Ann Surg Oncol DOI 10.1245/s10434-014-3532-x
ORIGINAL ARTICLE – BREAST ONCOLOGY
MRI Volumetric Analysis of Breast Fibroglandular Tissue to Assess Risk of the Spared Nipple in BRCA1 and BRCA2 Mutation Carriers Heather L. Baltzer, MSc, MD1, Olivier Alonzo-Proulx, PhD2,3, James G. Mainprize, PhD2, Martin J. Yaffe, MSc, PhD2,3, Kelly A. Metcalfe, RN, PhD4,5, Steve A. Narod, MD, FRCPC, FRSC4, Ellen Warner, MD, FRCPC, FACP, MSc2,6, and John L. Semple, MD, MSc, FRCS(C), FACS1,4 Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, ON, Canada; 2Sunnybrook Research Institute, Toronto, ON, Canada; 3Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; 4 Women’s College Research Institute, Toronto, ON, Canada; 5Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON, Canada; 6Division of Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada 1
ABSTRACT Objective. Prophylactic nipple-areolar complex (NAC)sparing mastectomy (NSM) in BRCA1/2 mutation carriers is controversial over concern regarding residual fibroglandular tissue (FGT) with malignant potential. The objective of this study was to model the volume of FGT in the NAC at a standard retroareolar margin (5 mm) and examine the change in this amount with a greater retroareolar margin or areola-sparing technique. Methods. A segmentation protocol was applied to breast MRIs from 105 BRCA1/2 patients to quantify volumes of FGT for total breast and NAC. The proportion of FGT in the NAC relative to the breast was calculated as the primary outcome and was compared for 5 mm versus 10 mm retroareolar depths. The proportion of FGT in the areola was compared with the NAC. Results. At 5 mm retroareolar thickness, residual NAC FGT comprised 1.3 % of the total breast FGT. This amount
Heather L. Baltzer and Olivier Alonzo-Proulx shared first authorship This study has been presented at the American Society for Clinical Oncology Annual Meeting, Chicago, IL, USA, 2013; Canadian Society of Plastic Surgeons Annual Meeting, Calgary, AB, Canada, 2013; Novartis Oncology Young Clinical Investigator Awards Ceremony, Chicago, IL, USA, 2013. Ó Society of Surgical Oncology 2014 First Received: 8 November 2013 J. L. Semple, MD, MSc, FRCS(C), FACS e-mail: [email protected]
was not significantly greater than the proportion in the areola (p = 0.3, d = 0.1). Increasing the retroareolar thickness to 10 mm led to a statistically and possibly clinically significant increase in the amount of NAC FGT (p \ 0.001, d = 1.1). Conclusions. The proportion of FGT remaining in the spared NAC with a 5 mm margin is extremely small, suggesting that leaving the entire NAC would create very little added risk. Doubling the retroareolar margin may translate into a clinically meaningful increase. Overall, our findings support the safety of the current trend toward increased rates of prophylactic NSM performed in this high-risk population.
Women who have inherited a BRCA1 or BRCA2 gene mutation have a substantial risk of developing breast cancer from 30 years of age onwards, with a cumulative risk by 70 years of age of 45–84 %.1–3 Risk reduction for these women includes prophylactic surgery or chemoprevention. Risk-reducing mastectomy (RRM) offers a breast cancer risk reduction of 90–95 %.4–6 The majority of women who elect to undergo RRM also opt for immediate breast reconstruction (IBR)7 and have the option of either skinsparing mastectomy (SSM) with removal of the nippleareolar complex (NAC), areola-sparing mastectomy (ASM) with removal of the nipple only, or nipple-sparing mastectomy (NSM), which preserves the NAC (Fig. 1). Preserving the native breast envelope (with or without the NAC) is necessary for IBR using autogenous or alloplastic means, and improves the aesthetic outcome of the
H. L. Baltzer et al.
FIG. 1 Photographic images of the aesthetic appearance of an immediate breast reconstruction following prophylactic mastectomy using a skinsparing mastectomy; b areola-sparing mastectomy; and c nipple-areola complex-sparing mastectomy
reconstruction.8–12 Compared with delayed reconstruction, IBR benefits patients by reducing the number of surgeries required and avoiding the distress of living with a mastectomy defect.13 There is evidence that preservation of the NAC with IBR has psychosocial benefit.11,12,14–16 It has also been postulated that inability to have NAC preservation may be a barrier to undergoing RRM for some patients.17 Furthermore, if an NAC-sparing procedure does not take place, an additional reconstructive procedure is required to recreate the NAC *6 months after the IBR. Surgical reconstruction of the NAC can yield good aesthetic results; however, patients have expressed dissatisfaction with various aspects of their reconstructed NAC, including lack of projection and poor color match, shape, size, texture, and position.18 NAC-sparing improves upon these aesthetic concerns, yet the majority of patients regain fair to poor nipple sensation.15 Despite the potential benefits of prophylactic NSM for high-risk patients, this is an area of controversy due to the concern that tissue with malignant potential remains in the spared NAC.19 Most breast cancer is thought to arise in the terminal ductal-lobular unit (TDLU), and the presence of TDLUs has been identified in 10–25 % of nipple-areolar tissue specimens following RRM.19 Yet retrospective cohort studies of hereditary breast cancer patients having prophylactic NSM have demonstrated that primary tumor occurrence in the spared NAC is extremely rare.4,10,20,21 It is estimated that following NSM, 5–10 % of the total fibroglandular tissue (FGT) that would harbour TDLUs remains in the skin flaps, beneath the nipple, and in the tail of the axilla.22 However, the amount of FGT that would remain specifically behind the NAC and the oncologic risk this poses after NSM has not been described. It is thought that ASM may lower the potential cancer risk compared with NSM due to the fact that the ductal tissue in the nipple is removed;8, 23–26 however, there are no comparative studies demonstrating any added benefit of sparing only the areola versus the NAC. Some argue that the risk reduction is comparable due to the remaining
ductal tissue within the areola.27–29 Thin mastectomy flaps with narrow retroareolar margins are thought to be safer from an oncologic standpoint, but at the expense of greater rates of mastectomy flap and/or nipple necrosis.30 Nipple necrosis rates following NSM are estimated to range from 0.1 to 6 %.10,21,30–35 METHODS The primary objective of this study was to provide an accurate assessment of the proportion of FGT remaining in the spared NAC, as measured by magnetic resonance imaging (MRI), in order to estimate the breast cancer risk conferred by NSM. Such information would benefit patient counseling and decision making. We hypothesize that the ductal tissue contained in the NAC represents a negligible proportion of the total FGT in the breast. Secondarily, we used MRI volumetric analysis of FGT to address areas of controversy regarding the surgical management of the NAC, including retroareolar margin depth and ASM. Study Design and Patients We retrospectively reviewed data from an existing, anonymized database of a prospective multicenter study of women carrying a BRCA1 or BRCA2 gene mutation who underwent annual MRI breast cancer screening between 2004 and 2007.36 Patients provided information regarding age, BMI, menopausal status, parity, breast feeding history, and medications, including oral contraceptive, hormone replacement therapy, or selective estrogen receptor modifiers. These data were collected within 6 months of the initial screening MRI. In the original study, inclusion criteria were 25 % or higher lifetime risk of breast cancer based on family history or genetic testing, at least one breast untreated for breast cancer, capacity to consent, and no contraindication to MRI. In addition, our study excluded women who had a history of in situ or invasive carcinoma. Institutional ethics approval was granted for the original prospective study and the current retrospective review.
MRI Volumetric Analysis of Breast Fibroglandular
FIG. 2 Segmentation protocol of the entire breast, and a depiction of the nipple-areolar complex ROI: sagittal slice of breast MRI with segmentation of fibroglandular tissue and fatty breast tissue (right). The 1- and 4-cm ROIs represent the nipple and the nipple-areolar complex, respectively. The 0.5-depth posterior to the nipple
represents a standard retroareolar margin during NSM. All breast tissue anterior to this was included in the volumetric analysis. ROI region of interest, MRI magnetic resonance imaging, NSM nipplesparing mastectomy, FGT fibroglandular tissue, NAC nipple-areolar complex
Magenetic Resonance Imaging Volumetric Analysis
proportion of FGT in the NAC relative to the total breast FGT (Fig. 2). For each image series, three-dimensional ROIs were identified for both the nipple and the entire NAC, consisting of 10 and 40 mm-diameter cylinders, respectively. These diameters were based on morphologic studies of nipple and NAC dimensions.39,40 The posterior extent (depth) of the cylindrical ROI was set a depth 5 mm posterior to the base of the nipple, representing a standard retroareolar margin following an NSM.41 We modeled thick margins by increasing the depth of the ROI to 10 mm. The anterior extent of the ROI was the breast-air boundary. The areolar FGT was calculated by subtracting the FGT volume in the 10 mm-diameter nipple ROI from the 40 mm-diameter NAC ROI. The volumes were then translated into proportions by dividing by the total breast FGT.
MRI is an established means of quantifying the amount of FGT in the breast, a procedure that has generally been done to determine breast density.37,38 The primary outcome of this study was to evaluate the proportion of FGT present in the NAC relative to the entire breast, using MRI volumetric analysis. The main assumption of the analysis was that the FGT represents tissue with malignant potential, despite the fact that it is actually composed of many tissue types (ductal, lactiferous, stroma, etc.). All patients underwent dynamic gadolinium-enhanced MRI for screening purposes. Only the first screening MRI performed during the prospective study was used for the purpose of the current study. The amount of FGT was assessed from images that had been acquired using several different protocols—a T1 or T2 weighting, with or without fat suppression. The segmentation of the FGT was performed in four steps: (i) inhomogeneities in the breast coil sensitivity were corrected by applying a low-pass spatial frequency filter on each image slice in the volume and by manually adjusting the signal level on each slice; (ii) the boundary between the breast and the surrounding air was identified; (iii) partial volume effects at the breast edge were corrected by interpolation between image slices; and (iv) the FGT was identified by selecting a region of interest (ROI) in the central slice of the image containing fatty tissue and FGT, and the signal peaks corresponding to the two tissues were identified. A soft-threshold sigmoid function was then applied to transform the signal into fractional FGT content. Total breast FGT and NAC FGT were quantified by summing the fractional FGT over the breast volume and over the NAC ROI described below, respectively. From these volumes we identified the
Analysis The primary outcome of this study was the proportion of FGT present in the NAC relative to the entire breast expressed as a mean and standard deviation for the study population. The proportion of FGT for each subject was calculated by dividing the absolute volume of FGT in the NAC by the total breast FGT at a simulated surgical margin (5 mm). The aim of the secondary analysis was to obtain data to help resolve two areas of controversy: (i) the clinical benefit, if any, of areola-sparing versus NAC-sparing mastectomy; and (ii) the clinical significance of retroareolar margin thickness. Varied retroareolar margins and the areolar proportion of FGT were modeled as described above. The proportion of areolar FGT was compared with NAC FGT, as was the proportion of FGT with a 5 mm
H. L. Baltzer et al. TABLE 1 Patient characteristics: demographic information and breast and parity history Age [years; mean (range)]
42.5 (28–63)
BMI [mean (range)]
26.1 (17–41)
3
Breast volume [cm ; mean (range)]
TABLE 2 The proportion of nipple-areolar complex and nipple fibroglandular tissue relative to total breast fibroglandular tissue at 5 and mm retroareolar depths Nipple-areolar complex (40 mm diameter ROI)
654 (157–1758)
Hormone replacement therapy usea [n (%)] a
Oral contraceptive pill use [n (%)] a
Tamoxifen use [n (%)]
p value Effect size (d)
14 (13) 13 (12.4) 2 (1.9)
Parous [n (%)]
85 (81)
Multiparous [n (%)]
62 (59)
Retroareolar depth (mm)
5
Proportion of total breast 1.3 fibroglandular tissue (%)
10 3.0
\0.001 1.1
ROI region of interest
Menopausal status [n (%)] Pre-menopasual Post-menopausal Breastfeedingb [n (%)]
72 (69) 33 (31) 64 (61)
BMI body mass index, MRI magnetic resonance imaging a
At the time of study enrollment and screening MRI
b
Indicates any duration of breastfeeding
versus 10 mm retroareolar margin. Comparisons were made using Student’s t-test, with a p-value \ 0.05 required for statistical significance. For each comparison, the effect size was measured by calculating the Cohen d. Cohen d is defined as the difference between two means divided by the pooled standard deviation in which \0.2 indicates a ‘trivial’ effect size, 0.2–0.5 indicates a ‘small’ effect size, 0.5–0.8 indicates a ‘medium’ effect size, and [0.8 indicates a ‘large’ effect size.42 Analyses were performed using the SPSS statistical software package (version 17.0; SPSS Inc., Chicago, IL, USA). RESULTS Overall, 105 patient MRIs underwent volumetric analysis and were included in the data analysis. Patient demographics and information at the time of study entry are summarized in Table 1. Volumetric Analysis The mean breast volume was 654 cc (range 157– 1758 cc), containing, a mean of 194 cc (29 %) of FGT. At a retroareolar depth of 5 mm, modeling a standard surgical margin behind the NAC, the proportion of FGT relative to total breast FGT in the NAC was 1.3 %. Partitioning the NAC into anatomical components, the nipple and the areola accounted for 0.1 and 1.2 %, respectively, of the total breast FGT (Fig. 2). The proportion of FGT in the areola compared with the NAC was not significantly different (p = 0.38, d = 0.12). Increasing the retroareolar margin to 1 cm, modeling a thicker surgical margin behind the nipple, led to a statistically and clinically significant increase
FIG. 3 Distribution of the proportion of fibroglandular tissue in the breast with a simulated 5-mm retroareolar margin
in the proportion of FGT in the spared NAC compared with the modeled 0.5 cm standard margin (p \ 0.001, d = 1.1) (Table 2) (Fig. 3). DISCUSSION For patients undergoing RRM, the decision whether to spare the NAC or the areola is made in conjunction with surgeons. To date, this has often been a stressful decision as patients have felt they must choose between a procedure that will minimize their future breast cancer risk and one that will better preserve their body image but may lead to a higher cancer risk. In order to facilitate this decisionmaking process, we sought to estimate the difference in cancer risk between these procedures, using breast FGT as a surrogate marker of the malignant potential of the residual breast tissue. This study found that an extremely small amount of FGT, 1.3 % of the entire breast FGT, is present in the NAC at a depth of 5 mm. Of note, this is likely a conservative estimate of the actual residual ductal tissue since our measurement also includes stromal and
MRI Volumetric Analysis of Breast Fibroglandular
fibrous tissue as well as skin. It should also be noted that TDLUs are only present in this region in 10–25 % of breasts, which suggests an overall low risk of malignant potential in a spared nipple at this depth. The apparent safety of prophylactic NSM was first demonstrated among a cohort of 639 women at moderate to high risk of developing breast cancer, with only one developing cancer in the spared nipple after a median follow-up of 14 years.20 A subgroup of 26 of these patients carried the BRCA gene mutation, with none developing cancer in the spared nipple.4 More recently, in a retrospective cohort study of 80 women (mixed BRCA gene mutation carriers and non-carriers) who underwent prophylactic NSM, none developed a carcinoma in the NAC at a median follow-up of 3 years.21 While the results of these studies are encouraging,4,20,21 25 or 30 years of follow-up will be necessary in order to accurately estimate the lifetime risk of breast cancer after NSM. In the meantime, high-risk women who have opted for RRM, and their physicians, need some basis for knowing the extent to which breast cancer risk is increased with preservation of the NAC. We have taken a novel approach to estimating this risk. Using MRI volumetric analysis, we have demonstrated that the NAC itself accounts for an extremely small proportion. This suggests that NSM should not offer an appreciably increased risk of developing in cancer in the mastectomy flap over an SSM. Secondarily, we applied the findings of the volumetric analysis to address two areas of clinical controversy: retroareolar margin depth and ASM. Removing the nipple, but leaving the areola, has been considered a safer alternative to NAC-sparing surgery.8,23–26 Our analysis suggests very little risk reduction by removing the nipple and leaving the areola due to the fact that the majority of the FGT is found under the areola. The nipple represents a minute amount (0.1 %) of the total breast FGT and contributes \10 % of the FGT in the NAC. This finding is in agreement with histology studies19,27 and suggests very little risk reduction by removing the nipple and leaving the areola due to the fact that the majority of the FGT is found under the areola. Thin mastectomy flaps with narrow retroareolar margins are considered oncologically safer, but have the trade-off of greater rates of mastectomy flap and/or nipple necrosis.30 Nipple necrosis following NSM has been reported in 0.1– 6 % of cases and can lead to significant morbidity, ranging from prolonged wound healing with secondary NAC reconstruction to loss of the breast reconstruction due to infection involving the underlying implant.10,21,30–35 It is three times as likely that TDLUs exist in the retroareolar tissue as in the nipple, suggesting that the retroareolar margins are an important consideration for minimizing the risk of breast cancer in this high-risk population.19,41 There are no well-established guidelines for the depth of
retroareolar margins; however, a margin of up to 5 mm is considered acceptable as long as a retroareolar biopsy is taken to rule out an occult carcinoma.41 The optimal depth for retroareolar margins is controversial.30,32,34,41 This volumetric analysis suggests that doubling a standard margin of 5 mm to 1 cm, would result in a clinically meaningful increase in the amount of unresected FGT. This indicates that margin depth should be measured after riskreducing NSM in this high-risk population and correlated with long-term patient outcomes to better determine the safety (or lack thereof) of thicker retroareolar margins. CONCLUSIONS This study was to provide clinicians and patients with information to aid in the decision of whether to spare the nipple, an increasingly popular option for RRM. Overall, our findings support the safety of the current trend toward increased rates of prophylactic NSM performed in BRCA1 and BRCA2 mutation carriers. In addition, we found no evidence that sparing the areola alone is safer than sparing the entire NAC. Our findings did suggest that a retroareolar margin of 10 mm might leave behind significantly more breast tissue with malignant potential than the standard 5 mm margin, but observational studies of patients who have undergone NSM will be necessary to confirm or refute this. ACKNOWLEDGMENT Dr. Semple is supported by the Canadian Breast Cancer Foundation (Ontario Chapter). DISCLOSURE
The authors have no conflicts of interest to declare.
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H. L. Baltzer et al. 7. Semple J, Metcalfe KA, Lynch HT, Kim-Sing C, Senter L, Pal T, et al. International rates of breast reconstruction after prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers. Ann Surg Oncol. 2013;20(12):3817–22. 8. Carlson GW, Bostwick J 3rd, Styblo TM, Moore B, Bried JT, Murray DR, et al. Skin-sparing mastectomy. Oncologic and reconstructive considerations. Ann Surg. 1997;225(5):570–5; discussion 575-8. 9. Craig ES, Walker ME, Salomon J, Fusi S. Immediate nipple reconstruction utilizing the DIEP flap in areola-sparing mastectomy. Microsurgery. 2013;33(2):125–9. 10. de Alcantara Filho P, Capko D, Barry JM, Morrow M, Pusic A, Sacchini VS. Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the Memorial Sloan-Kettering Cancer Center experience. Ann Surg Oncol. 2011;18(11):3117–22. 11. Didier F, Arnaboldi P, Gandini S, Maldifassi A, Goldhirsch A, Radice D, et al. Why do women accept to undergo a nipple sparing mastectomy or to reconstruct the nipple areola complex when nipple sparing mastectomy is not possible? Breast Cancer Res Treat. 2012;132(3):1177–84. 12. Petit JY, Veronesi U, Lohsiriwat V, Rey P, Curigliano G, Martella S, et al. Nipple-sparing mastectomy–is it worth the risk? Nat Rev Clin Oncol. 2011;8(12):742–7. 13. Sinno H, Izadpanah A, Thibaudeau S, Christodoulou G, Lin SJ, Dionisopoulos T. An objective assessment of the perceived quality of life of living with bilateral mastectomy defect. Breast. 2013;22(2):168–72. 14. Didier F, Radice D, Gandini S, Bedolis R, Rotmensz N, Maldifassi A, et al. Does nipple preservation in mastectomy improve satisfaction with cosmetic results, psychological adjustment, body image and sexuality? Breast Cancer Res Treat. 2009;118(3):623–33. 15. Djohan R, Gage E, Gatherwright J, Pavri S, Firouz J, Bernard S, et al. Patient satisfaction following nipple-sparing mastectomy and immediate breast reconstruction: an 8-year outcome study. Plast Reconstr Surg. 2010;125(3):818–29. 16. Wellisch DK, Schain WS, Noone RB, Little JW 3rd. The psychological contribution of nipple addition in breast reconstruction. Plast Reconstr Surg. 1987;80(5):699–704. 17. Metcalfe KA, Semple JL, Narod SA. Time to reconsider subcutaneous mastectomy for breast-cancer prevention? Lancet Oncol. 2005;6(6):431–4. 18. Jabor MA, Shayani P, Collins DR Jr, Karas T, Cohen BE. Nippleareola reconstruction: satisfaction and clinical determinants. Plast Reconstr Surg. 2002;110(2):457–63; discussion 464–5. 19. Reynolds C, Davidson JA, Lindor NM, Glazebrook KN, Jakub JW, Degnim AC, et al. Prophylactic and therapeutic mastectomy in BRCA mutation carriers: can the nipple be preserved? Ann Surg Oncol. 2011;18(11):3102–9. 20. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340(2):77–84. 21. Spear SL, Willey SC, Feldman ED, Cocilovo C, Sidawy M, AlAttar A, et al. Nipple-sparing mastectomy for prophylactic and therapeutic indications. Plast Reconstr Surg. 2011;128(5):1005–14. 22. Temple WJ, Lindsay RL, Magi E, Urbanski SJ. Technical considerations for prophylactic mastectomy in patients at high risk for breast cancer. Am J Surg. 1991;161(4):413–5. 23. Kroll SS, Schusterman MA, Tadjalli HE, Singletary SE, Ames FC. Risk of recurrence after treatment of early breast cancer with skin-sparing mastectomy. Ann Surg Oncol. 1997;4(3):193–7.
24. Ma G, Richardson H, Pacella SJ, Codner MA. Single-stage breast reconstruction following areola-sparing mastectomy. Plast Reconstr Surg. 2009;123(5):1414–7. 25. Simmons RM, Hollenbeck ST, Latrenta GS. Two-year follow-up of areola-sparing mastectomy with immediate reconstruction. Am J Surg. 2004;188(4):403–6. 26. Simmons RM, Hollenbeck ST, Latrenta GS. Areola-sparing mastectomy with immediate breast reconstruction. Ann Plast Surg. 2003;51(6):547–51. 27. Schnitt SJ, Goldwyn RM, Slavin SA. Mammary ducts in the areola: implications for patients undergoing reconstructive surgery of the breast. Plast Reconstr Surg. 1993;92(7):1290–3. 28. Stolier AJ, Grube BJ. Areola-sparing mastectomy: defining the risks. J Am Coll Surg. 2005;201(1):118–24. 29. Vlajcic Z, Zic R, Stanec Z. Has the time come to change the breast-conserving treatment for skin and nipple-areola complexsparing mastectomy? Plast Reconstr Surg. 2010;125(3):1043–4; author reply 1044–5. 30. Algaithy ZK, Petit JY, Lohsiriwat V, Maisonneuve P, Rey PC, Baros N, et al. Nipple sparing mastectomy: can we predict the factors predisposing to necrosis? Eur J Surg Oncol. 2012;38(2): 125–9. 31. Harness JK, Vetter TS, Salibian AH. Areola and nipple-areolasparing mastectomy for breast cancer treatment and risk reduction: report of an initial experience in a community hospital setting. Ann Surg Oncol. 2011;18(4):917–22. 32. Petit JY, Veronesi U, Rey P, Rotmensz N, Botteri E, Rietjens M, et al. Nipple-sparing mastectomy: risk of nipple-areolar recurrences in a series of 579 cases. Breast Cancer Res Treat. 2009;114(1):97–101. 33. Stolier AJ, Levine EA. Reducing the risk of nipple necrosis: technical observations in 340 nipple-sparing mastectomies. Breast J. 2013;19(2):173–9. 34. Stolier AJ, Sullivan SK, Dellacroce FJ. Technical considerations in nipple-sparing mastectomy: 82 consecutive cases without necrosis. Ann Surg Oncol. 2008;15(5):1341–7. 35. Jensen JA, Orringer JS, Giuliano AE. Nipple-sparing mastectomy in 99 patients with a mean follow-up of 5 years. Ann Surg Oncol. 2011 June;18(6):1665–70. 36. Passaperuma K, Warner E, Causer PA, Hill KA, Messner S, Wong JW, et al. Long-term results of screening with magnetic resonance imaging in women with BRCA mutations. Br J Cancer. 2012;107(1):24–30. 37. Ortiz CG, Martel AL. Automatic atlas-based segmentation of the breast in MRI for 3D breast volume computation. Med Phys. 2012;39(10):5835–48. 38. Thompson DJ, Leach MO, Kwan-Lim G, Gayther SA, Ramus SJ, Warsi I, et al. Assessing the usefulness of a novel MRI-based breast density estimation algorithm in a cohort of women at high genetic risk of breast cancer. The UK MARIBS Study. Breast Cancer Res. 2009;11(6):R80. 39. Hauben DJ, Adler N, Silfen R, Regev D. Breast-areola-nipple proportion. Ann Plast Surg. 2003;50(5):510–3. 40. Sanuki J, Fukuma E, Uchida Y. Morphologic study of nippleareola complex in 600 breasts. Aesthetic Plast Surg. 2009;33(3): 295–7. 41. Murthy V, Chamberlain RS. Nipple-sparing mastectomy in modern breast practice. Clin Anat. 2013;26(1):56–65. 42. Livingston EH, Elliot A, Hynan L, Cao J. Effect size estimation: a necessary component of statistical analysis. Arch Surg. 2009;144(8):706–12.
ORIGINAL ARTICLE – BREAST ONCOLOGY
MRI Volumetric Analysis of Breast Fibroglandular Tissue to Assess Risk of the Spared Nipple in BRCA1 and BRCA2 Mutation Carriers Heather L. Baltzer, MSc, MD1, Olivier Alonzo-Proulx, PhD2,3, James G. Mainprize, PhD2, Martin J. Yaffe, MSc, PhD2,3, Kelly A. Metcalfe, RN, PhD4,5, Steve A. Narod, MD, FRCPC, FRSC4, Ellen Warner, MD, FRCPC, FACP, MSc2,6, and John L. Semple, MD, MSc, FRCS(C), FACS1,4 Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, ON, Canada; 2Sunnybrook Research Institute, Toronto, ON, Canada; 3Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; 4 Women’s College Research Institute, Toronto, ON, Canada; 5Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON, Canada; 6Division of Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada 1
ABSTRACT Objective. Prophylactic nipple-areolar complex (NAC)sparing mastectomy (NSM) in BRCA1/2 mutation carriers is controversial over concern regarding residual fibroglandular tissue (FGT) with malignant potential. The objective of this study was to model the volume of FGT in the NAC at a standard retroareolar margin (5 mm) and examine the change in this amount with a greater retroareolar margin or areola-sparing technique. Methods. A segmentation protocol was applied to breast MRIs from 105 BRCA1/2 patients to quantify volumes of FGT for total breast and NAC. The proportion of FGT in the NAC relative to the breast was calculated as the primary outcome and was compared for 5 mm versus 10 mm retroareolar depths. The proportion of FGT in the areola was compared with the NAC. Results. At 5 mm retroareolar thickness, residual NAC FGT comprised 1.3 % of the total breast FGT. This amount
Heather L. Baltzer and Olivier Alonzo-Proulx shared first authorship This study has been presented at the American Society for Clinical Oncology Annual Meeting, Chicago, IL, USA, 2013; Canadian Society of Plastic Surgeons Annual Meeting, Calgary, AB, Canada, 2013; Novartis Oncology Young Clinical Investigator Awards Ceremony, Chicago, IL, USA, 2013. Ó Society of Surgical Oncology 2014 First Received: 8 November 2013 J. L. Semple, MD, MSc, FRCS(C), FACS e-mail: [email protected]
was not significantly greater than the proportion in the areola (p = 0.3, d = 0.1). Increasing the retroareolar thickness to 10 mm led to a statistically and possibly clinically significant increase in the amount of NAC FGT (p \ 0.001, d = 1.1). Conclusions. The proportion of FGT remaining in the spared NAC with a 5 mm margin is extremely small, suggesting that leaving the entire NAC would create very little added risk. Doubling the retroareolar margin may translate into a clinically meaningful increase. Overall, our findings support the safety of the current trend toward increased rates of prophylactic NSM performed in this high-risk population.
Women who have inherited a BRCA1 or BRCA2 gene mutation have a substantial risk of developing breast cancer from 30 years of age onwards, with a cumulative risk by 70 years of age of 45–84 %.1–3 Risk reduction for these women includes prophylactic surgery or chemoprevention. Risk-reducing mastectomy (RRM) offers a breast cancer risk reduction of 90–95 %.4–6 The majority of women who elect to undergo RRM also opt for immediate breast reconstruction (IBR)7 and have the option of either skinsparing mastectomy (SSM) with removal of the nippleareolar complex (NAC), areola-sparing mastectomy (ASM) with removal of the nipple only, or nipple-sparing mastectomy (NSM), which preserves the NAC (Fig. 1). Preserving the native breast envelope (with or without the NAC) is necessary for IBR using autogenous or alloplastic means, and improves the aesthetic outcome of the
H. L. Baltzer et al.
FIG. 1 Photographic images of the aesthetic appearance of an immediate breast reconstruction following prophylactic mastectomy using a skinsparing mastectomy; b areola-sparing mastectomy; and c nipple-areola complex-sparing mastectomy
reconstruction.8–12 Compared with delayed reconstruction, IBR benefits patients by reducing the number of surgeries required and avoiding the distress of living with a mastectomy defect.13 There is evidence that preservation of the NAC with IBR has psychosocial benefit.11,12,14–16 It has also been postulated that inability to have NAC preservation may be a barrier to undergoing RRM for some patients.17 Furthermore, if an NAC-sparing procedure does not take place, an additional reconstructive procedure is required to recreate the NAC *6 months after the IBR. Surgical reconstruction of the NAC can yield good aesthetic results; however, patients have expressed dissatisfaction with various aspects of their reconstructed NAC, including lack of projection and poor color match, shape, size, texture, and position.18 NAC-sparing improves upon these aesthetic concerns, yet the majority of patients regain fair to poor nipple sensation.15 Despite the potential benefits of prophylactic NSM for high-risk patients, this is an area of controversy due to the concern that tissue with malignant potential remains in the spared NAC.19 Most breast cancer is thought to arise in the terminal ductal-lobular unit (TDLU), and the presence of TDLUs has been identified in 10–25 % of nipple-areolar tissue specimens following RRM.19 Yet retrospective cohort studies of hereditary breast cancer patients having prophylactic NSM have demonstrated that primary tumor occurrence in the spared NAC is extremely rare.4,10,20,21 It is estimated that following NSM, 5–10 % of the total fibroglandular tissue (FGT) that would harbour TDLUs remains in the skin flaps, beneath the nipple, and in the tail of the axilla.22 However, the amount of FGT that would remain specifically behind the NAC and the oncologic risk this poses after NSM has not been described. It is thought that ASM may lower the potential cancer risk compared with NSM due to the fact that the ductal tissue in the nipple is removed;8, 23–26 however, there are no comparative studies demonstrating any added benefit of sparing only the areola versus the NAC. Some argue that the risk reduction is comparable due to the remaining
ductal tissue within the areola.27–29 Thin mastectomy flaps with narrow retroareolar margins are thought to be safer from an oncologic standpoint, but at the expense of greater rates of mastectomy flap and/or nipple necrosis.30 Nipple necrosis rates following NSM are estimated to range from 0.1 to 6 %.10,21,30–35 METHODS The primary objective of this study was to provide an accurate assessment of the proportion of FGT remaining in the spared NAC, as measured by magnetic resonance imaging (MRI), in order to estimate the breast cancer risk conferred by NSM. Such information would benefit patient counseling and decision making. We hypothesize that the ductal tissue contained in the NAC represents a negligible proportion of the total FGT in the breast. Secondarily, we used MRI volumetric analysis of FGT to address areas of controversy regarding the surgical management of the NAC, including retroareolar margin depth and ASM. Study Design and Patients We retrospectively reviewed data from an existing, anonymized database of a prospective multicenter study of women carrying a BRCA1 or BRCA2 gene mutation who underwent annual MRI breast cancer screening between 2004 and 2007.36 Patients provided information regarding age, BMI, menopausal status, parity, breast feeding history, and medications, including oral contraceptive, hormone replacement therapy, or selective estrogen receptor modifiers. These data were collected within 6 months of the initial screening MRI. In the original study, inclusion criteria were 25 % or higher lifetime risk of breast cancer based on family history or genetic testing, at least one breast untreated for breast cancer, capacity to consent, and no contraindication to MRI. In addition, our study excluded women who had a history of in situ or invasive carcinoma. Institutional ethics approval was granted for the original prospective study and the current retrospective review.
MRI Volumetric Analysis of Breast Fibroglandular
FIG. 2 Segmentation protocol of the entire breast, and a depiction of the nipple-areolar complex ROI: sagittal slice of breast MRI with segmentation of fibroglandular tissue and fatty breast tissue (right). The 1- and 4-cm ROIs represent the nipple and the nipple-areolar complex, respectively. The 0.5-depth posterior to the nipple
represents a standard retroareolar margin during NSM. All breast tissue anterior to this was included in the volumetric analysis. ROI region of interest, MRI magnetic resonance imaging, NSM nipplesparing mastectomy, FGT fibroglandular tissue, NAC nipple-areolar complex
Magenetic Resonance Imaging Volumetric Analysis
proportion of FGT in the NAC relative to the total breast FGT (Fig. 2). For each image series, three-dimensional ROIs were identified for both the nipple and the entire NAC, consisting of 10 and 40 mm-diameter cylinders, respectively. These diameters were based on morphologic studies of nipple and NAC dimensions.39,40 The posterior extent (depth) of the cylindrical ROI was set a depth 5 mm posterior to the base of the nipple, representing a standard retroareolar margin following an NSM.41 We modeled thick margins by increasing the depth of the ROI to 10 mm. The anterior extent of the ROI was the breast-air boundary. The areolar FGT was calculated by subtracting the FGT volume in the 10 mm-diameter nipple ROI from the 40 mm-diameter NAC ROI. The volumes were then translated into proportions by dividing by the total breast FGT.
MRI is an established means of quantifying the amount of FGT in the breast, a procedure that has generally been done to determine breast density.37,38 The primary outcome of this study was to evaluate the proportion of FGT present in the NAC relative to the entire breast, using MRI volumetric analysis. The main assumption of the analysis was that the FGT represents tissue with malignant potential, despite the fact that it is actually composed of many tissue types (ductal, lactiferous, stroma, etc.). All patients underwent dynamic gadolinium-enhanced MRI for screening purposes. Only the first screening MRI performed during the prospective study was used for the purpose of the current study. The amount of FGT was assessed from images that had been acquired using several different protocols—a T1 or T2 weighting, with or without fat suppression. The segmentation of the FGT was performed in four steps: (i) inhomogeneities in the breast coil sensitivity were corrected by applying a low-pass spatial frequency filter on each image slice in the volume and by manually adjusting the signal level on each slice; (ii) the boundary between the breast and the surrounding air was identified; (iii) partial volume effects at the breast edge were corrected by interpolation between image slices; and (iv) the FGT was identified by selecting a region of interest (ROI) in the central slice of the image containing fatty tissue and FGT, and the signal peaks corresponding to the two tissues were identified. A soft-threshold sigmoid function was then applied to transform the signal into fractional FGT content. Total breast FGT and NAC FGT were quantified by summing the fractional FGT over the breast volume and over the NAC ROI described below, respectively. From these volumes we identified the
Analysis The primary outcome of this study was the proportion of FGT present in the NAC relative to the entire breast expressed as a mean and standard deviation for the study population. The proportion of FGT for each subject was calculated by dividing the absolute volume of FGT in the NAC by the total breast FGT at a simulated surgical margin (5 mm). The aim of the secondary analysis was to obtain data to help resolve two areas of controversy: (i) the clinical benefit, if any, of areola-sparing versus NAC-sparing mastectomy; and (ii) the clinical significance of retroareolar margin thickness. Varied retroareolar margins and the areolar proportion of FGT were modeled as described above. The proportion of areolar FGT was compared with NAC FGT, as was the proportion of FGT with a 5 mm
H. L. Baltzer et al. TABLE 1 Patient characteristics: demographic information and breast and parity history Age [years; mean (range)]
42.5 (28–63)
BMI [mean (range)]
26.1 (17–41)
3
Breast volume [cm ; mean (range)]
TABLE 2 The proportion of nipple-areolar complex and nipple fibroglandular tissue relative to total breast fibroglandular tissue at 5 and mm retroareolar depths Nipple-areolar complex (40 mm diameter ROI)
654 (157–1758)
Hormone replacement therapy usea [n (%)] a
Oral contraceptive pill use [n (%)] a
Tamoxifen use [n (%)]
p value Effect size (d)
14 (13) 13 (12.4) 2 (1.9)
Parous [n (%)]
85 (81)
Multiparous [n (%)]
62 (59)
Retroareolar depth (mm)
5
Proportion of total breast 1.3 fibroglandular tissue (%)
10 3.0
\0.001 1.1
ROI region of interest
Menopausal status [n (%)] Pre-menopasual Post-menopausal Breastfeedingb [n (%)]
72 (69) 33 (31) 64 (61)
BMI body mass index, MRI magnetic resonance imaging a
At the time of study enrollment and screening MRI
b
Indicates any duration of breastfeeding
versus 10 mm retroareolar margin. Comparisons were made using Student’s t-test, with a p-value \ 0.05 required for statistical significance. For each comparison, the effect size was measured by calculating the Cohen d. Cohen d is defined as the difference between two means divided by the pooled standard deviation in which \0.2 indicates a ‘trivial’ effect size, 0.2–0.5 indicates a ‘small’ effect size, 0.5–0.8 indicates a ‘medium’ effect size, and [0.8 indicates a ‘large’ effect size.42 Analyses were performed using the SPSS statistical software package (version 17.0; SPSS Inc., Chicago, IL, USA). RESULTS Overall, 105 patient MRIs underwent volumetric analysis and were included in the data analysis. Patient demographics and information at the time of study entry are summarized in Table 1. Volumetric Analysis The mean breast volume was 654 cc (range 157– 1758 cc), containing, a mean of 194 cc (29 %) of FGT. At a retroareolar depth of 5 mm, modeling a standard surgical margin behind the NAC, the proportion of FGT relative to total breast FGT in the NAC was 1.3 %. Partitioning the NAC into anatomical components, the nipple and the areola accounted for 0.1 and 1.2 %, respectively, of the total breast FGT (Fig. 2). The proportion of FGT in the areola compared with the NAC was not significantly different (p = 0.38, d = 0.12). Increasing the retroareolar margin to 1 cm, modeling a thicker surgical margin behind the nipple, led to a statistically and clinically significant increase
FIG. 3 Distribution of the proportion of fibroglandular tissue in the breast with a simulated 5-mm retroareolar margin
in the proportion of FGT in the spared NAC compared with the modeled 0.5 cm standard margin (p \ 0.001, d = 1.1) (Table 2) (Fig. 3). DISCUSSION For patients undergoing RRM, the decision whether to spare the NAC or the areola is made in conjunction with surgeons. To date, this has often been a stressful decision as patients have felt they must choose between a procedure that will minimize their future breast cancer risk and one that will better preserve their body image but may lead to a higher cancer risk. In order to facilitate this decisionmaking process, we sought to estimate the difference in cancer risk between these procedures, using breast FGT as a surrogate marker of the malignant potential of the residual breast tissue. This study found that an extremely small amount of FGT, 1.3 % of the entire breast FGT, is present in the NAC at a depth of 5 mm. Of note, this is likely a conservative estimate of the actual residual ductal tissue since our measurement also includes stromal and
MRI Volumetric Analysis of Breast Fibroglandular
fibrous tissue as well as skin. It should also be noted that TDLUs are only present in this region in 10–25 % of breasts, which suggests an overall low risk of malignant potential in a spared nipple at this depth. The apparent safety of prophylactic NSM was first demonstrated among a cohort of 639 women at moderate to high risk of developing breast cancer, with only one developing cancer in the spared nipple after a median follow-up of 14 years.20 A subgroup of 26 of these patients carried the BRCA gene mutation, with none developing cancer in the spared nipple.4 More recently, in a retrospective cohort study of 80 women (mixed BRCA gene mutation carriers and non-carriers) who underwent prophylactic NSM, none developed a carcinoma in the NAC at a median follow-up of 3 years.21 While the results of these studies are encouraging,4,20,21 25 or 30 years of follow-up will be necessary in order to accurately estimate the lifetime risk of breast cancer after NSM. In the meantime, high-risk women who have opted for RRM, and their physicians, need some basis for knowing the extent to which breast cancer risk is increased with preservation of the NAC. We have taken a novel approach to estimating this risk. Using MRI volumetric analysis, we have demonstrated that the NAC itself accounts for an extremely small proportion. This suggests that NSM should not offer an appreciably increased risk of developing in cancer in the mastectomy flap over an SSM. Secondarily, we applied the findings of the volumetric analysis to address two areas of clinical controversy: retroareolar margin depth and ASM. Removing the nipple, but leaving the areola, has been considered a safer alternative to NAC-sparing surgery.8,23–26 Our analysis suggests very little risk reduction by removing the nipple and leaving the areola due to the fact that the majority of the FGT is found under the areola. The nipple represents a minute amount (0.1 %) of the total breast FGT and contributes \10 % of the FGT in the NAC. This finding is in agreement with histology studies19,27 and suggests very little risk reduction by removing the nipple and leaving the areola due to the fact that the majority of the FGT is found under the areola. Thin mastectomy flaps with narrow retroareolar margins are considered oncologically safer, but have the trade-off of greater rates of mastectomy flap and/or nipple necrosis.30 Nipple necrosis following NSM has been reported in 0.1– 6 % of cases and can lead to significant morbidity, ranging from prolonged wound healing with secondary NAC reconstruction to loss of the breast reconstruction due to infection involving the underlying implant.10,21,30–35 It is three times as likely that TDLUs exist in the retroareolar tissue as in the nipple, suggesting that the retroareolar margins are an important consideration for minimizing the risk of breast cancer in this high-risk population.19,41 There are no well-established guidelines for the depth of
retroareolar margins; however, a margin of up to 5 mm is considered acceptable as long as a retroareolar biopsy is taken to rule out an occult carcinoma.41 The optimal depth for retroareolar margins is controversial.30,32,34,41 This volumetric analysis suggests that doubling a standard margin of 5 mm to 1 cm, would result in a clinically meaningful increase in the amount of unresected FGT. This indicates that margin depth should be measured after riskreducing NSM in this high-risk population and correlated with long-term patient outcomes to better determine the safety (or lack thereof) of thicker retroareolar margins. CONCLUSIONS This study was to provide clinicians and patients with information to aid in the decision of whether to spare the nipple, an increasingly popular option for RRM. Overall, our findings support the safety of the current trend toward increased rates of prophylactic NSM performed in BRCA1 and BRCA2 mutation carriers. In addition, we found no evidence that sparing the areola alone is safer than sparing the entire NAC. Our findings did suggest that a retroareolar margin of 10 mm might leave behind significantly more breast tissue with malignant potential than the standard 5 mm margin, but observational studies of patients who have undergone NSM will be necessary to confirm or refute this. ACKNOWLEDGMENT Dr. Semple is supported by the Canadian Breast Cancer Foundation (Ontario Chapter). DISCLOSURE
The authors have no conflicts of interest to declare.
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