Invasive breast cancer following bilateral subcutaneous mastectomy in a BRCA2 mutation carrier: a case report and review of the literature
© Kasprzak et al; licensee BioMed Central Ltd. 2005
Received: 25 May 2005
Accepted: 04 August 2005
Published: 04 August 2005
Primary prevention of breast cancer through prophylactic mastectomy can reduce the risk of malignancy in high-risk individuals. No type of mastectomy completely removes all breast tissue, but a subcutaneous mastectomy leaves more tissue in situ than does a simple mastectomy.
We report a case of invasive breast cancer in a BRCA2-positive woman 33 years after bilateral subcutaneous mastectomy. To our knowledge, only one case of primary breast cancer after prophylactic mastectomy in a BRCA1-positive patient has been reported in the literature and none in BRCA2-positive individuals.
Careful documentation and long follow-up is essential to fully assess the benefits and risks of preventive surgical procedures in BRCA1 and BRCA2 mutation carriers.
The risk of breast cancer in women who inherit a germline mutation in the BRCA1 ge ne can be as high as 20% by the age of 40 and 50% by the age of 50  and as high as 13% by the age of 40 and 60% by the age of 50 in BRCA2 mutation carriers . These estimates apply to individuals who belong to very high risk, multiple-case breast cancer families. Prophylactic surgery to reduce cancer risk remains an option for carriers of BRCA gene mutations; however, its efficacy is likely to depend on the ability to remove nearly all breast tissue. Different surgical procedures, (subcutaneous or a simple mastectomy), limited patient follow-up and lack of adequate control population confound the numerous studies on this subject. Only three reports have specifically addressed the extent of risk reduction by prophylactic breast removal in BRCA1 and BRCA2-positive individuals [3–5]. Most surgeons believe that subcutaneous mastectomy (SCM) is not optimal for prophylaxis because a substantial amount of breast tissue remains in the nipple-areola complex and on the skin flaps, and therefore it has fallen into disuse. Here, we report a case of breast cancer occurring following a SCM. A literature review using PubMed, searching from 1994 to the present, revealed this to be the first reported case of breast cancer occurring post-SCM in a carrier of a BRCA2 gene mutation. We discuss the possible implications of this seemingly uncommon finding.
Given the diagnosis of invasive breast cancer and BRCA2 mutation carrier status, our proband opted for prophylactic bilateral salpingo-oophorectomy with hysterectomy, as well as removal of the nipple-areola complex along with remaining breast tissue. The pathology examination identified the presence of bilateral adnexal stromal hyperplasia, several leiomyomata in the myometrium as well as simple ductal epithelial hyperplasia without atypia in the mastectomy specimen. There was no evidence of malignancy.
Currently available management strategies for women who carry inherited predisposition to develop breast cancer are limited given the lack of prevention methods with proven efficacy. Furthermore, there have been no prospective, controlled trials of the breast cancer risk reduction associated with bilateral prophylactic mastectomy. Such studies are unlikely to take place due to ethical and practical considerations. Prophylactic mastectomy, whether subcutaneous or total, significantly reduces, but does not eliminate, the risk of breast cancer in high-risk individuals.
Several studies showed that breast reduction procedures substantially lower the risk of breast cancer. Recently, Brinton et al  confirmed that the magnitude of cancer risk reduction is directly related to the amount of tissue removed during the operation. With a SCM, the nipple-areola complex is preserved and some of the underlying breast tissue remains on the skin flaps. When SCM is intended as prophylaxis against breast cancer, the surgeon's aim is to remove as much tissue as possible. It is plausible that a less thorough removal of glandular tissue may have taken place given the indication for surgery in our patient's case. It is generally agreed that the prophylactic nature of bilateral mastectomy in an unaffected BRCA1 or BRCA2 mutation carrier calls for the most complete breast tissue removal. This viewpoint makes SCM a less desirable choice. Skin-sparing mastectomy  could be seen as a partial compromise and appears to be an increasingly popular option for women at high risk. More recently, geneticists have questioned the rejection of simple SCM as a viable procedure in such women. It is argued that the magnitude of the risk reduction offered by SCM, when combined with its greater cosmetic acceptability, is sufficient to keep this option available to women .
There are numerous reports in the literature describing the occurrence of breast cancer after SCM [10, 11]. Subsequently, the perception exists that SCM fails to eliminate the risk of breast cancer. Although the extent of risk reduction achieved by SCM is limited given that about 5–10% of the mammary tissue remains in situ, it is thought to be of the order of >85% [4, 12]. As stated above , at this level of risk reduction, SCM would have a greater effect on breast cancer rates in BRCA1/2 carriers than would total mastectomy if at least 50% of BRCA1/2 carriers chose preventive SCM. Currently, preventive bilateral total mastectomy rates are about 20% in most populations.
The first retrospective study of efficacy of prophylactic mastectomy carried out by Hartmann et al  included 18 subjects later confirmed to be carriers of deleterious mutations in the BRCA genes but, unfortunately, it had insufficient statistical power to detect a difference in the risk reduction between total and SCM. In this cohort, all breast cancers (n = 7) were diagnosed in women who had undergone SCM (total of 950). None were known to be BRCA1/2 mutation carriers. Of the seven cases, only one occurred in the nipple-areolar area. Not surprisingly, the majority of the high-risk women (n = 17) described in the subsequent report  underwent SCM. After a median of 13.4 years of follow-up, none of the BRCA1/2 germ-line mutation carriers has developed breast cancer. The authors concluded that at least 90% risk reduction could be expected among women with confirmed BRCA mutation status following prophylactic bilateral SCM. Meijers-Heijboer et al  report the initial results of a prospective study of 76 women with deleterious BRCA1 or BRCA2 mutations who chose to undergo bilateral simple mastectomy and no breast cancers were observed after a mean follow-up of 2.9 ± 1.4 years. The Prevention and Observation of Surgical End Points (PROSE) Study Group findings  support the notion that bilateral mastectomy results in approximately 90% breast cancer risk reduction. Of 105 BRCA mutation carriers, only two women (1.9%) developed breast cancer 2.3 and 9.2 years after SCM. The first breast cancer case was diagnosed at the age of 28 years in the BRCA2 mutation carrier who presented with a palpable axillary mass at 27 months post-SCM. Subsequently, metastatic adenocarcinoma in an axillary lymph node was identified and it was most likely consistent with a primary breast cancer already present at the time of SCM. It is important that this case is not considered as a failure of SCM, and it should be therefore classified as a recurrence which would have likely taken place despite the surgery. The second breast cancer case occurred in a BRCA1 carrier at the age of 41 years.
When hereditary predisposition to breast cancer is being assessed, it is important to consider the impact of the age-related penetrance of the BRCA1 and BRCA2 genes. BRCA1 has a higher penetrance than BRCA2 in the pre-menopausal years . The benefits of preventive surgery will be proportionally greater for an older BRCA2 carrier than an older BRCA1 carrier, and therefore if a BRCA2 carrier discovers her mutation status when she is peri- or post-menopausal, the potential benefits of preventive mastectomy should not be understated, as the breast cancer risks do not significantly diminish following menopause.
Studies assessing efficacy of bilateral prophylactic mastectomy (PM) in BRCA1 and BRCA2 carriers
Hartmann et al 
Meijers-Heijboer et al 
Rebbeck et al 
Study recruitment centers
USA, Canada, UK, Netherlands
Median follow-up (yrs)
Mean age at surgery (yrs)
Number of PM patients
Number of controls
Type of study
Primary invasive breast cancer
- in cases (after PM)
1 (BRCA1 carrier)
- in controls
The existing literature on the mammographic and sonographic appearance of breast cancer in BRCA-positive patients' reconstructed breasts is rather scanty. Pathologic studies have demonstrated that tumors in BRCA1 and BRCA2 mutation carriers are associated with morphologic features of continuous pushing margins , with a reduced potential for stromal infiltration explaining that this appearence might mimic benign-looking lesions at mammography  and breast sonography as well. Indeed, sonographic criteria of the mass in our case – ovoid axis, thin pseudocapsule, posterior enhancement, and well defined margins – were in keeping with a benign nodule . In addition, according to Giovagnorio criteria , the lesion described in our case, with a single vascular pole (type 2), was compatible with a benign lesion. Cconsistent with the Lamb et al study , this lesion appeared benign but was in fact a moderate to high-grade invasive cancer.
We report an unusual case of late occurrence of breast cancer after SCM in a BRCA2 mutation carrier. As these cases are so rare, the long-term risk of breast cancer following preventive mastectomy in BRCA1/2-positive individuals is likely to be very low. Nevertheless, vigilant, long-term surveillance based on clinical examination combined with breast sonography when indicated remains necessary, as delayed malignancy can occur.
Written consent was obtained from the patient for publication of the case report. The authors thank Dr. D. Gareth Evans for helpful comments.
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