Open Access

Metaplastic breast cancer: histologic characteristics, prognostic factors and systemic treatment strategies

  • Theresa L Schwartz1Email author,
  • Harveshp Mogal1,
  • Christos Papageorgiou2,
  • Jula Veerapong1 and
  • Eddy C Hsueh1
Experimental Hematology & Oncology20132:31

https://doi.org/10.1186/2162-3619-2-31

Received: 23 September 2013

Accepted: 8 November 2013

Published: 14 November 2013

Abstract

Metaplastic breast cancer (MBC) is a rare subtype of invasive breast cancer that tends to have an aggressive clinical presentation as well as a variety of distinct histologic designations. Few systemic treatment options are available for MBC, as it has consistently shown a suboptimal response to standard chemotherapy regimens. These characteristics result in a worse overall prognosis for patients with MBC compared to those with standard invasive breast cancer. Due to its rarity, data focusing on MBC is limited. This review will discuss the clinical presentation, breast imaging findings, histologic and molecular characteristics of MBC as well as potential future research directions.

Keywords

Metaplastic breast cancerMetaplasticBasal like breast cancerCarcinosarcoma

Introduction

Metaplastic breast cancer (MBC) is a rare and histologically diverse subtype of breast carcinoma. It accounts for less than 1% of all breast cancers [1, 2]. MBC was not officially recognized as a distinct histologic entity until 2000, and research on this disease process has been limited due to its rarity and the variety of tumor types included in this diagnosis [3]. This category of breast malignancies encompasses tumors in which adenocarcinoma is found to co-exist with an admixture of spindle cell, squamous, chondroid or bone-forming neoplastic cells [4]. Most metaplastic cancers are estrogen receptor (ER), progesterone receptor (PR) and Her2-neu negative [57] and tend to have a worse prognosis than other triple negative breast cancers [4, 810] with fewer therapeutic options. In this review, we discuss the histopathology and clinical features of MBC and their relevance to prognosis and systemic treatment options as well as future directions for research.

Clinical features

The clinical presentation of MBC has several differences from the presentation of other invasive ductal carcinomas (IDC). The median age at time of presentation ranges in the literature from 48 to 59 years [2, 4, 7]. MBC more commonly presents as a rapidly growing mass, and it has been consistently reported to present larger than typical breast cancers, generally greater than 2 cm [2, 1113]. Fixation to the underlying deep tissues or to the skin has been reported in one study in over 20% of patients [11]. MBC presents with axillary nodal involvement less frequently than standard invasive breast cancer, despite the larger tumor size. The incidence of axillary lymph node metastases spans between 6% and 26%, [4, 1417] which is substantially lower than the expected frequency of axillary nodal involvement in larger invasive breast cancers of greater than 50% [18].

The recommendations for diagnostic imaging are the same as that for other palpable masses. All palpable masses should be investigated with both diagnostic mammography and targeted ultrasound. MBC have been described as having a high density on mammogram with either circumscribed, obscured, irregular and/or spiculated margins. Yang et al. reported a more benign appearance on mammography including a round or oval shape and circumscribed margins. The lesions are often non-calcified [19]. If calcifications are present, the pattern is amorphous, coarse, punctuate or pleomorphic [20, 21]. Park et al. described a high rate of architectural distortion associated with MBC [21]. The sonographic appearance of MBC has been previously described as a heterogeneous or hypoechoic solid mass or a mixed cystic and solid mass [1922]. The complex nature of MBC is consistent with cystic degeneration and necrosis found on pathologic evaluation [22, 23]. MBC often demonstrate posterior acoustic enhancement, as opposed to the posterior shadowing commonly seen with IDC [22]. The MRI features described for MBC are an irregular mass with speculated margins, often intermediate to increased T2 signal intensity and isointense or hypointense on T1 weighted imaging [20, 24]. Velasco et al. reported an increase in T2 hyperintensity in cancers of 91% of patients with MBC [24]. Although T2 hyperintensity is often associated with benign lesions, it can be secondary to necrosis or mucoid production in malignancies.

The incidence of stage IV disease at presentation for MBC is higher than what is seen with IDC. In one single institution study, 10.3% of patients with MBC had metastatic disease at the time of diagnosis, compared to only 0.9% of patients with IDC [25]. An analysis of the National Cancer Database from 2006 demonstrated that patients with MBC were more likely to present with stage III disease (10.6% vs 8.4%) and stage IV disease (4.6% vs. 3.4%) when compared to patients with other invasive breast cancers [26]. An increased risk of local recurrence (LR) has also been reported in multiple studies. Rayson et al. noted a 53% risk of LR at 2 years, consistent with previous studies documenting LR from 35 – 62% in node negative MBC within 5 years of diagnosis [4, 1417]. This is significantly higher than the expected 17 - 20% 5-year LR for other invasive breast cancers [18]. In one study, age younger than 39, presence of skin invasion and presence of squamous cell carcinoma in lymph node metastases significantly increased the risk for LR and cancer related deaths. The hazard ratios (HR) for tumor recurrence increased to 14.1, 24.8 and 2.2, whereas the HR for tumor related death increased to 34.4, 39.1 and 5.6 respectively based on these factors [9].

The response of MBC to systemic chemotherapy has been consistently poor. Neoadjuvant chemotherapy is minimally effective at reducing tumor burden and preventing progression of disease. Chen et al. reported an 83% progression rate in patients who received neoadjuvant chemotherapy. This group also found that, in their single institution retrospective study, no patient responded to anthracycline, vinorelbine or cyclophosphamide based regimens and a partial response was noted in 3 of 17 patients with a taxane based regimen (17.6%) [27]. These results are similar to the MD Anderson Cancer Center data from 2006 which showed only a 10% complete response rate in patients with MBC undergoing neoadjuvant chemotherapy [28]. Efficacy in metastatic disease is also limited. Cardoso et al. documented a 16.7% response rate to chemotherapy in metastatic MBC, whereas that in metastatic IDC was noted to be between 21 and 75% [29]. Due to the low response rate with chemotherapy, surgical intervention should be the first step in management of patients with operable tumors, regardless of tumor size.

Pathogenesis

Histologic characteristics

The term metaplastic carcinoma was first introduced by Huvos et al. [30]. Histologically, it is a poorly differentiated heterogeneous tumor containing ductal carcinoma cells admixed with areas of spindle, squamous, chondroid, or osseous elements. The wide range of microscopic appearance of MBC has resulted in a variety of classifications and designations. The World Health Organization (WHO) classifies MBC into (1) epithelial type and (2) mixed type [31]. Epithelial-type MBC is, in turn, classified into (1) squamous cell carcinoma, (2) adenocarcinoma with spindle cell differentiation, and (3) adenosquamous carcinoma. Mixed type MBC is classified into (1) carcinoma with chondroid metaplasia, (2) carcinoma with osseous metaplasia, and (3) carcinosarcoma [31].

The spindle cell subtype, which is the most common, demonstrates cells forming poorly cohesive sheets of predominant spindle cell morphology. The spindle cell component often resembles a low-grade sarcoma or reactive process such as granulation tissue, which can be challenging to differentiate [1]. The squamous cell carcinoma subtype demonstrates infiltrating squamous carcinoma with polygonal cells, eosinophilic cytoplasm, and possible keratin pearl formation [1, 6]. The carcinosarcoma contains both malignant epithelium and malignant stroma [1, 22]. The matrix-producing subtype contains overt carcinoma with a transition to cartilaginous and/or osseous stromal matrix without a spindle component [22, 32]. MBC with osteoclastic giant cells subtype shows intraductal or infiltrating carcinoma contiguous or mixed with spindle cell or sarcomatous stroma plus osteoclastic cells [1]. See Table 1 for an outlined description of these classifications according to the WHO.
Table 1

World Health Organization histologic classification of metaplastic breast cancer

Epithelial type metaplastic breast cancer

Histologic features

Squamous cell carcinoma

Infiltrating squamous carcinoma with polygonal cells, eosinophilic cytoplasm and possible keratin pearl formation.

Adenocarcinoma with spindle cell differentiation

Poorly cohesive sheets of predominant spindle cell morphology; resembles a low grade sarcoma.

Adenosquamous carcinoma

Glands display varying degrees of squamous differentiation, characterized by pavement-like architecture, prominent intercellular bridges and, to a lesser extent, keratin formation.

Mixed-type metaplastic breast cancer

Histologic features

Carcinoma with chondroid metaplasia

Immunoreactive for S-100, patchy for cytokeratin while being negative for smooth muscle antigen.

Carcinoma with osseous metaplasia

Infiltrating carcinoma with osseous differentiation of the mesenchymal component.

Carcinosarcoma

Infiltrating carcinoma with a malignant mesenchymal component.

Adapted from Tavassoli FA, Devilee P: World Health Organization classification of tumors: tumors of the breast and female genital organs. Pathology and genetics of tumors of the digestive system. In World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2003:37-41 [33].

Tse et al. classified MBC into 3 groups: epithelial-only carcinoma, biphasic epithelial and sarcomatoid carcinoma, and monophasic spindle-cell carcinoma [6]. Wargotz and Norris classified MBC into five subtypes: matrix-producing carcinoma, squamous cell carcinoma, spindle cell carcinoma, carcinosarcoma, and metaplastic carcinoma with osteoclastic giant cells [14, 15, 18, 33, 34].

Alternatively, Oberman classified MBC into spindle-cell carcinoma, invasive ductal carcinoma with extensive squamous metaplasia, and invasive carcinoma with pseudosarcomatous metaplasia. He showed a lack of correlation between the microscopic pattern and the prognosis. This paper concluded that pathologic subclassification has no clinical significance, and that MBC should be considered as one entity [35].

Molecular/genetic features

Classically, MBC is biphasic and contains both a carcinomatous component (CC) and a heterogeneous sarcomatous component (HSC). Whether the HSC in a single case are all derived from a common precursor is unknown, and whether this precursor is identical to that of the CC is still controversial. Three major theories have been proposed to explain the co-existence of biphasic components [36]. In the collision theory for a biclonal origin, synchronous growth of the CC and HSC from separate progenitor cells collide to form one tumor. In the combination theory for a monoclonal origin, a common multipotential progenitor cell gives rise to both the CC and the HSC. In the conversion/metaplastic theory for a monoclonal origin, the HSC are derived from the CC through a conversion or metaplastic process.

The presence of transitional areas and epithelial differentiation, such as tight junctions or desmosomes in some HSC supports a metaplastic process [37]. Additionally, the co-expression of S-100 (a myoepithelial marker), vimentin (a mesenchymal marker), and/or cytokeratin (an epithelial marker) in both the CC and the HSC is also evidence for a metaplastic process [38]. These findings suggest that the HSC have an epithelial or myoepithelial origin and undergo subsequent metaplastic changes, but definitive genetic evidence for a monoclonal origin is still very limited [36, 39, 40].

p53 is a nuclear protein with a tumor suppressor function related to sequence-specific DNA binding and repair of damaged DNA. Wild-type p53 has a short half-life and is not detected by immunohistochemistry (IHC), whereas mutant p53 is stable and detectable by IHC. Non-mutational stabilization of p53 with overexpression has also been demonstrated by IHC. The frequencies of p53 mutations and overexpression are both around 20–40% in conventional breast cancer [4145]. In MBC, even though there is currently no data on the frequency of p53 mutations, the frequency of p53 overexpression may be as high as 61%, suggesting the involvement of p53 in the pathogenesis of MBC [38]. In addition, p53 alterations might be part of the mechanism underlying the morphological progression of MBC from ductal carcinoma in situ (DCIS) to CC and HSC [46]. In one study, all evaluated biphasic MBC showed concordant and equivalent staining for p53 between the CC and the HSC. The rate of concordance (100%) is higher than that previously reported (64%) for MBC [47]. Further evaluation of the p53 gene mutation status of CC and HSC revealed four mutations, one in each case. For these four cases, identical mutations between the CC and the HSC were found. Additionally, there were also identical mutations between DCIS, CC, and HSC in one case with an available DCIS component. This result provides strong and convincing evidence of the monoclonality not only between CC and each of the HSC, but also among the DCIS, invasive cancer, and HSC of MBC, since it would be extremely unlikely for these morphologically different tumor components to share identical point mutations if they were from different progenitor cells [47].

The fact that identical p53 point mutations have been identified in both stromal and epithelial components in metaplastic carcinomas in not only breast but also urinary bladder and uterus suggest that the combination or conversion theories, which are not mutually exclusive, are the prime modes of histogenesis of neoplasms in these organs [48, 49]. There are immunohistochemical and molecular studies that support the hypothesis that the epithelial component is actually the driving force behind the high proliferation rate in these metaplastic carcinomas. For example, vascular endothelial growth factor expression [50] and matrix metalloprotease 7, [51] both of which contribute to invasiveness of tumor, were much more highly expressed in the epithelial aspect of carcinosarcomas.

In one study, transcriptional profiling was performed using half-a-genome oligonucleotide microarrays to elucidate genetic profiles of MBC and their differences to those of IDC using discarded specimens of 4 MBC and 34 IDC. Unsupervised clustering disclosed distinctive expression profiles between MBC and IDC. Supervised analysis identified gene signatures discriminating MBC from IDC as well as between MBC subclasses. Notably, many of the discriminator genes were associated with down regulation of epithelial phenotypes, and with synthesis, remodeling and adhesion of extracellular matrix. Some of them have known or inferred roles related to Epithelial-Mesenchymal transition (EMT). Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MBC. In addition, the identification of SPARC and vimentin as poor prognostic factors have reinforced the role of EMT in cancer progression [52]. The use of certain microRNAs, most notably miR-200f, has also been described. This microRNA is an important modulator of EMT and is found in low levels in MBC. The substantial decrease in miR-200f expression levels was found to be accompanied by an upregulation of EMT transcriptional inducers, further demonstrating the association between EMT and MBC [53]. This finding has been supported by the work of Hayes et al. which showed evidence of Wnt pathway activation, which results in EMT, in nearly all primary metaplastic carcinomas [54].

By transcriptional profiling, MBC is characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and EMT. In contrast to other breast cancers, most MBC showed a significant similarity to a “tumorigenic” signature defined using CD44+/CD24- breast tumor–initiating stem cell–like cells. MBC is enriched in EMT and stem cell–like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers [55]. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and further highlight the need for novel therapeutic targets [55].

Several authors have demonstrated that MBC consistently harbor a basal/myoepithelial phenotype, therefore suggesting that they may be part of the morphological spectrum of 'basal-like’ breast carcinomas [5662]. One of the defining features of basal-like breast cancer is epidermal growth factor receptor (EGFR) overexpression [63, 64]. Studies have shown that MBC consistently overexpress EGFR but usually lack Her2-neu overexpression and amplification [6567]. Even though MBC are reported to harbor EGFR overexpression in up to 80% of cases, EGFR gene amplification is the underlying genetic mechanism in up to one-third of cases. Given that MBC are poorly responsive to conventional chemotherapy or hormone therapy regimens and that tumors with EGFR amplification are reported to be sensitive to EGFR tyrosine kinase inhibitors, these findings indicate that further studies are warranted to explore EGFR tyrosine kinase inhibitors as potential therapeutic agents for metaplastic breast carcinomas harboring amplification of 7p11 [65, 68]. The potential drug targets that could be used for development of more directed therapy for metaplastic breast cancer are listed in Table 2.
Table 2

Potential drug targets for directed therapy against metaplastic breast cancer

Signaling pathways

Possible drug targets

Epithelial-mesenchymal transition pathway

E-cadherin repressor molecules

Vimentin

MAP kinase signaling pathway

Raf protein kinase

Mitogen activated protein kinase kinase (MEK)

Mitogen activated protein kinases (ERK)

PI3K/AKT pathway

PI3 kinase

Protein kinase 3 (Akt)

Mammalian target of rapamycin (mTOR)

Epithelial growth factor pathway

Epithelial growth factor receptor (EGFR)

Adapted from Hennessy et al. Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol. 2006, 17:605–613 [28].

Sebolt-Leopold. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene. 2000, 19:6594-6599 [69].

Future directions

Research investigating the development of novel systemic therapeutic regimens is paramount. Studies focusing on finding new molecular markers would allow for the creation of clinical trials, especially in the setting of metastatic disease. Unveiling biological prognostic factors for MBC would also advance our understanding of the progression of this aggressive disease.

The observation that MBCs seem to represent a subset of tumors enriched in EMT and cancer stem-cell (CSC) characteristics, may account for their resistance to therapy and propensity to metastasize [55]. Like tumors that arise from CSCs, MBC display high activation of phosphoinositide 3-kinase (PI3K) pathway components and commonly carry mutations in PI3K or loss of phosphatase and tensin homolog (PTEN) [55]. MBCs also show strong correlation with a CSC-derived genomic profile that is heavily weighted for PI3K activity. Like CSC-derived tumors, most MBCs also display high levels of angiogenesis and commonly express VEGF and HIF-1α [7072]. In vitro studies have demonstrated that treatment with mTOR inhibitors, such as temsirolimus, results in reduced levels of both hypoxia-inducible factor 1 and vascular endothelial growth factor, which further enhances the effects of inhibition of vasculogenesis by bevacizumab [7376]. This and other agents targeted against these receptors or pathways could potentially be an area of further research to develop novel therapeutic options for patients with MBC [76].

Conclusions

MBC is a rare subtype of invasive breast cancer that accounts for less than 1% of all diagnoses. It is characterized by a larger tumor size at presentation, lower rates of axillary nodal involvement, higher rates of both local and distant recurrence, higher rates of ER, PR and Her2 negativity as well as a sub-optimal response to systemic therapies when compared to other invasive breast cancers. Further research studies will be required to develop targeted treatments with the goal of improving clinical outcomes.

Declarations

Authors’ Affiliations

(1)
Department of Surgery, Saint Louis University School of Medicine
(2)
Department of Internal Medicine, Division of Medical Oncology, Saint Louis University School of Medicine

References

  1. Luini A, Aguilar M, Gatti G, 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 Treat 2007, 101: 349–353. 10.1007/s10549-006-9301-1PubMedView ArticleGoogle Scholar
  2. Tavassoli FA: Classification of metaplastic carcinomas of the breast. Pathol Annu 1992,27(Pt 2):89–119.PubMedGoogle Scholar
  3. Fritz A, Percy C, Jack A, Solin LH: In International Classification of Diseases of Oncology 3. Geneva: World Health Organization; 2000.Google Scholar
  4. Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN: Metaplastic breast cancer: Prognosis and response to systemic therapy. Ann Oncol 1999,10(4):413–419. 10.1023/A:1008329910362PubMedView ArticleGoogle Scholar
  5. Weigelt B, Kreike B, Reis-Filho JA: Metaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis. Breast Cancer Res Treat 2009, 117: 273–280. 10.1007/s10549-008-0197-9PubMedView ArticleGoogle Scholar
  6. Tse GM, Tan PH, Putti TC, et al.: Metaplastic carcinoma of the breast: a clinicopathological review. J Clin Pathol 2006, 59: 1079–1083. 10.1136/jcp.2005.030536PubMed CentralPubMedView ArticleGoogle Scholar
  7. Al Sayed AD, El Weshi AN, Tulbah AM, et al.: Metaplastic carcinoma of the breast clinical presentation, treatment results and prognostic factors. Acta Oncol 2006, 45: 188–195. 10.1080/02841860500513235PubMedView ArticleGoogle Scholar
  8. Jung SY, Kim HY, Nam BH, et al.: Worse prognosis of metaplastic breast cancer patients than other patients with triple negative breast cancer. Breast Cancer Res Treat 2000, 120: 627–637.View ArticleGoogle Scholar
  9. Okada N, Hasebe T, Iwasaki M, et al.: Metaplastic carcinoma of the breast. Hum Pathol 2010, 41: 960–970. 10.1016/j.humpath.2009.11.013PubMedView ArticleGoogle Scholar
  10. Bae SY, Lee SK, Koo MY, et al.: The prognoses of metaplastic breast cancer patients compared to those of triple negative breast cancer patients. Breast Cancer Res Treat 2011, 126: 471–478. 10.1007/s10549-011-1359-8PubMedView ArticleGoogle Scholar
  11. Kaufman MW, Marti JR, Gallager HS, Hoehn JL: Carcinoma of the breast with pseudosarcomatous metaplasia. Cancer 1984, 53: 1908–1917. 10.1002/1097-0142(19840501)53:9<1908::AID-CNCR2820530917>3.0.CO;2-FPubMedView ArticleGoogle Scholar
  12. Beatty JD, Atwood M, Tickman R, Reiner M: Metaplastic breast cancer: clinical significance. Am J Surg 2006, 191: 657–664. 10.1016/j.amjsurg.2006.01.038PubMedView ArticleGoogle Scholar
  13. Chao TC, Wang CS, Chen SC, Chen MF: Metaplastic carcinomas of the breast. J Surg Oncol 1999, 71: 220–225. 10.1002/(SICI)1096-9098(199908)71:4<220::AID-JSO3>3.0.CO;2-LPubMedView ArticleGoogle Scholar
  14. Wargotz ES, Norris HJ: Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma. Hum Pathol 1989, 20: 628–635. 10.1016/0046-8177(89)90149-4PubMedView ArticleGoogle Scholar
  15. Wargotz ES, Deos PH, Norris HJ: Metaplastic carcinomas of the breast. II. Spindle cell carcinoma. Hum Pathol 1989, 20: 732–740. 10.1016/0046-8177(89)90065-8PubMedView ArticleGoogle Scholar
  16. Gutman H, Pollock RE, Janjan NA, et al.: Biologic distinctions and therapeutic implications of sarcomatoid metaplasia of epithelial carcinoma of the breast. J Am Coll Surg 1995, 180: 193–199.PubMedGoogle Scholar
  17. Wargotz ES, Norris HJ: Metaplastic carcinomas of the breast. III. Carcinosarcoma. Cancer 1989, 64: 1490–1499. 10.1002/1097-0142(19891001)64:7<1490::AID-CNCR2820640722>3.0.CO;2-LPubMedView ArticleGoogle Scholar
  18. Carter CL, Allen C, Henson DE: Relation of tumor size, lymph node status and survival in 24,740 breast cancer cases. Cancer 1969, 63: 181–187.View ArticleGoogle Scholar
  19. Yang WT, Hennessy B, Broglio K, Mills C, Sneige N, Davis WG, Valero V, Hunt KK, Gilcrease MZ: Imaging differences in metaplastic and invasive ductal carcinomas of the breast. Am J Roentgenol 2007, 189: 1288–1292. 10.2214/AJR.07.2056View ArticleGoogle Scholar
  20. Shin HJ, Kim HH, Kim SM, Kim DB, Kim MJ, Gong G, et al.: Imaging of metaplastic carcinoma with chondroid differentiation of the breast. Am J Roentgenol 2007, 188: 691–696. 10.2214/AJR.05.0831View ArticleGoogle Scholar
  21. Park JM, Han BK, Moon WK, Choe YH, Ahn SH, Gong G: Metaplastic carcinoma of the breast: Mammographic and sonographic findings. J Clin Ultrasound 2000, 28: 179–186. 10.1002/(SICI)1097-0096(200005)28:4<179::AID-JCU5>3.0.CO;2-YPubMedView ArticleGoogle Scholar
  22. Brenner J, Turner RR, Schiller V, Arndt RD, Giuliano A: Metaplastic carcinoma of the breast: report of three cases. Cancer 1998,82(6):1082–1087. 10.1002/(SICI)1097-0142(19980315)82:6<1082::AID-CNCR11>3.0.CO;2-2PubMedView ArticleGoogle Scholar
  23. Gunhan-Bilgen I, Memis A, Ustun EE, Zekioglu O, Ozdemir N: Metaplastic carcinoma of the breast: clinical, mammographic and sonographic findings with histopathologic correlation. Am J Roentgenol 2002, 178: 1421–1425. 10.2214/ajr.178.6.1781421View ArticleGoogle Scholar
  24. Velasco M, Santamaría G, Ganau S, Farrús B, Zanón G, Romagosa C, et al.: MRI of metaplastic carcinoma of the breast. Am J Roentgenol 2005, 184: 1274–1278. 10.2214/ajr.184.4.01841274View ArticleGoogle Scholar
  25. Park HS, Park S, Kim JH, Lee JH, Choi SY, Park BW, Lee KS: Clinicopathologic features and outcomes of metaplastic breast carcinoma: comparison with invasive ductal carcinoma of the breast. Yonsei Med J 2010,51(6):864–869. 10.3349/ymj.2010.51.6.864PubMed CentralPubMedView ArticleGoogle Scholar
  26. Pezzi CM, Patel-Parekh L, Cole K, Franko J, Klimberg S, Bland K: Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the National Cancer Database. Ann Surg Onc 2006,14(1):166–173. 10.1245/s10434-006-9124-7View ArticleGoogle Scholar
  27. Chen IC, Lin CH, Huang CS, Lien HC, Hsu C, Kuo WH, Lu YS, Cheng AL: Lack of efficacy to systemic chemotherapy for treatment of metaplastic carcinoma of the breast in the modern era. Breast Cancer Res Treat 2011, 130: 345–351. 10.1007/s10549-011-1686-9PubMedView ArticleGoogle Scholar
  28. Hennessy BT, Giordano S, Broglio K, Duan Z, Trent J, Buchholz TA, Babiera G, Hortobagyi GN, Valero V: Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol 2006, 17: 605–613. 10.1093/annonc/mdl006PubMedView ArticleGoogle Scholar
  29. Cardoso F, Bedard PL, Winer EP, Pagani O, Senkus-Konefka E, Fallowfield LJ, Kyriakides S, Costa A, Cufer T, Albain KS: International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J Natl Cancer Inst 2009, 101: 1174–1181. 10.1093/jnci/djp235PubMed CentralPubMedView ArticleGoogle Scholar
  30. Huvos AG, Lucas JC Jr, Foote FW Jr: Metaplastic breast carcinoma: rare form of mammary cancer. N Y State J Med 1973, 73: 1078–1082.PubMedGoogle Scholar
  31. Tavassoli FA, Devilee P: World Health Organization classification of tumors: tumors of the breast and female genital organs. Pathology and genetics of tumors of the digestive system. In World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2003:37–41.Google Scholar
  32. Ayar S, Dysee L, Carter E: Matrix-producing carcinoma: a rare variant of metaplastic breast carcinoma with heterologous elements. Breast J 2010, 16: 420–423.PubMedGoogle Scholar
  33. Wargotz ES, Norris HJ: Metaplastic carcinomas of the breast. V: Metaplastic carcinoma with osteoclastic giant cells. Hum Pathol 1990, 21: 1142–1150. 10.1016/0046-8177(90)90151-TPubMedView ArticleGoogle Scholar
  34. Wargotz ES, Norris HJ: Metaplastic carcinomas of the breast. IV: Squamous cell carcinoma of ductal origin. Cancer 1990, 65: 272–276. 10.1002/1097-0142(19900115)65:2<272::AID-CNCR2820650215>3.0.CO;2-6PubMedView ArticleGoogle Scholar
  35. Oberman HA: Metaplastic carcinoma of the breast. Am J Surg Pathol 1987, 11: 918–929. 10.1097/00000478-198712000-00002PubMedView ArticleGoogle Scholar
  36. Zhuang Z, Lininger RA, Man YG, Albuquerque A, Merino MJ, Tavassoli FA: Identical clonality of both components of mammary carcinosarcoma with differential loss of heterozygosity. Mod Pathol 1997, 10: 354–362.PubMedGoogle Scholar
  37. George E, Manivel JC, Dehner LP, Wick MR: Malignant mixed Mullerian tumors: an immunohistochemical study of 47 cases, with histogenetic considerations and clinical correlation. Hum Pathol 1991, 22: 215–223. 10.1016/0046-8177(91)90153-GPubMedView ArticleGoogle Scholar
  38. Chhieng C, Cranor M, Lesser ME, Rosen PP: Metaplastic carcinoma of the breast with osteocartilaginous heterologous elements. Am J Surg Pathol 1998, 22: 188–194. 10.1097/00000478-199802000-00006PubMedView ArticleGoogle Scholar
  39. Wada H, Enomoto T, Tsujimoto M, Nomura T, Murata Y, Shroyer KR: Carcinosarcoma of the breast: molecular-biological study for analysis of histogenesis. Hum Pathol 1998, 29: 1324–1328. 10.1016/S0046-8177(98)90266-0PubMedView ArticleGoogle Scholar
  40. Wang X, Mori I, Tang W, et al.: Metaplastic carcinoma of thebreast: p53 analysis identified the same point mutation in the three histologic components. Mod Pathol 2001, 14: 1183–1186. 10.1038/modpathol.3880456PubMedView ArticleGoogle Scholar
  41. Borresen-Dale AL: TP53 and breast cancer. Hum Mutat 2003, 21: 292–300. 10.1002/humu.10174PubMedView ArticleGoogle Scholar
  42. Soussi T: The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci 2000, 910: 121–137. discussion 137–139PubMedView ArticleGoogle Scholar
  43. Berns EM, van Staveren IL, Look MP, Smid M, Klijn JG, Foekens JA: Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer. Br J Cancer 1998, 77: 1130–1136. 10.1038/bjc.1998.187PubMed CentralPubMedView ArticleGoogle Scholar
  44. DeCremoux P, Salomon AV, Liva S, et al.: p53 mutation as a genetic trait of typical medullary breast carcinoma. J Natl Cancer Inst 1999, 91: 641–643. 10.1093/jnci/91.7.641View ArticleGoogle Scholar
  45. Marchetti A, Buttitta F, Pellegrini S, et al.: p53 mutations and histological type of invasive breast carcinoma. Cancer Res 1993, 53: 4665–4669.PubMedGoogle Scholar
  46. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B: Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 1992, 355: 846–847. 10.1038/355846a0PubMedView ArticleGoogle Scholar
  47. Lien HC, Lin CW, Mao TL, Kuo SH, Hsiao CH, Huang CS: p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components. J Pathol 2004,204(2):131–139. 10.1002/path.1624PubMedView ArticleGoogle Scholar
  48. McCluggage WG: Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas? J Clin Pathol 2002,55(5):321–325. 10.1136/jcp.55.5.321PubMed CentralPubMedView ArticleGoogle Scholar
  49. Wada H, Enomoto T, Fujita M, Yoshino K, Nakashima R, Kurachi H, Haba T, Wakasa K, Shroyer KR, Tsujimoto M, Hongyo T, Nomura T, Murata Y: Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Res 1997,57(23):5379–5385.PubMedGoogle Scholar
  50. Emoto M, Iwasaki H, Ishiguro M, Kikuchi M, Horiuchi S, Saito T, Tsukamoto N, Kawarabayashi T: Angiogenesis in carcinosarcomas of the uterus: differences in the microvesel density and expression of vascular endothelial growth factor between the epithelial and mesenchymal elements. Hum Pathol 1999,30(10):1232–1241. 10.1016/S0046-8177(99)90043-6PubMedView ArticleGoogle Scholar
  51. Tanimoto H, Shigemasa K, Sasaki M, Katayama H, Kusumi I, Parmley TH, O’Brien TJ, Ohama K: Differential expression of matrix metalloprotease-7 in each component of uterine carcinosarcoma. Oncol Rep 2000,7(6):1209–1212.PubMedGoogle Scholar
  52. Lien HC, Hsiao YH, Lin YS, et al.: Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition. Oncogene 2007, 26: 859–871. 10.1038/sj.onc.1209840View ArticleGoogle Scholar
  53. Castilla MA, Diaz-Martin J, Sarrio D, Romero-Perez L, Lopez-Garcia A, Vieites B, Biscuola M, Ramiro-Fuentes S, Isacke C, Palacios J: MicroRNA-200 family modulation in distinct breast cancer phenotypes. PLoS One 2012,7(10):1–9.View ArticleGoogle Scholar
  54. Hayes MJ, Thomas D, Emmons A, Giordano T, Kleer C: Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res 2008,14(13):4038–4044. 10.1158/1078-0432.CCR-07-4379PubMed CentralPubMedView ArticleGoogle Scholar
  55. Hennessy BT, Gonzalez-Angulo A-M, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee J-S, Fridlyand J, Sahin A, Agarwal R, Joy C, Liu W, Stivers D, Baggerly K, Carey M, Lluch A, Monteagudo C, He X, Weigman V, Fan C, Palazzo J, Hortobagyi GN, Nolden LK, Wang NJ, Valero V, Gray JW, Perou CM, Mills GB: Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 2009, 69: 4116–4124.PubMed CentralPubMedView ArticleGoogle Scholar
  56. Reis-Filho JS, Milanezi F, Steele D, Savage K, Simpson PT, Nesland JM, Pereira EM, Lakhani SR, Schmitt FC: Metaplastic breast carcinomas are basal-like tumours. Histopathology 2006,49(1):10–21. 10.1111/j.1365-2559.2006.02467.xPubMedView ArticleGoogle Scholar
  57. Leibl S, Gogg-Kammerer M, Sommersacher A, Denk H, Moinfar F: Metaplastic breast carcinomas: are they of myoepithelialdifferentiation? Immunohistochemical profile of the sarcomatoid subtype using novel myoepithelial markers. Am J Surg Pathol 2005, 29: 347–353. 10.1097/01.pas.0000152133.60278.d2PubMedView ArticleGoogle Scholar
  58. Dunne B, Lee AH, Pinder SE, Bell JA, Ellis IO: An immunohistochemical study of metaplastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast. Hum Pathol 2003, 34: 1009–1015. 10.1053/S0046-8177(03)00414-3PubMedView ArticleGoogle Scholar
  59. Popnikolov NK, Ayala AG, Graves K, Gatalica Z: Benign myoepithelial tumors of the breast have immunophenotypic characteristics similar to metaplastic matrix-producing and spindle cell carcinomas. Am J Clin Patho 2003, 120: 161–167. 10.1309/G6CTR8MDTFUW19XVView ArticleGoogle Scholar
  60. Reis-Filho JS, Steele D, Di Palma S, Jones RL, Savage K, James M, et al.: Distribution and significance of nerve growthfactor receptor (NGFR/p75 (NTR)) in normal, benign andmalignant breast tissue. Mod Pathol 2006, 19: 307–319. 10.1038/modpathol.3800542PubMedView ArticleGoogle Scholar
  61. Reis-Filho JS, Milanezi F, Paredes J, Silva P, Pereira EM, Maeda SA, et al.: Novel and classic myoepithelial/stem cell markers inmetaplastic carcinomas of the breast. Appl Immunohistochem M M 2003, 11: 1–8.Google Scholar
  62. Carter MR, Hornick JL, Lester S, Fletcher CDM: Spindle cell(sarcomatoid) carcinoma of the breast: a clinicopathologic andimmunohistochemical analysis of 29 cases. Am J Surg Pathol 2006, 30: 300–309.PubMedGoogle Scholar
  63. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al.: Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006, 19: 264–271. 10.1038/modpathol.3800528PubMedView ArticleGoogle Scholar
  64. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al.: Immunohistochemical and clinical characterization of the basallike subtype of invasive breast carcinoma. Clin Cancer Res 2004, 10: 5367–5374. 10.1158/1078-0432.CCR-04-0220PubMedView ArticleGoogle Scholar
  65. Reis-Filho JS, Milanezi F, Carvalho S, Simpson PT, Steele D, Savage K, et al.: Metaplastic breast carcinomas show EGFR, but not HER2, gene amplification and overexpression: immunohistochemical and chromogenic in situ hybridization analysis. Breast Cancer Res 2005, 7: 1028–1035. 10.1186/bcr1341View ArticleGoogle Scholar
  66. Leibl S, Moinfar F: Metaplastic breast carcinomas are negative forHer-2 but frequently express EGFR (Her-1): potential relevance toadjuvant treatment with EGFR tyrosine kinase inhibitors? J Clin Pathol 2005, 58: 700–704. 10.1136/jcp.2004.025163PubMed CentralPubMedView ArticleGoogle Scholar
  67. Bossuyt V, Fadare O, Martel M, Ocal IT, Burtness B, Moinfar F, et al.: Remarkably high frequency of EGFR expression in breast carcinomas with squamous differentiation. Int J Surg Pathol 2005, 13: 319–327. 10.1177/106689690501300403PubMedView ArticleGoogle Scholar
  68. Reis-Filho JS, Pinheiro C, Lambros MB, et al.: EGFR amplification and lack of activating mutations in metaplastic breast carcinomas. J Pathol 2006, 209: 445–453. 10.1002/path.2004PubMedView ArticleGoogle Scholar
  69. Sebolt-Leopold JS: Development of anticancer drugs targeting the MAP kinase pathway. Oncogene 2000, 19: 6594–6599. 10.1038/sj.onc.1204083PubMedView ArticleGoogle Scholar
  70. Calabrese C, Poppleton H, Kocak M, et al.: A perivascular niche for brain tumor stem cells. Cancer Cell 2007, 11: 69–82. 10.1016/j.ccr.2006.11.020PubMedView ArticleGoogle Scholar
  71. Bellino R, Arisio R, D’Addato F, et al.: Metaplastic breast carcinoma: Pathology and clinical outcome. Anticancer Res 2003, 23: 669–673.PubMedGoogle Scholar
  72. Kochhar R, Howard EM, Umbreit JN, et al.: Metaplastic breast carcinoma with squamous differentiation: Molecular and clinical analysis of six cases. Breast J 2005, 11: 367–369. 10.1111/j.1075-122X.2005.00031.xPubMedView ArticleGoogle Scholar
  73. Pantuck AJ, Zeng G, Belldegrun AS, et al.: Pathobiology, prognosis, and targeted therapy for renal cell carcinoma: exploiting the hypoxia-induced pathway. Clin Cancer Res 2003, 9: 4641–4652.PubMedGoogle Scholar
  74. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al.: Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer 2006, 66: 5549–5554.Google Scholar
  75. Huynh H, Chow PK, Palanisamy N, et al.: Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Hepatol 2008, 49: 52–60. 10.1016/j.jhep.2008.02.022PubMedView ArticleGoogle Scholar
  76. Moulder S, Moroney J, Helgason T, Wheler J, Booser D, Albarracin C: Responses to liposomal doxorubicin, bevacizumab, and temsirolimus in metaplastic carcinoma of the breast: biologic rationale and implications for stem-cell research in breast cancer. J Clin Oncol 2011, 29: e572–575. 10.1200/JCO.2010.34.0604PubMedView ArticleGoogle Scholar

Copyright

© Schwartz et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement