Background

Most germline BRCA mutation-positive breast cancers are invasive ductal carcinoma of the non-special type; the frequency of special types, such as metaplastic carcinoma, is low. Here, we report a rare case of gBRCA1 mutation-positive breast cancer with chondroid metaplasia and review the literature on gBRCA1 mutation-positive metaplastic carcinoma of the breast.

Case presentation

A 39-year-old woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother noticed a lump in her left breast and consulted her primary care doctor. Because of the examination, the possibility of breast cancer was considered, and she was referred to our hospital for detailed examination.

A 1.4-cm tumor was palpated in the upper-outer region of left breast, an enlarged lymph node was not palpated, and there was no nipple discharge.

According to mammography (Fig. 1), an equal density mass with a margin showing a circumscribed irregular shape was observed in the outer upper quadrant of the left breast at one o’clock in the anterior portion, and calcification was found inside of the mass. By ultrasonography, a 1.4 × 1.4 × 1.0-cm clear and rough, microlobulated marginal heterogeneous mass was observed in the outer upper quadrant of the left breast, along with calcification and enhanced posterior features (Fig. 2b).

Fig. 1
figure 1

Family pedigree. The family history related to hereditary breast cancer and ovarian cancer syndrome includes breast cancer in the mother and ovarian cancer in her maternal grandmother

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Fig. 2
figure 2

Imaging results. a Mammography; an equal density mass with calcification. b Ultrasound; a 1.4-cm microlobulated heterogeneous mass. c Contrast-enhanced ultrasound; arrows indicate contrast loss area

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Invasive ductal carcinoma and adjacent chondroid metaplastic breast cancer were diagnosed by needle biopsy. Positron emission spectroscopy-computed tomography revealed a tumor of maximum standardized uptake value of 7.7 in the outer upper quadrant of the left breast, with no lymph node metastasis or distant metastasis.

Based on these results, we diagnosed the patient with left breast cancer, cT1cN0M0, Stage I.

We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion as well as silicone implant replacement surgery approximately 6 months later.

In the outer upper quadrant of the whole breast resection specimen, 1.5 cm of metaplastic carcinoma (Fig. 3a), a component of chondroid metaplasia (Fig. 3b), and a component of ductal carcinoma (Fig. 3c) were mixed. Breast cancer invaded the fat tissue, the nuclear grade was 3 (atypia: 3, mitosis: 3), and the surgical margin was negative. Lymph node metastasis was not observed. The results of immunohistochemistry analysis were as follows: estrogen receptor: negative (0%), progesterone receptor: negative (0%), HER-2: negative (0), and MIB-1 index: 70–80%. These results suggested triple-negative breast cancer (TNBC).

Fig. 3
figure 3

Pathological findings. a Low-magnification image (× 10); bright part on the right area is a metaplastic carcinoma component containing cartilage matrix, and the part with a large number of nuclei on the left area is a ductal carcinoma component. b High-magnification image: metaplastic carcinoma lesion (× 20); component of metaplastic carcinoma, type of chondroid metaplasia. c High-magnification image: ductal carcinoma lesion(× 40); component of ductal carcinoma, strong atypia, and mitosis in the nuclei

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As a postoperative course, we conducted genetic counseling because of the young onset of TNBC with a family history of both breast cancer and ovarian cancer. She wished to undergo genetic testing, and thus we evaluated BRCA1 and BRCA2. The results confirmed the presence of the pathogenic mutation c. 188 T>A (L63*) in BRCA1. Four courses of doxorubicin+ cyclophosphamide therapy were performed as postoperative adjuvant chemotherapy. In addition, after disclosing the genetic test results, periodic surveillance of ovarian cancer was started. She did not want to undergo contralateral mastectomy; therefore, surveillance of the contralateral breast was started. The patient has asthma and cannot be evaluated by contrast-enhanced magnetic resonance imaging, and thus mammography and ultrasonography are performed once per year. Currently, she has been alive without relapse for 2 years post-surgery.

Discussion and conclusions

Metaplastic carcinoma includes a group of tumors in which adenocarcinoma has caused “metaplasia” to differentiate into the squamous epithelium, mesenchymal component, spindle cell, cartilage, bone, and others [1].

The frequency of metaplastic carcinoma in breast cancer is reported to be approximately 1%, making this condition quite rare [1]. Almost all metaplastic breast cancers are classified as TNBC [2].

Approximately 80–90% of breast cancers developed in carriers with pathological mutations in gBRCA1 are classified as the basal-like subtype in the gene expression profile, most of which show characteristics of TNBC [3]. Based on this, Perou et al. reported that BRCA1 is frequently observed in different stages of epithelial cell development; a BRCA1 mutation is linked to this luminal progenitor/basal-like phenotype, and loss of BRCA1 may block further differentiation and retain a cell in this stage of development [4].

Our case and only 5 other cases have been reported according to PubMed, showing that a gBRCA1 mutation-positive status may lead to metaplastic cancer development [5,6,7,8].

All six cases were TNBC; however, the BRCA1 mutation site and tissue type of metaplastic carcinoma differed (Table 1). In previous reports, gBRCA1 mutation-positive metaplastic carcinomas included carcinosarcoma in 2 cases, osseous and chondroid metaplasia in 1 cases, squamous cell carcinoma in 1 case, and adenosquamous carcinoma in 1 case. A case of osseous and chondroid metaplasia was examined for breast cancer tissue at the Foundation One CDx and it is unclear whether it is a germ line mutation or a somatic mutation [9]. Another case of BRCA1 mutation-positive metaplastic breast carcinoma was reported many years ago [10] but a search in the current database revealed that the mutations were not pathogenic.

Table 1 Reported cases
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Recently, in subtype classification based on the gene expression profile, TNBC was divided into four subtypes: BL1, BL2, M, and LAR [11]. BL1 and BL2 are characterized by the expression of genes related to the cell cycle and DNA damage response and are cisplatin-sensitive in cell lines.

M is characterized by epithelial mesenchymal transition-related gene expression, the expression of genes involved in the growth factor pathway, and sensitivity to the PI3K/mTOR inhibitor NVP-BEZ235 and the abl/src inhibitor dasatinib. The LAR subtype is characterized by an androgen receptor signal and is sensitive to the AR antagonist bicalutamide.

In a previous report, among the 10 patients with BRCA mutation in the TNBC subtype of breast cancer, 3 cases were reported for BL1, 4 for BL2, and 3 for M [12]. In another report, among the 28 metaplastic cancers, 12 cases were reported for M, 1 for BL1, 2 for BL2, and the 4 for MSL (currently, MSL is reclassified as BL or M), and 9 for unstable/unknown. The results of these two studies suggested that TNBC with BRCA germline mutation and metaplastic breast cancer are the same subtype, BL1, BL2, or M type TNBC [13].

Patients with BRCA1 mutations may develop basal-like subtypes or the M type of TNBC, in addition to metaplastic breast cancers. There are no reports of LAR type breast cancer in either gBRCA1 mutation-positive breast cancer or metaplastic breast cancer, suggesting that the disease is another strain.

In addition, according to gene expression analysis of somatic cells from patients with metaplasia breast cancer, the BRCAness signature is found in 5/8 of squamous cell carcinoma cases, 2/8 of chondroid metaplasia cases, and 1/10 spindle cell carcinoma case.

The BRCAness signature differed depending on the type of metaplastic carcinoma.

Thus, gBRCA1 mutations cause metaplastic breast carcinomas, particularly chondroid metaplastic carcinomas, carcinosarcoma, and squamous cell carcinomas.

Only 6 cases of gBRCA1 mutation-positive metaplastic breast carcinoma have been reported; however, based on developmental hypotheses and the results of gene expression analysis, gBRCA1 mutations may be found in patients with metaplastic carcinoma at rates at least as high as those in TNBC. To determine the relationship between metaplastic carcinoma of the breast and pathogenic mutations in BRCA1, investigation of additional cases is necessary.