, and none of those demonstrated neoplastic proliferation at the time of excision (Table 3). 7 9,17 Combined, the data indicate that risk of neoplastic proliferation in the nipple at time of risk-reduction surgery is minimal. Moreover, as seen from our data and those of Brachtel et al, 9 younger patients for whom NSM is more likely to be applied underwent prophylactic mastectomies and showed no pathologic abnormalities in the nipples, warranting this procedure for such age group. Regarding the remote outcome, we share the impression of Reynolds et al 8 that there are limited data and that long-term clinical follow-up trials are needed to establish the significance of residual TDLU in the nipple, particularly in breast cancer germline mutation carriers. In conclusion, around one-fourth of the nipples contain TDLU, which does not depend on the patient s age or hormonal status. Contrary to the classical view, TDLU is frequently seen in the nipple papilla when entire nipple is submitted for histologic evaluation. Around 5% of therapeutic mastectomies at the time of excision contain occult involvement of the grossly and clinically unremarkable nipple. Pagetoid spread is the dominant way of extension of underlying malignancy. Overall, nipple involvement is associated with larger tumors closer to the nipple, higher tumor grade, and regional lymph node metastases. None of the risk-reduction mastectomies in this series and reported in the literature had neoplastic proliferation in the nipple. The significance of residual TDLU in the nipple is not clear, especially in breast cancer germline mutation carriers seeking prophylactic NSM at young age, and needs to be determined by future long-term prospective trials. The authors thank Adrian Ormsby, MD, for helping organize and facilitating performance of the study at Henry Ford Hospital, Detroit, Michigan. Arch Pathol Lab Med Vol 137, July 2013 TDLU and Neoplasia in the Nipple Kryvenko et al 959

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