Abstract

Biphasic metaplastic sarcomatoid carcinoma (MSC) of the breast is rare and aggressive. Patients with metaplastic breast carcinomas tend to have poor outcomes with a high risk of recurrence following primary surgery. Most reports have shown that systemic therapy appears to be less effective. We report a case of a 42-year-old female who presented with a large (14 cm) cauliflower breast mass. Biopsy revealed a poorly differentiated sarcoma. Initially, neo-adjuvant concurrent chemoradiotherapy with a sarcoma regimen was prescribed, and the tumor regressed to a large ulcer. Subsequent biopsy showed invasive ductal carcinoma (estrogen receptor, progesterone receptor stained weakly, 5%, Her2:2+) and disappearance of the sarcomatous component. Second-line neoadjuvant therapy was designed according to the histologic features of infiltrating ductal carcinoma, which led to nearly a complete response. A modified radical mastectomy of the right breast and axillary dissection was performed followed by monoclonal antibody (trastuzumab) therapy for 6 months due to the surgical specimen showing Her2:3+. The treatment course went smoothly with a good response. The patient had no evidence of disease at 18 months.

Biphasic metaplastic sarcomatoid carcinoma (MSC) of the breast accounts for <0.1% of all breast malignancies and has an uncertain prognostic significance.^1,2 It is a form of metaplastic breast cancer with overt carcinomatous and sarcomatous features apparent with both light microscopy and immunohistochemical testing.^2-4 MSC is usually associated with a lower incidence of axilary nodal involvement than would be expected from similar sized typical breast adenocarcinomas. MSC has also been found to infrequently express hormone receptors with estrogen and or progesterone (ER/PR) positivity and there are limited data regarding HER2/neu overexpression in MSC.⁵ The diagnostic category includes squamous, adenosquamous and spindle cell/sarcomatoid carcinomas, as well as so-called carcinosarcoma, matrix-producing carcinoma, and carcinoma with pseudosarcomatous metaplasia.⁶ Our case was a carcinosarcoma subtype. Carcinosarcoma is a generic term for biphasic neoplasms having both malignant epithelium (carcinoma) and malignant stroma (sarcoma), with a 5-year survival of 49% and 68%, respectively.^3,7 Wargotz³ and Rayson⁸ also suggest that a metaplastic carcinoma prognosis is worse than that of typical breast carcinoma. As a consequence of the relative rarity and diagnostic heterogeneity of these tumors, it has been difficult to determine optimal management for MSC. We describe a case of successfully treated biphasic metaplastic sarcomatoid carcinoma of the breast by evaluation of the immunohistochemistry markers of the tumor cells.

Case

A 42-year-old female, who denied any systemic disease, came to our oncology outpatient department in May 2008 with an initial presentation of a large, painless cauliflower-like mass (14 cm) arising from the right breast. She had noted the rapidly growing mass (from 3 to 4 cm) for two months, but ignored it because it was painless at first. She was also embarrassed to see the doctor because of the conservative culture and a poor educational background. We were astonished with the large tumor, which occupied the whole right breast with a reddish margin and necrosis that bled easily upon touching (Figure 1A, B). There were fixed, confluent axillary lymph nodes palpable during the physical examination. An incisional biopsy revealed a poorly differentiated neoplasm with sarcomatoid features. Immunohistochemical stains including cytokeratin (CKAE1/AE3), vimentin, CD31, CD34, CD68,CD117, factor VIII, S100, desmin, epithelial membrane antigen, HMB-45, leukocyte common antigen, synaptophycin and chromogranin were performed. All markers were essentially negative for tumor cells except for focally positive vimentin and factor VIII (Figure 2). The pathological features were described as poorly differentiated sarcoma and tumor cells were scattered individually in a pattern-less structure, with pleomorphic nuclei and high mitotic activity. This mesenchymal tumor had a rich vascular network in the background, and the vascular networks were positive for CD31 and CD34 (negative in tumor cells), but the specimen was small and limited, so lymphovascular permeation was not found. The CT scan showed a 14-cm lobulated heterogeneous hypodense mass over the right breast (Figure 3) with a 1.8 cm right axillary lymph node. The complete blood count and biochemistry were within normal limits and the tumor marker showed CEA of 1.4 ng/mL and CA153 of 8.1U/mL. The final diagnosis was poorly differentiated sarcoma, clinical stage IIIB (cT4N2Mx).

We treated the tumor as a sarcoma, with a chemotherapy regimen of adriamycin, dacarbazine, and the anti-VEGF agent, bevacizumab (Adriamycin 20 mg 24-hour continuous infusion on day 1 and day 2, dacarbazine 400 mg on day 1 to day 4, with a 21-day cycle, bevacizumab 300 mg (5 mg/kg) every 2 weeks, for 4 courses and accompanied with hyper-fractional irradiation to the right breast tumor (120cGy times 44 fractions). The tumor shrank dramatically in size and became an ulcerative wound. Re-biopsy from the edge of the ulcerative wound showed residual invasive ductal carcinoma (IDC) with ER of 5% (positive, weakly stained), PR of 5% (positive, weakly stained), Her2:2+, cytokeratin (CKAE1/AE3) and E-cadherin positive. The second course treatment was designed to treat IDC with a regimen of paclitaxel and gemcitabine (paclitaxel 120 mg/m² on day 1, gemcitabine 800 mg/m₂ on day 1 and day 8, with a 21-day cycle times 5 courses). A right modified radical mastectomy with axillary lymph node dissection was performed after a nearly complete response to pre-operative therapy (Figure 1C) and the residual tumor revealed Her2:3+, ER 25%, PR 50%. As a result, of the tumor marker evaluation, trastuzumab was given for 6 months and then an anti-estrogen agent (tamoxifen) for maintenance therapy. The patient was without evidence of disease at 18 months.

Discussion

Biphasic metaplastic sarcomatoid carcinoma (MSC) is a rare disease with little information available to guide therapy.1,8 It is usually seen in women who are over 50 years of age.^3,4,7 MSC differs from typical adenocarcinomas in a number of pathologic and clinical variables. In the breast, the most popular theory regarding the histogenesis of the sarcomatous component is transformation of myoepithelial cells.^3,7,9,10 In support of this is the finding of a cuff-like proliferation of neoplastic myoepithelial cells around residual breast ducts in some tumors.^9,11 An alternative theory is that malignant epithelial cells undergo myofibroblastic metaplasia.^9,12

It has also been observed that some tumors classified as MSC behave in a manner similar to pure sarcomas, with an absence of regional lymph node involvement, an aggressive vascular pattern of metastasis, and a predication for pulmonary involvement.¹³ Hormone receptor expression in MSC is uncommon with a reported estrogen/progesterone positivity in 0 to 17% of cases.^3,4,14 Rayson indicated that MSC presenting with nodal involvement and hormone receptor expression is seen significantly less often.^14,15 Axillary lymph node involvement is reported in 6%,³ 26%,4 and 25-30%¹⁶ of cases. Overexpression of HER2/neu was 4% (26 cases between 1971 and 2000 were retrieved from Canada).^5,13 The risk of developing metastatic disease, however, is greater than expected based on historical comparisons to more common breast carcinoma variants. Most published data on metastases of metaplastic carcinoma have shown hematogenous (lung and bone) metastases rather than lymphatic spread.^3,4,17 Recurrence rates for node-negative MSC have ranged from 35% to 62% within 2 to 5 years of initial diagnosis. This compares with a 17% to 20% risk of disease recurrence for invasive ductal carcinoma.^15,18

Little has been reported on the systemic management of MSC. A previous series on the use of systemic therapy did not report obvious evidence of benefit for adjuvant chemotherapy or significant response rates to systemic chemotherapy and hormonal therapy for those with metastatic disease.5,8 The regimens used in MSC have included AC, AT (anthracycline/taxane), CMF (cyclophosphamide, methotrexate, flurouracil),  CAF (cyclophosphamide, Adriamycin, fluorouracil) and rarely, tamoxifen in hormone-positive patients. Hennessy et al2 reported that the outcome of CMF-treated breast MSC patients was very poor, while patients treated with adjuvant anthracyclines seemed to do better, suggesting that CMF chemotherapy is less effective than anthracycline-based therapy in breast MSC. In the same study, a few cases (3 patients) treated with adjuvant sarcoma-type chemotherapy were relapse free. A sarcoma-like chemotherapy regimen may be useful as a potential starting approach.

A study from MD Anderson Cancer Center suggested that modified radical mastectomy should be considered for patients with breast MSC, particularly for patients with T2 and higher-stage disease.² Certainly, the optimization of loco-regional control is critical in these high-grade patients. New radiation approaches and possibly concomitant radio-sensitizing agents are needed. The initial stage of the tumor had a strong association with outcome, and the pathologic complete response rate to neo-adjuvant chemotherapy was only 10%.² However, the case we reported was a bulky tumor diagnosed with core needle biopsy. For the limited volume of specimen, which showed sarcoma only in the beginning, the carcinoma may be masked until the re-biopsy is performed after neo-adjuvant therapy. This case of biphasic breast metaplastic sarcomatoid carcinomas was eventually treated successfully with a sarcoma or invasive ductal cancer regimen and then anti-HER2 (trastuzumab). A long follow-up is necessary since five other large series have found similar poor outcomes with reported disease-free survival rates of 35% to 62% at median follow-up intervals of 2 to 5.4 years.^3,4,10,14

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