Cancer is a condition wherein abnormal cells grow at an uncontrolled rate. Breast cancer is a malignant cancerous growth that begins in the tissues of the breast . It is the most common type of cancer prevalent among women. While the overwhelming majority of breast cancer patients are women, breast cancer can also occur in men . Breast cancer usually originates from the inner lining of the milk ducts or the lobules that supply the ducts with milk . Cancers originating from ducts are known as ductal carcinomas, while those originating from lobules are known as lobular carcinomas. Apart from humans, breast cancer also occurs in other mammals .
Worldwide statistics indicate that breast cancer comprises 22.9% of all cancers (excluding non-melanoma skin cancers) in women. In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women) . Breast cancer is over 100 times more common in women than in men, although men tend to have poorer outcomes due to delays in diagnosis . Current statistical research points out that any woman that lives to the age of 85 carries a 12% risk of developing breast cancer at some point in her life. As a woman ages, her risk of developing breast cancer rises dramatically regardless of her family history [3-4]. While the breast cancer risk of a 25-year-old woman is only 1 in 19,608, it rises to 1 in 93 by the time she is 45 years old. In fact, fewer than 5% of cases are discovered before the age of 35, and the majority of all breast cancers is found in women over the age of 50 .
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Breast cancer prognosis and survival rates vary greatly depending on the cancer type, stage, treatment, and geographical location of the patient . The prognosis is dependent on tumor size, lymph node involvement, distant metastasis at presentation, tumor grade and histologic type, proliferation rate, estrogen receptor status, and aneuploidy [5-6].
Metaplastic breast cancer is a type of breast cancer, which develops as a result of one adult cell type being replaced by another adult cell type . It is currently thought to arise from genetic processes that cause reprogramming of stem cells . Metaplastic carcinoma of the breast describes a wide group of tumors, which includes both sarcomatous and carcinomatous features such as heterologous elements . These tumors are thought to arise through metaplasia of carcinoma cells, with some ultrastructural evidence confirming a myoepithelial cell origin. Metaplastic carcinoma is a rare type of cancer, comprisiong of less than 1% of all breast cancers .
Based on the macroscopic and microscopic ï¬ndings, metaplastic carcinoma of the breast can be grouped into four groups: 1) stromal sarcomas such as osteogenic sarcoma of the breast, 2) adenocarcinomas containing bone and cartilage due to metaplasia of the epithelial cells, 3) intra-ductal papillomas with stromal metaplasia (mixed tumours) and, 4) phyllode cystosarcoma with bone and cartilage as stromal components . The purpose of this project is to determine which of the breast cell types (if any) are producing ectopic bone and/or cartilage formation, as well as identify possible treatment targets. A panel of six antibodies including estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor (HER2), p63,CK5,vimentin, Ki67 would be employed to identify possible treatment targets by using immunohistochemistry (lHC). The main objective of this review is to outline the updated criteria for Osseous metaplasia in breast tumours.
2.0 Dogs as models for human breast cancer
In recent studies, canines have been used as models in the study of breast cancer, since human and canine mammary tumors share many important biochemical features such as epidemiological, clinico-pathological and morphological aspects . It was observed that the risk of both human and canine breast cancer increases with age and, also most of the malignant breast tumor develop from epithelial tissue and metastasizes to the lungs or other organs [16-17]. Canines was preferred to rats as a model due to their body size, which simplifies the collection of serum, urine, and serial tissue biopsy samples from the same dog during exposure to an experimental treatment .
Another great advantage of canine clinical studies is that the hepatic enzyme homology of dogs is very similar to humans than that of rodents to humans, which is critical in the translation of new discoveries into useful human therapies . Furthermore, canine tumors often exhibit the same molecular targets as humans and thus can be readily used for a proof-of-concept and in the proof-of-target analysis . Moreover, since dogs have a shorter natural life span compared to humans, the rapid conclusion of the clinical trials is easy [15-16].
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Clinical trials on pet dogs with cancer is of great value and importance in developing and testing new cancer treatments that will benefit both humans and canines, as well as setting important targets for the development of anticancer therapies . Cancer is one of the leading causes of death in both humans and canines. Both mammals share many clinical, biological, and epidemiological features such as histological morphology, tumor genetics, molecular targets, biologic behavior, and response to conventional therapies [18-19]. In addition, the recent release of the entire canine genome sequence showing the high homology and close similarity with the human genome (closer to the human than to the rodent genome) highlights the relevance of using naturally occurring cancer in canines as a valuable tool for translating cancer research for humans [19-20].
3.0 Osseous metaplasia in breast and histological characteristics
Breast cancer with cartilaginous and/or osseous metaplasia is a type of invasive breast neoplasm and has been shown to occur in only 1% of cases . This breast cancer is classified as either cartilaginous or osseous metaplasia or both in the mammary cancer tissue, and as a transitional zone between carcinoma and sarcoma-like metaplastic lesions . Therefore, as the criteria for diagnosis is complicated, histological diagnosis is difficult in some cases, metaplastic carcinomas are a histologically heterogeneous and unique group of tumors defined by the presence of glandular and nonglandular components . The non-glandular component usually results from mesenchymal differentiation and includes cells with spindle, osseous, or cartilaginous features. Although the histological picture may differ, the clinical presentation of metaplastic carcinoma is the same in most reports .
A histopathological study of 22 cases of breast cancer estimated that occurrence of osteosarcomas increased in 1.3% of phyllodes neoplasms and their histological appearance resembled those of skeletal origin . In 40% of cases, osteogenic sarcoma of the breasts increased in a phyllode tumor. Osteogenic sarcomas of the breast may also arise from the transformation of connective tissue elements that are sarcomatuous in nature in pre-existing benign breast neoplasms, especially ï¬broadenomas and intra-ductal papillomas [13-14].
In very rare cases, osteogenic sarcoma might represent a non-phyllodes sarcoma of the breast, resulting from soft tissues of a previously normal breast. Breast tumors that become a malignant bone are usually metaplastic carcinomas . These tumors are characterized by rapid growth after an initial period of being latent, haematogenous spread occurs most commonly to the lungs . Less commonly, the metaplastic bone formation may be found in other sarcomas of the breast such as malignant melanoma, malignant ï¬brous histiocytoma, angiosarcoma, and pleomorphic liposarcoma .
3.1 Classification and diagnosis of Osseus metaplasia
To describe the lesions and their subtypes, the tumors are referred to as spindle cell carcinoma, sarcomatoid carcinoma and carcinosarcoma [8-9]. There is a wide range in histological appearance of lessions; overt in-situ lesions or invasive breast carcinoma may be absent, minimal or may even constitute the majority of lesions . The appearance of the stroma may also be described as low or high in grade; heterologous components such as bone or cartilage could be present in varying amounts . In more than 90% of such cases, immunostaining is usually positive for cytokeratin (CKs). Metaplastic carcinoma is a rare type of cancer, consisting of less than 1% of all breast cancers .
3.2 Molecular subtypes of Metaplastic carcinoma
Most cases of Metaplastic carcinoma are sporadic. The spindle cell subtype is the most common of the five subtypes classified by Kaufman . The spindle cell subtype demonstrates cells forming poorly cohesive sheets or 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 .
The squamous cell carcinoma subtype demonstrates infiltrating squamous carcinoma with polygonal cells, eosinophilic cytoplasm, and possible keratin pearl formation . The carcinosarcoma contains both malignant epithelium and malignant stroma. The matrix-producing subtype contains overt carcinoma with transition to cartilaginous and/or osseous stromal matrix without a spindle component. Metaplasic carcinoma (MPC) with osteoclastic giant cell subtype shows intraductal carcinoma or infiltrating carcinoma, contiguous or mixed with spindle cell or sarcomatous stroma plus osteoclastic cells .
3.3 Clinical presentations and radiological features of Osseus metaplasia
The clinical and radiographic presentation may differ depending on the tissue subtypes within the lesion . The usual presentation is a breast mass, which tends to grow rapidly. Metaplastic carcinoma has a low potential for lymph node metastasis. Macroscopic findings in 28 cases, showed that all tumors were firm and white, and ranged from 1.2-7.0 cm in greatest dimension (average, 2.7 cm). Metaplastic carcinomas may have a dominant tissue subtype or contain mixed elements of squamous cell, spindle cell, chondroid, or osseous metaplasia. Generally, the patient's age ranges from 50-60 years old with single palpable masses. Mammography shows an irregular mass, sometimes with coarse calcifications .
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Metaplastic carcinomas are bigger (3.5-7 cm), with lower rates of estrogen receptor positivity (0-13%) and axillary node involvement (5%-25%) compared with infiltrating ductal carcinomas . Reports show radiologic ï¬ndings in osseous metaplastic carcinoma with macrocalciï¬cations on mammography and ultrasound. In two of the cases densely calciï¬ed masses on were demonstrated on radiography as in our case . It is radiographically important to differentiate an osteoid matrix from a dense calciï¬cation in a breast lesion because the bone formation can occur in both benign and malignant neoplasms and in non-neoplastic benign processes, whereas a dense calciï¬cation typically suggests a benign neoplasm .
3.4 Pathology of Osseus metaplasia
As metaplasia is signified by the transformation of one cell type to another, it has been shown that part or all of the neoplastic cells show nonglandular growths by metaplasia and proceeds through reprogramming of pluripotent stem cells . This characterises the special type of breast carcinoma termed metaplastic carcinoma. Although it remains to be determined if metaplastic carcinomas arise from malignant transformation of particular cancer stem cells or through a process of dedifferentiation , cytogenetic and molecular studies suggest that the glandular and nonglandular components of these tumors originated from a common cell population .
Several studies in comparative oncology have been developed to evaluate novel therapeutic strategies for a variety of cancers describing the use of pet dogs for human translational cancer treatment. Recently, a phase one clinical trial using dogs with spontaneous cancers has characterised the toxicity and biologic effective doses of a potential new agent with antitumor activity (PEGylated-tumor necrosis factor-a), supporting its clinical evaluation in human cancers . This helped to understand more on how the metaplasia process occurs in human breast cells and also the way the tumor grow and spreads.
3.5 Prognosis and Treatment of Osseus metaplasia
Although metaplastic carcinomas of the breast are uncommon, they exhibit an aggressive behavior and poor clinical outcome . Furthermore, patients with MPC are thought to exhibit a poorer outcome than patients with invasive ductal carcinoma (IDC). In invasive breast carcinoma, the survival periods of patients with MPC and IDC, exhibit a poorer outcome than patients with invasive ductal carcinoma (IDC) alone or invasive breast carcinoma .
Treatment most often consists of modified radical mastectomy without adjuvant treatment. However, wide local excision, postoperative radiation, and systemic chemotherapy have also been used. Survival rates of 40%-68% have been reported, with tumor size and stage being the most important prognostic factors . Low-grade versus high-grade stromal appearance may also affect recurrence rates. Outcome relative to nodal status is poorer than for infiltrating ductal carcinoma, and the pattern of recurrence tends to be locoregional or pulmonary . Although individualized salvage treatment (excision and/or radiation therapy) may benefit patients with local recurrence, 90% of all patients with recurrent disease ultimately die of the disease .
Metaplastic breast carcinoma, a rare tumor composed of adenocarcinomatous and nonglandular growth patterns, is characterized by a propensity for distant metastases and resistance to standard anticancer therapies . It was sought to confirm that the tumor wass a basal-like breast cancer, expressing epidermal growth factor receptor (EGFR) and stem cell factor receptor (KIT). EGFR activating mutations and high copy number (associated with response to tyrosine kinase inhibitor gefitinib) and KIT activates mutations (associated with imatinib sensitivity) were then investigated . Seventy-seven metaplastic cases were identified (1976-2006); 38 with tumor blocks available underwent pathologic confirmation before EGFR and KIT immunohistochemical analyses .
A tissue microarray of malignant glandular and metaplastic elements was constructed and analyzed immunohistochemically for cytokeratin 5/6, estrogen receptor, progesterone receptor, and p63, and by fluorescence in situ hybridization for EGFR and HER-2/neu. DNA isolated from individual elements was assessed for EGFR and KIT activating mutations [27-28]. All assessable cases were negative for estrogen receptor, progesterone receptor, and (except one) HER2. The majority were positive for cytokeratin 5/6 (58%), p63 (59%), and EGFR overexpression (66%); 24% were KIT positive .
No EGFR or KIT activating mutations were present; 26% of the primary metaplastic breast carcinomas were fluorescence in situ hybridization-positive, displaying high EGFR copy number secondary to aneusomy (22%) and amplification (4%). It is reported that metaplastic breast carcinoma is a basal-like breast cancer lacking EGFR and KIT activating mutations but exhibiting a high EGFR copy number (primarily via aneusomy), suggesting that EGFR tyrosine kinase inhibitors should be evaluated in this molecular subset of breast carcinomas .
4.0 Immunohistochemistry ( ICH) and diagnosis of Osseous metaplasia in breast tumors
Metaplastic breast carcinomas are regarded as ductal carcinomas that undergo metaplasia into a nonglandular growth pattern . The mixed cell origin is corroborated by histopathologic staining for mesenchymal cells (vimentin), epithelial cells (cytokeratin), and myoepithelial cells (S-100 protein, actin, and high-molecular-weight cytokeratin). Immunohistochemical analysis for epithelial differentiation was performed in a study that had 22 cases. In 18 cases (81.8%) the spindle cells were focally positive for at least 1 cytokeratin subtype, and 4 cases (18.2%) were negative .
The strongest marking was obtained with the antibodies against AE1/AE3 and HMW-K. Weaker reactions were obtained for the low molecular weight keratins (CAM 5.2 and CK 7) . Both types of cells, epithelioid and spindled, expressed cytokeratins, but the epithelioid cells showed stronger cytoplasm positivity. Staining intensity gradually decreased in the transition to the spindle cell component. Few epithelioid cells and rare spindle cells were weakly positive for epithelial membrane antigen (EMA) . The squamous and glandular elements stained for all types of cytokeratins tested. The squamous component stained more strongly with HMW-K and AE1/AE3 compared with glandular elements .
Metaplastic breast carcinomas are a heterogeneous group of tumors in which the adenocarcinomatous element is admixed with one or more squamous, spindle, chondroid, or osseous neoplastic components. Metaplastic breast cancer may be rare, with an incidence of <5% in all breast malignancies, but are composed of adenocarcinomatous and nonglandular growth patterns, which are characterized by a propensity for distant metastases and resistance to standard anticancer therapies.
As metaplastic breast carcinoma is more aggressive than breast adenocarcinoma without metaplasia, there is an increased risk of locally recurrent and metastatic disease. Furthermore, regimens conventionally employed for metastatic breast cancer appear to be less effective for metastatic metaplastic breast carcinoma in this series.
But studies have shown that bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption; accordingly it has been shown that the use of bisphosphonates delay the time to an SRE among breast cancer patients. More research should be done to help with ease of differentiating metaplastic carcinoma from invasive ductal or invasive lobular carcinoma and primary breast sarcoma in order to determine appropriate treatment options, management considerations, and patient outcome.