Carcinosarcoma of the breast: Facing the challenge of a rare nosologic entity

Abstract

Carcinosarcoma (CS), also known as metaplastic breast carcinoma with mesenchymal differentiation, is one of the five distinct subtypes of metaplastic breast cancer. It is considered as a mixed, biphasic neoplasm consisting of a carcinomatous component combined with a malignant nonepithelial element of mesenchymal origin without an intermediate transition zone. Although cellular origin of this neoplasm remains controversial, most researchers declare that neoplastic cells derive from a cellular structure with potential biphasic differentiation. Despite recent research on the therapeutic strategies against CS neoplastic disorders, surgical resection appears the only potentially curative approach. Since CS metastasize by the lymphatic route, axillary assessment with sentinel lymph node biopsy and/or axillary lymph node dissection is always implemented. Nevertheless, the tumor also presents a hematogenous metastatic pattern including pleural, pulmonary, liver, brain and less commonly bone metastases. Thus, surgical removal of breast CS does not necessarily ensure patient’s long-term recovery. Moreover, alternative therapies, such as radio- and chemotherapy proved insufficient and 5-year survival rate is limited. Nevertheless, there is evidence that following surgery, the combination of radio and chemotherapy is associated with a better prognosis than either treatment alone. The aim of this review is to evaluate the results of surgical treatment for breast CS with special reference to the extent of its histological spread. Clinical features, histogenesis, morphological and immunochemical findings are discussed, while the role of current diagnostic and therapeutic management of this aggressive neoplasm is emphasized.

Key Words: Carcinosarcoma; Breast; Diagnostic approach; Therapeutic management; Prognostic parameters

Core Tip: Carcinosarcoma is one of the five distinct subtypes of metaplastic breast cancer. It is considered as a mixed, biphasic neoplasm consisting of a carcinomatous component combined with a malignant nonepithelial element of mesenchymal origin without an intermediate transition zone. Since surgical removal of breast Carcinosarcoma does not necessarily ensure patient’s long-term recovery, treatment protocols in the literature include combinations of mastectomy with or without axillary dissection and various postoperative chemo-radiotherapy regimens. Nevertheless, 5-year survival rate is limited.

INTRODUCTION

Carcinosarcoma (CS), also known as metaplastic breast carcinoma with mesenchymal differentiation, is one of the five distinct subtypes of metaplastic breast cancer (MBC)[1]. Other MBC categories include squamous cell, low-grade adenosquamous, spindle cell and fibromatosis-like metaplastic carcinoma. CS of the breast is a rare, poorly differentiated, malignant tumor which represents less than 0.1% of all BC cases and 11.7% among MBC[2,3]. It is considered as a mixed, biphasic neoplasm consisting of a carcinomatous component combined with a malignant nonepithelial element of mesenchymal origin without an intermediate transition zone[4,5]. Moreover, CS stimulates the mesothelial tissue to undergo a true sarcomatous alteration. Therefore, two malignant tumors originate separately as well as simultaneously and grow towards each other producing coalescence[6-8]. Clinically, CS presents as a tumor of variable size and may appear in such diverse locations beside the breast as the uterus, thyroid, lung, colon, esophagus, prostate and pancreas[2]. Although cellular origin of this neoplasm remains controversial, most researchers lead to believe that neoplastic cells derive from a cellular structure with potential biphasic differentiation[9]. The malignant mesenchymal component in these tumors can include elements of chondroid, osseous, rhabdomyoid and even neuroglial differentiation. In the majority of breast CSs expression of estrogen and progesterone as well as HER2-neu receptors are absent[10-12].

Despite recent research on the therapeutic strategies against CS neoplastic disorders, surgical resection appears the only potentially curative approach. Since CS metastasize by the lymphatic route, axillary assessment with sentinel lymph node biopsy and/or axillary lymph node dissection is always implemented. Nevertheless, the tumor also presents a hematogenous metastatic pattern including pleural, pulmonary, liver, brain and less commonly bone metastases[9]. Thus, surgical removal of breast CS does not necessarily ensure patient’s long-term recovery. Moreover, alternative therapies, such as radio- and chemotherapy proved insufficient and 5-year survival rate is limited (49%)[9,13]. The aim of this review is to evaluate the results of surgical treatment for breast CS with special reference to the extent of its histological spread. Clinical features, histogenesis, morphological and immunochemical findings are discussed, while the role of current diagnostic and therapeutic management of this aggressive neoplasm is emphasized.

EPIDEMIOLOGY AND CLASSIFICATION

The World Health Organization recognized and classified MBC in 2003[7,8]. Breast CS is extremely rare and accounts of less than 0.1% of all retrospectively diagnosed BCs[2,4]. It commonly occurs in a wide spectrum of patients, aged from 16-82, mainly in middle-aged postmenopausal females. Mean age at diagnosis varies between the fourth and fifth decade of life[2]. Due to its rarity, potential predisposing factors such as smoking, alcohol consumption or obesity, exploring any established links to CS have not been elucidated. Nevertheless, CS seems to present better survival rates compared to other subtypes of MBC such as squamous and adenosquamous carcinoma[3,9,14]. Associated cumulative 5-year survival rate is estimated to 49% while relevant 5-year rates for stage I, II, III and IV have been reported as 73%, 59%, 44% and 0% respectively[2,11]. Although the vast majority of the tumors are accepted as a variant of MBC that arises from myo-epithelial cells, several cases of breast CS developing on the ground of fibroadenomas and phyllodes tumors have been reported in the literature. However, primary sarcomas of the breast are infrequent and constitute 0.6%-1.2% of all BCs[4,11].

The true definition of MBC is a tumor of malignant epithelial tissue (carcinoma) mixed with malignant cells of mesenchymal origin (sarcoma) with apparent histologic and cytologic features present on light microscopy and immunohistochemical examination[15]. Indeed, CS is often referred to as MBC, characterized as an unusual and uncommon neoplasm that is comprised by an admixture of two or more components. The cells of origin of this neoplasm have yet to be agreed upon, however recent research leads us to verify relevant myoepithelial origin. In accordance with most MBCs, CSs are poorly differentiated, high grade and highly cellular, with mitotically active pleomorphic spindle cells[15]. These tumors are supposed to develop from existing cystosarcoma, phyllodes, fibroadenoma and cystic background[5,16,17]. Furthermore, this uncommon neoplastic lesion consists of intraductal or infiltrating carcinoma contiguous or subtly merged with a highly cellular, mitotically active pleomorphic spindle cell stroma[2].

The epithelial component of the tumor may be composed of undifferentiated carcinoma, adenocarcinoma, in situ carcinoma, infiltrative ductal or squamous carcinoma as well. Mesenchymal components may contain different elements ranging from undifferentiated mesenchymal areas to fibroblastic, chondroblastic or osteoblastic lesions. Irrespective of origin, it is usually poorly differentiated and behaves aggressively[3,16,17]. The most important CS evidence is the absence of a transition area between the above-mentioned elements[5]. Nevertheless, demarcation between the carcinomatous and sarcomatous components is usually unclear in all light microscopic fields. Therefore, the tumor should be distinguished from other types of MBC, including spindle cell carcinoma, carcinoma with cartilaginous or osseous metaplasia, matrix producing carcinoma, malignant phyllodes tumor and fibrosarcoma[2,15].

HISTOLOGY AND IMMUNOHISTOCHEMISTRY

Clinicopathological factors, including tumor size, differentiation rate, histological grade and the presence of atypia or active pleomorphic spindle cells are essential parameters in associated prognosis. However, no significant difference was identified when breast CSs were compared to high grade receptor negative infiltrative carcinomas[18]. When present, complete microscopic circumscription plays a pivotal role in establishing the diagnosis. Also, the evidence of an admixed inflammatory infiltrate may have clinical significance[19,20]. The most important indication of its presence is the non-existent region of transition between the two elements. Thus, a detailed pathological search for the transitional area is always crucial. CS can also present as malignant phyllodes tumor accompanied by malignant epithelial components which may constitute only a small proportion of the entire tumor. Such presentation will frequently be misdiagnosed by pathologists as sarcoma, especially if sampling is insufficient or microscopic investigation inadequate[5].

Immunohistochemical staining indicates positivity of the epithelial part for specific membrane antigens (EMA), cytokeratins, DF3, AE1/3, MNF-116, CAM5.2 pancytokeratin, CK7/19 and p63 as well[11]. Further investigation of sarcomatous cells reveals positive expression of smooth-muscle actin (SMA), desmin, neuron-specific enolase (NSE), PGP 9.5, myoglobin and p53. Both components proved vimentin positive[2,11,13,17,21]. More specifically, the sarcomatous component of CS is immunoreactive for cytokeratin in 55% of cases, regardless of the presence or absence of overt transitional areas. While vimentin expression predominated in the mesenchymal component of the malignancy, staining for cytokeratin 8 and multicytokeratin antibodies was mostly observed in the epithelial part of the tumor mass. It is possible to differentiate this instance from spindle cell cancer because the sarcomatous cells do not exhibit cytokeratin. Hence, the lack of the typical leaf-like architecture serves as the basis for the differential diagnosis vs phyllodes tumors.

On the other hand, the expression of actin and S-100 was observed in the two stromal and epithelial components in 13% of affected cases[12,19]. CSs are characterized as aggressive tumors, due to their estrogen, progesterone and HER-2/neu receptor negativity, also known as the “triple negative pattern”[3,11,14]. Furthermore, approximately 70% among the lesions present epidermal growth factor receptor (EGFR) gene amplification and overexpression[8]. In addition, an immunohistochemical analysis revealed a 70%-80% Ki67 proliferation index indicating an HER1/EGFR receptor over-expression in the majority of CS cases[11]. Finally, a recent survey has elucidated that biallelic inactivation of BRCA1 gene might contribute to CS’s onset and rather dismal outcome. Abnormality of PI3K/AKT and MARK pathway components has also been implicated in breast CS development[9]. A population-based study assessed, that compared to IDC, CS was correlated with higher grade and stage, larger tumor size, lower lymph node association and a higher proportion of triple negative breast cancer[7]. Relevant diagram to summarize the key points on histology and immunohistochemical markers of breast CS has been described in Table 1.

Table 1 Key points on histological and immunohistochemical markers for the diagnosis of breast carcinosarcoma.

Key points on histological and immunohistochemical markers
Apparent presence of sarcomatous and epithelial components
Non-existent region of transition between the two elements
Atypia or active pleomorphic spindle cells
Inflammatory infiltration
Immunoreactivity for keratin and vimentin
Positivity for AE1/AE3 and CAM5.2
Positivity for specific membrane antigens (EMA), cytokeratins, DF3, MNF-116, pancytokeratin, CK7/19 and p63
Absence of HER-2 receptor positivity
Negativity for estrogen and progesteron receptors
Epidermal growth factor receptor (EGFR) gene amplification and overexpression
Positive expression of smooth-muscle actin, desmin, neuron-specific enolase, PGP 9.5, myoglobin and p53

CLINICAL PRESENTATION

Even though CS is a rare highly aggressive malignant tumor that bears an heterogenicity in its histology, the associated clinical features are often similar[22,23]. The patients’ most common complaint is breast lump identification[5]. Additional clinical findings often reveal mild to moderate pain, breast swelling or a rapidly growing palpable mass[16-18,21-25]. Usually, the tumor is firm, well-defined, solid and nodular with a round or oval typical shape[8,13]. Even though CS is characterized by a variable size, the lesion tends to be relatively large at the time of diagnosis, with a median tumor size between 3 cm to 5 cm (range from 0.5 cm to 21 cm)[11,21]. The overlying skin may be tense and shiny or even accompanied with subcutaneous bleeding[17,24]. Bloody nipple discharge, nipple retraction and skin ulceration have also been described as common manifestations[18,25,26]. Breast CSs are usually unilateral, while bilateral cases have also been documented[1].

Distant CS metastases at presentation are an important risk factor for overall survival, as they are associated with an unfavorable prognosis with a median survival rate limited to 8-14 months[21]. Metastatic foci occur with lymphatic and hematogenous spread, with the latter to be more frequent[9-11,21-23,27]. Concerning hematogenous metastases, pleural and pulmonary lesions are more common in comparison with skeletal, liver or brain foci[18-21,23,25-27]. Metastases in axillary lymph nodes are relatively uncommon (26%) and less frequent in CS compared to the conventional adenocarcinoma[2,3,5,9,16]. Nevertheless, despite the biphasic metastatic potential and the initial tumor’s large size, absence of distant metastases has been elucidated in the majority of CSs cases[11].

DIAGNOSTIC APPROACH

The challenging preoperative diagnosis distinguishes CS from all other BC cases, as the latter does not display any specific pathognomonic imaging features. Therefore, the three commonly applied imaging techniques in the diagnosis of breast neoplasms including mammography, ultrasonography (U/S) and magnetic resonance imaging (MRI), present unsatisfactory specificity in the diagnosis of breast CS[1,5,9,23,25]. Indeed, a lump may appear well distinct with relatively regular borders and benign appearance in the imaging studies. As a result, a well-defined lump on mammography and U/S may be confused either as a benign lesion or a breast abscess[14,17,28]. Accordingly, proper non-operative diagnosis is further challenging as fine needle biopsy (FNB) may not provide an adequate specimen. Hence, the golden standard for CS identification remains the postoperative histologic examination of an entire surgical specimen[9,25]. Overall, high rates of specificity (99%) and sensitivity (90%) are observed in frozen section examinations of breast masses. Nevertheless, in certain instances of breast CS, the small part of the tumor provided for frozen section examination would not be adequate to disclose the tumor's general characteristics[25]. Nonetheless, initial assessment relies on mammography and US as all cancer categories. Therefore, radiologic imaging is essential but it cannot provide the diagnostic confirmation of the histopathological findings.

Firstly, concerning mammography, CS may indeed bear some typical imaging findings. The tumor usually manifests as a circular or oval, noncalcified high density polylobulated mass with uneven borders and spiculations. Furthermore, CS might sometimes present pleomorphic calcifications[2,8]. Microcalcifications and architectural distortion have been documented in 63% and 26% of the cases respectively, with the latter occurring more frequently in cases involving osteosarcomatous differentiation or chondrosarcoma[21]. In addition, typical U/S malignant findings are not apparent. Due to the fact that solid and cystic components are present, MBC can appear as a heterogeneous hypoechoic round or oval mass with well-defined edges and complex heterogenicity and might also be accompanied by micro-calcifications as well as thickening of the posterior wall of the abscess cavity along with a soft tissue lesion[9,11,14,16,21,23,25]. Likewise, the specificity of MRI for the diagnosis of CS is insufficient and is not recommended as a preoperative assessment in all studies. Lesions usually appear iso-hypointense on T1 MRI images, due to the glandular component[25]. T2-weighted images often reveal a hyperintense lesion due to the mucoid and necrotic components[23,25].

It is common knowledge that FNB and core biopsy remain the most frequently applied techniques in the preoperative diagnosis of breast lesions. However, in a series of 24 patients, only one was promptly diagnosed with MBC before surgery[28]. In addition, only 4.2% of MBC cases had a core needle biopsy that yielded an accurate preoperative diagnosis[21]. Moreover, some institutions do not consider FNB as an adequate method to diagnose the disease. Additionally, in an effort to guarantee a drastic and secure surgical technique in every case of breast neoplasm, sentinel node biopsy is typically avoided as well[2]. Conclusively, due to the lack of adequate specimens and the fact that a selected slice of tissue might be unrepresentative of the whole tumor, FNB has been associated with high false negative rates[9,21,23]. Therefore, the biopsy site should be carefully elucidated, and an adequate volume of specimens is always implemented to distinguish MBC from other BC types[11,28].

Intraoperatively, frozen section diagnosis of breast lumps is of high accuracy, with a sensitivity and specificity of more than 90 and 99%, respectively[25]. However, in breast CS there may be some limitations as the small piece of the tumor provided for frozen section examination may not be sufficient to reveal the overall tumor profile[5,25]. Finally, pre-operative disease staging with computed tomography and on occasion MRI and positron emission tomography, play a crucial role in the diagnostic approach of metastatic BC. The pleura and lungs presented the most frequent pattern of metastasis, followed by the bone, liver, and brain, while local recurrence is not as threatening and can generally be treated surgically[2,4,13,19]. Overall even with core needle biopsies and the mammotome establishing a preoperative diagnosis of MBC is frequently problematic[9,21,25]. Consequently, thorough sampling and/or total excision combined with precise immunohistochemistry panels are necessary for the accurate CS diagnosis[21].

THERAPEUTIC INTERVENTIONS

Treatment protocols in the literature include combinations of mastectomy with or without axillary dissection and various postoperative chemo-radiotherapy regimens. Explicitly, radical mastectomy seems to be the only curative alternative[25]. Surgical strategy of breast CS corresponds to the general approach of other common pathological BC types usually based on the NCCN guidelines that are recommended for invasive BC patients. More specifically modified radical mastectomy (MRM) is an efficient and practical choice in the treatment of breast CS particularly when the lesion is highly suspicious of malignancy, or a definite diagnosis has already been accomplished[5,29,30]. It is common knowledge that, the axillary nodes are one of the typical sites of metastasis (26%) from either the carcinomatous or sarcomatous component of the primary site[18]. Thus, mastectomy coupled with axillary dissection is often performed in the surgical treatment of breast CS. Nevertheless, given the relatively low likelihood of axillary nodal involvement, it has been suggested that axillary dissection could be omitted. Nevertheless, it seems more appropriate to employ sentinel node biopsy to determine the status of the axillary lymph nodes[21]. With a view to potential breast reconstruction, a nipple-sparing MRM may be performed, but lumpectomy and axillary dissection remain also an alternative of surgery in selected patients[31]. Studies have shown no difference in overall disease-free survival in patients undergoing MRM and breast conservation therapy[21]. Even so, due to the large BC size at diagnosis, the latter is usually avoided[5,8,17,21].

It is common knowledge that R1 resection or positive surgical margins are associated with unfavourable prognosis among breast CS patients, consistent with the non-CS literature. While adjuvant therapy may reduce recurrence risk in the setting of a positive margin, it has not been assessed to completely mitigate the worse outcome encountered in these patients. In terms of conservative therapeutic opportunities, chemotherapy and radiotherapy may be applied in various combinations as adjuvant therapy. Since no particular clinical trials for breast CS are available, the exact relevant effect of systemic treatment is still undefined and any data are based on small number of cases. Thus, medical oncologists usually apply in their clinical practice one of the adjuvant treatment protocols similar to the other BC types. Besides, while cross-trial comparisons limit the number of patients and the importance of results, the relevant prognosis of BC patients who are treated with adjuvant chemotherapy is comparable to the survival rate of untreated cases. Thus, the role of chemotherapy before or after surgery has not yet been established.

The administration of conventional radiation may not be sufficient to lower the frequency of local recurrence in patients undergoing breast conserving surgery, although the retrospective and uncontrolled character of the results limits the interpretation of the data. Still, in some studies, adjuvant radiotherapy has been assessed to decrease the risk of death by 33% in mastectomy patients. In accordance with recent investigations, individuals submitted to mastectomy who appear with a tumor less than 5 cm in size along with less than four axillary lymph nodes involved, do not benefit from radiation. Besides, while cross-trial comparisons limit the number of patients and the importance of results, the relevant prognosis of BC patients who are treated with adjuvant chemotherapy is comparable to the survival rate of untreated cases. Thus, the role of chemotherapy before or after surgery has not yet been elucidated.

It is well documented that, CSs are poorly differentiated aggressive neoplasms that often tend to be triple-negative[32]. Hence, adjuvant chemoradiotherapy is crucial for locoregional control whereas hormonal therapy is ineffective. Anthracycline/taxane-based chemotherapy is more effective than cyclophosphamide, methotrexate, fluorouracil regimen, as evidence from existing clinical research into adjuvant chemotherapy in BC suggests[18]. Overall, chemotherapy based on anthracycline and taxane is still less effective than the one administered for conventional BC[18]. However, patients with CS tend to receive chemotherapy more often than invasive ductal carcinoma due to their hormone triple negative-receptor status and larger tumor size. This kind of treatment is also estimated to be more beneficial in certain series, but only in individuals with axillary lymph node positivity. It is also noteworthy that most BC survivors who receive adjuvant sarcoma-type treatment do not experience relapse[27]. Furthermore, patients with locally advanced (T3/T4 or N2/N3) tumors require tumor downstaging for breast conservative surgery. Therefore, treatment in the neoadjuvant setting has become the conventional technique for possibly operable breast carcinomas, with benefits such as tumor shrinkage, early treatment of micrometastatic disease and the possibility for immediate response to the therapy in investigation.

There is evidence that following surgery, the combination of radio and chemotherapy is associated with a better prognosis than either treatment alone. One study verified that a 49-year old patient with triple-negative breast CS responded well to treatment with 50 Gy radiation given in addition to taxanes and anthracyclines, showing no signs of recurrence in the fourth year of follow-up[32]. In addition, a 34-year old patient diagnosed with PR-positive CS underwent a comparable course of treatment and experienced similarly favorable outcome five years following surgery[33]. Despite being widely used in BC chemotherapy, paclitaxel did not show positive results in prior publications when administered as neoadjuvant chemotherapy for breast CS[9]. Finally, overexpression of HER1/EGFR suggests that agents like cetuximab, which target the EGFR, may play an important role in the treatment of metaplastic carcinoma[5,22].

CONCLUSION

Nowadays, most of the studies have addressed the role of EGFR inhibitors for the potential treatment of breast CS as amplification and overexpression of EGFR gene occurred in the majority of affected patients. Nevertheless, whether targeted drugs such as gefitinib or cetuximab can be beneficial should be further clarified[34]. It is generally believed that more aggressive treatment is required, so as a consequence, new molecular cancer therapeutics including protein kinase (gefitinib), angiogenesis (bevacizumab) as well as mTOR inhibitors (everolimus, sirolimus) are included in an extremely active area of research[30]. Finally, examination of microdissected tumor samples determined that both epithelial and mesenchymal components contained deletion of the wild-type BRCA1 allele[31]. Therefore, it has been exemplified that even very uncommon breast tumor types may develop through biallelic inactivation of BRCA1 gene that has to be considered in the future genetic testing settings.