Metaplastic carcinoma of the breast with mesenchymal differentiation (carcinosarcoma). A unique presentation of an aggressive malignancy and literature review

Abstract

Metaplastic carcinoma of the breast with mesenchymal differentiation (MCMD), previously known as carcinosarcoma, is a very rare and aggressive tumor that has been recently classified as a subtype of metaplastic breast carcinoma. It accounts for 0.08%–0.2% of all breast cancers, with only a few cases reported in the literature. Histologically, MCMD is characterized by a biphasic pattern of malignant epithelial and sarcomatous components without evidence of a transition zone between the two elements. We herein describe a unique case of metaplastic carcinoma of the breast with chondrosarcomatous differentiation in a postmenopausal woman who presented with a large, rapidly growing, ulcerated, bleeding mass and signs of impending sepsis. Metaplastic breast carcinomas (MBC) are rare and aggressive tumors. They are characterized by larger size, lower rates of axillary node involvement, higher rates of triple negativity and distal metastases, earlier local recurrence and poorer survival compared with classic invasive breast cancer. Because of the rarity of MBC, the optimal treatment has not been well defined. Surgery is the main curative treatment modality since MBC has shown a suboptimal response to standard chemotherapy. Patients with MBC may be appropriate candidates for novel targeted therapies.

Introduction

Metaplastic carcinoma of the breast with mesenchymal differentiation (MCMD), previously known as carcinosarcoma, [3], is a very rare and aggressive tumor that has been recently classified by WHO as a subtype of metaplastic breast carcinoma [27]. It accounts for 0.08%–0.2% of all breast cancers [1,21], with only a few cases reported in the literature [1,10,13,15,19,21,30,31,35,37]. MCMD is a heterogeneous group of tumors that are histologically characterized by the presence of a biphasic pattern of malignant epithelial and sarcomatous components without evidence of a transition zone between the two elements [1,30,31]. The sarcomatous component can be chondroid, osseous, rhabdomyoid or even neuroglial [3]. Although the exact histogenesis has not been clearly defined, MCMD has been suggested to derive from malignant transformation of myoepithelial cells or myofibroblastic metaplasia of malignant epithelial cells [11]. We herein describe a unique case of MCMD of the breast in a postmenopausal patient who presented with a large, rapidly growing, ulcerated and bleeding mass and signs of impending sepsis. Diagnostic evaluation and management are discussed along with a review of the literature.

Case presentation

A 62-year-old woman presented with a six-month history of a large rapidly growing, ulcerated and fungating left breast mass. She stated that she had first noticed a small lump one year ago. She had then undergone a tru-cut needle biopsy that revealed a high grade invasive ductal breast carcinoma, but she refused any treatment. Her past medical history was unremarkable and she had no family history of breast or ovarian cancer.

Physical examination revealed a giant fungating and extensively necrotic left breast mass measuring approximately 17 × 14  cm . The mass had exophytic growth pattern and was bleeding. (Fig. 1). There was no axillary, cervical or supraclavicular lymphadenopathy. Her body temperature was 38.2 ^∘ C . Laboratory tests revealed leukocytosis with neutrophilia (WBC 15000  mm⁻³ ) and anemia with a hematocrit level of 21%. Ultrasonography of the ipsilateral axilla was negative for lymphadenopathy. After a thorough preoperative evaluation, a total mastectomy was performed. (Fig. 2). Histological examination was suggestive of metaplastic breast carcinoma with mesenchymal differentiation consisting of high grade epithelial and chondrosarcomatous components. (Fig. 3). All surgical margins were free of tumor. Tumor cells were negative for estrogen and progesterone receptors but they were amplified for the HER-2/neu gene via fluorescence in situ hybridization. Immunohistochemical analysis revealed positivity for CK5/6 and S-100 protein in epithelial component and positivity for S-100 protein and SMA in the sarcomatous component (Figs 4 and 5). Computed tomography scans of chest and abdomen and bone scans were unremarkable. The patient received adjuvant chemotherapy consisting of four cycles of Doxorubicin/cyclophosphamide (AC) followed by four cycles of Docetaxel plus trastuzumab and radiotherapy to the chest wall and the axilla. She is asymptomatic, free of disease five years after surgery.

Discussion

Metaplastic breast carcinoma (MBC) constitutes a rare, aggressive and highly heterogeneous group of tumors that are histologically characterized by an admixture of epithelial and mesenchymal components [2,32]. MBC was first described by Huvos in 1973 [12] and accounts for less than 5% of all breast cancers [9,20,27,28,36]. According to 2012 WHO classification, MBC was classified into low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, squamous cell carcinoma, spindle cell carcinoma, carcinoma with mesenchymal differentiation and mixed metaplastic carcinoma [27]. MCMD was further classified into carcinoma with chondroid differentiation, carcinoma with osseous differentiation and carcinoma with other types of differentiation [27].

MBCs are rare and aggressive tumors associated with larger tumor size at presentation, less frequent axillary node involvement, higher negativity rates for hormone receptors and Her-2, higher rates of distal metastases, higher rates of P53, CK5/6, Ki-67 and EGFR expression and poorer response to systemic treatment compared with classic invasive breast carcinoma (IBC) [2,7,11,14,16,22,23,25,27].

Patients with MBC range in age from 16 to 90 years but are most commonly affected during their fifth decade of life, (mean age 55–57) [2,7–9,11,14,16,18,22,23,25,26,33,35–37]. Clinical features are similar to those of classic IBC. The most common clinical presentation is that of a large rapidly growing firm breast mass [10,13,21,24,29,31,36]. Nipple retraction or ulceration and nipple discharge are rare [13,35]. Fixation to the underlying structures or the overlying skin has been reported in 20% of the cases [29], whereas in extremely rare cases the tumor may resemble inflammatory breast cancer [3]. Median tumor size at presentation is 3–5 cm ranging from 0.5 to 21 cm [27,37].

Patients with MBC present at a higher stage than patients with classic IBC [25]. Park et al. [23] reported that 10.3% of the patients with MBC had stage IV disease at presentation compared to 0.9% of patients with IBC. In another study by El Zein et al. [8] including 46 MBC cases and 508 triple negative IBCs, it was found that MBC patients presented at a more advanced stage than patients with IBC (34% versus 15.5% respectively). Metaplastic carcinoma is more aggressive than IBC because there is often a higher stage at presentation.

MBCs do not have pathognomonic imaging features, but in some cases, the findings are not indicative of malignancy [5,10,20]. On mammogram, the tumor may appear as a high-density polylobulated, round or ovoid noncalcified mass with irregular margins and spiculations [24,29,33]. Architectural distortion and microcalcifications have been reported in 63% and 26% of the cases respectively [2,24], the latter being more frequent in cases with chondrosarcomatous or osteosarcomatous differentiation [2,33]. On ultrasonography, MBC may appear as a heterogeneous hypoechoic round or ovoid mass with well-defined margins and complex heterogenicity, due to the presence of solid and cystic components [2,10,20,24,29].

There are not enough data regarding MRI appearance of MBCs. In a series of 12 patients, Velasco et al. [33], found an increased signal intensity associated with a ring-like morphology on T2 weighted images in 91% of the cases. The specific morphology was attributed to the presence of central necrosis that may be associated with MBCs. The authors, however, suggested that a biopsy is necessary because similar findings can also be seen in mucinous carcinomas and in infiltrative ductal carcinomas with central necrosis [33].

Establishing a preoperative diagnosis of MBC is often challenging [5], even with core needle biopsies and mammotome [2,15,19]. Therefore, extensive sampling and/or complete excision with detailed immunohistochemistry panels are essential for the correct diagnosis [21]. Park et al. [23] reported that a correct preoperative diagnosis with a core needle biopsy was established in only 4.2% of MBC cases. In addition, frozen section of a small piece of the tumor may also be inconclusive [30,37].

The use of FNA in the preoperative diagnosis of MBC is limited [37] and has been associated with high false negative rates [2]. Velasco et al. reported that FNA suggested the correct diagnosis of MBC in only 8% of their series [33].

The differential diagnosis is essential in MBCs. The differential diagnosis of MCMD mainly includes spindle-cell carcinoma, matrix-producing carcinoma, fibrosarcoma, osteosarcoma, malignant fibrous histiocytoma, stromal sarcoma, primary breast sarcoma, high-grade phyllodes tumor and myoepithelial carcinoma [1,20]. The key feature in the differential diagnosis of MCMD from MBC is the absence of the transition zone between the two elements [31]. Detailed immunohistochemistry panels are essential to establish the diagnosis.

Because of the rarity of MBCs, there are not enough data and standard guidelines for the optimal treatment. Information about management is mainly based on small retrospective studies, rather than randomized trials and usually follows the NCCN guidelines for IBC treatment [9,20,25,28,37].

Surgery is the main curative approach for MBC. Mastectomy rather than breast conservation has been reported as the preferable surgical approach for MBCs because of the larger size of the tumors at presentation [10,19,22,28,35,37]. However, no significant difference in disease-free survival and overall survival has been observed between these approaches [21]. Although it has been suggested that axillary dissection could be omitted because of the low rate of axillary nodal involvement, it, however, seems more appropriate that the axillary lymph nodes status should only be assessed with the sentinel node biopsy [19]. Axillary node involvement has been reported in only 6–26% of MBC cases, thus representing a significantly lower incidence than in IBC cases [29].

MBCs are malignancies with poor response to conventional chemotherapy [2,6,11,26], possibly because they are part of basal-like carcinomas and display a myoepithelial and epithelial to mesenchymal molecular profile [29,36]. Genetic analysis revealing a complex genome has been performed in a few cases. Mutations of the tumor suppressor gene TP53 have been reported in most cases [27], as well as significant down-regulation of PTEN and TOP2A [10]. Chemotherapy is minimally effective both in reducing the tumor burden and preventing disease progression [29].

Chen et al. [6], reported that only 18.2% of the patients with bulky disease who received neoadjuvant chemotherapy exhibited a partial response. In addition, of 12 patients with distant metastases who received palliative chemotherapy only 8.3%, 10% and 0% responded to first, second and third line chemotherapy respectively. A partial response (17.6%) was observed only in patients who received taxane-based chemotherapy [6]. In another study by Rayson et al. [26], including 27 patients with MBC, only one response was observed with the use of ten different chemotherapy regimens.

Some series, however, have reported a benefit of chemotherapy but only to the subgroup of patients with axillary node metastases [36]. Cisplatin-based regimens and CMF regimens may be considered in selected patients [9,36].

MBC is an aggressive tumor associated with a poorer prognosis compared to IBC despite the significantly lower rate of axillary node involvement [7,8,14,22,28]. The 5-year survival ranges from 40–65% [2,7,36,37]. At least 30% of the patients will die from the disease [3].

Factors that have associated with a worse prognosis include age younger than 39-year, tumor invasion of the skin, and squamous carcinoma with axillary node involvement [16,20]. Distant metastases at presentation is an important risk factor for overall survival [16]. In a study by Bae et al. [2], the three-year disease-free survival was 78.1% in the patients with MBC compared to 91.1% in the IBC group. In the subgroup of patients who received chemotherapy the three-year disease-free survival for MBC and IDC patients was 44.% and 72.5% respectively.

MBC has been associated with increased risk of early local recurrence [20,23,31]. In a study by El Zein et al. [8] including 46 MBC and 508 triple negative IBC cases, it was found that patients with MBC had twice the risk of local recurrence, whereas more MBC patients died from the disease compared to IBC patients (29% versus 16%). Rayson et al. [26] reported that 48.5% of the MBC patients developed metastases after a mean disease-free survival of 2.4 years. Almost all recurrences occur within the first five years [10,23]. The median survival after the diagnosis of metastatic disease is 8–14 months [11,26].

Some studies, however, report no significant difference in survival and recurrence rates between MBC and matched IBC cases [4,23,37]. A study by Leyer et al. including 113 MBC patients demonstrated no significantly different outcome among various histological subtypes [18]. However, in a study by Esbah et al. [9] including 13 patients with MBC, the subgroup of MCMD patients had a tendency towards a better survival although it was not statistically significant.

Adjuvant hormonal therapy and trastuzumab are not usually recommended because MBCs are in their vast majority hormone receptor and Her 2-neu negative tumors [10,28]. However, in cases with hormonal and Her 2-neu positivity, the above treatments should be considered.

The reported data about the use of radiotherapy in MBC is sparse [28]. Tseng and Martinez [32] in a study from the SEER database including 1501 MBC patients reported a ten-year overall and disease-specific survival of 53.2% and 68.3% respectively. Among 580 (38.6%) patients in whom radiotherapy was given, there was a 36% and 26% decrease in death from any cause and breast-related mortality respectively. In addition, mastectomy patients with large (>5 cm) tumors or 4 or more positive nodes derived a 47% and 42% decreased risk of death from any cause and breast related mortality respectively. Conversely, mastectomy patients with tumors <5 cm and fewer than 4 positive nodes did not benefit from radiotherapy [32].

MBCs express more frequently Epidermal Growth Factor Receptor (EGFR) than other types of breast cancer. Leibl et al. [17], reported that 70% of immunohistochemically tested MBCs were positive for EGFR. The authors suggested that patients with MBCs might benefit from treatment with drugs targeting protein-kinase inhibitors such as gefitinib. In another study by Beaty et al. [4], all seven tested cases were positive for EGFR suggesting the necessity for targeted treatment.

MBC is associated with more frequent hematogenous dissemination than regional lymphatic spread [3,20,30]. The most common sites of metastatic disease are the lungs and pleura [9,13,21], whereas brain, hepatic and skeletal metastases are uncommon [10].

Due to the nature of MBCs, a multidisciplinary approach should always be considered. Although larger prospective studies are needed, they are very unlikely to be conducted, due to the rarity of the disease. Participation of patients in clinical trials incorporating agents targeting PI3K and EMT pathways should be considered [2]. Intensive follow-up of patients with MBC is mandatory due to the aggressive clinical course of the tumor.

In conclusion, we describe a unique presentation of metaplastic breast cancer with mesenchymal differentiation in a postmenopausal patient who presented with a giant bleeding and necrotic breast mass and signs of impending sepsis. MCDM is a very rare and aggressive malignancy associated with worse outcome comparing to the other types of invasive breast cancers and may represent a diagnostic and therapeutic challenge. A correct preoperative diagnosis is difficult to establish. The tumor has been shown to be resistant to conventional breast cancer therapy. Because of the rarity of the tumor, there are not enough data and standard guidelines for the optimal treatment and information about management is based on small retrospective studies rather than randomized trials. Surgery is the main curative approach. Anthracycline-taxane based regimens should be considered based on the few existing data and radiotherapy should be considered in high-risk patients. Hormonal therapy and trastuzumab should be considered in patients with hormone receptor and Her 2-neu positive tumors respectively. MBC patients may be appropriate candidates for novel targeted therapies. An intensive follow-up is required for the detection of an early recurrence of the disease.