Primary Osteosarcoma of the Breast: Report of 2 Cases

Primary osteosarcoma of the breast, which is histologically indistinguishable from conventional osteosarcoma of the bone and other extraskeletal sites, is an extremely rare tumor. In comparison, bone-producing spindle cell neoplasms with an epithelial origin, so-called metaplastic (sarcomatoid) carcinomas, are far more common. The histogenesis of primary osteosarcoma of the breast is not clear, but an origin from totipotent mesenchymal cells of the breast stroma or a transformation from a preexisting fibroadenoma or phyllodes tumor has been suggested.1–4 Primary breast osteosarcomas are considered highly aggressive tumors associated with early recurrence and a propensity for hematogenous rather than lymphatic spread, most commonly to the lungs.5,6 In this report, we describe the cases of 2 patients with this rare tumor.

An 88-year-old woman with a medical history of hypothyroidism presented with shortness of breath and swelling of the legs secondary to congestive heart failure. When she was 4 years old, she experienced an accidental burn to her right breast and shoulder that resulted in the loss of the right nipple-areola complex. Physical examination at admission revealed a large mass in her right breast, estimated to be at least 15 cm. The mass was not attached to the sternum or the underlying rib. She reported that this mass had developed slowly over many years without causing any pain. No axillary lymphadenopathy was detected on physical examination. The left breast was unremarkable. No mammographic examination had been performed in the past. Findings on limited clinical workup, including chest radiography and liver profile, were within normal limits.

An initial incisional biopsy of the mass revealed a fragment of skin with an underlying mature cartilaginous neoplasm. On histologic examination, the neoplastic cells had no nuclear atypia or mitotic activity. The initial differential diagnoses included a benign or malignant cartilaginous neoplasm, metaplastic carcinoma, a mixed tumor of salivary gland type, and phyllodes tumor with cartilaginous metaplasia. The patient underwent simple mastectomy without postoperative adjuvant chemotherapy or radiation therapy. Sixteen months after mastectomy, the patient was alive and well with no clinical evidence of local recurrence or distant metastasis.

A 96-year-old woman with a history of chronic mild thrombocytopenia and carpal tunnel syndrome presented with a recently self-detected palpable mass in her left breast and 4.5-kg weight loss during the past year. Mammography done 2 years previously had shown no suspicion of malignancy. Physical examination on admission confirmed the presence of a firm mobile mass in the left breast. No axillary lymphadenopathy was noted. On mammography, the mass was relatively well demarcated and partially calcified. An incisional biopsy was performed, and poorly differentiated malignancy was diagnosed. The patient declined to undergo comprehensive metastatic workup. Findings on a limited study that included measurement of alkaline phosphatase and chest radiography were negative. The patient underwent a simple mastectomy without axillary lymph node sampling. She opted for a conservative approach, and no further postoperative staging, chemotherapy, or radiation therapy was performed. The patient made an uneventful recovery; 4 months after the surgery, she was alive and well with no clinical evidence of local recurrence or distant metastasis.

Hematoxylin-eosin–stained histologic sections of formalin-fixed, paraffin-embedded tissue of case 1 were prepared at the Methodist Hospital; sections from case 2 were sent to M. D. Anderson Cancer Center, Houston, Tex, from an outside institution for consultation. Immunohistochemical studies were performed on paraffin-embedded tissue by using the standard avidin-biotin immunoperoxidase technique at the Methodist Hospital and M. D. Anderson Cancer Center. No ultrastructural studies were conducted in either case.

The mastectomy specimen from case 1 contained an 18-cm relatively well-circumscribed mass, which on cross-section had a predominance of tan-gray necrotic tissue with focally gray-white cartilaginous to firm calcified areas (Figure 1). The tumor was adherent to the overlying skin. Most of the grossly viable tissue from the tumor was submitted in 16 blocks for histologic examination.

The mastectomy specimen from case 2 revealed a 7.5-cm well-delineated oval mass with a focally very firm, partially calcified cut surface. The mass had no direct extension onto the chest wall. Representative sections of the tumor were submitted in 22 blocks for histologic evaluation.

Multiple sections of the mastectomy specimen from case 1 disclosed a predominantly necrotic tumor with a cartilaginous background (Figure 2). The abundant cartilaginous proliferation varied from mature lacunar cartilage to poorly differentiated areas displaying myxoid changes with no lacunar arrangement. In only a few sections was there transition from cartilaginous proliferation to large pleomorphic epithelioid cells with high mitotic activity. The epithelioid cells had a diffuse arrangement and were intimately associated with production of lacelike to frankly calcified osteoid (Figure 3).

In case 2, the tumor cells were epithelioid, arranged in a syncytial pattern with finely ramifying calcified and noncalcified intercellular osteoid matrix. Higher-power magnification revealed that the tumor was composed of osteoblast-like cells entrapped within the osteoid matrix (Figure 4). The cells had a plasmacytoid appearance with enlarged, slightly irregular nuclei and prominent nucleoli. Mitotic figures were easily found (>10 mitoses/10 high-power microscopic fields). Some areas of the tumor demonstrated a prominent population of bland-appearing osteoclast-like multinucleated giant cells associated with the osteoid matrix. Foci of necrosis and hemorrhage within the tumor were evident.

In neither case was there histologic evidence of an epithelial or a carcinomatous component, despite extensive sampling of both tumors. No evidence of a preexisting cystosarcoma phyllodes was present in any of the examined sections. The surrounding nonneoplastic breast parenchyma revealed compressed lobular units in case 1 and focally mild ductal hyperplasia of usual type in case 2. Additionally, several small hyalinized and calcified fibroadenomas in the nonneoplastic breast parenchyma of case 2 were noted. The epidermis of the overlying skin was unremarkable and uninvolved in either case.

Immunohistochemical studies in each case were performed on 1 tissue block containing proliferating epithelioid cells. In both cases, the epithelioid cells stained intensely for vimentin, but no immunoreactivity for AE1/ AE3, CAM 5.2, high-molecular-weight cytokeratin 34βE12 (CK903), epithelial membrane antigen (EMA), polyclonal carcinoembryonic antigen, CK5/6, p63, and CD34 was detected. The epithelioid cells in case 1 also did not stain for smooth muscle actin and S100. The cartilaginous cells, however, stained strongly for S100, as was expected. The EMA immunostain in case 1 yielded a focal granular pattern of cytoplasmic staining in cartilaginous cells within the lacunae without a membranous component, a pattern that is known to have no diagnostic significance for epithelial differentiation.7 Additional keratin stains conducted in case 2, including CK7, CK8, and CK20, were all negative, as were immunoassays for estrogen and progesterone receptors. There was also no overexpression of the HER-2/neu oncoprotein.

Primary osteosarcoma of the breast has been recognized as an independent entity in the breast, but the precise frequency of this neoplasm is difficult to determine not only because of its extreme rarity but also because metaplastic carcinoma or an underlying phyllodes tumor were not clearly excluded in some case reports. In general, mammary sarcomas are considered very uncommon and make up less than 1% of all primary breast malignancies.1,5,6 Primary breast osteosarcoma has been reported to account for 12.5% of mammary sarcomas, reflecting its extremely rare incidence.1 In a retrospective report of 50 patients with primary breast osteosarcoma documented in the Armed Forces Institute of Pathology (AFIP) files, the patients' ages ranged from 27 to 89 years (median, 64.5 years), and the tumor size varied from 1.4 to 13 cm at the time of diagnosis.5 The most common presentation was that of a progressively enlarging mass that was associated with pain in 18% of the cases.5 Only 1 patient in that series had a history of irradiation.5 In some instances, patients have had a slow-growing or relatively stable mass for many years with a sudden increase in size. Occasionally a history of trauma to the breast has been provided.1,3,5 Dormant growth was reported in patient 1, who had a childhood history of burn injury to her breast. Nonetheless, there was no evidence that the current tumor could be related to the past burn or scar tissue. There was no evidence of squamous atypia in the overlying skin and no associated superficial fibrosarcomatous element. The tumor was so large that it occupied almost the entire breast; however, the tumor did not involve the underlying bone or overlying epidermis.

Mammographically, these tumors often present as a well-circumscribed dense lesion within the breast parenchyma with focal or extensive coarse calcifications.2,5,8 The mammographic features may be deceptively benign2,3; for instance, in the AFIP case series, the mammographic impression was that of a benign fibroadenoma in 33% of patients.5 Osteosarcoma of the breast, similar to other extraskeletal osteosarcomas, may have a broad spectrum of histologic features. The most frequently observed histologic variants in the primary osteosarcomas of the breast are fibroblastic, osteoblastic, and osteoclastic (giant cell– rich) variants.5 In the osteoblastic osteosarcoma, the osteoid is deposited in a fine, ramifying, lacelike, or coarsely trabecular pattern and sometimes in sheaths of osteoid or bone. Atypical cartilage has been reported in 36% of primary breast osteosarcomas.5 Neoplastic cartilage, however, has rarely been the dominant feature (chondroblastic osteosarcoma), as observed in case 1. Necrotic foci identified in 30% of these tumors5 made up more than 90% of the mass lesion in case 1.

The diagnosis of metaplastic mammary carcinoma should be excluded before primary breast osteosarcoma is diagnosed. Metaplastic mammary carcinoma is a general term referring to a heterogeneous group of neoplasms characterized by an admixture of a carcinoma with areas of squamous, spindle, or heterologous mesenchymal differentiation.5,9 The term spindled or sarcomatoid carcinoma has been adapted to reflect the appearance of a mesenchymal neoplasm in these epithelial malignancies. The term carcinosarcoma has commonly been used to describe biphasic tumors composed of distinguishable malignant epithelial and sarcomatoid components with heterologous elements.8 For simplicity in this article, however, we have used sarcomatoid/metaplastic carcinoma as an umbrella term to encompass carcinosarcoma.

Immunohistochemistry plays a major role in differentiating sarcomatoid carcinoma from primary breast sarcoma. The work-up of a tumor suspected to be metaplastic carcinoma requires the use of more than one epithelial marker, such as AE1/AE3, CK7, CAM 5.2, EMA, and the high-molecular-weight cytokeratin 34βE12 (K903)8,9 because of the varied and seemingly unpredictable cytokeratin immunoreactivity in sarcomatoid carcinomas. Of note, areas with cartilaginous differentiation in breast osteosarcoma may be focally immunoreactivate for EMA.5,8 In case 1, as previously mentioned, the EMA immunostain showed only a nonspecific granular cytoplasmic staining in cartilaginous cells. Caution should be exercised with the use of cytokeratins because a positive cytokeratin result cannot be considered a specific feature of carcinomas: for example, aberrant cytokeratin expression may be rarely seen in sarcomas, including osteosarcoma.10 Therefore, a generous sampling of the specimen is still a crucial step in documenting any missing component of carcinoma.

Fine-needle aspiration specimens of primary osteosarcoma of the breast may show pleomorphic spindle cells, osteoclast-like giant cells, and plaques of osteoid;3,11 however, similar cytologic patterns may be seen in sarcomatoid carcinoma. If spindle and giant cells are the predominant elements, the distinction between primary sarcoma, malignant phyllodes tumor, and sarcomatoid carcinoma cannot be made with confidence.8 Pettinato et al11 suggested that epithelial components may be identified immunocytochemically by applying a spectrum of cytokeratins, which might help distinguish a sarcomatoid carcinoma from a true sarcoma.

A metastatic lesion from a primary osteosarcoma of the bone should be considered in the differential diagnosis. In addition, the diagnosis of primary breast osteosarcoma similar to that of other extraskeletal tumors requires the absence of a direct connection between the tumor and the underlying skeleton. These possibilities were excluded in our cases because of the lack of evidence of a primary osseous osteosarcoma, and no connection between the tumors and the underlying skeleton. Osteosarcomas of the bone chiefly occur during the first 2 decades of life.12 In contrast, extraskeletal osteosarcomas are rarely seen in patients younger than 40 years of age. When arising in older patients, osteosarcoma of the bone is generally secondary to irradiation, Paget disease of bone, or a dedifferentiated chondrosarcoma.

Treatment should include complete surgical removal of the tumor with an adequate margin. Although no final conclusion on the optimal treatment approach for these lesions has been made, most authors have included mastectomy in the standard therapy for breast sarcomas to ensure a complete excision with adequate margins.5,6,13 Axillary lymph node dissection is essentially not indicated because axillary node involvement is exceptional.6,13 Sarcomatoid carcinomas, in contrast, often require axillary node dissection, as do primary breast carcinomas. In a recent report, however, Carter et al9 raised the question of benefit from axillary dissection in the absence of adenopathy in a subset of metaplastic carcinoma with a predominant spindle component, given the rarity of lymph node metastasis in their 29 cases. Although adjuvant combination chemotherapy has dramatically increased the survival of patients with primary osteosarcomas of the bone, the response of osteosarcomas of the breast is still unclear because of the limited data.

Although sarcomas of the breast usually appear to be associated with a better prognosis than conventional breast carcinomas of the same size,6 reports on the prognosis of patients with osteogenic sarcomas of the breast in general indicate a poor outcome.6,14 Exceptions to this generally aggressive behavior do occur, based on the reports of long-term survivals among some of these patients.15 The 5-year survival rate of primary breast osteosarcoma among the AFIP case series was 38%, and metastases developed in 42% of cases, most commonly to the lung.5 The most significant predictor of survival was tumor size.5 Although most metastases developed within 3 years of diagnosis,5 late-onset metastasis to the lung, up to 9 years after diagnosis, has been reported.6 Among the AFIP case series, patients with fibroblastic osteosarcoma had a significantly better survival outcome than those with osteoblastic or osteoclastic subtypes; however, no case in that series was classified as chondroblastic osteosarcoma.5 Although our patients have not shown any evidence of local recurrence or hematogenous spread after mastectomy, our follow-up is too short to allow us to predict the true behavior of these tumors.

In summary, we reported 2 rare examples of primary osteosarcoma of the breast occurring in elderly patients. This tumor must be differentiated from metaplastic carcinoma because these neoplastic entities have different biological behaviors and require different treatments.

The authors thank Del Rainosek, MD, for contributing case 2 and the clinical and follow-up information.