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Metaplastic breast carcinoma with extensive osseous differentiation: a report of two cases and review of the literature
Ronggang Lang, Yu Fan, Xilin Fu, and Li Fu
Department of Breast Cancer Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
metaplastic breast carcinoma, osseous differentiation.
Conflict of interest:
The authors have no conflicts of interest.
We gratefully acknowledge Professor Vincenzo Eusebi, MD, FRCPath, Department of Oncology, Section of Anatomic Pathology M. Malpighi, University of Bologna, Bellaria Hospital, Bologna, Italy, for his critical review of the paper.
The study was supported by the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) IRT0743.
Li Fu MD, PhD, Professor and Head, Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, China 300060.
Received June 25, 2010;
accepted September 9, 2010.
Invasive breast cancer with osseous metaplasia is rare. Here we report two cases of metaplastic breast carcinoma with extensive osseous differentiation. Case 1: The patient was a 60-year-old woman with a right breast tumor, about 4 cm in diameter. Mammogram and ultrasound presented an irregular-shaped mass suspected for malignancy. Core needle biopsy confirmed invasive carcinoma and the patient underwent a modified radical mastectomy. Case 2: The patient was a 48-year-old woman with a left breast tumor, about 3 cm in diameter. Mammogram demonstrated a well-circumscribed mass with extensive dense calcifications. Frozen section biopsy confirmed invasive carcinoma and a modified radical mastectomy was performed. The two patients had no metastatic carcinoma in the axillary lymph nodes and remained free of recurrence and systemic metastases in a 13- and 4-month follow-up period, respectively. Histopathologically, patient 1 had an adenocarcinoma with prominent sarcomatous (osteosarcomatous) differentiation with intervening spindle cells. The sarcomatous areas showed high nuclear atypia, pleomorphism and a high Ki-67 index. In Case 2, the neoplasm consisted of invasive ductal carcinoma of no special type with an osseous metaplasia component and showed a direct transition from the carcinoma to the osseous elements. The distinction between the different types of metaplastic carcinomas, specifically the distinction between benign and malignant metaplastic (osteoid) elements, should be taken into consideration.
Metaplastic breast carcinoma is a rare form of breast cancer. It comprises a heterogeneous group of neoplasms generally characterized by an intimate admixture of adenocarcinoma with areas of spindle, squamous, chondroid and osseous differentiation
. Osseous metaplasia is an exceptionally rare component in metaplastic breast carcinoma
. We report 2 cases of metaplastic breast carcinoma with extensive osseous differentiation and discuss the related literature.
The patient was a 60-year-old woman with a chief complaint of a lump in her right breast. Examination revealed a hard tumor with an unclear boundary and a diameter of about 4 cm in the inner-upper quadrant of the right breast. Mammogram and ultrasound showed an irregular-shaped mass suspected for malignancy. Core needle biopsy confirmed invasive carcinoma and was followed by a modified radical mastectomy. The specimen was a gray-whitish firm tumor 3.0 × 2.5 × 2.0 cm in size and was poorly circumscribed with an irregular periphery.
Histologically, the neoplasm had an infiltrative border with extensions into the adjacent breast parenchyma. The tumor showed adenocarcinoma merging with undifferentiated sarcomatous components with prominent ossification (Figure 1A). The carcinomatous component was invasive ductal carcinoma, not otherwise specified. The carcinoma cells grew in sheets, nests or trabeculae with marked nuclear variation. Ductal carcinoma
with comedo necrosis was also found. Irregular lace-like osteoid was surrounded by malignant osteoblast-like cells. Undifferentiated sarcomatous areas accounted for 60% of the tumor and showed high nuclear atypia and pleomorphism (Figure 1B). Mitotic figures were frequently seen in both areas. The morphological transition from the carcinoma to the sarcomatoid element with intermediate cells was evident.
The results of the immunohistochemical studies are summarized in Table 1. In brief, the sarcomatous component showed focal positive staining for epithelial membrane antibody (EMA) (Figure 1C) and was positive for vimentin. The carcinomatous component was positive for cytokeratin AE1/AE3, cytokeratin 34
E12, and EMA. The final diagnosis was metaplastic breast carcinoma with extensive osseous (osteosarcomatous) differentiation. All tumor cells were negative for estrogen receptor (ER), progesterone receptor (PR), HER2/neu overexpression, and p53, and showed a high Ki-67 index. There were no metastases in the 29 dissected right axillary lymph nodes. At 13-month follow-up the patient showed no clinical or radiographic evidence of recurrence.
A 48-year-old woman presented with a palpable lump in her left breast. On clinical examination, a hard mass with a diameter of about 3 cm was noted at the 10 o’clock position in the posterior part of the left breast. The mass had well-defined margins without fixation to the skin or chest wall. Mammogram showed a mass with extensive dense calcifications in the area of the clinically palpable lump. The patient underwent a lumpectomy. Gross examination of the specimen revealed a relatively well circumscribed tumor measuring 4.0 × 3.5 × 3.0 cm. The mass was gray-white in color with part of the border appearing to be bone-like tissue (Figure 1D).
Microscopically, the neoplasm consisted of relatively well-circumscribed invasive ductal carcinoma of no special type with an extensive osteoid component. The carcinoma cells were arranged in small clusters with irregular nuclei. Ductal carcinoma
was not found in the tumor. The trabecular osteoid lay in a vascular bland stroma containing osteoblastic cells (Figure 1E). The mesenchymal component comprised 80% of the tumor. Invasive cancer cells transformed to the metaplastic lesion without intervening spindle cells.
Immunohistochemical staining was also performed (Table 1). The mesenchymal component showed positive staining for vimentin. The carcinomatous component was positive for cytokeratin AE1/AE3 and EMA, and focally positive for vimentin (Figure 1F). The final diagnosis was metaplastic breast carcinoma with extensive osteoid differentiation. In addition, about 30% of the carcinoma cells were positive for ER. All tumor cells were negative for PR, HER2/neu overexpression, and p53, and showed a low Ki-67 index. Modified radical mastectomy was performed subsequently. Pathological examination showed no residual carcinoma. The 18 axillary lymph nodes were negative for metastatic carcinoma. The patient showed no clinical or radiographic evidence of recurrence at 4-month follow-up.
Metaplastic breast carcinomas are a highly heterogeneous group of tumors characterized by ductal carcinoma with areas of spindle, squamous, chondroid and/or osseous differentiation. Chondroid and osseous differentiation occur focally in 0.2% of breast carcinomas
, and osseous metaplasia is the rarest component
. Breast carcinoma with osseous metaplasia is classified as mixed epithelial/mesenchymal metaplastic carcinoma according to the World Health Organization Classification of Tumors
Adenocarcinomas showing heterologous osteoid or cartilage differentiation are generally reported together, and as a result there is limited information on either as a separate entity. The age range at diagnosis and the clinical features are similar to those of other series of metaplastic mammary carcinoma and of patients with typical invasive mammary carcinoma
. Radiographically, there are no specific features. In the rare cases of metaplasia with predominately osseous differentiation, macroscopic dense calcifications may be seen on mammography, as in Case 2
In patients with metaplastic carcinoma containing heterologous elements, the correlation between nodal metastases and survival or recurrence is not clear. Compared with other types of breast cancer, this type of carcinoma without nodal metastasis does not always predict a favorable prognosis
. Statistically significant factors for recurrence in metastatic carcinoma are larger tumor size, diffuse cellularity and atypical metaplasia. Nuclear grade and surgical margin status do not appear to be significantly related to tumor progression
. The expression of p53, retinoblastoma protein, cyclin D1, epidermal growth factor receptor, and HER2/neu were not found to be associated with clinicopathological features and disease-free or overall survival
. ER and PR status are often negative in this type of tumors. Chhieng
analyzed the expression of ER and PR in 24 of 32 cases in their study. None of these tumors showed nuclear reactivity for ER or PR in the adenocarcinoma or heterologous components, and only 1 case was positive for ER and PR in the intraductal carcinoma component.
The osseous foci in metaplastic carcinoma may appear histologically benign or malignant. Carcinomas with osseous differentiation have generally been put together with those displaying chondroid differentiation, and it is not clear what proportion of these has malignant (osteosarcoma) or benign osseous differentiation
The 5-year survival rate of a few series of patients with metaplastic carcinoma containing heterologous elements was significantly different and ranged from 38% to 68%
. The difference was influenced by the variable duration of follow-up, the differences in treatment, and the small number of cases in these series. In addition, the type of heterologous elements, the presence or absence of intervening spindle cells, the proportion of metaplastic elements and the malignant potential also apparently influenced survival.
In metaplastic breast cancer, poor prognosis was associated with high predominance of intervening spindle cells, high cellularity, high mitotic activity and high nuclear pleomorphism similar to sarcoma
. The presence of a sarcomatoid metaplastic element in carcinoma of the breast, be it chondroid, osteoid, or unspecified in nature, is a poor prognostic factor, especially when it predominates the histological findings
The survival rate for patients with metaplastic breast cancer that had histologically benign heterologous elements without intervening spindle cells was relatively more favorable. In the study by Wargotz and Norris
, metaplastic breast cancer had overt carcinoma with direct transition to a bland or atypical cartilaginous and/or osseous stromal matrix without intervening spindle cells, which was designated as a matrix producing carcinoma. The cumulative 5-year survival rate of the patients was 68%. The factors that favored recurrence were diffuse cellularity and atypical cartilaginous metaplasia
reported 32 metaplastic breast carcinomas with heterologous osteocartilaginous elements. Ten cartilaginous and/or osseous components appeared to be histologically benign or atypical. The overall 5-year survival rate was 60%. The presence of intervening spindle cells, the proportion of metaplastic elements, and the malignant potential seem to be important for the evaluation of outcome in metaplastic breast cancer
The 2 cases presented here had extensive osseous differentiation, but there are differences in their histological features. In Case 1, the tumor was an adenocarcinoma showing prominent osteosarcomatous differentiation with intervening spindle cells. The sarcomatous areas showed high nuclear atypia, pleomorphism, and a high Ki-67 index. In Case 2, the neoplasm was a carcinoma admixed with a bland osseous component and there was a direct transition from the carcinomatous to the osseous component. Although these patients both had prominent osseous elements, the appearance of the heterologous elements was significantly different. They might turn out to have a different prognosis and survival, and a long period of follow-up will be necessary to find out the difference. Because it has been reported that different morphological subtypes have different prognoses, subclassification of metaplastic carcinoma seems to be necessary
Due to the lack of a large series of observational data, the efficacy of adjuvant chemotherapy and the proper treatment of metaplastic breast cancer are uncertain
recommended that surgical and adjuvant treatment be performed according to the guidelines for most other common breast cancers.
Metaplastic breast carcinoma with ossification is rare. The distinction between the different types of metaplastic carcinomas, specifically between benign and malignant metaplastic (osteoid) elements, should be emphasized.
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