Metaplastic Carcinoma Including Low-grade Adenosquamous Carcinoma

Metaplastic Carcinoma Including Low-grade Adenosquamous Carcinoma

Edi Brogi


Metaplastic carcinomas are malignant tumors of epithelial origin that exhibit nonglandular morphology, such as squamous, spindle cell, chondroid, and osseous features. These phenotypic alterations are the expression of a process of genomic dedifferentiation, scientifically referred to as “epithelial to mesenchymal transition” (EMT) (1). There are no criteria regarding the extent of metaplasia required to diagnose metaplastic carcinoma, and mention of the presence and type of metaplasia(s) should always be included in the diagnostic report. Metaplastic carcinomas of the breast are usually “triple-negative” and, with very few exceptions, have a poor prognosis.

Metaplastic low-grade adenosquamous carcinoma (LGASC) has characteristic morphology and clinical behavior, and it is discussed separately at the end of this chapter.

Clinical Presentation


Metaplastic carcinomas are rare, and the precise incidence is difficult to establish. In a study based on data from the National Cancer Database, metaplastic carcinomas constituted only 0.24% of 365,464 breast malignant tumors diagnosed between 2001 and 2003 (2).

Age, Gender, and Genetic Predisposition

Metaplastic carcinomas can occur in women of any age, but peri- or postmenopausal women are affected more commonly (2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21). In one study (2), the mean age at diagnosis was 61 years, with 13.5% of cases occurring in women older than 80 years of age, and 8% in women younger than 40 years of age. Other series report younger median age (22), or no age differences (12) compared to women with invasive ductal carcinomas of no special type. More than 70% (2,8) of metaplastic carcinomas occur in white women. Metaplastic carcinomas do not affect men. Rare cases have been reported in BRCA1 germline mutation carriers (13,23,24,25).

Imaging Studies

Mammographically and sonographically, metaplastic carcinomas tend to be more nodular and less infiltrative than invasive ductal carcinomas (19,22). They have fewer calcifications and less acoustic shadowing (22). Microcalcifications are present in about 20% of the cases (19), and sometimes they are found in ductal carcinoma in situ (DCIS) rather than in the metaplastic carcinoma. Rarely, calcified areas in carcinomas with chondroid and osseous metaplasia are detected mammographically (26,27,28,29). Sonographically, metaplastic carcinomas have a parallel orientation to the skin in 97% of the cases, complex echogenicity in 81%, irregular shape in 60%, posterior acoustic enhancement in 50%, and microlobulated margin in 41% of the cases (19). The most common MRI findings included an irregular heterogeneous enhancing mass, with an irregular shape (52.4%) and margin (57%). High T2-weighted signal intensity is detected in nearly 60% of the cases (19), correlating with necrosis (27) and chondroid areas (28). The tumors are highly metabolic on F18-fluorodeoxyglucose PET. Cystic areas may be present, especially in tumors with squamous metaplasia. Hemorrhagic areas may occur in metaplastic carcinomas with choriocarcinomatous morphology.

Microscopic Pathology

The diagnosis of metaplastic carcinoma requires evidence of epithelial origin and/or differentiation such as identification of DCIS and/or focal invasive carcinoma with epithelial morphology, and/or positive immunoreactivity for keratin and/or (myo)epithelial markers. Metaplastic changes are more common in poorly differentiated invasive ductal carcinomas but rarely
occur in other types of carcinomas, or near papillary lesions. The extent of metaplasia varies from microscopic foci to complete involvement of the tumor. Metaplastic carcinomas encompass a wide morphologic spectrum, and their precise subclassification is limited by their extreme morphologic heterogeneity and the difficulty in quantifying the metaplastic components in each tumor. In resection specimens of metaplastic carcinomas, DCIS is identified in 10% (30) to 65% (31) of the cases, and it tends to have high or intermediate nuclear grade. Rarely, only lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH) is found. A papillary or sclerosing lesion sometimes is present near a metaplastic carcinoma, especially metaplastic spindle cell carcinoma (MSpCC) with “fibromatosis-like” morphology or LGASC. Chronic inflammation often occurs at the periphery and within a metaplastic carcinoma.

Histologic examination of the entire tumor is required to assess all different patterns of metaplasia present in a metaplastic carcinoma, but in some cases a definitive diagnosis of metaplastic carcinoma can be rendered on review of the morphologic features and immunoreactivity in the needle core biopsy (NCB) material. Metaplastic carcinoma is often part of the differential diagnosis of a malignant spindle cell tumor in the breast. Traditionally, metaplastic carcinomas are divided into carcinomas with squamous and/or spindle cell metaplasia, and carcinomas with heterologous component(s), such as chrondromyxoid and/or osseous matrix.

FIGURE 13.1 Invasive Carcinoma with Squamoid Morphology. A: A needle core biopsy specimen from a 3-cm mass in the breast of a 66-year-old woman shows a carcinoma with squamous morphology, well to moderately differentiated. B: The carcinoma consists of squamous nests with low-grade nuclear atypia, in a background of stromal desmoplasia. Lymphocytes are also noted (arrows). A benign duct is present (arrowhead). C, D: Another needle core biopsy specimen showing focal squamous differentiation in a poorly differentiated infiltrating duct carcinoma.

Squamous Cell Carcinoma

Morphologically, mammary squamous cell carcinomas (SCCs) resemble squamous carcinomas that arise in other sites (Figs. 13.1 and 13.2). The diagnosis of SCC of the breast applies to carcinomas in which the squamous component represents at least 90% of the tumor. Consequently, this diagnosis cannot be rendered definitively on review of only NCB material. Some tumors show cytoplasmic clearing. A spindle cell component may be present, but it may be difficult to distinguish from the reactive stroma, especially in NCB material. The neoplastic spindle cells can be highlighted with immunohistochemical stains for high-molecular-weight and basal cytokeratins (CKs), such as 34βE12 (K903), CK14, CK5/6, and also for p63. An inflammatory infiltrate rich in granulocytes and lymphocytes is often present in association with SCC, especially in necrotic and/or keratinized areas (Figs. 13.1 and 13.2), accounting for the common clinical impression of an abscess. DCIS of intermediate
or high nuclear grade can be associated with mammary SCC, or very rarely it has squamous morphology (Fig. 13.3).

FIGURE 13.2 Invasive Squamous Carcinoma. A, B: A needle core biopsy specimen showing well to moderately differentiated invasive squamous carcinoma and invasive poorly differentiated carcinoma. C: A part of the same tumor with poorly differentiated squamous carcinoma. D: An area in the surgically excised tumor that duplicates the appearance of the needle core biopsy specimen. Note the cystic degeneration and the lymphoplasmacytic stromal infiltrate, frequent components of primary squamous carcinoma of the breast.

Rare cases of SCC or squamous carcinoma in situ arising in malignant phyllode tumors (PTs) have been reported (32,33). Squamous metaplasia can occur in benign mammary ducts (Fig. 13.4).

FIGURE 13.3 Intraductal Squamous Carcinoma. This needle core biopsy sample shows two contiguous ducts occupied by centrally keratinizing, well-differentiated squamous carcinoma.

FIGURE 13.4 Squamous Metaplasia in a Hyperplastic Duct. Benign squamous metaplasia tends to be more common in ducts closer to the nipple or in the context of reactive changes.

Differential Diagnosis at Needle Core Biopsy

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.

Metaplastic Spindle Cell Carcinoma (MSpCC)

MSpCCs are usually split into two groups having low-grade and intermediate- to high-grade morphology. The two different morphologies correspond to different differential diagnoses and clinical behavior.

MSpCC with Intermediate- and High-grade Morphology

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).

FIGURE 13.5 Metaplastic Carcinoma with High-grade Morphology. A, B: This needle core biopsy sample from a rapidly growing mass in the breast of a 34-year-old woman shows a high-grade malignant tumor composed for most part of spindle cells with a focal epithelial component. B: The carcinomatous component consists of few irregular clusters, whereas the sarcomatoid component is composed of large and bizarre spindle cells. C-H: Needle core biopsy and excision specimens of a mass in the breast of an 85-year-old woman. The needle core biopsy material shows a high-grade malignant spindle and epithelioid neoplasm (C-D). Reportedly, the neoplastic cells were positive for CK7 and SOX10 (not shown). The tumor in the excision specimen has high-grade morphology (E). The neoplastic cells show weak nuclear staining for GATA3. Nuclear staining in the benign epithelium of a duct is also present (arrow) (F). The neoplastic cells show weak nuclear staining for SOX10 (G). The benign epithelium of a duct (arrow) shows focal membranous reactivity but no nuclear staining. The neoplastic spindle cells are strongly positive for keratin 34βE12 (H). This pattern of immunoreactivity supports the diagnosis of carcinoma with high-grade metaplastic spindle cell morphology.

FIGURE 13.5 (continued)

Differential Diagnosis at Needle Core Biopsy

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.

Low-grade Fibromatosis-like Metaplastic Spindle Cell Carcinoma

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).

FIGURE 13.6 Metaplastic Spindle Cell Carcinoma, Low-grade Fibromatosis-like. A, B: The bland spindle cells comprising this “low-grade” metaplastic spindle cell carcinoma are arranged in short and haphazardly fascicles. The storiform pattern is suggestive of metaplastic carcinoma. No obvious epithelial component is seen in the moderately cellular tumor tissue composed of uniform spindle cells, but some of the spindle cells have epithelioid morphology and are arranged in structures that resemble capillaries. Cytokeratin AE1/AE3 reactivity highlights the epithelioid cells (C). D-F: A spindle cell metaplastic carcinoma with bands of keloid-like collagen (D). The neoplastic spindle cells shown in D display nuclear reactivity for p63 (E) and cytoplasmic positivity for 34βE12 (F). G-H: The spindle cell metaplastic carcinoma in this needle core biopsy sample has storiform architecture and no overt epithelial elements.

FIGURE 13.6 (continued)

FIGURE 13.7 Metaplastic Spindle Cell Carcinoma, Low-grade Fibromatosis-like. A tumor with features that resemble an inflammatory lesion. A: The pattern of infiltration into fat and lymphocytic reaction shown in this needle core biopsy specimen were mistaken for fat necrosis. B: Cytokeratin 34βE12 expression is demonstrated in some of the spindle cells.

FIGURE 13.8 Metaplastic Spindle Cell Carcinoma, Low-grade Fibromatosis-like. A: This area in the needle core biopsy specimen has a storiform pattern. B: Another region with a component that resembles (A) on the right. A keloidal area composed of dense collagen and a pseudoangiomatous appearance is shown on the left. These findings resemble an area of scarring. C: A fully developed keloid-like area with prominent spaces between collagen bands. D: Some spindle cells among the collagen bands are immunoreactive for cytokeratin 34βE12. E: A densely cellular metaplastic spindle cell carcinoma. F: Nuclear reactivity for p63 is present in the carcinoma shown in D.

FIGURE 13.8 (continued)

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).

Differential Diagnosis at Needle Core Biopsy

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.

FIGURE 13.9 Primary Mammary Fibromatosis. A, B: This needle core biopsy sampled a mass in the breast of a 32-year-old woman. The spindle cell proliferation is cytologically bland and arranged in broad sweeping fascicles. Blood vessels are conspicuous. C: A β-catenin stain decorates the cytoplasm and the nuclei of nearly all lesional cells; p63 and cytokeratins were negative (not shown). The tumor morphology and immunoprofile support the diagnosis of fibromatosis.

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.

FIGURE 13.10 Metaplastic Carcinoma, Osteocartilaginous Metaplasia. A: The tumor has poorly formed osteoid and chondroid matrix. B: Cytokeratin CAM5.2 expression is demonstrated in spindle and round cells (arrows).

Metaplastic Carcinoma with Heterologous Elements

Metaplastic carcinoma with heterologous elements is traditionally defined as an “overt carcinoma with direct transition to a cartilaginous and/or osseous stromal matrix without an intervening spindle cell zone or osteoclastic cells” (54). Some carcinomas show only matrix production (Fig. 13.10), whereas others have foci that resemble cartilage (Fig. 13.11); osteosarcomatous, rhabdomyosarcomatous, liposarcomatous, and angiosarcomatous metaplasia are less common (Fig. 13.12).

Epithelial foci with glandular and/or squamous morphology are usually present. Myxoid areas are also common (Fig. 13.13).

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Metaplastic Carcinoma Including Low-grade Adenosquamous Carcinoma
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