A definitive diagnosis of primary SCC of the breast is possible only after a metastasis from an extramammary primary carcinoma (34,35,36), such as the lung, uterine cervix, urinary bladder and carcinomas of the head and neck region (37),
and secondary extension into the breast of a primary SCC arising in the overlying skin have been ruled out. Clinical and radiologic correlation is required to exclude the aforementioned scenarios.

Most or all of the neoplasm consists of spindle cells with moderate to marked nuclear atypia; tumor cellularity is also moderate to marked (Fig. 13.5). Mitoses are easily identified and usually numerous. Necrosis is common, especially in high-grade tumors. Focal areas of squamous differentiation, DCIS, or invasive carcinoma of no special type (Fig. 13.5) may be identified, but most cases have no obvious epithelial component, especially in NCB material. In one study (38), DCIS was present in the surgical excision specimen only in 14% of the cases. Usual ductal hyperplasia of the gynecomastoid type is often present in the mammary ducts at the periphery of the tumor. Immunohistochemical stains for epithelial markers, such as CK 34βE12, CK14, CK 5/6, CK18, and p63 can be positive, but the expression of epithelial antigens in MSpCC with intermediate- and high-grade morphology tends to be very focal, if any, even in the main resection specimen, and a NCB sample may not show any staining for epithelial markers. Positivity for GATA3 has also been reported (39) (Fig. 13.5).

The identification of a focal attenuated epithelium lining a hypercellular stromal fragment is often the only evidence differentiating high-grade malignant phyllodes tumor from MSpCC with intermediate- or high-grade morphology (see Chapter 7). NCB sampling of areas of stromal expansion or overgrowth in a borderline or malignant PT may yield no ductal epithelial component, raising the differential diagnosis of high-grade MSpCC. It has been reported that the neoplastic cells of PTs may be focally positive for CKs (40). PTs are usually positive for CD34, whereas MSpCCs are usually CD34-negative (41). S-100 can be positive in some MSpCCs and PTs (41). A malignant tumor entirely composed of spindle cells of intermediate- and high-grade atypia and having no overt epithelial component or frond-like architecture cannot reliably be classified in a NCB, and both MSpCC and malignant PT need to be included in the differential diagnosis. Focal staining for CK favors MSpCC, but caution is recommended when the positivity is extremely focal, limited to epithelium near foci of necrosis, and limited to only one of the CKs less sensitive for the detection of MSpCC, such as CAM5.2. It is worth noting that definitive diagnosis of MSpCC, a “triple-negative” carcinoma, at the time of NCB may lead to treatment with neoadjuvant chemotherapy, which is usually not indicated for the treatment of malignant PTs. Patient prognosis also differs greatly.

Primary sarcomas of the breast are extremely rare, with angiosarcoma being the most common type (see Chapter 20 for detailed discussion). A clinical history of prior ipsilateral breast carcinoma treated with breast-conserving surgery and radiotherapy is often obtained in cases of radiation-induced sarcoma. Sporadic primary mammary angiosarcomas tend to occur in young women. The NCB sample of an angiosarcoma is characteristically very hemorrhagic. Most angiosarcomas are positive for CD31 and ERG, and negative for CKs and epithelial markers, but focal positivity for CKs has been reported (42), especially in epithelioid angiosarcomas. A group reported p63 positivity in angiosarcomas (43), but others have not observed this finding (44). Awareness of the patient’s prior clinical history is important to rule out sarcoma metastatic from an extramammary site.

The differential diagnosis of any epithelioid and spindle cell malignant tumor includes melanoma and requires the appropriate immunohistochemical workup. S-100 can be positive in some MSpCC with intermediate- and high-grade morphology (41). SOX10, a Schwann cell and melanocytic marker, has been detected in some metaplastic carcinomas (45) (Fig. 13.5). Rarely, p63 is focally and weakly positive in melanoma (personal observation).

In the absence of definitive reactivity for vascular or melanocytic markers in NCB material of an intermediate- to high-grade malignant spindle cell tumor, the diagnosis of MSpCC is the most likely, but the need for further evaluation of the entire tumor in the surgical excision specimen should be indicated.

MSpCC with dense, keloid-like areas of fibrosis, storiform pattern, and minimal cytologic atypia is referred to as “fibromatosis-like” (46) or “low grade” (47) (Figs. 13.6, 13.17, 13.8). This tumor often shows heterogeneous cellularity, with closely juxtaposed hypercellular and hypocellular areas. Collagenous fibrosis can be extensive and deceivingly hypocellular to nearly acellular, especially in the center of the tumor. The neoplastic cells are haphazardly arranged in short interlacing fascicles, and tend to be inconspicuous, with

ill-defined cell borders, no obvious cytoplasm, and elongated nuclei. In the more cellular areas, the spindle cells may have slightly more abundant and denser cytoplasm, and align in short files and chords that superficially resemble capillaries but are not associated with red blood cells. These epithelioid foci usually are positive for CKs with a characteristic linear and branching arrangement (Figs. 13.6 and 13.7). Atypical spindle cells with enlarged and hyperchromatic nuclei may be identified focally, but the nuclear atypia tends to be of low grade. Mitoses are sparse, ranging from <2 mitoses/10 HPFs to 3-5 mitoses/10HPFs (46,47). Atypia and mitoses are more common in the cellular or epithelioid areas. Chronic inflammation is scattered throughout the tumor and at its periphery; it can be substantial and raise the differential diagnosis of inflammatory PT with inflammation or nodular fasciitis (Figs. 13.6 and 13.7).

Invasive carcinoma with epithelial morphology and low-grade atypia can constitute up to 5% of the tumor mass in the surgical excision specimen (46,47). Invasive lobular carcinoma is extremely rare (3). Focal low-grade squamous morphology is uncommon. Low-grade DCIS (46,47), classic LCIS (47), and ADH (3,46) have been described, but usual ductal hyperplasia of gynecomastoid type is the most common intraductal epithelial alteration.

MSpCCs with “low-grade” “fibromatosis-like” morphology can arise in association with papillomas (47,48), complex sclerosing lesions, and nipple adenomas (49,50).

Fibromatosis may arise primarily in the breast parenchyma (primary mammary fibromatosis) or extend into the breast from the chest wall. Fibromatosis tends to occur in women of reproductive age, whereas metaplastic carcinoma is most common in peri- and postmenopausal women, but there are exceptions. The myofibroblasts composing fibromatosis are arranged in broad, sweeping fascicles and show no cytologic atypia. Mitoses are extremely infrequent. Fibromatosis usually shows diffuse nuclear staining for β-catenin (Fig. 13.9). Focal nuclear staining for β-catenin has been documented in about 25% of metaplastic carcinomas, as well as in most PTs (51). Limited nuclear staining for β-catenin in the NCB material of a cytologically bland spindle cell lesion in the breast should thus be interpreted cautiously. In particular, the current clinical management of fibromatosis may not necessarily include surgical excision of the lesion, or excision of a local recurrence, whereas the clinical management of “fibromatosis-like” MSpCC requires complete resection of the tumor with negative margins and radiation therapy, or mastectomy. There is no definitive consensus regarding the use of adjuvant chemotherapy in patients with “fibromatosis-like” MSpCC.

Nodular fasciitis, a transient neoplasia secondary to USP6 gene rearrangement (52), and inflammatory pseudotumor, a benign neoplasm secondary to ALK1 gene overexpression (53)
are very infrequent in the breast (see Chapter 20) and usually limited in size. Prominent inflammation is present in both lesions. Both neoplasms are negative for CKs.

Myofibroblastoma (see Chapter 20) may occasionally enter the differential diagnosis of “fibromatosis-like” MSpCC when evaluating NCB material. The myofibroblasts of myofibroblastoma have no cytologic atypia, do not express CKs, but are positive for PR and ER. Epithelioid cells in a linear arrangement are absent. Scattered mast cells are common, but chronic inflammation is rare.