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Arch Pathol Lab MedVol 131, May 2007 Primary Osteosarcoma of the BreastBahrami et al 793

Figure 1. Case 1. Gross appearance of a section from the right breastmass showing a large, relatively well-circumscribed and predominantlynecrotic tumor with foci of cartilaginous and calcified tissue. The miss-

ing portion of this section was removed for tissue sampling before thespecimen was photographed.

Figure 2. Case 1. Photomicrograph showing a dominant nodule com-posed of cartilaginous cells surrounded by smaller anaplastic cells,which in turn are covered by necrotic tissue (hematoxylin-eosin, orig-inal magnification 40).

Figure 3. Case 1. Photomicrograph displaying atypical cells with rel-atively round nuclei and prominent nucleoli (upper half of the illustra-tion) associated with production of irregular lacelike osteoid (lower halfof the illustration) (hematoxylin-eosin, original magnification, 100).

Figure 4. Case 2. Photomicrograph of a high-grade osteosarcomacomposed of osteoblast-like and giant cells within an osteoid matrix(hematoxylin-eosin, original magnification 200).

derson Cancer Center, Houston, Tex, from an outside institutionfor consultation. Immunohistochemical studies were performedon paraffin-embedded tissue by using the standard avidin-biotinimmunoperoxidase technique at the Methodist Hospital andM. D. Anderson Cancer Center. No ultrastructural studies wereconducted in either case.

PATHOLOGIC FINDINGS

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 tissuewith focally gray-white cartilaginous to firm calcified ar-

eas (Figure 1). The tumor was adherent to the overlyingskin. Most of the grossly viable tissue from the tumor wassubmitted 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 ex-tension onto the chest wall. Representative sections of thetumor were submitted in 22 blocks for histologic evalua-tion.

Multiple sections of the mastectomy specimen from case1 disclosed a predominantly necrotic tumor with a carti-laginous background (Figure 2). The abundant cartilagi-nous proliferation varied from mature lacunar cartilage topoorly differentiated areas displaying myxoid changes

with no lacunar arrangement. In only a few sections wasthere transition from cartilaginous proliferation to largepleomorphic epithelioid cells with high mitotic activity.The epithelioid cells had a diffuse arrangement and wereintimately associated with production of lacelike to frank-ly calcified osteoid (Figure 3).

In case 2, the tumor cells were epithelioid, arranged ina syncytial pattern with finely ramifying calcified andnoncalcified intercellular osteoid matrix. Higher-powermagnification revealed that the tumor was composed ofosteoblast-like cells entrapped within the osteoid matrix(Figure 4). The cells had a plasmacytoid appearance with


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794 Arch Pathol Lab MedVol 131, May 2007 Primary Osteosarcoma of the BreastBahrami et al

enlarged, slightly irregular nuclei and prominent nucleoli.Mitotic figures were easily found (10 mitoses/10 high-power microscopic fields). Some areas of the tumor dem-onstrated a prominent population of bland-appearing os-teoclast-like multinucleated giant cells associated with theosteoid matrix. Foci of necrosis and hemorrhage withinthe tumor were evident.

In neither case was there histologic evidence of an epi-thelial or a carcinomatous component, despite extensivesampling of both tumors. No evidence of a preexisting

cystosarcoma phyllodes was present in any of the exam-ined sections. The surrounding nonneoplastic breast pa-renchyma revealed compressed lobular units in case 1 andfocally mild ductal hyperplasia of usual type in case 2.Additionally, several small hyalinized and calcified fibro-adenomas in the nonneoplastic breast parenchyma of case2 were noted. The epidermis of the overlying skin wasunremarkable and uninvolved in either case.

Immunohistochemical studies in each case were per-formed on 1 tissue block containing proliferating epithe-lioid cells. In both cases, the epithelioid cells stained in-tensely for vimentin, but no immunoreactivity for AE1/AE3, CAM 5.2, high-molecular-weight cytokeratin 34E12(CK903), epithelial membrane antigen (EMA), polyclonal

carcinoembryonic antigen, CK5/6, p63, and CD34 was de-tected. The epithelioid cells in case 1 also did not stain forsmooth muscle actin and S100. The cartilaginous cells,however, stained strongly for S100, as was expected. TheEMA immunostain in case 1 yielded a focal granular pat-tern of cytoplasmic staining in cartilaginous cells withinthe lacunae without a membranous component, a patternthat is known to have no diagnostic significance for epi-thelial differentiation.7 Additional keratin stains conductedin case 2, including CK7, CK8, and CK20, were all nega-tive, as were immunoassays for estrogen and progesteronereceptors. There was also no overexpression of the HER-2/neu oncoprotein.

COMMENT

Primary osteosarcoma of the breast has been recognizedas an independent entity in the breast, but the precise fre-quency of this neoplasm is difficult to determine not onlybecause of its extreme rarity but also because metaplasticcarcinoma or an underlying phyllodes tumor were notclearly excluded in some case reports. In general, mam-mary sarcomas are considered very uncommon and makeup less than 1% of all primary breast malignancies.1,5,6 Pri-mary breast osteosarcoma has been reported to accountfor 12.5% of mammary sarcomas, reflecting its extremelyrare incidence.1 In a retrospective report of 50 patientswith primary breast osteosarcoma documented in theArmed Forces Institute of Pathology (AFIP) files, the pa-tients ages ranged from 27 to 89 years (median, 64.5

years), and the tumor size varied from 1.4 to 13 cm at thetime of diagnosis.5 The most common presentation wasthat of a progressively enlarging mass that was associatedwith pain in 18% of the cases.5 Only 1 patient in that serieshad a history of irradiation.5 In some instances, patientshave had a slow-growing or relatively stable mass formany years with a sudden increase in size. Occasionallya history of trauma to the breast has been provided.1,3,5

Dormant growth was reported in patient 1, who had achildhood history of burn injury to her breast. Nonethe-less, there was no evidence that the current tumor couldbe related to the past burn or scar tissue. There was no

evidence of squamous atypia in the overlying skin and noassociated superficial fibrosarcomatous element. The tu-mor was so large that it occupied almost the entire breast;however, the tumor did not involve the underlying boneor overlying epidermis.

Mammographically, these tumors often present as awell-circumscribed dense lesion within the breast paren-chyma with focal or extensive coarse calcifications.2,5,8 Themammographic features may be deceptively benign2,3; forinstance, in the AFIP case series, the mammographic im-

pression was that of a benign fibroadenoma in 33% ofpatients.5 Osteosarcoma of the breast, similar to other ex-traskeletal osteosarcomas, may have a broad spectrum ofhistologic features. The most frequently observed histo-logic variants in the primary osteosarcomas of the breastare fibroblastic, osteoblastic, and osteoclastic (giant cellrich) variants.5 In the osteoblastic osteosarcoma, the oste-oid is deposited in a fine, ramifying, lacelike, or coarselytrabecular pattern and sometimes in sheaths of osteoid orbone. Atypical cartilage has been reported in 36% of pri-mary breast osteosarcomas.5 Neoplastic cartilage, howev-er, has rarely been the dominant feature (chondroblasticosteosarcoma), as observed in case 1. Necrotic foci iden-tified in 30% of these tumors5 made up more than 90% of

the mass lesion in case 1.The diagnosis of metaplastic mammary carcinomashould be excluded before primary breast osteosarcoma isdiagnosed. Metaplastic mammary carcinoma is a generalterm referring to a heterogeneous group of neoplasmscharacterized by an admixture of a carcinoma with areasof squamous, spindle, or heterologous mesenchymal dif-ferentiation.5,9 The term spindled or sarcomatoid carcinomahas been adapted to reflect the appearance of a mesen-chymal neoplasm in these epithelial malignancies. Theterm carcinosarcoma has commonly been used to describebiphasic tumors composed of distinguishable malignantepithelial and sarcomatoid components with heterologouselements.8 For simplicity in this article, however, we haveused sarcomatoid/metaplastic carcinoma as an umbrella term

to encompass carcinosarcoma.Immunohistochemistry plays a major role in differenti-

ating sarcomatoid carcinoma from primary breast sarco-ma. The work-up of a tumor suspected to be metaplasticcarcinoma requires the use of more than one epithelialmarker, such as AE1/AE3, CK7, CAM 5.2, EMA, and thehigh-molecular-weight cytokeratin 34E12 (K903)8,9 be-cause of the varied and seemingly unpredictable cytoker-atin immunoreactivity in sarcomatoid carcinomas. Ofnote, areas with cartilaginous differentiation in breast os-teosarcoma may be focally immunoreactivate for EMA.5,8

In case 1, as previously mentioned, the EMA immunostainshowed only a nonspecific granular cytoplasmic stainingin cartilaginous cells. Caution should be exercised with the

use of cytokeratins because a positive cytokeratin resultcannot be considered a specific feature of carcinomas: forexample, aberrant cytokeratin expression may be rarelyseen in sarcomas, including osteosarcoma.10 Therefore, agenerous sampling of the specimen is still a crucial stepin documenting any missing component of carcinoma.

Fine-needle aspiration specimens of primary osteosar-coma of the breast may show pleomorphic spindle cells,osteoclast-like giant cells, and plaques of osteoid;3,11 how-ever, similar cytologic patterns may be seen in sarcoma-toid carcinoma. If spindle and giant cells are the predom-inant elements, the distinction between primary sarcoma,


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Arch Pathol Lab MedVol 131, May 2007 Primary Osteosarcoma of the BreastBahrami et al 795

malignant phyllodes tumor, and sarcomatoid carcinomacannot be made with confidence.8 Pettinato et al11 sug-gested that epithelial components may be identified im-munocytochemically by applying a spectrum of cytoker-atins, which might help distinguish a sarcomatoid carci-noma from a true sarcoma.

A metastatic lesion from a primary osteosarcoma of thebone should be considered in the differential diagnosis. Inaddition, the diagnosis of primary breast osteosarcomasimilar to that of other extraskeletal tumors requires the

absence of a direct connection between the tumor and theunderlying skeleton. These possibilities were excluded inour cases because of the lack of evidence of a primaryosseous osteosarcoma, and no connection between the tu-mors and the underlying skeleton. Osteosarcomas of thebone chiefly occur during the first 2 decades of life.12 Incontrast, extraskeletal osteosarcomas are rarely seen in pa-tients younger than 40 years of age. When arising in olderpatients, osteosarcoma of the bone is generally secondaryto irradiation, Paget disease of bone, or a dedifferentiatedchondrosarcoma.

Treatment should include complete surgical removal ofthe tumor with an adequate margin. Although no finalconclusion on the optimal treatment approach for these

lesions has been made, most authors have included mas-tectomy in the standard therapy for breast sarcomas toensure a complete excision with adequate margins.5,6,13 Ax-illary lymph node dissection is essentially not indicatedbecause axillary node involvement is exceptional.6,13 Sar-comatoid carcinomas, in contrast, often require axillarynode dissection, as do primary breast carcinomas. In arecent report, however, Carter et al9 raised the question ofbenefit from axillary dissection in the absence of adenop-athy in a subset of metaplastic carcinoma with a predom-inant spindle component, given the rarity of lymph nodemetastasis in their 29 cases. Although adjuvant combina-tion chemotherapy has dramatically increased the survivalof patients with primary osteosarcomas of the bone, theresponse of osteosarcomas of the breast is still unclear be-cause of the limited data.

Although sarcomas of the breast usually appear to beassociated with a better prognosis than conventionalbreast carcinomas of the same size,6 reports on the prog-nosis of patients with osteogenic sarcomas of the breast ingeneral indicate a poor outcome.6,14 Exceptions to this gen-erally aggressive behavior do occur, based on the reportsof long-term survivals among some of these patients.15 The5-year survival rate of primary breast osteosarcoma

among the AFIP case series was 38%, and metastases de-veloped in 42% of cases, most commonly to the lung.5 Themost significant predictor of survival was tumor size.5 Al-though most metastases developed within 3 years of di-agnosis,5 late-onset metastasis to the lung, up to 9 yearsafter diagnosis, has been reported.6 Among the AFIP caseseries, patients with fibroblastic osteosarcoma had a sig-nificantly better survival outcome than those with osteo-blastic or osteoclastic subtypes; however, no case in thatseries was classified as chondroblastic osteosarcoma.5 Al-

though our patients have not shown any evidence of localrecurrence or hematogenous spread after mastectomy, ourfollow-up is too short to allow us to predict the true be-havior of these tumors.

In summary, we reported 2 rare examples of primaryosteosarcoma of the breast occurring in elderly patients.This tumor must be differentiated from metaplastic car-cinoma because these neoplastic entities have different bi-ological behaviors and require different treatments.

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

References1. Jernstrom P, Lindberg AL, Meland ON. Osteogenic sarcoma of the mam-

mary gland.Am J Clin Pathol. 1963;40:521526.2. Remadi S, Doussis-Anagnostopoulu I, Mac GW. Primary osteosarcoma of

the breast.Pathol Res Pract. 1995;191:471474.3. Mertens HH, Langnickel D, Staedtler F. Primary osteogenic sarcoma of the

breast. Acta Cytol. 1982;26:512516.4. Going JJ, Lumsden AB, Anderson TJ. A classical osteogenic sarcoma of the

breast: histology, immunohistochemistry and ultrastructure. Histopathology.1986;10:631641.

5. Silver SA, Tavassoli FA. Primary osteogenic sarcoma of the breast: a clini-copathologic analysis of 50 cases. Am J Surg Pathol. 1998;22:925933.

6. Barnes L, Pietruszka M. Sarcomas of the breast: a clinicopathologic analysisof ten cases. Cancer. 1977;40:15771585.

7. Dabbs DJ. Diagnostic Immunohistochemistry. 2nd ed. Philadelphia, Pa:Churchill Livingstone; 2006:70.

8. Rosen PP. Rosens Breast Pathology. 2nd ed. Philadelphia, Pa: LippincottWilliam & Wilkins; 2001:425453, 818819.

9. Carter MR, Hornick JL, Lester S, Fletcher CD. Spindle cell (sarcomatoid)carcinoma of the breast: a clinicopathologic and immunohistochemical analysisof 29 cases. Am J Surg Pathol. 2006;30:300309.

10. Okada K, Hasegawa T, Yokoyama R, Beppu Y, Itoi E. Osteosarcoma withcytokeratin expression: a clinicopathological study of six cases with an emphasis

on differential diagnosis from metastatic cancer.J Clin Pathol.2003;56:742746.11. Pettinato G, Manivel JC, Petrella G, De Chiara A, Cali A. Primary osteo-

genic sarcoma and osteogenic metaplastic carcinoma of the breast: immunocy-tochemical identification in fine needle aspirates.Acta Cytol.1989;33:620626.

12. Sordillo PP, Hajdu SI, Magill GB, Golbey RB. Extraosseous osteogenic sar-coma: a review of 48 patients. Cancer. 1983;51:727734.

13. Ciatto S, Bonardi R, Cataliotti L, Cardona G. Sarcomas of the breast: amulticenter series of 70 cases.Neoplasma.1992;39:375379.

14. Azzopardi JG.Problems in Breast Pathology. Vol 11. Philadelphia, Pa: WBSaunders; 1979:366367.

15. Kennedy T, Biggart JD. Sarcoma of the breast.Br J Cancer. 1967;21:635644.


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