Metaplastic breast carcinoma (MBC) encompasses a heterogeneous group of neoplasms that generally show a pattern of squamous, spindle cell, or mesenchymal differentiation, mixed with a component of adenocarcinoma, although the adenocarcinoma portion may be absent or minimal (Shin et al., 2007). This entity has been known historically by many different names such as adenosquamous or spindle cell/sarcomatoid carcinoma, carcinosarcoma, squamous cell carcinoma, and matrix-producing carcinoma (Ellis et al., 2003; Carter et al., 2006). MBC is uncommon, accounting for fewer than 5% of breast carcinomas (Yang et al., 2007). Molecular studies have confirmed the origin of MBC from the myoepithelial cell or its precursor and from the basal epithelial cell. Multiple progressive mutations can lead to clonal evolution of the metaplastic component from the carcinomatous component, with bidirectional progression (Teixeira et al., 1998).
With few published reports, it was hypothesized that MBC may have markedly different characteristics at presentation compared with that of typical invasive duct carcinoma (IDC) and may be managed differently (Pezzi et al., 2007). It often manifests as a rapidly growing palpable mass that has high density on mammography and appears microlobulated on ultrasonography. Complex echogenicity with solid and cystic components may be seen ultrasonographically and is related to the necrosis and cystic degeneration found histopathologically (Yang et al., 2007). Axillary lymph node metastases are reported in 5–30% of patients with metaplastic carcinomas (Günhan-Bilgen et al., 2002). In almost half the cases, the diagnosis is not possible by fine needle aspiration cytology (Ribeiro-Silva et al., 2001; Lui et al., 2007). Usually, the diagnosis of MBC cannot be established until the entire breast mass is resected and examined by light microscopy, immunohistochemical analysis, and even electron microscopy (Ribeiro-Silva et al., 2001). MBC is associated with poor prognostic indicators and is mostly negative for hormone receptors and Her2/neu. However, outcomes comparable with those of matched typical breast cancer patients can be achieved with routine aggressive multidisciplinary care (Pezzi et al., 2007). The frequent expression of the epidermal growth factor receptor (EGFR), as shown in some studies in the absence of steroid receptors or Her2 overexpression, might render MBC more sensitive to EGFR tyrosine kinase inhibitors (Bhargava et al., 2005; Leibl and Moinfar, 2005).
Aim of the study
The present work aimed at revision of the clinicopathological features, prognostic factors, and treatment outcome of metaplastic breast cancer patients presented at the National Cancer Institute (NCI), Cairo University, in order to establish proper management of such a disease.
Patients and methods
The medical index of the surgical pathology unit of the Department of Pathology at the NCI, Cairo, is a computerized record of all diagnoses made or revised at the institute. The NCI, Cairo, is the largest multidisciplinary cancer center in Egypt (about 500 beds) to which patients are referred from different provinces of Egypt. A search of the index from January 1998 to December 2009 using the term ‘metaplastic carcinoma, carcinosarcoma and squamous cell carcinoma’ revealed 38 cases. The pathologic material, including immunostained slides, was meticulously reviewed for all patients by study pathologists. All 38 patients presented with locoregional disease and had been treated with surgery, either with or without adjuvant therapy. Paraffin blocks were available and were valid for marker study for 30 patients. For these 30 patients, immunostaining for the estrogen receptor (ER), the progesterone receptor (PR), the EGFR, and Her2/neu receptors was performed. Medical records of all patients were revised. The overall survival (OS) and disease-free survival (DFS) rates were estimated using the Kaplan–Meier method. The OS was defined as the time from diagnosis to death. DFS was defined as the time from diagnosis to the date of first recurrence. Patients who lost their documents for a recurrent disease were censored at the last date their disease status was known for estimating the DFS. The log-rank test for comparing survival distribution was used to assess whether any patient characteristic or tumor feature was significantly associated with OS or DFS.
Formalin-fixed, paraffin wax-embedded tissue blocks were cut into 4 μm thick serial sections that were mounted on precoated slides. The sections were dewaxed, rehydrated, and rinsed in distilled water. Immunohistochemical assays were performed according to manufacturer’s instructions, using monoclonal antibodies against EGFR (clone EGFR.25; Novocastra, Newcastle, UK), Her2/neu (clone SPM495; Labvision, Fremont, California, USA), ER (clone 1D5; Dako, Glostrup, Denmark), and PR (clone PgR636; Dako). Antigen retrieval was achieved by microwave heating in a citrate buffer (pH 6.0) for 30 min at 160 W. The Dako Envision detection kit (Dako Corporation, Carpinteria, California, USA) was used for antigen receptor visualization. Thereafter, all slides were gently rinsed with warm tap water, counterstained with hematoxylin, dehydrated, and mounted after xylol treatment. Colorectal adenocarcinoma was used as a positive external control for EGFR studies. For estimation of levels of Her2/neu, ER, and PR, breast ductal carcinomas previously known to be positive for these markers were used as positive controls. Tumor tissues, processed in the above-mentioned sequence with substitution of the primary antibody by phosphate-buffered saline, were used as negative controls. For estimation of EGFR levels, the cytoplasmic membrane positivity was considered positive. Staining intensity was scored as 0 (no staining), 1+ (weak), 2+ (moderate), and 3+ (strong) (Teng et al., 2011). For Her2/neu scoring, the intensity and the percentage of positive staining in tumor cells (0, 1+, 2+, or 3+) were assessed according to previously published guidelines (Bhargava et al., 2005). The results were interpreted manually as follows: 0, no membrane staining; 1+, faint, partial membrane staining; 2+, weak, complete membrane staining in greater than 10% of invasive cancer cells; 3+, intense complete membrane staining in greater than 10% of invasive cancer cells. A 3+ membranous staining was required for Her2/neu overexpression. ER or PR results were interpreted as positive when more than 1% of tumor cells showed positive nuclear staining.
The characteristics of the 38 patients are presented in Table 1. All were females. The mean age at diagnosis was 46.5 years (range 25–68). The mean follow-up was 32 months (range 5–59 months). Sixteen (42%) women were premenopausal and 22 (58%) were postmenopausal. Two patients reported a family history of breast cancer. Only three patients were operated upon with conservative surgery, whereas mastectomy was the most common procedure (35 patients). The most frequent site was the upper outer quadrant and was reported in 20 patients. The mean tumor size was 12.7 cm (range 1.5–24 cm). According to the WHO grading criteria (Ellis et al., 2003), the majority (20) of patients were of histological grade 3, 17 were of grade 2, and only one patient was of 1. As regards the tumor stage, two patients presented with a T1 tumor, 11 with a T2, 14 with a T3, and 11 patients with a T4 tumor. The mean number of dissected nodes was 15 (range 3–28 lymph nodes). Lymph nodes were negative in 18 patients and positive in 20. The mean number of positive nodes was eight (range 2–15). Twenty-five patients were of UICC stage III and 13 were of stage II.
Four subtypes of metaplastic carcinoma were presented: (a) carcinosarcomas with a high-grade invasive ductal carcinoma mixed with a sarcomatoid spindle cell component (15 patients); (b) pure spindle cell proliferations arranged in fascicles or a whorled pattern (six patients); (c) pure squamous cell carcinomas (11 patients); and (d) squamous cell carcinoma mixed with a high-grade invasive ductal carcinoma (six patients) (Table 1).
Immunohistochemically, 16 (53.3%) of the 30 MBCs were positive for EGFR. Among these, 1+ (Fig. 1), 2+ (Fig. 2), and 3+ (Fig. 3) reactivity was seen in five, seven, and four patients, respectively. The percentage of positive tumor cells ranged from 40 to 60%, with a mean of 50%. Her2/neu was present in 20 of 30 patients: six squamous cell carcinomas, four adenosquamous carcinomas, four spindle cell carcinomas, and in the epithelial component of six carcinosarcomas (Table 2). Three of these 20 patients (10% of all cases) showed overexpression of Her2/neu (3+ reactivity). All patients were negative for ER and PR.
As regards adjuvant treatment characteristics, chemotherapy was administrated to 31 patients. In eight patients, part of the chemotherapy was received as neoadjuvant (range from 3–9 courses, with a mean of six courses). The most frequently used regimen was FAC (florouracil, adriamycin, and cyclophosphamide) and was administered to 22 patients (58%). FEC (florouracil, epirubicin, and cyclophosphamide) was administered to six patients (15.8%), and CMF (cyclophosphamide, methotrexate, and florouracil) was administered to three patients (7.8%). Tamoxifen was used in eight patients: after chemotherapy in five patients and alone in three patients. Adjuvant radiotherapy was used in 25 patients: four patients received 50 Gy/5 weeks, 16 patients received 45 Gy/4 weeks, and five patients received 40 Gy/3 weeks. The gap between surgery and start of chemotherapy ranged from 3 to 12 weeks, with a mean of 7.5 weeks.
At the time of last follow-up, 17 patients failed (45%) therapy: nine patients died of disease (24%) and eight patients were alive with disease (21%). Locoregional failure was reported in three patients (8%), distant failure in 10 (26%), and both local and distant failure in four patients (10.5%). The 4-year OS was 59±13% (Fig. 4). The OS was not significantly affected by any of the prognostic factors (Table 3). The 4-year DFS was 37±12% (Fig. 5 and Table 4). The DFS was lower in grade 3 tumors compared with grade 1 and 2 tumors, with a borderline significance (P=0.08). Patients who received neoadjuvant chemotherapy fared worse than those who did not receive this therapy (Fig. 6) (P=0.008). The 4-year distant metastasis-free survival was 43±13% (Fig. 7). The local failure-free survival was 74±11% at 4 years (Fig. 8).
Metaplastic breast cancer is a rare disease with little published information and a behavior that appears different from conventional ductal adenocarcinoma of the breast. Squamous cell carcinoma of ductal origin is identified by the presence of an infiltrating carcinoma, which is exclusively squamous. There is no involvement of the overlying skin or intraductal carcinoma and it has an OS rate of 63% (Wargotz and Norris, 1990); however, the rate observed in our study was 73±16%. Carcinosarcoma is a generic name given to a biphasic neoplasm having both malignant epithelium and malignant stroma and has a 5-year survival rate of 49% (Pezzi et al., 2007); however, the rate observed in our study was 45±21%. Spindle cell carcinoma is a rare neoplasm in which spindle cells predominate, resembling a low-grade sarcoma, and has a 5-year survival rate of 64% (Carter et al., 2006); however, the rate observed in our study was 50±35%. Pezzi et al. (2007) analyzed the characteristics of and treatment strategies against metaplastic breast cancer in 892 cases from the National Cancer Data Base and compared them with classic ductal adenocarcinoma of the breast; they found fewer T1 tumors (29.5 vs. 65.2%), more N0 tumors (78.1 vs. 65.7%), more poorly or undifferentiated tumors (67.8 vs. 38.8%), and fewer ER-positive tumors (11.3 vs. 74.1%) among metaplastic breast cancers. This was consistent with our data in which the mean tumor size was 12.8 cm (range 1.5–24 cm), with two-thirds of cases belonging to grade T3 and T4, nearly half of the cases being N0, 45% of cases being grade 3 tumors, and no cases of ER-positive or PR-positive tumors in the 30 samples immunostained for hormone receptors. Similarly, Luini et al. (2007) found no ER or PR expression in 37 MBC patients retrieved from the European Institute of Oncology.
There was a low percentage of Her2/neu expression (score 2 and score 3) in our patients (23%), which is in agreement with the 0–25% reported in the literature (Leibl and Moinfar, 2005; Beatty et al., 2006; Tse et al., 2006). EGFR, which is associated with poor prognosis in breast carcinomas (Bhargava et al., 2005; Beatty et al., 2006), was found to be frequently expressed in some reports on MBC: in 57% of 65 patients in the study by Reis Filho et al. (2006), in 70% of 20 patients in the study by Leibl and Moinfar (2005), and in 100% of seven patients in the study by Beatty et al. (2006). These findings are similar to ours, as we detected an expression of EGFR in 53.3% of our patients. This suggested MBCs as potential targets to EGFR tyrosine kinase inhibitors, in view of the absence of endocrine and Her2-dependent stimuli for cell proliferation in these tumors.
Patients with MBC were treated with breast-conserving surgery less frequently than were patients with ductal adenocarcinoma (38.5 vs. 55.8%) in the studyby Pezzi et al. (2007); in our study, however, this figure was 8%, because of the larger tumor size. Because of a more advanced AJCC stage, chemotherapy was used more often in our patients (81.6%), which is comparable to the results of Pezzi (53.4% for MBC vs. 42.1% for IDC). The OS in our study was 59±13%, compared with 55% in MBC patients in the study by Luini et al. (2007) (which was significantly worse than that in the control group of patients with poorly differentiated IDC). Rayson et al. (1999) reported, in 27 metaplastic carcinomas of the breast, a 3-year OS of 71%. In their study, the 3-year DFS was 40%, compared with 37±12% in our study. The only factor associated with a significantly poor DFS was the use of neoadjuvant chemotherapy, which is likely related to advanced disease presentation.
MBC is a rare entity among breast carcinomas among Egyptian patients, which is more or less similar to the results from worldwide reports on MBC. The diagnosis of MBC is difficult in some cases and requires rigorous use of immunohistochemistry. Most patients present with poor prognostic indicators and show lack of expression of hormone receptors and Her2/neu. The tendency for EGFR expression in MBC necessitates further investigation of anti-EGFR therapy as a treatment option for patients. This has to be verified by further combined immunohistochemical and molecular studies. Because of the rarity of the disease, a multicenter approach is recommended for large-scale studies.
Conflicts of interest
There are no conflicts of interest.
Beatty JD, Atwood M, Tickman R, Reiner M.Metaplastic breast cancer: clinical significance.Am J Surg2006;191:657–664.
Bhargava R, Gerald WL, Li AR, Pan Q, Lal P, Ladanyi M, Chen B.EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations.Mod Pathol2005;18:1027–1033.
Carter MR, Hornick JL, Lester S, Fletcher CDM.Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases.Am J Surg Pathol2006;30:300–309.
Ellis IO, Schnitt SJ, Sastre Garau XTavassoli FA, Devilee P.Invasive breast carcinoma.WHO classification of tumours. Pathology and genetics of tumours of the breast and female genital organs2003.Lyon:IARC Press;13–59.
Günhan-Bilgen I, Memiş A, Üstün EE, Zekioglu O, Özdemir N.Metaplastic carcinoma of the breast: clinical, mammographic, and sonographic findings with histopathologic correlation.Am J Roentgenol2002;178:1421–1425.
Leibl S, Moinfar F.Metaplastic breast carcinomas are negative for Her-2 but frequently express EGFR (Her-1): potential relevance to adjuvant treatment with EGFR tyrosine kinase inhibitors?J Clin Pathol2005;58:700–704.
Lui PCW, Tse GMK, Puay HT, Jayaram G, Putti TC, Chaiwun B, et al..Fine-needle aspiration cytology of metaplastic carcinoma of the breast.J Clin Pathol2007;60:529–533.
Luini A, Aguilar M, Gatti G, Fasani R, Botteri E, Brito JAD, et al..Metaplastic carcinoma of the breast, an unusual disease with worse prognosis: the experience of the European Institute of Oncology and review of the literature.Breast Cancer Res Treat2007;101:349–353.
Pezzi CM, Patel Parekh L, Cole K, Franko J, Klimberg VS, Bland K.Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the national cancer data base.Ann Surg Oncol2007;14:166–173.
Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN.Metaplastic breast cancer: prognosis and response to systemic therapy.Ann Oncol1999;10:413–419.
Reis Filho JS, Milanezi F, Steele D, Savage K, Simpson PT, Nesland JM, et al..Metaplastic breast carcinomas are basal-like tumours.Histopathology2006;49:10–21.
Ribeiro-Silva A, Luzzatto F, Chang D, Zucoloto S.Limitations of fine-needle aspiration cytology to diagnose metaplastic carcinoma of the breast.Pathol Oncol Res2001;7:298–300.
Shin HJ, Kim HH, Kim SM, Kim DB, Kim M-J, Gong G, et al..Imaging features of metaplastic carcinoma with chondroid differentiation of the breast.Am J Roentgenol2007;188:691–696.
Teixeira MR, Qvist H, Bøhler PJ, Pandis N, Heim S.Cytogenetic analysis shows that carcinosarcomas of the breast are of monoclonal origin.Genes Chromosomes Cancer1998;22:145–151.
Teng YH-F, Tan W-J, Thike A-A, Cheok P-Y, Tse GM-K, Wong N-S, et al..Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy.Breast Cancer Res2011;13:R35.
Tse GM, Tan PH, Putti TC, Lui PCW, Chaiwun B, Law BKB.Metaplastic carcinoma of the breast: a clinicopathological review.J Clin Pathol2006;59:1079–1083.
Wargotz ES, Norris HJ.Metaplastic carcinomas of the breast. IV. Squamous cell carcinoma of ductal origin.Cancer1990;65:272–276.
©2013Egyptian Journal of Pathology
Yang WT, Hennessy B, Broglio K, Mills C, Sneige N, Davis WG, et al..Imaging differences in metaplastic and invasive ductal carcinomas of the breast.Am J Roentgenol2007;189:1288–1293.