Breast cancer arising within fibroadenoma: collective analysis of case reports in the literature and hints on treatment policy
World Journal of Surgical Oncologyvolume 12, Article number: 335 (2014)
Breast cancer arising within a fibroadenoma (BcaFad) is rare; the rate varies from 0.002% to 0.125% in fibroadenoma specimens. Owing to its rarity, the clinicopathologic feature and treatment principle of BcaFad is still not clear. Therefore, the aim of this study was to perform a collective analysis of case reports in the literature to identify the characteristics and optimal treatment for BcaFad.
We analyzed an aggregated sample of 30 patients with BcaFad from case reports in the literature (n =24 cases) and our present study (n =6 cases). We collected and analyzed the clinicopathologic features and prognoses of patients with BcaFad, as well as treatments they received.
The patients’ mean age at diagnosis was 46.9 years. Twenty BcaFad patients (66.7%) received breast-conserving surgery (BCS), and nine other patients (30.0%) were treated with mastectomy. The rate of lymph node metastasis in BcaFad patients was 23.8%. The breakdown of the histological types of BcaFad was invasive ductal carcinoma (53.3%), followed by ductal carcinoma in situ (23.3%), lobular carcinoma in situ (16.7%) and invasive lobular carcinoma (13.3%). More than half of patients with positive hormone receptor status received hormone therapy. Most BcaFad patients with lymph node metastases received chemotherapy, and 20.0% of BcaFad patients treated with BCS received further radiotherapy. Only one patient had recurrence after surgery, and another had lung metastasis when diagnosed with BcaFad.
Most BcaFad patients could be managed by BCS. Adjuvant radiotherapy could be performed, but was not mandatory. Chemotherapy should be considered as a treatment option in the presence of lymph node metastasis.
Fibroadenoma is the most common cause of discrete breast lumps in young females[1, 2] and occurs in 25% of asymptomatic women. Benign, asymptomatic fibroadenomas usually can be managed with nonoperative follow-up[3–5]. Symptomatic, progressively enlarging masses or atypical presentations, however, may warrant surgical excision.
Although very rare, breast cancer arising within fibroadenoma (BcaFad) can still be found. The incidence of BcaFad ranges from 0.125% to 0.02%, according to different reports[6–8]. In such circumstances, carcinomas in situ (66.9% lobular carcinoma in situ (LCIS) and 12.4% ductal carcinoma in situ (DCIS)) are found to be more common than invasive carcinomas (11% invasive ductal carcinoma (IDC) and 3.4% invasive lobular carcinoma (ILC)). The optimal management of patients with BcaFad is still not clear. Little information is available in current breast cancer management consensus guidelines[10–13]. It is unknown whether such patients should be treated similarly to those with breast cancer.
Owing to the rarity of BcaFad cases, clinicians in individual medical institutions have very little experience in treating these patients. Therefore, a collective case study is needed for more information about the optimal management of BcaFad. In this article, we present our experience with six BcaFad cases and used a systematic literature review process to find some characteristics of and hints for the optimal care of these patients.
To further elucidate the characteristics and optimal management of patients with BcaFad, we performed a collective analysis of case reports in the literature and our six cases. The literature review was performed through PubMed searches to collect English-language articles about BcaFad published between January 1986 and January 2013. The keywords used in the search use were "fibroadenoma", "carcinoma", "breast", "ductal" and "lobular".
The literature search was limited to studies focused on BcaFad with descriptions of diagnosis and/or treatment. The investigated parameters included age, gender, tumor size, diagnostic image, operation method, histology, hormone receptor status (including estrogen receptor (ER) and progesterone receptor (PR)), Human epidermal growth factor receptor 2 (HER2) status, chemotherapy and radiation therapy. The searches were limited to human studies. Articles were excluded if they did not present BcaFad, patient information or treatment details. Articles published in any language other than English were also excluded.
Demographic data collected and analyzed included age, gender, size of the primary lesion, duration of follow-up, image findings, fine-needle aspiration cytology or core-needle biopsy results, pathology, operation method, postoperative therapy and recurrence or metastasis of the tumor.
In our literature review, we collected 24 cases with detailed information from 21 English-language articles. After combining these with our 6 cases, the study population comprised 30 BcaFad patients (Figure 1 and Table 1). All of the patients were female, and their mean age at diagnosis was 46.9 years old (range, 27 to 80 years old). The mean duration from the finding of fibroadenoma to surgical excision was 61.2 months (range, 0.5 to 600 months). The mean tumor size of the fibroadenoma was 2.46 cm (range, 0.8 to 5.1 cm). Most of the cancers found inside the breast fibroadenoma were in situ carcinoma or early breast cancer with minimal or small tumor size. The distribution of tumor locations was the right side (53.3%), followed by the left side (40.0%) and bilateral breast (3.3%). The clinicopathologic data of these 30 patients are summarized in Table 1.
Twenty (66.7%) of thirty patients with BcaFad received breast-conserving surgery (BCS), and nine other patients (30.0%) received mastectomies. One (patient 26) of these nine mastectomy patients received immediate breast reconstruction (Figure 2). Furthermore, five (23.8%) of twenty-one patients with the diagnosis of lymph node status had lymph node metastasis. Most patients were diagnosed with IDC (16 cases, 53.3%), followed by DCIS (7 cases, 23.3%), LCIS (5 cases, 16.7%) and ILC (4 cases, 13.3%) (Table 2). Among these patients, only one patient (patient 2) had both LCIS and IDC and another (patient 5) had both DCIS and LCIS. The TNM stages recorded were major in TisN0M0, T1aN0M0 stage to T1bN0M0. A T1aN1M0 tumor was also noted.
Regarding hormone receptor status and HER2 status, there were only 16 patients (53.3%) with data mentioned about ER and PR status. Eleven (68.8%) of these sixteen patients had ER + breast cancer, and ten patients (62.5%) had PR + cancer. Of ten patients with known HER2 status, only one patient (10.0%; patient 16) was found to have HER2-overexpressing breast cancer. Among 11 patients with hormone receptor–positive BcaFad, 6 patients (54.5%) received tamoxifen treatment. Four (80%) of five patients with lymph node metastasis received chemotherapy.
Nine patients were treated with mastectomy, and another twenty patients were treated with BCS. However, only four (20.0%) of the twenty patients who underwent BCS received radiotherapy[15, 19, 25]. Patient 17 received radiotherapy to the chest wall following a mastectomy performed for lymph node metastasis. Of the four BCS patients with IDC, only one (25.0%) received radiation therapy. In addition, among six BCS patients with DCIS, only two (33.3%) received radiotherapy. Of fifteen patients with descriptions of outcome and distant metastasis, only one (patient 22) was found to have lung metastasis at diagnosis. Another patient (patient 14) had a local recurrence 5 months after surgery.
It is very unusual for a carcinoma of the breast to arise within a fibroadenoma. In this report, we present our 6 cases together with 24 previously reported cases for a collective case analysis. Among these 30 cases, the mean age at diagnosis of BcaFad was 46.9 years, which was older than that at diagnosis of benign fibroadenoma (age range from 20s to 30s)[5, 35]. The mean duration from finding a fibroadenoma to surgical excision was 61.2 months (range from 0.5 to 600 months). This long duration can be explained by the large size of the breast tumors (mean 2.46 cm) in this group of patients. This tumor size refers to the diameter of the fibroadenoma in which the malignant component was identified. In our present study, most BcaFads were predominantly found to be small cancers in relatively large fibroadenomas. However, the tumor size was not reported in most of the reviews we included, so we could not present the actual pathologic tumor size in each individual (Tables 1 and2). Half of the data did not contain details regarding TNM stage; the other half were for stages TisN0M0, T1aN0M0, T1bN0M0 and T1aN1M0. However, we could assume that most of the limited data were for early breast cancer according to the descriptions of histology.
According to our collective case analysis, the major histological type of BcaFad was IDC (53.3%), followed by DCIS (23.3%), LCIS (16.7%) and ILC (13.3%) (Table 2). These findings are not consistent with previous reports that BcaFads were mainly carcinomas in situ (66.9% LCIS and 12.4% DCIS), followed by invasive carcinoma (11% IDC and 3.4% ILC). This discrepancy might be due to selection bias. Our present study is a collective analysis of case reports in the literature. Patients with invasive carcinoma inside fibroadenoma are rare and tend to be presented as case reports. In our six cases, the cancerous parts of the tumors were limited within the capsule of the underlying fibroadenoma without extension to peripheral breast tissue. In those BcaFad with DCIS, the DCIS was limited inside the fibroadenoma without invasion into the adjacent nonfibroadenoma breast tissue. In the LCIS-containing tumors, three patients had pure LCIS, one patient had both IDC and LCIS and two patients had both ILC and LCIS. None of them were found to have bilateral breast cancer. In our present analysis, we found that LCIS may be associated with invasive breast cancer.
In this study, 20 (66.7%) of 30 patients with BcaFad could be managed by BCS, and another 9 patients (30.0%) received mastectomies. The treatment principle for benign fibroadenomas is surgical excision with a thin ring of benign breast tissue, and breast conservation is usually feasible. BcaFad is usually found incidentally during the pathologic check when the breast tumor is being excised. This could explain why most of these patients (66.7%) received BCS as their surgical treatment. This breast-conserving rate is compatible with the reported data (19.6-58.0%) in the management of breast cancer with the same tumor size in the NASBP B-06 trial (National Surgical Adjuvant Breast and Bowel Project) and the National Cancer Database in the United States[36, 37].
Another reason for the high breast-conserving rate of the patients in this group is that most fibroadenomas are well-defined, with a "capsule"[2, 5]. If the initial resection margin is free of cancer or only LCIS is inside the fibroadenoma, then a tumorectomy or lumpectomy alone may be sufficient[15, 25, 38]. These facts could explain why the high rate of patients with BcaFad received BCS in this study. If the resection margin is involved or close, however, then a further wide excision may be needed.
Mastectomy (30.0% in this study) may still be needed in some circumstances—usually in large, multifocal or central located tumor. One of our six patients (patient 26) received an endoscopically assisted, nipple-sparing mastectomy combined with immediate breast reconstruction using a gel implant because of the large size and central location of the breast tumor (Figure 2). Owing to the favorable prognosis, mastectomy with immediate breast reconstruction can be considered in patients with BcaFad when a mastectomy is needed.
Radiotherapy can effectively reduce local recurrence, and this reduction in disease relapse may translate to prolonged overall survival[11, 12, 40]. Nowadays, there is an established rule that, in order to decrease the risk of local recurrence, radiotherapy should be delivered to breast cancer patients receiving BCS[10, 13]. Should patients with BcaFad have to receive radiotherapy after partial mastectomy? Tiu et al. stated that BcaFad behaves like breast cancer at the same stage and that therefore the treatment should follow the same modality. However, only four (20.0%) of the BCS patients received radiotherapy according to our collective case analysis[15, 19, 25]. Of four BCS patients with IDC, only one patient (25.0%; patient 15) received radiation therapy. In addition, among six BCS patients with DCIS, only two (33.3%) received radiotherapy.
According to our collective case analysis in this study, it seemed as though not all surgeons agreed that radiotherapy should be delivered to patients with BcaFad after BCS. To date, to our knowledge, no randomized controlled trials or large cohort studies have been conducted to answer this question. According to our literature review (Figure 1), fewer than 250 patients with BcaFad have been reported to date, and only 8 of them were reported to have received radiotherapy[14, 19, 25, 27, 30]. Whether radiotherapy is necessary for BcaFad patients after BCS is still unknown; more solid evidence is needed to establish the role of radiotherapy for this particular group of patients. To the best of our knowledge, radiotherapy seems optional rather than mandatory for BcaFad patients after partial mastectomy.
Owing to the limitations of a literature review, hormonal and HER2 receptor status was incompletely reported. In our collective case analysis, the incidence of hormone receptor–positive BcaFad was 68.8% ER + and 62.5% PR+, which is compatible with of the incidence in common types of breast cancer (range, approximately 60% to 90%)[42, 43]. However, the rate of HER2 overexpression was only 10.0%, which is a little lower than that of common types of breast cancer (approximately 15% to 25%)[44–46].
According to reports in the literature, most BcaFad cases are carcinoma in situ (79.3%), and less than 15% are invasive carcinomas. BcaFad with lymph node metastasis is unusual, but can still occur[15, 19, 25, 27, 47, 48]. A sentinel lymph node biopsy should be performed if there is a pathologic confirmation of the presence of invasive carcinoma of BcaFad. Furthermore, axillary lymph node dissection should be performed in the presence of lymph node metastasis. Lymph node metastasis, rather than tumor size or hormone status, is the main concern underlying the use of chemotherapy for patients with BcaFad[19, 25, 27, 49].
The prognosis for patients with BcaFad was reported to be more favorable than that in other common types of breast cancer[19, 25]. In our collective case analysis, among 15 patients with descriptions of long-term results, 1 patient (6.67%, patient 14) had local recurrence 5 months after surgery and another (patient 22) was found to have lung metastasis when diagnosed with BcaFad. Death caused by BcaFad was uncommon, but still can occur in cases of invasive carcinomas at a late stage[50, 51].
BcaFad is an infrequent malignancy and carries a favorable prognosis. Most BcaFads can be managed with BCS, and radiotherapy can be delivered optionally even when patient has undergone BCS. A sentinel lymph node biopsy should be performed if invasive carcinoma is present. In the presence of lymph node metastasis, chemotherapy should be considered to prevent distant metastasis.
YTW, STC, DRC, SJK and HWL: Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua, Taiwan. YTW: Department of Surgery, Sinying Hospital, Ministry of Health and Welfare, Tainan, Taiwan. CJC: Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan. YLK: Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan. LMT: Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Breast cancer arising within fibroadenoma
Ductal carcinoma in situ
Invasive ductal carcinoma
Human epidermal growth factor receptor 2
Invasive lobular carcinoma
Lobular carcinoma in situ
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This study was supported by the research program at Changhua Christian Hospital. The authors thank the research nurse specialists of Changhua Christian Hospital, National Cheng-Kung University Hospital and Taipei Veterans General Hospital.
The authors declare that they have no competing interests.
HWL, STC and YTW designed the study. YTW, STC, YLK, LMT and CJC collected data. YTW, HWL, YLK and CJC prepared the manuscript. DRC, SJK and LMJ revised the manuscript. All authors read and approved the final manuscript.
Yu-Ting Wu, Shou-Tung Chen contributed equally to this work.