1 4 5 10 11 12 13 5 14 11 15 16 In the current analysis, we report on an extended series with longer follow-up of women having undergone a PM at the Rotterdam Family Cancer Clinic because of either a proven BRCA1/2 mutation or a genetic susceptibility (50% risk carriers from a HB(O)C family). Our study sample was large enough to discriminate between unaffected women and women with a history of BC (affected). Special attention is paid to the prevalence of (pre)malignant lesions in prophylactically removed mastectomy specimens. Further, we report on the postoperative complications of PM in combination with breast reconstruction. PATIENTS AND METHODS As of the start of the Rotterdam Family Cancer Clinic in 1991, PM and/or PBSO are being discussed as risk-reducing strategies with women at increased risk of hereditary BC and/or ovarian cancer. In early years, PM was discussed with BRCA1/2 mutation carriers as well as with women from a HB(O)C family without a proven mutation (so-called 50% risk carriers), and applied for unaffected as well as affected (with a history of breast cancer) women. Due to the development of more advanced mutation-detection methods enabling the performance of a complete gene mutation screen, there has been a shift in more recent years to discuss the option of PM only with identified mutation carriers. Before 1996, the decision to undergo a PM and/or PBSO was discussed individually by the doctor and the woman in question. As of 1996, women opting for either PM and/or PBSO are additionally discussed in the multidisciplinary Committee on Hereditary Tumors. For this purpose, institutional guidelines concerning the surveillance schedule and indications regarding PM/PBSO have been further elaborated and implemented as of 2000, which were updated as knowledge progressed and more evidence-based data became available. Before 2000, no additional examinations were performed before PM, irrespective of the individual situation (unaffected/affected; mutation/50% risk carrier). Women were seen biannually for physical examination, while a mammography was performed annually. As of 2000, institutional guidelines from the working party on hereditary tumors recommended to perform clinical breast examination (CBE) and imaging examination within 3 months prior to PM, to minimize the risk of finding unexpected malignant changes at PM. At first, imaging examination consisted of either mammography or magnetic resonance imaging (MRI) scan, while more recently MRI has been preferred. Breast ultrasound (US) and, if necessary, fine-needle aspiration cytology (FNAC) are additionally performed in case lesions are found at CBE or one of the imaging examinations. Further, the guidelines recommend the discussion of the case in the multidisciplinary Committee on Hereditary Tumors and a standard visit with a psychologist. For affected women, the guidelines are extended with dissemination investigations to rule out recurrent or distant breast cancer activity (chest x-ray, liver ultrasound, bone scan, liver functions and determination of Ca15.3/Ca125). Where women with a history of ovarian cancer were previously eligible for PM, at the moment this is not discussed anymore in this setting, because the prognosis is mainly dictated by the ovarian cancer. In the sample, these women were classified as “unaffected,” unless they also had a history of BC. To evaluate the short-term and long-term medical effects of prophylactic surgery in high-risk women, a combined retrospective and prospective, longitudinal study was activated at our institution, including all genetically susceptible women who had opted for prophylactic surgery (either PM and/or PBSO). Women were informed by oral and written information and were asked for written consent. The protocol was approved by the institutional review board (project EMC-DDHK 98-15). Surgical Technique At our institute, the oncological and plastic surgeon perform the PM and BR as a team. During the operation, the patient is under general anesthesia in a half-supine position. A skin-sparing mastectomy is performed through a vertical, peri-areolar incision, which extends from just above the nipple down the submammary fold. The breast tissue, including the superficial fascia (creating thin skin flaps), the axillary tail, the inframammary fold, the nipple-areolar complex, and the fascia of the pectoral muscle are removed. In case of immediate breast reconstruction, either a subpectoral silicone implant is inserted in a pocket created below the pectoral muscles in a one-stage procedure, or autologeous tissue is used. Autologeous reconstruction encompasses a broad range of procedures incorporating the patient’s own tissues to recreate the breast. The transverse rectus abdomis myocutaneous (TRAM) flap and latissimus dorsi flap are two standard myocutaneous flaps used for breast reconstruction. More recent modifications to the traditional techniques led to the use of the deep inferior epigastric perforator (DIEP) flap. Nipple reconstruction is offered after 6 months and consists of three small transposition flaps; the areola is mimicked by tattooing the desired skin color. Breast reconstruction is not always performed in the same operation as the mastectomy; the techniques for these delayed reconstructions, however, are as described previously. Microscopic Examination of Mastectomy Specimens As of 1995, a standard procedure has been followed for meticulous microscopic examination of prophylactically removed mastectomy specimens to rule out the presence of “occult” (microscopic) malignant alterations. The protocol prescribes that mastectomy specimens are cut into slices of 0.5–1 cm thickness, whereby each slice is carefully inspected and palpated for abnormalities. Standard, three randomly selected parenchymal tissue samples from each quadrant and a transverse section through the nipple are submitted for histology, in addition to samples of all visible or palpable abnormalities. Further, three samples from each quadrant of the mastectomy specimens are snap frozen for the tissue bank. Radiographic examination of breast tissue specimens is not performed on a routine basis. Study Design 17 18 19 Relevant data were extracted from the hospital records. For each woman, including deceased women, the following information was obtained: date of birth, death, and PM, performance (yes/no) and type of breast reconstruction, PBSO, diagnosis of breast and/or ovarian cancer, mutation status, duration of follow-up after PM (end date being either the date of death or the date of last clinic visit in case of loss to follow-up, or the end date of this study, i.e. December 31, 2004), and type and number of complications after breast reconstruction. Regarding the latter, we distinguished between early (within 6 weeks) and late postoperative complications (after 6 weeks). Early complications consisted of infection, necrosis, bleeding, and luxation of the prosthesis. Late complications were divided in surgical complications (such as capsular formation, infection, necrosis, and luxation of the prosthesis), and complaints related to cosmetic outcome (such as poor symmetry and dog ears). Nipple reconstruction is regarded as part of the breast reconstruction and therefore has not been registered as a cosmetic complication. A computerized database (MS-Access) was used to process the data. Data were entered retrospectively as well as prospectively after each clinic visit. Statistical Analysis t P RESULTS Study Population 1 P P P TABLE 1. Characteristics of the study population HISTORY OF BC n n P d BRCA HB(O)C BRCA HB(O)C n a n a n a n a N 145 b 32 b 91 c 90 c e   Death due to cancer 0 (0) 1 (3) 9 (10) 7 (8)  Age at PM (years)   Median 36.0  38.5  42.0  47.0  <.001   Range 22–65  28–55  25–65  26–68     <30 years 18 (12) 3 (9) 6 (7) 2 (2) <.001   30–39 years 74 (51) 14 (44) 26 (29) 22 (24)    40–49 years 36 (25) 10 (31) 38 (42) 31 (34)     ≥50 years 17 (12) 5 (16) 21 (23) 35 (39)  Duration of follow-up (years) 4.4  4.7  3.9  4.5   Mutation status   BRCA1 115 (79) –  76 (84) –     BRCA2 30 (21) –  15 (16) –   PBSO   Yes 83 (57) 3 (9) 61 (67) 12 (13) .13   No 62 (43) 29 (91) 30 (33) 78 (87)  Age at PBSO (years)   Median 40.0  45.0  43.0  49.0  <.01   Range 29–57  35–45  32–65  37–58   Timing of PBSO   Before PM 18 (22) 2 (67) 14 (23) 6 (50) .11   At PM 35 (42) 1 (33) 16 (26) 5 (42)    After PM 30 (36) 0 (0) 31 (51) 1 (8)  Ovarian cancer before PM 4 (3) 0 (0) 2 (2) 1 (1)  Unexpected (p)MF at PM 3 (2) 2 (6) 4 (4) 1 (1)  Cancer after PM   Breast cancer 1 (1) 0 (0) 0 (0) 0 (0)    Ovarian cancer 2 (1) 0 (0) 1 (1) 0 (0)  BC, breast cancer; HB(O)C, hereditary breast(/ovarian) cancer; PM, prophylactic mastectomy; PBSO, prophylactic bilateral salpingo-oophorectomy; (p)MF, (pre)malignant findings. a b c d e 2 P P P TABLE 2. Comparison between unaffected and affected women  Unaffected Affected P N 177 (%) 181 (%)  Age at PM (years)   Median 37 44 <.001   Range 22–65 25–68    <30 years 21 (12)  8 (4) <.001   30–39 years 88 (50) 48 (27)    40–49 years 46 (26) 69 (38)    ≥50 years 22 (12) 56 (31)  PBSO   Yes 86 (49) 73 (40) .12   No 91 (51) 108 (60)  Age at PBSO (years)   Median 40 44 <.001   Range 29–57 32–65  PM, prophylactic mastectomy; PBSO, prophylactic bilateral salpingo-oophorectomy. 1 FIG. 1. Annual number of PM in unaffected/affected BRCAa/2 mutation carriers and 0% risk carriers from HB(O)C families.  In the affected group, however, the pattern was different, whereby a shift has taken place through the years. In the early years of the study period (1994–1997), mainly women without a proven mutation underwent PM in this group. Between 1997 and 2001, approximately as many mutation carriers as 50% risk carriers underwent a PM. As of 2002, more mutation carriers have undergone a PM, although the number of PMs in 2004 again was not different between mutation and 50% risk carriers. Prophylactic Bilateral Salpingo-oophorectomy 1 P P P 2 P P 1 (Pre)malignant Findings at PM 1 3 x 1 o TABLE 3. Characteristics of unexpected (pre)malignant findings in the PM specimens  Preoperative  Year of PM Genetic risk group History of BC before PM Histology Grade Tumor size (mm) ER/PR status CBE Mx MRI 1995 HB(O)C No IDC NA NA NA SC SC  a, b 1996 HB(O)C No DCIS II <2 NA PB nl  a 1996 BRCA1 No LCIS NA NA NA nl nl   1997 HB(O)C Yes DCIS I NA NA nl   c 1997 BRCA1 Yes DCIS II <2 NA nl PB  a 1997 BRCA1 Yes IDC II 3 Negative nl   c 1998 BRCA1 Yes DCIS NA <2 NA nl nl   2000 BRCA1 Yes LCIS NA NA NA nl nl   2002 BRCA1 No IDC III 5 Negative nl nl PB a    IMC III 6 Positive     2003 BRCA2 No DCIS II <2 NA nl nl   PM, prophylactic mastectomy; BC, breast cancer; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; IDC, invasive ductal carcinoma; IMC, invasive medullar carcinoma; CBE, clinical breast examination; Mx, mammography; MRI, magnetic resonance imaging; SC, suspicion of cancer; PB, probably benign; nl, normal; NA, not applicable. a b c Cancer During Follow-up After PM After PM, no incident breast cancer cases were observed in 50% risk carriers. 1 One BRCA1 mutation carrier from the unaffected group presented in 2001, 3.5 years after PM (no malignant findings at histological examination), with metastatic adenocarcinoma in an axillary lymph node, morphologically and immunohistochemically consistent with breast cancer. Additional dissemination examinations also revealed metastases in bone and liver. Review of the preoperative data (physical examination and mammography) at the presentation of metastatic disease did not show malignant alterations, while meticulous reexamination of all pathology slides and additional investigation of frozen tissue material did not detect a primary breast cancer. Reconstructive Breast Surgery 4 n P P P P P P TABLE 4. Breast reconstruction (BR) in women undergoing PM History of BC No (Unaffected) Yes (Affected) P Number of women 177 (%) 181 (%) Breast reconstruction (BR)   No 9 (5) 68 (37) <.001   Yes 166 (94) 110 (61)  a 2 (1) 3 (2)  Type of BR   Silicon prosthesis 159 (96) 95 (86) .004   Autologeous tissue 6 (3) 14 (13)  a 1 (1) 1 (1)  b   BCT – – 7 (6)    BCT/RT – – 33 (30)    MAST – – 67 (67)    MAST/RT – – 3 (3)  Women with complications after BR   No 84 (51) 55 (50) .92   Yes 82 (49) 55 (50)  c 127  88     Early (<6 weeks after BR) 42 (33) 31 (35) .74   Late (>6 weeks after BR) 85 (67) 57 (65)  Surgery due to late complication   No 38 (30) 24 (27) .67   Yes 89 (70) 64 (73)  Early complications Surgery due to early complication   No 27 (64) 17 (55) .42   Yes 15 (36) 14 (45)  Type of early complication  Infection 8 (19) 14 (45) .09  Necrosis 11 (26) 4 (13)   Bleeding 20 (48) 12 (39)   Prosthesis luxation 2 (5) 0 (0)   Poor arterial inflow 0 (0) 1 (3)   Pneumothorax 1 (2) 0 (0)  Late complications Surgery due to late complication   No 11 (13) 7 (12) .91   Yes 74 (87) 50 (88)  Type of late complication   Infection 4 (4) 0 (0) .33   Necrosis 1 (1) 3 (5)    Capsular formation 31 (37) 20 (35)    Prosthesis luxation 2 (2) 3 (5)  d 31 (37) 19 (34)    Dog ear 16 (19) 12 (21)  PM, prophylactic mastectomy; BC, breast cancer; BR, breast reconstruction; BCT, breast conserving therapy; BCT/RT, BCT in combination with radiotherapy; MAST, therapeutic mastectomy; MAST/RT, MAST in combination with radiotherapy. a P b c d In 137 of 276 women opting for BR (49.6%) one or more complications were registered, totaling 215 complications. Surgical reinterventions were performed in 153 cases (124 for late complications). P P P P DISCUSSION 20 21 22 23 24 25 26 27 5 8 27 29 30 31 32 5 15 33 34 35 11 15 33 36 11 15 33 34 36 We found no differences in the numbers of complications after (immediate) breast reconstruction in unaffected women compared with previously affected women in this study. This finding appears to be in contrast with earlier reports (also from our institution) describing the occurrence of more complications after mastectomy followed by (immediate) breast reconstruction in affected women. These studies report negative effects of preoperative radiotherapy on the cosmetic outcome of the reconstruction, in particular the risk of capsular formation would be increased, having negative consequences on the symmetry of the breasts. Further, asymmetry can be expected to occur more often after previous therapeutic mastectomy. Although we have no explanation for our findings, it is possible that the experience of the surgeons at our institution is important. Indeed, where previously BR by means of silicon prosthesis after breast conserving therapy was performed, this is not done anymore. In summary, we confirmed our previous findings that prophylactic mastectomy strongly reduces the risk of developing breast cancer in both BRCA1/2 mutation carriers and 50% risk carriers. As the frequency of unexpected cancers in this high-risk group remains real, preoperative imaging and careful histological examination is warranted. Further, we found a substantial complication rate after breast reconstruction, which mainly concerned late cosmetic issues, almost always leading to additional surgery. In this respect, patients should be informed preoperatively that an optimal cosmetic effect cannot unconditionally be achieved in just one single operation. Concerning the complication rate after BR, we did not find a significant difference between affected and unaffected women. In our opinion, our data are providing additional data on this issue and may help to inform women considering prophylactic mastectomy and their physicians, in the complex process of decision-making.