Spindle Cell Lesions of the Breast: A Diagnostic Algorithm

The Table lists the classification of common spindle cell lesions of the breast, and is not exhaustive. Morphologically, spindle cell lesions can be simply classified into biphasic or monophasic, further subdividing into low-grade and high-grade lesions in each group. In the biphasic category, low-grade lesions include fibroadenoma, benign phyllodes tumor, hamartoma, adenomyoepithelioma, and pseudoangiomatous stromal hyperplasia (PASH); high-grade lesions include borderline/malignant phyllodes tumor and biphasic metaplastic carcinoma. In monophasic spindle cell lesions, the main considerations in the low-grade category include reactive spindle cell nodule, nodular fasciitis, desmoid fibromatosis, fibromatosis-like metaplastic carcinoma, and myofibroblastoma; the high-grade category includes spindle cell metaplastic carcinoma, primary breast sarcoma, and metastases.

Fibroadenoma is the most common low-grade biphasic lesion, and usually presents as a painless, solitary, firm, slow-growing, and well-defined mass less than 3 cm. Fibroadenoma is hormone sensitive and may grow rapidly during pregnancy. Histologically, the stromal component is usually of low, uniform cellularity. The stromal cells are bland looking; mitosis is uncommon. Focal hypercellularity can be seen, especially in young women. Myxoid change, hyalinization, calcification, ossification, lipomatous component, and smooth muscle and osteochondroid metaplasia may occur. The presence of bizarre multinucleated giant cells does not upgrade the tumor. The stroma expansion can either grow around open ducts in a circumferential fashion to form a pericanalicular pattern or compress the ducts into clefts to form an intracanalicular pattern (Figure 1, A). The epithelial component may show squamous metaplasia, apocrine metaplasia, and usual ductal hyperplasia. Fibroadenoma may infrequently be involved by atypical ductal/lobular hyperplasia, ductal/lobular carcinoma in situ, and invasive carcinoma.^5,6  Complex fibroadenoma is a subtype of fibroadenoma harboring at least one of the following features: papillary apocrine metaplasia, sclerosing adenosis, epithelial calcifications, and cysts larger than 3 mm. Although its risk for breast cancer is not well established, complex fibroadenoma does not confer increased breast cancer risk beyond that of other established histologic features in a large cohort.⁷  The stroma cells can be immunoreactive to CD34 and β-catenin (nuclear staining).⁸  About 60% of fibroadenomas harbor MED12 mutation in the stromal component, revealed by sequencing study, and this mutation is associated with estrogen-signaling dysregulation and extracellular matrix organization.⁹  Diagnosis of the majority of fibroadenomas is straightforward, and ancillary tests are unnecessary. However, cellular fibroadenoma of pronounced intracanalicular pattern and juvenile fibroadenoma may need to be differentiated from benign phyllodes tumor, as will be discussed in the corresponding sections.

Benign phyllodes tumor is a well-circumscribed fibroepithelial tumor exhibiting a prominent intracanalicular pattern with leaflike stroma fronds lined by luminal epithelium and myoepithelial cells (Figure 1, B). The stroma is usually mildly cellular. The lack of frank cytologic atypia and the low mitotic activity (<5 per 10 high-power fields), together with the absence of stromal overgrowth or malignant heterologous element, confirm the diagnosis. As with fibroadenoma, presence of giant cells does not represent a high-grade lesion.¹⁰  One commonly encountered problem is the distinction of benign phyllodes tumor from cellular fibroadenoma. Although the presence of phyllodal fronds, stromal mitotic rate less than 2 per 10 high-power fields, elevated Ki67 index, stromal overgrowth, core fragmentation, adipose tissue infiltration, and subepithelial stromal condensation^11–15  favor phyllodes tumor more than cellular fibroadenoma, an accurate distinction may still be problematic, particularly in CNB, as some of the histologic features overlap. The interobserver variability in classification of these lesions is very high, even among breast pathology experts, and agreement was as low as 9.5% (2 of 21 cases) in challenging cases.¹⁶  Around 20% (3 of 14 cases) of benign phyllodes tumors were diagnosed as fibroadenoma by a substantial percentage of pathologists in a recent study.¹⁷  Thus, in some cases, there is a practical difficulty of accurate differentiation; also, the generally reported recurrence rate for benign phyllodes tumor is 10% to 17%,¹⁸  which is similar to the recurrence rate of up to 17% in fibroadenoma.^19,20  Although the traditional management goals of phyllodes tumor and fibroadenoma differ, with surgeons preferring to achieve a negative excision margin for the phyllodes tumor, there is a recent trend to adopt expectant management in those benign phyllodes tumors with a positive margin at initial excision.^21–23  The World Health Organization consensus group recognizes these issues in CNB and suggests the term benign fibroepithelial tumor in the event of uncertainty.¹⁸ 

For benign phyllodes tumor, the IHC marker expression is similar to that of fibroadenoma. MED12 mutation is also prevalent in benign phyllodes tumor, with the reported mutation rate ranging from 58% to 88%.^9,24,25  The comparable MED12 mutation rate to that of fibroadenoma supports their close molecular relationship.

Breast hamartoma is a well-circumscribed, generally encapsulated mass composed of normal breast tissue components. Conventionally, it is not considered a spindle cell lesion, but the extremely rare myoid subtype contains bundles of smooth muscle tissue, resulting in spindle cell morphology.²⁶  Diagnosis of hamartoma on excisional specimen is usually straightforward, but its recognition in CNB is difficult. The clues include intralobular fibrosis and encapsulated fat. Correlation with the imaging findings and clinical impression is useful.

Adenomyoepithelioma is a rare breast tumor, and its true incidence is unknown. It is a biphasic tumor composed of a variable number of myoepithelial cells surrounding epithelial-lined space.

Five variants of adenomyoepithelioma have been described, namely spindle cell, tubular, lobulated, papillary, and adenosis.²⁷  The variant relevant to the context of this review is spindle cell adenomyoepithelioma. It features prominent spindle cell proliferation compressing glandular architecture, which can become inconspicuous. The diagnosis of adenomyoepithelioma can be challenging in CNB because of the morphologic heterogeneity, and the sampled tissue may even be misinterpreted as invasive carcinoma. Scrutinizing the sampling and performing ancillary tests to identify dual cell populations are helpful. Immunohistochemically, the myoepithelial cells and epithelial cells can be revealed by antibodies specific to these 2 components, such as AE1/3, EMA, CAM5.2, and CK7 for the glandular epithelial cells and p63, CK5/6, CK14, smooth muscle myosin heavy-chain (SMMHC), SMA, calponin, muscle-specific actin (MSA), CD10, and S-100 protein for the myoepithelial cells. One needs to note that the myoepithelial cells are often subtly and weakly reactive to AE1/3,²⁸  and this should not be interpreted as one cell population.

The majority of adenomyoepitheliomas are benign, and complete excision is curative. Rarely, malignant transformations are also documented.²⁹  The malignant components can arise from either the epithelial or myoepithelial components, or even both, and this is termed as malignant adenomyoepithelioma in the fifth World Health Organization classification of breast tumors.²⁹ 

PASH is a stromal myofibroblastic proliferation resembling a vascular lesion. Usually it is an asymptomatic incidental finding. Occasionally, it may present as a palpable mass or associated with other breast tumors, including hamartoma, fibroadenoma, phyllodes tumor, etc. PASH is characterized by complex interanastomosing channels resembling vascular spaces lined by bland spindle cells in a paucicellular or fibrotic background (Figure 1, C). Fascicular area with obliteration of pseudoangiomatous space is a common finding. The spindle cells are positive for CD34, SMA, and desmin and negative for endothelial markers. The expression of hormonal receptors supports hormonal dependency. Expression of progesterone receptor (PR) is intense and more frequent than that of estrogen receptor (ER).³⁰  Previous studies suggested CNB is an adequate sampling modality to appropriately diagnose PASH, obviating the need for further surgical biopsy when pathology is considered concordant with imaging findings.³¹ 

Malignant phyllodes tumors are less common than benign phyllodes tumors, accounting for 8% to 20% of all phyllodes tumors.¹⁸  Malignant phyllodes tumors feature leaflike stromal fronds, permeative tumor border, cellular stroma with marked cytologic atypia, abundant mitosis (≥5 mitoses/mm²), and stromal overgrowth (Figure 2, A). The presence of malignant heterologous elements may confirm a diagnosis of malignant phyllodes tumor even in the absence of other features. However, the finding of pure well-differentiated liposarcoma does not upgrade a phyllodes tumor because of the low accompanying metastatic risk.³² 

Not a typical high-grade tumor, borderline phyllodes tumor is the lesion between its benign and malignant counterparts. Its diagnostic criteria are not well defined. A diagnosis of borderline phyllodes tumor is made when some but not all adverse stromal features are seen. Diagnostic agreement of borderline phyllodes tumor is suboptimal, with a concordance rate being less than 50%.¹⁷  In spite of the association of tumor grade with expression of biomarkers, including Ki67, CD10, CD117, CD34, and p53,^33–36  their use in defining tumor grade and potential clinical behavior in specific cases remains limited. Recurrent MED12 mutations are also present in both borderline and malignant phyllodes tumors, although malignant tumors have a lower rate.^9,24,25  In routine practice, it is recommended to examine multiple slides and process more tissue, which may lead to upgrading some cases to the malignant category.¹⁷  Seeking a second opinion is also advised when encountering such cases.

Metaplastic carcinoma is a group of histologically diverse neoplasms characterized by differentiation of the neoplastic epithelium into squamous cells and/or mesenchymal-looking elements. Based on morphologic features, metaplastic carcinoma is subclassified into low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, spindle cell carcinoma, squamous cell carcinoma, metaplastic carcinoma with heterologous mesenchymal element, and mixed metaplastic carcinoma. As one of the differential diagnoses in the biphasic high-grade spindle cell lesion group, high-grade biphasic metaplastic carcinoma will be discussed here. High-grade biphasic metaplastic carcinoma is composed of a malignant epithelial component with glandular or squamous differentiation, as well as spindle cells in variable arrangements with severe atypia and pleomorphism (Figure 2, B), sometimes with heterologous mesenchymal components, including chondroid, osseous, rhabdomyoid, and neuroglial components.

Within this category, the accurate differentiation between malignant phyllodes tumor and biphasic spindle cell metaplastic carcinoma is crucial. Although metaplastic carcinoma rarely occurs in phyllodes tumor,³⁷  the architectural hallmark of leaflike fronds surmounted by benign glandular epithelium serves to delineate phyllodes tumor from its mimic. Biphasic spindle cell metaplastic carcinoma contains varying amounts of epithelial components, which may be squamous, glandular, or adenosquamous, all of which are frankly malignant. In cases where the spindle cell component predominates, the identification of the epithelium can be very challenging, especially in the setting of CNB. Diffuse immunoreactivity to cytokeratin or p63 supports the diagnosis of metaplastic carcinoma,^38,39  but focal p63 and cytokeratin expression should be interpreted with caution, as these expressions have been reported in the stromal cells of phyllodes tumor.^40,41  Adequate to extensive sampling and meticulous morphologic assessment remain the golden rules of diagnosis, and should be supplemented by clinical, radiologic, and IHC correlation.

Reactive spindle cell nodule is a benign, nonneoplastic postoperative reactive lesion. Usually it occurs within a month following any breast procedures, including fine-needle aspiration, CNB, excision, and trauma. Histologically, it features a vague proliferation of spindle cells with a mild to moderate degree of nuclear pleomorphism with prominent nucleoli, with mononuclear inflammatory cells, foreign body–type giant cells, foamy macrophages, and hemosiderin-laden macrophages and granulation tissue seen in the background (Figure 3, A). Mitosis is sometimes visible. Occasionally, entrapped epithelial elements are intermixed with the proliferating spindle cells,⁴²  and these should not be misinterpreted as metaplastic carcinoma. The spindle cells are myofibroblasts expressing SMA, MSA, and vimentin. Ancillary tests are usually unnecessary, and the diagnosis is usually straightforward when the history of trauma or procedures is known.

Nodular fasciitis is a benign and self-limited spindle cell neoplasm triggered by local trauma or injury. Clinically it can mimic malignancy because of its rapid growth. Breast involvement of nodular fasciitis is extremely rare. Generally, the lesion shows a circumscribed nodular mass with varying degrees of encapsulation. In the largest case series of nodular fasciitis of breast, almost all cases showed at least focal infiltration into adjacent tissue.⁴³  This finding should not be misconstrued as invasive malignancy. Other diagnostic features include myxoid stroma, microcystic change, uniform spindle cells, and extravasated erythrocytes and lymphoid cells. Mitotic figures are frequently encountered and can occasionally be numerous. The spindle cells are of myofibroblastic lineage and are immunoreactive to SMA and vimentin. USP gene rearrangement has been reported in 75% (9 of 12 cases) of breast nodular fasciitis in the largest cohort.⁴³ 

Myofibroblastoma is a benign tumor predominantly seen in postmenopausal women and older men without sex predilection. The classical morphologic features are short fascicles of myofibroblasts with bland nuclei and indistinct pale cytoplasm with indistinct cell borders in a background with thick and ropy collagen bundles. Recently, myofibroblastoma has been thought to belong to a heterogeneous group of tumors exhibiting a wide spectrum of morphologic features including infiltrative growth pattern, myxoid change, deciduoid change, lipomatous change, cartilaginous differentiation, epithelioid change, and high cellularity with cytologic degenerative atypia.^44–47  The epithelioid features and infiltrative growth pattern may mimic invasive carcinoma, thus requiring careful interpretation. Negative cytokeratin immunoreactivity helps to rule out invasive carcinoma. Desmin and CD34 are expressed in the majority of myofibroblastomas, with their expression rates being 91% and 89%, respectively, and their coexpression is detected in 84% of cases.⁴⁴  Coexpression of desmin and CD34, as well as positivity of ER, PR, and AR, is useful in differentiation from other low-grade monomorphic spindle cell lesions. A 13q14 deletion resulting in loss of the RB gene is confirmatory by fluorescence in situ hybridization in 70% to 80% of cases,⁴⁸  and loss of RB staining is found in 90% of cases.⁴⁹ 

Desmoid-type fibromatosis is a locally invasive tumor that does not metastasize. It rarely involves the breast. Most of these tumors are sporadic, and a subset occurs in familial adenomatous polyposis patients with germline APC gene inactivation. In desmoid-type fibromatosis, bland-looking fibroblasts and myofibroblasts are arranged in characteristic hypocellular, long, sweeping fascicles (Figure 3, B). The fibroblastic cells infiltrate normal ducts and lobules, adipose tissue, and skeletal muscle, thus mimicking an invasive process. Mitosis is rare. Background stroma exhibits thickened collagen resembling keloid. Nuclear staining of β-catenin is a key IHC indicator for desmoid fibromatosis, and it has been detected in 80% of cases.⁵⁰  However, this is not specific, as aberrant nuclear staining of β-catenin is also observed in 23% of metaplastic carcinomas and up to 93% of benign phyllodes tumors.⁵¹  The use of β-catenin as a single confirmatory marker is not recommended. Most sporadic cases harbor CTNNB1 gene mutation, and demonstration of this can facilitate the diagnosis in problematic cases.

Fibromatosis-like metaplastic carcinoma is a morphologically low-grade variant of metaplastic carcinoma resembling fibromatosis. These tumors can be locally aggressive with an increased incidence of local recurrence, but the potential for lymph node or distant metastasis is low.⁵²  This tumor shows spindle cell proliferation of low to moderate cellularity forming wavy fascicles with infiltrating edges entrapping adjacent breast lobules. The spindle cells are bland looking, and they exhibit pale eosinophilic cytoplasm and slender nuclei with tapered edges. Focal plump or more epithelioid cells are often present. The stroma shows varying degrees of collagenization. The diagnosis is potentially challenging, particularly in CNBs, because of the morphologic overlap with other low-grade spindle cell lesions. A panel of IHC markers is necessary in making the diagnosis, especially in the distinction from fibromatosis. Reactivity to cytokeratin and to p63, as well as lack of SMA expression and nuclear β-catenin staining, are the key features in distinction from fibromatosis.

Monophasic spindle cell metaplastic carcinoma is an aggressive metaplastic carcinoma. The tumor cells are spindle but highly pleomorphic, and the cells can be variably arranged from long herringbone fascicles to short storiform fascicles (Figure 4, A).⁵³  Frank carcinomatous features, including prominent cellular cohesion, glandular formation, and squamous differentiation, are usually lacking. In spite of this, subtle cellular cohesion may be appreciated, at least focally. A diagnosis can be rendered based on the evidence indicating epithelial differentiation by histopathologic and/or IHC analysis (Figure 4, B), as discussed previously (see Biphasic Spindle Cell Metaplastic Carcinoma).

Primary breast sarcoma, arising from mesenchymal breast tissue, is extremely rare, and accounts for less than 1% of all primary breast malignancies and no more than 5% of all sarcomas.⁵⁴  Breast sarcomas usually have a poor prognosis, with high risk of recurrence, 80% developing during the first 2 years after diagnosis.⁵⁵  Primary breast sarcoma encompasses a heterologous group of lesions, with angiosarcoma being the most common. Angiosarcoma can present either as primary tumor of the breast (primary angiosarcoma of the breast) or as a secondary lesion associated with previous radiotherapy (postradiation angiosarcoma of the breast), which shows a consistent high-level amplification of the MYC gene.⁵⁶  Other sarcomas include leiomyosarcoma, osteosarcoma, rhabdomyosarcoma, liposarcoma, pleomorphic sarcoma, myofibroblastic sarcoma, etc.^57–59  Primary breast sarcomas demonstrate identical morphologic features and IHC profile to their soft-tissue counterparts. A word of caution is in order. As phyllodes tumors and metaplastic carcinoma are more common than primary breast sarcoma, the former need to be excluded before a diagnosis of primary breast sarcoma can be made with confidence.

Metastases to the breast are malignancies in the breasts originating from an extramammary site. They are rare, representing 0.2% to 1.3% of breast malignancies. More often the patients have a prior history of malignant tumor, although metastases to the breast may also be the first sign of an extramammary breast primary malignancy. Metastatic spindle cell squamous cell carcinoma and spindle cell melanoma are potential imitators of high-grade spindle cell lesions. Relevant clinical history is the most important clue for diagnosis, further supported by ancillary site-specific IHC tests.

An algorithmic approach has been proposed for refining the diagnosis of spindle cell lesions of the breast (Figure 5).

With extensive sampling to exclude epithelial entrapment, spindle cell lesions of the breast are simply classified into biphasic and monophasic, and each category is further subclassified into low-grade and high-grade lesions. In the biphasic low-grade group, fibroadenoma and benign phyllodes tumor are the most common lesions. The distinction relies on the cellularity of the spindle cells and the predominance of an intracanalicular pattern. Other uncommon lesions in this category include hamartoma, adenomyoepithelioma, and PASH. For the biphasic high-grade group, borderline/malignant phyllodes tumor and biphasic metaplastic carcinoma are the main lesions to consider. The presence of fronded benign epithelial clefts or malignant epithelial component, with or without the molecular study of MED12 mutation, are the diagnostic clues. In the monophasic low-grade group, reactive spindle cell nodule, nodular fasciitis, myofibroblastoma, fibromatosis, and fibromatosis-like metaplastic carcinoma have to be considered. The former 2 exhibit reactive growth features, whereas the latter 3 demonstrate a fascicular growth pattern. A known history of trauma or procedure facilitates the diagnosis of reactive spindle cell nodule, and USP gene rearrangement confirms nodular fasciitis. Cytokeratin negativity with diffuse β-catenin nuclear staining suggests fibromatosis, which can be further supported by the genetic study of CTNNB1 mutation. Fibromatosis-like metaplastic carcinoma is immunoreactive to cytokeratin and p63, but not to β-catenin. Myofibroblastoma shows its distinct morphology and immune profile of coexpression of desmin with CD34, ER, PR, and AR. In the monophasic high-grade group, the possible lesions are monophasic spindle cell metaplastic carcinoma, primary breast sarcoma, and metastases. Knowing the clinical history and demonstrating the epithelial differentiation with a wide IHC panel are crucial in the distinction.