Primary Osteosarcoma of the Breast

Transcription

1 J Med Sci 2011;31(5): Copyright 2011 JMS Shang-Tao Lin, et al. Primary Osteosarcoma of the Breast Shang-Tao Lin *, Chia-Hui Chen, and Chien-Long Kuo Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan, Republic of China We describe a case of primary osteosarcoma of the breast in a 56-year-old woman. She presented with a 3-month history of a palpable, painless right breast mass without axillary lymphadenopathy. Neither past radiotherapy nor family history of breast cancer was found. She received a right modified radical mastectomy under the diagnosis of breast cancer. Grossly, the specimen mass was not attached to the underlying ribs or the sternum. Histopathologically, the sections of tumor revealed a high-grade osteoblastic osteosarcoma with characteristic neoplastic osteoid formation. Postoperative radiation therapy was performed subsequently. Six years later, she experienced local recurrence and soon suffered from metastases to lung and bone. The sections of recurrent and metastatic tumors showed morphology identical to the original breast tumor. Finally, she died 75 months after the initial diagnosis. Primary mammary osteosarcoma is an extremely rare tumor. The differential diagnoses for primary osteosarcoma of the breast based on the histopathology and immunohistochemistry as well as the clinical features are demonstrated. Key words: primary osteosarcoma, breast, metaplastic carcinoma, differential diagnoses INTRODUCTION Extraskeletal osteosarcomas are relatively uncommon neoplasms, representing less than 1% of all soft tissue sarcomas and 2-4% of all osteosarcomas. 1,2,3 The most commonly involved site is the deep soft tissue of proximal lower extremities. 1,2,3 Primary mammary sarcomas are also very unusual and make up 0.1% of all primary breast malignancies. 4,5,6 Primary breast osteosarcoma has been reported to account for 12% of all mammary sarcomas, reflecting its extremely rare incidence. 4,5,6,7,8 We report a case of a 56-year-old woman diagnosed with primary osteosarcoma of the breast. She received a right modified radical mastectomy and postoperative radiation therapy, and survived for 75 months. The pathological findings of our case are presented in detail. The literature is reviewed to clarify the clinically and pathologically diagnostic approaches. The data demonstrate that primary mammary osteosarcoma must be distinguished from osteoid/bone-producing metaplastic carcinoma or malignant phyllodes tumor because it has different biological behaviors and requires different treatment protocols. 4,5,6,7 Received: February 14, 2011; Revised: March 31, 2011; Accepted: April 25, 2011 * Corresponding author: Shang-Tao Lin, Department of Pathology, Show Chwan Memorial Hospital, No. 542, Sec. 1, Chung-Shan Road, Changhua 500, Taiwan, Republic of China. Tel: ext 81688; Fax: ; willy861210@yahoo.com.tw CASE REPORT A previously healthy 56-year-old female patient presented with a palpable, painless right breast mass for 3 months. There was neither family history of breast cancer nor remarkable past history. Physical examination revealed that she had a well-defined firm mass measuring up to cm in size over the lateral upper quadrant of right breast without skin involvement. The mass was not attached to the underlying ribs or the sternum. In addition, no axillary lymphadenopathy or left mammary lump was detected on physical examination. The mammography disclosed a relatively well demarcated mass with scattered microcalcifications. Liver ultrasonography, chest radiography and bone scan were negative for tumor. According to the clinical and radiographic findings, a diagnosis of a locally-advanced cancer of the right breast was made and an invasive carcinoma was most likely followed by a malignant phyllodes tumor. Excisional biopsy and intraoperatively frozen section analysis confirmed the malignant nature of the lump, either an osteoid-producing metaplastic carcinoma or malignant phyllodes tumor. The patient eventually underwent a modified radical mastectomy of the right breast, including dissection of axillary lymph nodes. Grossly, the mastectomy specimen revealed a welldelineated oval mass with a partially firm, calcified cut surface and focal necrosis. The mass had no involvement of the underlying ribs or the overlying epidermis. Histopathologically, the tumor was essentially well circum- 231

2 Primary osteosarcoma of the breast Fig. 1. Histopathology of primary osteosarcoma of the breast. (A) The tumor was essentially well circumscribed and associated with a focally infiltrative growth margin and residual benign atrophic mammary ducts. (H&E, 40 ). (B) The large pleomorphic epithelioid tumor cells had a syncytial arrangement and were entrapped in the coarsely lacelike osteoid with atypical mitoses. (H&E, 200 ). (C) The dominant population of spindle-shaped neoplastic cells were arranged in a vaguely storiform pattern with finely filigree osteoid matrix and atypical mitoses. (H&E, 200 ). (D) Bizarre anaplastic tumor giant cells and osteoblast-like tumor cells containing diverse large nuclei, prominent nucleoli and neoplastic osteoid were present. (H&E, 200 ). scribed and associated with a focally infiltrative growth margin and residual benign atrophic mammary ducts (Figure 1A). The large pleomorphic epithelioid tumor cells had a syncytial arrangement and were entrapped in the coarsely lacelike osteoid (Figure 1B). Some areas of the tumor demonstrated a dominant population of spindle-shaped neoplastic cells arranged in a vaguely storiform pattern with finely filigree intercellular osteoid matrix (Figure 1C). Bizarre anaplastic tumor giant cells and osteoblast-like tumor cells containing diverse large nuclei, prominent nucleoli and neoplastic osteoid were also present (Figure 1D). Brisk mitotic figures with a mitotic count over 10 per 10 HPFs and scattered atypical mitoses were easily recognized (Figure 1B and 1C). Multifocal areas of necrosis and hemorrhage within the tumor were seen. There was no histological evidence of an epithelial or a carcinomatous component despite extensive sampling of the tumor. Additionally, a preexisting phyllodes tumor was not present in any of the examined sections. Immunohistochemical studies displayed diffuse positivity of the neoplastic mesenchymal cells for vimentin. The tumor cells had no immunoreactivity for 232

3 Shang-Tao Lin, et al. pan-cytokeratin (AE1/AE3), CK7, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), high-molecular-weight cytokeratin 34BetaE12, smooth muscle actin (SMA), CD117, CD34, HMB-45, S-100, myoglobin, desmin and CD99. The tumor cells are also negative for HER-2/neu oncoprotein as well as estrogen and progesterone receptors. The immunohistochemical studies showed no evidence of epithelial differentiation. According to the above pathological findings, a primary osteoblastic osteosarcoma was diagnosed. The sections of axillary lymph nodes revealed free of tumor metastasis. Subsequently, the patient underwent postoperative radiation therapy with a total dose of 40 Gy. She survived thereafter for 6 years without evidence of recurrence or metastasis. However, a local recurrence in the chest wall occurred after that. She received a wide excision of the recurrent tumor mass and 2 courses of postoperative chemotherapy with Epirubicin 100 mg IV. Unfortunately, metastatic lesions involving lungs, bones and scalp developed within the following weeks in spite of the preceding administration of combined surgery and chemotherapy. The histopathology of the recurrent and metastatic lesions demonstrated a high-grade osteoblastic osteosarcoma morphologically identical to the original neoplasm. Consequently, the patient died 75 months after the initial diagnosis. DISCUSSION Extraosseous osteosarcomas are rare tumors and account for less than 1% of soft tissue sarcomas. 1,2,3 Mammary sarcomas are also relatively unusual, representing 0.1% of all primary breast malignancies. 4,5,6 The most frequent histological subtype is malignant fibrous histiocytoma, followed by angiosarcoma and liposarcoma, but almost all subtypes of sarcomas have been observed in the breast. 4,5,6,7,8 Primary mammary osteosarcoma is an exceptionally rare tumor. Fewer than 100 cases of primary osteosarcoma of breast have been reported in the medical literature in the last 50 years. 5,8,9,10 Its histopathology is indistinguishable from conventional osteosarcomas of the bone and other extraskeletal sites. 4,5,7,8,10 In comparison, bone-producing spindle cell neoplasms with an epithelial origin, so-called metaplastic (sarcomatoid) carcinomas, are far more common. 4,5,7,8,10 A metastatic lesion from a primary osseous osteosarcoma should also be considered in the differential diagnoses. 4,8,9,10 In addition, the diagnosis of primary breast osteosarcoma similar to that of other extraosseous osteosarcomas requires the absence of a direct connection between the tumor and the underlying skeleton. 4,8,9,10 These possibilities have been excluded in our case owing to the lack of evidence of a primary osseous osteosarcoma, and no connection between the tumor and the underlying skeleton. The largest collection of primary breast osteosarcomas is a retrospective clinicopathological analysis of 50 cases seen over a 38-year period documented by the Armed Forces Institute of Pathology (AFIP), the United States. 6 The patients ages range from 27 to 89 years (median, 64.5 years). The mean age of 64 years in patients is comparable to the older age of patients with soft tissue osteosarcomas and contrasts with the significantly younger age of patients with skeletal osteosarcomas. 6 The typical clinical presentation of primary mammary osteosarcoma is a relatively well-defined, enlarging, firm to hard breast mass for a few months without axillary lymphadenopathy. The tumor size varies from 1.4 to 13 cm (mean, 4.6 cm) at the time of diagnosis. Neoplasms larger than 4.6 cm in diameter are associated with a conspicuously lower survival than smaller tumors. 6 Mammographic features of primary breast osteosarcomas vary considerably. The most common mammographic finding is coarse, speckled microcalcifications associated with a relatively well-defined, irregular or lobulated mass. 4,6,11,12 The mammographic appearances may be deceptively benign in over one third of cases. 6,11,12 Both CT scan and MR images usually show similar and nonspecific findings, as do mammography. 6,11,12 Furthermore, 99m Tc-diphosphonate is a specific radionuclide marker for osteoid tumoral tissue. Intense focal uptake of this radionuclide in a soft-tissue tumor is strongly suggestive of osteoid/bone-forming neoplasms. 11,12 However, the presence of osteoid/bone in breast lesions is not diagnostic of osteosarcoma because osteoid tissue has been reported in epithelial and mesenchymal neoplasms, both benign and malignant, such as fibroadenoma, phyllodes tumor, and metaplastic carcinomas. 4,6,7,11,12 Preoperative radiographic diagnosis of primary mammary osteosarcomas is difficult. 6,7,8 Thus, the correct diagnosis is definitely based on the pathological findings of surgical specimen. 4,6,7 The main histopathological differential diagnoses with primary mammary osteosarcoma are metaplastic (sarcomatoid) carcinoma and malignant phyllodes tumor with osseous differentiation. 4,6,7,13,14 Metaplastic carcinoma of breast is referred to as a heterogeneous group of neoplasms characterized by an intimate admixture of adenocarcinoma with dominant areas of spindle cell, squamous and/or mesenchymal differentiation. 4,6,7,13 Metaplastic carcinomas can be classified into broad subtypes according 233

4 Primary osteosarcoma of the breast to the phenotypic appearance of the tumors. 4,6,7,13 Malignant phyllodes tumor is a group of biphasic tumors and consists of a benign epithelial component and a hypercellular malignant stromal component. 4,6,7,14 Both metaplastic carcinoma and phyllodes tumor contain epithelial differentiation. Our case fulfills the criteria for the histopathological diagnosis of extraosseous osteosarcoma, the exclusion of skeleton origin, the presence of neoplastic osteoid, and the absence of an epithelial component. 1,2,3,4,6 Primary osteosarcomas of the breast, similar to other extraskeletal osteosarcomas, may have a broad spectrum of histological features. 3,4,5,6,7 The most frequently observed histological variants of primary mammary osteosarcomas in the AFIP series are fibroblastic, osteoblastic, and osteoclastic variants. 6 Our case is a typical osteoblastic osteosarcoma with characteristic osteoid matrix deposited in finely ramifying, lacelike and coarsely trabecular patterns. In addition, it is not associated with sarcomatous components displaying other types of mesenchymal differentiation. Immunohistochemistry plays a major role in differentiating metaplastic (sarcomatoid) carcinomas from true primary breast osteosarcomas. 4,5,6,13 The work-up of a tumor suspected to be a metaplastic carcinoma requires the use of more than one epithelial marker, such as pan-cytokeratin (AE1/AE3), CK7, EMA, and highmolecular-weight cytokeratin 34BetaE12 because of the variable, unpredictable cytokeratin immunoreactivity in metaplastic carcinomas and the aberrant cytokeratin expression occasionally seen in true sarcomas, including osteosarcomas. 4,5,6,13 Immunohistochemical studies of our case shows no evidence of malignant epithelial differentiation. Distinguishing metaplastic carcinoma from primary mammary osteosarcoma is important because the former necessitates treatment as primary breast carcinomas. 4,6,9,10,15 The optimal management of primary mammary osteosarcomas should include total excision of the neoplasm with an adequate resection margin. Mastectomy may be indicated to ensure complete excision of large tumors with cryptically infiltrative margins. 6,9,10,15 Osteosarcomas of the breast, similar to other extraskeletal osteosarcomas, have a propensity for hematogenous rather than lymphatic spread. None of the reported patients has metastases to axillary lymph nodes, not even in advanced disease with lung metastases. 5,6,8,9,10 When lymph node metastases is evident, the diagnosis of a metaplastic carcinoma should be considered even though a pure spindle cell neoplasm is present. Accordingly, axillary lymph nodes dissection as well as sentinel lymph node biopsy is not indicated in the setting of clinically negative nodes. 5,6,8,9,10 Metaplastic (sarcomatoid) carcinomas, in contrast, often require axillary lymph nodes dissection, as do primary breast carcinomas. 5,6,10,13,15 Moreover, adjuvant radiotherapy to the chest wall may reduce the risk of local recurrence. 16 Although adjuvant chemotherapy with doxorubicin-, cisplatin- and ifosfamide-based regimens have markedly increased the survival of primary osteosarcomas of the bone. The benefit of the use of these regimens in primary mammary osteosarcoma is uncertain because of limited cases reported in the medical literature. 6,9,10,15 The adjuvant combination chemotherapy may be considered in the presence of systemic metastases. 6,9,10,15 Although primary mammary sarcomas usually appear to be associated with a better prognosis than conventional breast carcinomas of the same size, reports on the prognosis of primary osteosarcomas of the breast generally indicate a poor outcome. 6,7,9,10,15 Primary osteosarcomas of the breast are biologically aggressive neoplasms characterized by early recurrences and hematogeneous metastases, frequently to the lungs, bones and liver. 6,9,10,15 Initial metastatic lesions are clinically apparent within 1 year of diagnosis in half of the cases. These patients all die of a progressive disease within 2-10 months after detection of metastases. 6,9,10,15 Albeit most metastases develop within 3 years of diagnosis, late-onset metastases to the lung, up to 9 years after diagnosis, has been reported. 6,9,10,15 The overall 5-year survival rate of 38% for primary mammary osteosarcomas in some studies is comparable to that reported for soft tissue osteosarcomas. 6,7,9,10,15 Prognostic factors include tumor size, histological subtype, resection margin involvement, number of mitoses and distant metastases at presentation. 6,7,9,10,15 Fibroblastic osteosarcomas of breast are associated with a better survival than osteoblastic or osteoclastic subtypes; similar findings have been reported for primary bone and soft tissue osteosarcomas. The most significant predictor of survival is tumor size. 6,7,9,10,15 In summary, primary mammary osteosarcoma is an exceptionally rare and highly aggressive neoplasm. This tumor should be distinguished from metaplastic carcinoma or malignant phyllodes tumor with heterologous osseous differentiation because it has different biological behaviors and requires different treatment approaches. FINANCIAL DISCLOSURE There was no conflict of interests in this article. 234

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