Clinicopathological features of metaplastic breast carcinoma

Material and methods. Metaplastic carcinoma of the breast was found in 7 out of 1,164 patients who had been diagnosed with breast cancer within the period of 12 years in our hospital. Demographic and clinical characteristics of the patients were retrieved from the patient files, and their final status was verified by a phone call. Diagnoses of the patients were confirmed by examining hematohylen and eosin (H&E) preparations. They were stained immunohistochemically for estrogen receptor (ER), progesterone receptor (PR), C-erbB-2, CK5/6 (Sitokeratin5/6), and EGFR (epidermal growth factor receptor), and the subgroups were determined according to the WHO classification.


Introduction
Breast cancer is the most frequent cancer in women.2][3] Metaplastic carcinoma of the breast is defined as a group of heterogeneous malignant neoplasms that contain glandular and non-glandular components with mixed epithelial and mesenchymal differentiations. 4Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu, c-erbB-2) are negative in more than 90% of MpBC, while cytokeratin 5/6 (CK5/6), cytokeratin 14, and epidermal growth factor receptor (EGFR) show expressions immunohistochemically. 5his subgroup, for which standard treatment protocols have different responses due to its heterogeneous nature, needs new and tumor-specific treatment methods.
In this study, the research of the clinical and pathologic characteristics of the MpBC that determine its rank among all breast cancers was aimed.

Methods
Metaplastic carcinoma of the breast was found in 7 out of 1,164 patients that had a diagnosis of breast cancer within the period of 12 years in our hospital.Demographic and clinical characteristics of the patients were retrieved from the patient files, and their final status was verified by a phone call.Histopathological findings of the patients were evaluated by examining the preparations fixed in formalin and stained with hematoxylen and eosin (H&E).

Results
All patients were female with a median age of 61 years (41-87 years).Two of them were premenopausal and 1 patient had 2 cases of breast cancer at her pedigree.Clinical and histological findings of the patients with metaplastic cancer are summarized in Table 2.
Two patients had draining wounds due to the tumor.Five patients had tumors with diameters <5 cm.The tumors were multi-centric in 2 patients and were associated with foci of carcinoma in situ.All patients had palpable and multiple axillary lymph nodes.Lymph nodes formed a conglomerate in 1 patient.This patient also had lung, bone and brain metastases at diagnosis.Two patients were diagnosed with stage IIIB and 1 patient had 3 cycles of neoadjuvant chemotherapy.Modified radical mastectomy was performed in the cases with stages IIA, IIB, and those that had neoadjuvant chemotherapy.Toilet mastectomy was performed in the case of stage IIIB with a draining wound.The patient with stage IV was diagnosed by a core biopsy, but was not operated.
The patient with metastatic disease refused chemotherapy.The 87-year-old patient with stage IV could not have any treatment due to her other health problems.Two patients did not keep their follow-up and no information could be obtained about their final status.Four patients had CA (doxorubicin and cyclophosphamide) chemotherapy regimen.Two of these patients had paclitaxel treatment for 12 weeks.The patient that was ER and PR positive had 4 cycles of CA and tamoxifen (2 × 10 mg) treatment later.
A locally advanced patient had 3 cycles of neoadjuvant and 3 cycles of postsurgical CAF (cyclophosphamide, doxorubicin and 5-florourasil) treatment.The median follow-up duration of the patients was 34 (10-58) months.Three out of 5 followed-up cases were diseasefree, while 2 of them died due to metastases (Table 3).

Histological and immunohistochemical analysis
After the examination of the H&E preparations, 4 patients were demonstrated to have a squamous type of metaplastic cell differentiations, 1 spindle, 1 adenosquamous, and 1 osseous.Six of 7 patients were found to be estrogen and progesterone receptors and C-erbB-2 expression negative.In 1 patient with squamous (adenosquamous) metaplasia, ER was 10% and PR was 5% positive.Conventional fluorescent in situ hybrilization (FISH) method did not show any HER2/neu gene amplification upon (+2) C-erB-2 expression score in the same patient.CK5/6 was positive in 5 patients.CK5/6 could not be evaluated in 1 patient despite consequent stains.It was negative in 1 patient.Epidermal growth factor receptor was positive in all patients (Table 4).

Discussion
DNA microarray and immunohistochemical methods have been quite popular recently in determining the subgroups of breast cancer biologically and clinically.Considering gene expressions, breast cancer that is ER (+) is classified into 2 subgroups as luminal A and luminal B, and ER (−) is classified into 3 subgroups as HER2 expressing, basal-like and null (similar to normal), although there have not been any certain criteria accepted yet. 7With this classification, we aim to obtain data that would present patient follow-up and treatment choice, demonstrating the molecular basis of the heterogeneity that is observed in breast cancer.
Triple-negative breast cancer (TNBC) is a heterogeneous tumor group that makes 10-20% of all breast cancers and has an aggressive clinical course. 8,955-80% of TNBC has a basaloid phenotype. 8,10Cytokeratin (CK) 14, CK5/6, CK 17,epithelial growth factor receptor (EGFR), p63, CD10, laminin, KIT, nestin, caveolin 1, and NGFR can be used as basal or myoepithelial cell determinant.Basal-like breast cancers show expressions of basal cytokeratin with a high molecular weight (CK5/6, CK14 and CK17), p-kadherin and fascin.In determining basal-like breast cancers, specificity of being ER (−), HER2 (−), CK5/6 and EGFR (+) is 100%, and sensitivity is 76%. 11In more than 90% of MpBC, CK5/6, CK14 and EGFR expressions are positive, while ER, PR and HER2 are negative immunohistochemically.Estrogen receptor or PR expression frequency is 0-17% in MpBC. 5 All our cases are triple-negative, except the patient in the grey zone.Considering this, all the presented patients can be accepted as TNBC.CK5/6 expression could not be evaluated in the case with adenosquamous differentiation, while it was negative in the case with osseous differentiation.MpBC can be evaluated as a subgroup of TNBC considering its immunohistochemical characteristics.Five of the patients presented with squamous differentiation resembled the subgroup of TNBC with a basaloid phenotype.Positivity of the EGFR expression in all cases of MpBC suggests that antiangiogenic treatment alternatives may be helpful. 2mmunohistochemically, C-erbB-2 scoring is a subjective evaluation.C-erbB-2 score was +2 in 1 patient of the group presented.However, there was no HER2/neu gene amplification with the FISH method.ER and PR positivity were within the grey zone limits in this patient.The patient, whose cancer was classified as T1N1M0 (stage IIA), had 4 cycles of AC chemotherapy.The patient used tamoxifen (2 × 10 mg) for 4 years and is disease-free at present.
The incidence of MpBC within breast cancers is reported as 0.02-0.5%. 1,2,12It made 0.6% of the cases that had been diagnosed with breast cancer at our pathology unit during 12 years.Metaplastic cell differentiation with squamous cells was the most frequent.However, 1 patient had sarcomatous changes that showed osseous differentiation.
Metoplastic carcinoma of the breast is mostly seen in the 5 th decade.4][15] Six of the 7 patients presented had a metastatic lymph node.Metoplastic carcinoma of the breast is observed to metastasize to the bones and lungs with hematogeneous spread rather than lymphatic spread.
The majority of MpBC tumors is estrogen receptor (ER), progesterone receptor (PR), and HER2 negative, triple-negative breast cancer (TNBC), and usually carries a worse prognosis compared to non-metaplastic TNBC. 3,5Metoplastic carcinoma of the breast is usually more aggressive than pure invasive ductal or invasive lobular cancers often presenting with larger staging (T2, T3); however, lymph node involvement is less likely to be noted. 2The prognosis of MpBC was poorer than that of invasive ductal carcinoma and TNBC; the 5-year overall survival rate was 54.5% in MpBC vs 85.1% in invasive ductal carcinoma and 73.3% in TNBC (p < 0.001). 16In a multicentric study of 405 patients, it was differently reported that there was no difference between ductal breast cancers and MpBC; however, spindle cell type shows aggressive biologic behavior and chemotherapy provides a longer survival in an early stage. 17linical findings are like in other breast cancers.MpBC can show benign characteristics at sonography, mammography and MRI as well as findings of invasive carcinoma.It has no specific radiologic findings. 13,18Radiologic findings can change according to the component the tumor contains. 19Metoplastic carcinoma of the breast is seen as a spiculated mass with irregular margins that often has intermediate to high signal intensity in T2W images and is low or isointense in T1W images in MRI. 13 Metaplastic carcinoma of the breast may be treated with breast-conserving surgery in suitable cases.It is reported that there is no difference in the survival rate between breast-conserving surgery and a radical mastectomy. 1,20owever, a modified radical mastectomy is the preferred method of treatment if the tumor is big at diagnosis and local recurrence rate is 35-62% in the first 2-5 years compared to the recurrence rate of 17-20% for invasive ductal carcinoma of similar tumor size. 1 There is no specific guideline for the treatment of MpBC.It is known that long-term adjuvant chemotherapy is not useful in such cases. 5,21In 42 out of 47 cases of breast cancer, no survival benefit from adjuvant chemotherapy. 5he heterogeneous nature and sarcoma-like characteristics of MpBC are blamed for the failure of standard chemotherapy schemes. 21Today, for the treatment of MpBC, a high-dose anthracycline is suggested as a chemotherapy regimen in the case of epithelial subgroups.There is a need for new studies that would evaluate different choices of treatment as MpBC has a bad prognosis and an aggressive nature.
In conclusion, MpBC is relatively rare and, in our series, its incidence was 0.6%.According to its immunohistochemical characteristics, MpBC can be interpreted as a subgroup of triple-negative breast cancers (TNBC).Most of the presented patients resembled the subgroup of TNBC with a basaloid phenotype.

Table 1 .
2HO classification of metaplastic carcinoma of the breast2

Table 2 .
Clinical and histologic findings in patients with metaplastic cancer

Table 4 .
Results of differentiation and immunohistochemical analyses