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Oncology
Metaplastic carcinoma of the breast (MpBC) is a very rare and aggressive type of breast cancer. Data focusing on MpBC are limited. The aim of this study was to describe the clinicopathological features of MpBC and evaluate the prognosis of patients with MpBC. Eligible articles about MpBC were identified by searching CASES SERIES gov and the MEDLINE bibliographic database for the period of 1 January 2010 to 1 June 2021 with the keywords metaplastic breast cancer, mammary gland cancer, neoplasm, tumor, and metaplastic carcinoma.
- breast cancer
- metaplastic carcinoma
- triple-negative breast cancer
1. Introduction
Breast cancer is the most common cancer and most common cancer-related cause of death in women worldwide [1]. During the last decades, screening programs for breast cancer have become widely available to a large part of the population. At the same time, subtypes of breast cancer have been recognized mainly based on histological type, hormone receptor expression, and human epidermal growth factor receptor 2 (Her2) amplification. Different subtypes have a distinct prognosis and response to treatment, underlying the heterogeneity of the disease [2]. Concurrently, novel specified agents have been developed, altering the landscape of the standard of care for breast cancer and allowing us to offer various individualized treatment options to our patients [3,4,5]. However, even if the mortality rates of breast cancer tend to decline, it remains a major health problem, especially for women. Reduced access to the healthcare facilities due to the COVID-19 pandemic also resulted in delays in diagnosis and treatment, which may lead to a short-term drop in cancer incidence followed by an increase in late-stage disease and, ultimately, increased mortality [1].
Great progress has been made in the treatment of invasive ductal carcinoma of the breast, however rare subtypes of breast cancer have not been adequately studied. Metaplastic breast cancer (MpBC) is an uncommon histological subtype of breast cancer, which was officially recognized as a distinct pathological diagnosis in 2000. It constitutes approximately 0.2–5% of breast cancer cases [6]. This rare type of breast cancer is a general term referring to a heterogeneous group of neoplasms characterized by an intimate admixture of adenocarcinoma with dominant areas of spindle cell, squamous, and/or mesenchymal differentiation [6,7]. Histopathologically, it consists of various components, including poorly differentiated ductal, sarcomatous, and other epithelial elements [7].
Several studies and case reports exist in the current literature describing patient symptoms and clinicopathologic parameters [7,8]. Generally, MpBCs are considered as more aggressive with worse clinical outcomes even when compared to triple-negative breast cancer; however, data about treatment options especially for this type of breast cancer as well as treatment outcomes are limited [8,9].
2. Classification of MpBC
MpBC is a heterogeneous disease with different subgroups concerning histogenesis, biology, and prognosis [5]. According to the 2012 World Health Organization classification [78], MpBCs are divided into low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, squamous cell carcinoma, spindle cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, myoepithelial carcinoma, and mixed metaplastic carcinoma. However, the classification of different subtypes of MpBC can be quite challenging. Several studies suggest that squamous cell carcinoma is the most commonly encountered subtype of MpBC [9]. The mixed type includes carcinoma with chondroid metaplasia, carcinoma with osseous metaplasia, and carcinosarcoma [31], while the sarcoma-like component may look like a malignant fibrous histiocytoma, chondrosarcoma, osteosarcoma, rhabdomyosarcoma, or a mixture of these [14]. Subcategorization of different subtypes of MpBC is crucial as prognosis varies between subtypes [35]. Yamaguchi et al. studied the prognosis of 53 cases of distinct subtypes of MpBC and showed that patients with high-grade spindle carcinoma or squamous carcinoma were at higher risk of recurrence and developing distant metastasis compared to patients with other MpBC subgroups [79]. In our study, patients of Alexandra Hospital with mixed or squamous carcinoma had local or distant relapse more often than patients with other MpBC subgroups.
3. Carcinogenesis
The histopathogenesis of this rare malignancy is unclear, as existing data remain limited. Several theories regarding the development of MpBCs have been proposed. MpBCs may derive from conventional mammary adenocarcinomas, which undergo metaplasis in a non-glandular growth pattern characterized by transepithelial differentiation and epithelial–mesenchymal phenotypic transition, following molecular genetic alterations associated with upregulation or downregulation of epithelial phenotypes [6,19]. Epithelial-to-mesenchymal transition could explain the more aggressive clinical course of MpBCs, as it is related to tumor invasion, migration, and metastasis. [6] Moreover, other studies suggest that malignant growth of intrinsic epidermal elements and metaplasis of breast parenchyma may lead to metaplastic breast carcinogenesis [48,65].
4. Genetic Mutations on MpBC
It is of interest that several genetic factors and pathways have been recently related to MpBC development. Molecular pathways including overexpression of CD44 (+) and yes-associated protein, which is associated with epithelial-to-mesenchymal transition, seem to play an important part in metaplastic breast carcinogenesis [15,23,41]. However, the expression of molecular markers related to carcinogenesis seems to depend on the histological subtype. More specifically, aberrant expression of Snail, a transcription factor that downregulates epithelial genes and is mostly observed in metaplastic carcinomas with chondroid difference, leads to changes in epithelial architecture, induction of epithelial-to-mesenchymal transition, and increases the risk of breast carcinogenesis and metastasis [23].
In addition, the genetic profile and landscape of gene mutations in breast cancer have been extensively studied in the past few years. As far as MpBC is concerned, several mutations have been identified. For example, p53, cyclin-dependent kinase inhibitor 2A, and epidermal growth factor genes play significant roles in cell cycle disruption and carcinogenesis, leading to a more aggressive phenotype and drug resistance in metaplastic carcinomas [6,15]. Somatic mutations in genes such as p53, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), breast cancer gene (BRCA), DNA topoisomerase II alpha (TOP2A), or more rarely phosphatase and tensin homolog (PTEN) have also been related to MpBC development [17,18,29,31,56]. Activating mutations of the phosphoinositide 3-kinase (PI3K) pathway and loss of the PTEN antagonist alter the microenvironment of the tumor and have been associated with resistance to therapy [38]. Furthermore, activation of the Wnt/β-catenin signaling pathway, which has been associated with dysregulated immune responses and cell cycle disruption, has been observed in MpBC cases [41].
According to the proteomic analysis performed by Djomehri et al., each MpBC subtype appears to have unique and active differentiation programs. However, they observed accumulated epithelial-to-mesenchymal transition and extracellular matrix production in MpBC cases compered to triple-negative breast cancers [29]. Additionally, Baum et al. reported that recurrent mutations in the HRAS and PIK3CA genes were related to activation of downstream pathways leading to excessive cell proliferation and tumor growth, especially in spindle cell carcinoma [17]. These molecular findings suggested not only a novel pathway of carcinogenesis but also potential therapeutic targets specific to each MpBC pathological subtype.
5. Clinicopathological Features
Despite the fact that the clinicopathological features of MpBC are similar to those of other high-grade breast carcinomas of no special type, metaplastic breast carcinoma is usually more aggressive than pure invasive ductal or invasive lobular cancers. It mainly affects post-menopausal women; however, cases in younger women have also been reported [6,19]. In our study, the mean age at diagnosis was 55 (±14.7 SD) years, while seven women younger than 45 years old were diagnosed with MpBC and treated in our institution and 44 women with MpBC younger than 45 years old were described in the literature. This neoplasm is often larger in size and presents as a rapidly growing palpable breast mass, with ill-defined borders on mammography, ultrasonography, and magnetic resonance imaging, as well as findings of invasive carcinoma [14]. Unfortunately, no specific radiological findings exist [34]. Mammography typically shows areas of a high-density mass with variable margins and no macrocalcifications, while ultrasound may show a microlobulated mass with complex echogenicity and solid and cystic components corresponding to necrosis and cystic degeneration [49,68]. On the other hand, MRI mammography, specifically T2-weighted imaging, shows a high-signal-intensity mass with neoplastic intensification similar to invasive breast carcinoma [68].
It is intriguing that invasion of the axillary lymph nodes is infrequent, while hematogenous metastasis occurs more often in cases of metaplastic carcinoma. MpBC shows a tendency for early hematogenous spread to distant organs such as the lungs, liver, and bones, while local recurrence is also quite frequent [9]. On the contrary, the rates of axillary metastasis may vary depending on tumor morphology. The hematogenous spreading route is particularly more common in subtypes with predominant sarcomatoid carcinoma in the spectrum [9,14,26]. Acar et al. reported that the risk of distant metastasis was higher in MpBC patients than in patients with ductal or lobular adenocarcinomas, while the risk of lymph node involvement was lower in MpBC patients [11].
6. Diagnosis of MpBC
It is well established that core needle biopsy is the gold standard method for the differential diagnosis of breast lesions, irrespective of breast tumor pathology, with both high sensitivity and specificity [80]. However, establishing the diagnosis of MpBC by fine needle aspiration (FNA) or needle core biopsy can be quite challenging, as the presence of metaplastic breast cancer cells can co-exist with poorly differentiated ductal breast carcinomas and rarely with other breast carcinoma types. The histopathological diagnosis of MpBC is based on the presence of clearly malignant cytological features associated with the presence of unusual cellular or stromal components. Therefore, the diagnosis of MpBC based on a small preoperative sample from a core needle biopsy can be elusive mainly because of the absence of standard cytological features of malignancy, either due to resemblance to benign breast lesions or due to the presence of poorly differentiated adenocarcinomas, as reported by Bataillon et al. [16].
7. Histopathology
Generally, breast carcinomas can be classified according to their microarray gene expression profiling. During the last decades, the use of DNA microarray and immunohistochemical methods has become quite popular in breast cancer research, altering the landscape of the standard of care by determining specific molecular subgroups of breast cancer, predicting prognosis, and guiding personalized therapy [2,6]. As far as metaplastic carcinoma is concerned, there is no pathognomonic pattern in the immunohistochemistry that is specific to MpBC diagnosis, although some characteristics prevail. Usually, MpBC does not express ER, PR, or HER2; thus, it can often be evaluated as a subgroup of triple-negative breast cancer (TNBC), considering its immunohistochemical characteristics [29]. However, its prognosis is worse than that of non-metaplastic TNBC. The plurality of MpBC is characterized as basal-like molecular subtypes according to the gene expression in microarrays [24,34,67]. Use of specific markers, such as antigens or antibodies, may facilitate the diagnosis of this type of breast cancer [34]. Various markers that can be easily detected by immunohistochemistry are expressed in the different histological subtypes of MpBC. For instance, specific markers such as cytokeratins and S100 protein present high sensitivity and specificity for spindle cell carcinoma [12]. It is of interest that the presence of different cell lines and thus distinct antigens, such as cytokeratins (AE1/AE3 and MNF116), basal cytokeratins (34βE12, CK5/6, CK14, and CK17), luminal cytokeratins (CK8/18, CK7, and CK19), and vimentin (mesenchymal cells), or myoepithelial cell markers (S-100 protein, actin, and high-molecular-weight cytokeratin) can establish the diagnosis of mixed metaplastic carcinoma [6,7,24,49].
In addition, myoepithelial markers, particularly p63, and EGFR are more frequently expressed in MpBC (approximately 70–80%) than in ductal carcinoma [7,20]. P63 has been proposed as a diagnostic marker for metaplastic carcinoma. The sensitivity and specificity of p63 for metaplastic breast carcinoma were 86.7% and 99.4%, respectively [46,49].
In addition to confirming the diagnosis, immunochemistry plays an important role in the sub-categorization of MpBCs as well as differentiation from other conditions, such as phyllodes tumor and pure sarcoma. A combination of molecular indicators, including myoepithelial and epithelial markers, has been proposed as a useful tool for confirming the diagnosis of metaplastic cancer in addition to the initial histopathological examination.
8. Treatment
Due to its rarity, the treatment guidelines for MpBC are still uncertain. Despite its worse prognosis and challenging treatment, there are no current, specific therapeutic guidelines for MpBC patients. Patients with MpBC are treated more aggressively than patients with ductal or lobular carcinoma, usually with mastectomy and adjuvant chemotherapy, in accordance with international guidelines depending on hormonal receptor and Her2 status and TNM stage [6]. MpBC patients usually present with a large breast mass, which indicates locally advanced disease, and typically patients are not candidates for breast-conserving surgery. Therefore, modified radical mastectomy or mastectomy with or without axillary dissection can be implemented [32,81]. The role of neoadjuvant chemotherapy in this setting remains unclear as MpBCs are relatively chemotherapy-refractory, especially compared to conventional triple-negative invasive breast cancers [24,32]. Henessy et al. reported a low rate of 10% for pathological complete response in patients with MpBCs following neoadjuvant chemotherapy [82]. Recently, the use of immunotherapy in the neoadjuvant setting has improved the rates of pathological complete response for triple-negative breast cancer [83]. It is of interest whether these results would also hold true for patients with metaplastic triple-negative carcinoma. Joneha et al. reported that PD-L1 was frequently overexpressed in MpBC, suggesting that patients with metaplastic carcinoma may benefit from immunotherapy [84].
As far as systemic therapy is concerned, several studies emphasized that the choice of appropriate chemotherapy regime depends on the histological type of metaplastic breast cancer. Chen et al. reported a modest response to taxane-based therapy [25]. Moreover, cases with a squamous epithelial component showed good response to cisplatin-based chemotherapy regimens, while cases with sarcomatous elements responded to doxorubicin- and ifosfamide-based regimens [7,22,26,32]. The intertumoral heterogeneity of the disease could explain the resistance to conventional chemotherapy [31,85].
On the other hand, targeted therapies have not been adequately studied for MpBC. As previously mentioned, BRCA mutations have been noted in MpBC cases, thus this group of patients could potentially benefit from treatment with poly (ADP-ribose) polymerase inhibitors, which are approved for patients with germline BRCA-mutated Her2-negative breast cancer [86,87].
Several studies reported mutations in the PIK3CA gene in patients with metaplastic carcinoma, implying a potential role for PI3K inhibitors in these patients [29,88]. Concurrently, patients with mutations in the PI3K/AKT/mTOR pathway may also benefit from mTOR inhibitors. Basho et al. treated patients with triple-negative breast cancer, including 59 patients with metastatic MpBC, with liposomal doxorubicin, bevacizumab, and an mTOR inhibitor, namely everolimus or temsirolimus, and reported better outcomes in MpBC cases than in non-metaplastic triple-negative tumors. Especially, patients with mutations in the PI3K pathway achieved complete responses, thus the role of mTOR inhibition in this setting should be furtherly studied [89].
Concurrently, adjuvant radiotherapy is recommended for MpBC patients, just as for patients with ductal carcinoma, and improved overall and disease-specific survival have been reported [36,72]. Hu et al. analyzed data from 1665 patients with metaplastic carcinoma in the Surveillance, Epidemiology, and End Results database and showed that adjuvant radiotherapy improved disease-related survival, especially in patients with triple-negative disease [85].
This entry is adapted from the peer-reviewed paper 10.3390/medsci11020035
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