Fibromatosis is an infiltrating, histologically low-grade, spindle cell proliferation composed of fibroblastic cells and variable amounts of collagen. Other terms applied to this lesion include extra-abdominal desmoid, low-grade fibrosarcoma, and aggressive fibromatosis, but most authors prefer the designation of fibromatosis.

Patients with mammary fibromatosis range from 14 to 83 years at diagnosis. Three series (1,2,3) report average ages from 37 to 49 years. Females are more commonly affected than males. Patients with mammary fibromatosis almost always present with a palpable, firm or hard tumor, which may suggest carcinoma on clinical examination. Dimpling or retraction of the skin may reinforce this clinical impression. Fibromatosis affects the left and right breasts approximately equally. It rarely involves the subareolar region. The masses are usually painless, but pain and tenderness have been described. Several cases of bilateral mammary fibromatosis have been reported; in most of the cases, the bilateral tumors presented simultaneously (4). Fibromatosis has arisen in axillary breast tissue (5).

Antecedent injury from trauma or surgery was noted in a few cases, and several examples developed following breast augmentation (1,6,7,8). The tumors came to attention after a mean interval of 3 years from the time of implant placement. They are typically unilateral and arise in or around the implant capsule. Current evidence does not suggest that the biomaterials by themselves cause fibromatosis. Rare examples of mammary fibromatosis have been associated with familial adenomatous polyposis, a condition in which somatic fibromatosis (desmoid tumor) frequently occurs (4). Other potential predisposing genetic conditions are not known. The positive family history of breast carcinoma mentioned in a few case reports is probably coincidental. Rarely, patients had invasive ductal carcinoma of the contralateral breast. A 22-year-old woman developed unilateral mammary fibromatosis 5 years after treatment of Hodgkin’s disease by chemotherapy alone (1). Despite the frequent association of abdominal desmoid tumors with pregnancy, only a few cases of mammary fibromatosis have been pregnancy-related. It seems likely that the two conditions occasionally coexist because of the broad age range of women with fibromatosis, many of whom are younger than 40 years.

Mammography reveals a stellate tumor that may be indistinguishable from carcinoma. Calcifications are rarely formed in mammary fibromatosis, but they may be present in a benign lesion such as sclerosing adenosis, which has been engulfed by the tumor.

The sizes of reported tumors vary from less than 1 to 17 cm and average 2.5 to 3.0 cm (1,2,9,10,11). Some examples of fibromatosis have a distinct stellate configuration; others are described as circumscribed or well-demarcated nodules. The masses consist of firm, white, tan, or gray fibrous tissue. Occasionally, the cut surface is said to have a whorled or trabecular appearance.

The histologic features of mammary fibromatosis are identical to those of the lesion when it develops in extramammary sites. Although the mass often exhibits varied growth patterns, spindle cells and collagen constitute consistent components. The spindle cells are usually distributed in broad sheets,
sometimes in a storiform configuration, or in interlacing bundles with a herringbone pattern. The cells usually have small, pale, oval or spindly, uniform nuclei (Fig. 20.1). Nuclear atypia and pleomorphism are uncommon. Mitotic figures are inconspicuous or undetectable in most cases, although a rate of 3 mitotic figures per 10 HPF has been reported (1). Areas in which the collagenous element overshadows the spindle cells have a keloidal appearance (Fig. 20.2). In certain tumors, the center appears more fibrous than the periphery, whereas others exhibit more pronounced collagenization in the outer regions. Myxoid areas sometimes occur. Focal lymphocytic infiltrates, some with germinal centers, are found in nearly half of the tumors (Fig. 20.3) and usually appear more prominent at the periphery. Small blood vessels are evenly distributed throughout the tumor. Stromal calcification is seen rarely.

Cytoplasmic inclusion bodies identical to those seen in infantile digital fibromatosis have been described in two mammary tumors that appear to be fibromatosis (12). Round eosinophilic cytoplasmic inclusions measuring 3 to 10 µm were observed in the cytoplasm of tumor cells, often in a juxtanuclear location. The inclusions stained red with Masson’s trichrome but did not stain with the periodic acid-Schiff method, nor did they stain for cytokeratin, desmin, or S-100. A ring of immunoreactivity for muscle-specific actin was apparent around the inclusion bodies. Similar inclusions in mammary fibroepithelial neoplasms consist of tightly packed actin filaments. These findings suggest that myofibroblasts play a role in this form of mammary fibromatosis.

No matter how well demarcated the masses appear grossly, all have invasive stellate extensions into the surrounding mammary parenchyma. It is generally possible to identify mammary ducts and lobules engulfed by these peripheral extensions (Fig. 20.4). The appearance created in these infiltrative areas may mimic the growth pattern of a phyllodes tumor. Glandular parenchymal elements are less conspicuous or absent toward the center of the mass. Rare cases of fibromatosis are entirely or almost entirely limited to the mammary subcutaneous fat with little or no parenchymal involvement.

The surrounding breast parenchyma usually appears inactive. Mild epithelial hyperplasia is sometimes present in ducts trapped by the infiltrating extensions of the tumor.

Nuclear localization of β-catenin, commonly seen in somatic fibromatosis, is also seen in mammary fibromatosis. Among 53 examples of mammary fibromatosis pooled from three series (9,11,13), 83% demonstrated nuclear β-catenin reactivity. The majority showed diffuse and intense nuclear staining, although occasional tumors demonstrated only focal reactivity. Nuclear staining for β-catenin is not limited to fibromatosis. One can observe it in spindle cell carcinomas, phyllodes tumors, and fibroadenomas. The intensity of the staining in the latter lesions varies, but it can appear moderate to strong, particularly in fibroepithelial tumors. The absence of β-catenin reactivity does not exclude the diagnosis of fibromatosis.

The spindle cells of fibromatosis virtually never react for CD34, but they demonstrate variable reactivity for actin and desmin. Anecdotal observations suggest that actin and desmin reactivity may be more common in subcutaneous than in parenchymal fibromatosis. The tumor cells are negative for cytokeratin. Mammary fibromatosis usually does not stain for estrogen receptor (ER)-α or progesterone receptor (PR).

It seems that pathologists do not commonly consider the diagnosis of fibromatosis when examining a needle core biopsy (NCB) specimen composed of bland spindle cells. In one group of 12 cases (11), the diagnosis of fibromatosis was either suggested or proposed in just three. Diagnoses such as fibroadenoma and stromal fibrosis were proffered for the remaining nine specimens.

The differential diagnosis of mammary fibromatosis includes neoplasms such as fibrous histiocytoma, spindle cell carcinoma, and sarcoma. Mammary fibromatosis may have storiform areas, but rarely does this pattern dominate, as it does in fibrous histiocytomas; furthermore, the epithelioid, histiocytic, and multinucleated cells often found in fibrous histiocytoma are not features of fibromatosis. One would not confuse spindle cell carcinomas showing obvious squamous or glandular elements with mammary fibromatosis, but certain spindle cell carcinomas are virtually devoid of such epithelial elements. One feature favoring metaplastic carcinoma or sarcoma is a highly cellular and pleomorphic spindle cell component with mitoses. Although a mitotic rate of 3 per 10 HPF has been described in fibromatosis, this value is exceptional, and such a lesion is more likely to be a low-grade malignant tumor. The typical mitotic rate in fibromatosis does not exceed 1 per 10 HPF, and usually one cannot find mitotic figures. Nuclear reactivity for Ki67 is very much lower in fibromatosis than in spindle cell carcinoma or sarcoma. An inflammatory reaction, which may be predominantly lymphocytic, occurs more diffusely in and around most metaplastic carcinomas than it does in fibromatosis. Immunoreactivity for proteins such as cytokeratin, p63, and CD10 characterizes metaplastic carcinoma, whereas nuclear reactivity for β-catenin commonly occurs in fibromatosis.

One can also confuse mammary fibromatosis with reparative and reactive processes. Scars from healed fat necrosis, remote trauma, and surgery must be distinguished from fibromatosis. Calcifications are more likely to be associated with fat necrosis, but they can occur in fibromatosis rarely. Foreign body granulomas, sometimes with partly absorbed suture material, indicate prior surgery. If the patient has recurrent fibromatosis, reparative changes caused by an earlier operation may mingle with recurrent tumor, further complicating the diagnosis. The presence of lymphoid infiltrates, which commonly occur in fibromatosis, should not lead to the erroneous diagnosis of an inflammatory condition such as nodular fasciitis. The inflammatory component of fibromatosis is typically limited to isolated separate lymphoid aggregates at the periphery of the lesion. In fasciitis, inflammatory cells are dispersed more diffusely at the periphery as well as within the lesion, although localized areas of inflammation also occur. Myoid and multinucleated cells characteristically found in nodular fasciitis are not a feature of fibromatosis.

Recommended treatment is wide local excision. When a tumor is adherent to fascia, muscle, or skin, the excision should be extended to include the involved tissue, and it may be necessary to perform a mastectomy to achieve adequate margins of resection around a bulky tumor.

Immediate re-excision of the biopsy site should be considered if the initial excision removed only a small amount of tissue, or the margins are positive. Re-excision seems especially important for lesions located deep in the breast or near the chest wall, because recurrences at these sites may be difficult to control. On the other hand, follow-up is preferable to re-excision for relatively superficial lesions or subareolar nodules, which might require excision of the nipple.

The frequency of local recurrence ranges from 23% to 29% (1,2,3,10). Although the risk of recurrence is higher in patients with positive margins, recurrences have been observed in cases with apparently negative margins. Patients with positive margins do not always develop recurrences, and locally advanced lesions have stabilized or regressed after incomplete excision (3). Most recurrences occur within 3 years of diagnosis; however, in a few instances, they were not detected for nearly a decade. Multiple recurrences have been documented (10). Evaluation of histologic features such as cellularity, mitotic activity, and cellular pleomorphism does not help to predict recurrence.

Oncologists have used irradiation, hormonal therapy, and chemotherapy to treat cases of fibromatosis arising outside the breast, but none of these approaches represents an established modality for the treatment of mammary fibromatosis.

Nodular fasciitis is a benign reactive fibroblastic and myofibroblastic proliferation. Although it is a common tumor-like lesion of the soft tissues, it affects the mammary gland only rarely. Most reports illustrate superficial, palpable nodules, but masses abutting the deep fascia have been described as well (14,15). A few descriptions (16,17) mention the presence of mammary glands at the edges of the masses, but none of the publications provides clear evidence that the nodules arose within the mammary parenchyma. Nevertheless, clinicians usually regard such nodules as breast masses, and pathologists must distinguish these tumors from spindle cell carcinoma with a fasciitis-like appearance and from fibromatosis. Because the latter two lesions involve the mammary glandular tissue, attention to the location of a mass as well as its morphologic characteristics provides important diagnostic information.

Nodular fasciitis of the mammary region occurs in both females and males. The ages of the patients range from 15 to 84 years. Most patients present with a recently discovered, palpable firm mass and they often describe rapid enlargement of the mass. Prior trauma is not usually mentioned.

The radiographic findings are often suspicious for carcinoma. Mammography demonstrates a high-density mass with spiculated or irregular margins, and ultrasonography reveals a hypoechoic mass with irregular borders (14,15,18). Magnetic resonance imaging (MRI) may also suggest the presence of a malignancy (19).

In a literature review by Squillaci et al. (18), reported examples ranged from 1 to 7 cm with an average size of 2.4 cm. The typical example is a firm, white-gray mass, which may display gelatinous areas.

The proliferative spindle cells form short bundles and fascicles randomly dispersed in a loose myxoid stroma (Fig. 20.5). The appearance is often described as having a feathery or tissue culture-like quality. Older lesions show greater collagenization. The spindle cells have bipolar to oval nuclei with delicate chromatin and small nucleoli. Atypia is lacking. Cellularity is high in early lesions, and mitotic activity may be brisk. Inflammatory cells, extravasated red blood cells, and prominent thin-walled vessels are present within the nodule. The borders of the mass are irregular. Benign ducts and lobules can become entrapped in the proliferation, but they usually do not do so.

The spindle cells in nodular fasciitis are positive for smooth muscle actin (SMA) and muscle-specific actin. The proliferative cells do not stain for CD34, nor do their nuclei stain for β-catenin. The cells are typically negative for keratin, but rare spindle cells may stain using the keratin AE1/AE3 mixture.

The differential diagnosis includes spindle cell carcinoma, fibromatosis, myofibroblastoma, and sarcoma. Spindle cell carcinoma can closely mimic the appearance of nodular fasciitis. The presence of nuclear atypia, clustered cell aggregates, or in situ carcinoma favors a diagnosis of spindle cell carcinoma. Some spindle cell carcinomas consist of bland cells that lack overt epithelial differentiation. Immunohistochemistry can be helpful to clarify the diagnosis in such cases, because spindle cell carcinoma usually demonstrates at least some reactivity for one or more cytokeratins and for p63. Fibromatosis is characterized by longer, sweeping fascicles and greater infiltration of the surrounding parenchyma, and most cases display nuclear reactivity for β-catenin cases. Myofibroblastoma demonstrates more clearly defined fascicles intermixed with conspicuous bands of bright, eosinophilic collagen. The usual example appears sharply circumscribed and stains for CD34. The absence of nuclear atypia and pleomorphism helps to distinguish nodular fasciitis from sarcoma.

Nodular fasciitis is a benign, self-limited process. Several reports document spontaneous resolution of mammary lesions within 3 to 6 months from the time of diagnosis (14,15,20). A conservative approach that includes careful and close monitoring for several months may provide adequate treatment for certain patients. Nevertheless, it may be difficult to exclude the diagnosis of other lesions such as spindle cell carcinoma based on the findings in a NCB sample, and excision of the mass should be considered in most circumstances. Recurrence after surgical excision is rare.

Fibrous tumor (focal fibrous disease) presents as a discrete breast mass composed of collagenized mammary stroma. It was first characterized by Haagensen as fibrous disease. Other names given to this entity include fibrous mastopathy, fibrosis of the breast, and focal fibrous disease. Because of the clinical presentation as a distinct mass, the term fibrous tumor is preferable to distinguish it from more frequent, nonspecific, and involutional stromal changes (21). A few tumors illustrated and described as focal fibrous disease and fibrous tumor appear to be examples of pseudoangiomatous hyperplasia of mammary stroma. On the other hand, certain cases sampled by NCB and classified as focal fibrosis probably represent examples of fibrous tumor (22).

Fibrous tumor is a disease of premenopausal women. Harvey et al. (23) studied 14 patients with “fibrous nodules,” which appear to correspond histologically to fibrous tumors. Ten patients (71%) were premenopausal, and three of the four postmenopausal women were receiving hormone replacement therapy. On palpation, fibrous tumor is a firm to hard, distinct tumor measuring 2 to 5 cm. Skin retraction and dimpling are not evident. Many examples are not palpable and are detected only by radiologic imaging.

Mammography often reveals a mass, asymmetric density, or architectural distortion, but imaging sometimes fails to disclose the lesion. When demonstrated, the abnormality may display a round, oval, irregular, or spiculated shape with either well-defined or indistinct margins (23). Calcifications are usually not a feature of fibrous tumor, but they have been reported in one example (24).

Fibrous tumor forms a firm to hard mass spanning a few centimeters. The excised specimen typically has the appearance
of a discrete tumor composed of white, homogeneous rubbery tissue.

Fibrous tumor consists of collagenous stroma that contains markedly decreased or absent ductal and lobular elements, which are atrophic. The findings in a NCB specimen are not specific and are usually reported as fibrosis (Fig. 20.6). Capillaries, other vascular structures, and nerves are very sparse; perivascular and perilobular inflammatory infiltrates are absent. Cysts, apocrine metaplasia, sclerosing adenosis, and duct hyperplasia are not features of fibrous tumor. One could suggest the diagnosis of fibrous tumor when a NCB sample from a nonpalpable, relatively discrete mammographically detected lesion consists of hypocellular collagenous tissue devoid of glandular structures.

Fibrous tumor is a benign, self-limited stromal proliferation adequately treated by local excision.

Pseudoangiomatous hyperplasia of mammary stroma (PASH) is a benign stromal proliferation characterized by the formation of slit-like spaces within dense collagenous stroma. The term “pseudoangiomatous” was introduced by Vuitch et al. (25) to
acknowledge the vascular-like appearance of the stromal proliferation. It has been suggested that the spaces in PASH are part of a prelymphatic pathway (26). The presence of myoid differentiation in examples of PASH has led some authors to classify certain examples as hamartomas; however, PASH is a myofibroblastic proliferation with entrapment of preexisting glandular elements rather than a malformation of mammary tissues.

Pseudoangiomatous stromal hyperplasia appears to be an exaggerated and localized form of physiologic proliferation of stromal cells. Ibrahim et al. (27) found microscopic foci of PASH in 23% of 200 consecutive breast specimens, and Degnim et al. (28) found evidence of PASH in 6% of 9,065 consecutive excision specimens showing only benign lesions. The nonlocalized form of PASH often accounts for the clinical impression of a mass in specimens in which the histologic findings are described as fibrocystic changes. In its localized form, the lesion can give rise to a palpable or radiographically detected mass.

With rare exceptions, reported patients with tumor-forming PASH have been females. The age at diagnosis ranges from 3 to 86 years, and the mean age in several series (25,29,30,31,32,33,34) ranges from 37 to 51 years. The vast majority of women are premenopausal, and postmenopausal women with PASH often have a history of hormone replacement therapy. Rare examples of mass-forming PASH have been described in children and adolescents. One of the youngest patients was a 3-year-old boy, who had a 5.5-cm tumor in the right breast (33). Singh et al. (35) described a menarchal 12-year-old girl with marked bilateral breast enlargement due to PASH. When it occurs in males, PASH usually represents an incidental component of gynecomastia. Investigators have observed nontumorous PASH in 24% to 54% of cases of gynecomastia (36,37), and 98% of samples showing PASH in men also harbored gynecomastia (38). Unusual examples include an 11-cm mass associated with gynecomastia in a 50-year-old man (39), 10-cm masses in both axillae of a 44-year-old man (40), and PASH associated with rapidly growing gynecomastia-like changes in the axilla of an immunosuppressed 39-year-old man (41). Immune system suppression was described in two other cases (42,43).

Patients typically describe a palpable, painless, unilateral mass, which feels rubbery or firm. Although the lesion tends to arise in the upper outer quadrant, any part of the breast, including the subareolar region, can be affected (44). Rare examples are located in the axillary tail (32) or vulva (45). Occasional patients have had asynchronous or concurrent, bilateral PASH. Diffuse breast enlargement is seen rarely, and rapid growth of the lesion may occur (46). One patient presented with unilateral, mildly painful breast enlargement with peau d’orange change suggesting inflammatory carcinoma (27), and peau d’orange change and skin necrosis have been observed during pregnancy in patients who have massive breast enlargement caused by diffuse PASH.

PASH is occasionally an incidental finding in breast specimens containing invasive or in situ carcinoma. The carcinomas and PASH are generally anatomically separate. In one unusual case, a 0.9-cm invasive ductal carcinoma was present within a 4-cm PASH tumor (32).

PASH has been detected by mammography in asymptomatic patients. Mammograms usually demonstrate a mass without calcification or, less frequently, a focal asymmetric density. The borders of the mass usually appear smooth, but the tumor can have spiculated or ill-defined margins sometimes obscured by surrounding tissue. Ultrasound reveals a well-defined hypoechoic mass (31,47). MRI often demonstrates focal or segmental clumped enhancement.

Nodules of PASH appear well demarcated, and the smooth external surfaces sometimes resemble a capsule. The tumors measure from less than 1 cm to 15 cm in greatest dimension and average about 5 cm. Postmenopausal patients tend to have smaller tumors than premenopausal patients (34). The masses usually consist of homogeneous fibrous tan, gray, or white tissue, occasionally containing cysts up to 1 cm in diameter. Hemorrhage and necrosis are not seen except in excised tumors previously subjected to NCB or needle aspiration.

The nodules are composed of intermixed stromal and epithelial elements. Abundant nonspecialized stroma separates the glandular structures. Collagenization of intralobular stroma and attenuation of ducts can create a fibroadenoma-like appearance. Nonspecific proliferative epithelial changes include mild hyperplasia of duct and lobular epithelium, often with some accentuation of myoepithelial cells, and apocrine metaplasia with or without cyst formation.

The most striking histologic finding is a complex pattern of largely empty, often anastomosing spaces in dense collagenous stroma. These slits, sufficiently large to be identified at low magnification, typically involve the perilobular nonspecialized stroma. In florid cases, the pseudoangiomatous changes come to involve the intralobular specialized stroma as well (Fig. 20.7). The spaces may contain a few red blood cells, and collagen fibrils may traverse the spaces. Basement membrane material is not demonstrable around the slit-like spaces. The stroma also contains genuine small blood vessels and capillaries (Fig. 20.8).

Myofibroblasts distributed singly and discontinuously at the margins of the spaces resemble endothelial cells. The nuclei of the myofibroblasts usually appear attenuated. They lack atypia and do not show mitotic activity. In uncommon cases,
some of these cells appear enlarged and they have noticeably hyperchromatic nuclei. Multinucleated cells may rarely line the slit-like spaces (38) (Fig. 20.9). One can find these cells in patients with PASH and neurofibromatosis type I (48), but the presence of multinucleated stromal giant cells is not limited to such patients (37). In an extremely unusual variant of PASH, the myofibroblasts contain cytoplasmic inclusion bodies of the type found in digital fibromas.

Cytologic alterations of myofibroblasts are sometimes encountered in PASH. Pleomorphic nuclei are infrequent, but they can be found in PASH displaying conventional and fascicular patterns, sometimes accompanied by mitotic activity (Fig. 20.10). Several instances of tumor-forming PASH in which the myofibroblasts demonstrate marked cytologic atypia, multinucleation, and mitotic activity have been encountered in teenage girls. These tumors appear to be examples of myofibroblastic sarcoma arising in PASH. The literature does not contain sufficient information to characterize the clinical course of these tumors.

When myofibroblasts accumulate in distinct bundles or fascicles, they give rise to the lesion known as fascicular PASH (Figs. 20.11 and 20.12). The presence of these bundles attests to a more robust proliferation of the myofibroblasts. Examples of fascicular PASH showing extreme myofibroblastic proliferation
display a growth pattern similar to that of myofibroblastomas. This similarity becomes especially evident when the myofibroblasts have abundant cytoplasm and grow as a localized tumor rather than a diffuse process. Myoid differentiation can occur in isolated myofibroblasts. When this phenomenon occurs in many cells, the resulting nodule comes to resemble an ill-defined leiomyoma.

The myofibroblasts lining pseudoangiomatous spaces usually stain for CD34. They exhibit strong immunoreactivity for vimentin and variable immunoreactivity for SMA, muscle-specific actin, and calponin, and they do not show immunoreactivity for cytokeratin, factor VIII-related antigen, or CD31. Fascicular and cellular variants of PASH retain immunoreactivity for CD34 and may be reactive for SMA, desmin, and calponin.

The results of studies of hormone receptor expression by the myofibroblasts in PASH have varied. Bowman et al. (34) found high rates of ER and PR immunoreactivity (79% and 63%, respectively), but most ER-positive cases showed only “occasional” positive cells. The propensity for tumorous PASH to affect premenopausal women and postmenopausal women taking hormone replacement therapy and the frequent coexistence of PASH and gynecomastia also suggest that hormonal factors contribute to the development of PASH.

The recommended treatment for tumorous PASH is local excision. Mastectomy may be necessary to control multiple recurrent tumors (35). A small number of patients have proceeded with clinical observation after a diagnosis of PASH by needle core or other type of percutaneous biopsy. Of 80 such cases with reported follow-up information, 78% had stable disease, 18% showed progression, and 4% had regression or resolution of the imaging findings (31,32). Most lesions that progressed were excised, and pathologic evaluation revealed PASH without atypical features. A few patients continued observation even after initial progression, and further follow-up demonstrated stable disease. Careful clinicopathologic correlation is required in such instances because PASH can be an incidental finding unrelated to the targeted abnormality. Isolated case reports document the response of PASH to selective ER modulators (49,50).

Most patients have remained well after excision of PASH. Ipsilateral recurrences have been reported in 2% to 30% of the patients (25,30), and rare patients have experienced multiple ipsilateral recurrences (30). Recurrent lesions do not ordinarily exhibit increased cellularity or other atypical features; moreover, examples that have recurred do not differ in their histologic attributes from those that did not recur.

PASH is not associated with an increased risk of subsequent breast carcinoma (28).

Myofibroblastoma is a benign tumor composed of myofibroblasts. These spindle-shaped mesenchymal cells occur in small numbers in virtually all tissues outside the central nervous system. When studied by electron microscopy, myofibroblasts, like myoepithelial cells, are found to contain cytoplasmic actin-like microfilaments 5 to 7 nm in diameter with focal dense bodies and pinocytotic vesicles; however, myofibroblasts lack the prekeratin tonofilaments and easily detected desmosomes characteristic of myoepithelial cells. Both types of cells can express actin and calponin, but only myoepithelial cells demonstrate immunoreactivity for high-molecular-weight cytokeratins and p63.

Myofibroblastomas typically afflict middle-aged to elderly patients (age range, 41-87 years; mean, seventh decade) (51,52,53). They are seen in younger patients only exceptionally, but one tumor presented in a 10-month-old boy (54). Although the initial description suggested a male predominance, the tumor occurs in women equally commonly.

Most patients present with a solitary, slow-growing, painless, mobile mass. Progressive enlargement of the tumor may occur over the course of years. In the case reported by Bégin (55), a 77-year-old patient experienced progressive breast enlargement over 7 years, resulting in a 6.5-cm tumor. Very rare tumors demonstrate rapid enlargement, and associated peau d’orange change of the skin has been described in one such case in a 65-year-old man (56). The vast majority of tumors are unilateral. Rare examples of bilateral myofibroblastomas have been reported in males. Two of the lesions described by Toker et al. (57) as “benign spindle cell breast tumors” in men are probably myofibroblastomas. One patient had two identical separate tumors in his left breast, which were treated by simple mastectomy, and 17 years later, he underwent a right mastectomy, which disclosed six foci of the same neoplastic process. A man with synchronous bilateral tumors was reported by Hamele-Bena et al. (52). Concurrent gynecomastia is reported in some patients.

Radiographically, the tumors are homogeneous, lobulated, well circumscribed, and lack microcalcifications (55,58). Mammography has detected nonpalpable myofibroblastomas (59). The findings evident by ultrasonography may suggest the diagnosis of fibroadenoma.

The average diameter of the tumors is approximately 2 cm; most are smaller than 4 cm. Size extremes include one lesion that measured 0.9 cm (52) and one 16-cm tumor (60). The excised mass has a lobulated contour and consists of homogeneous, bulging gray to pink, whorled, or lobulated tissue with a rubbery to firm consistency. An attempt at NCB in one case (61) was not successful because the tumor was “stony hard,” although the excised tumor was not calcified or ossified. Cystic degeneration, necrosis, and hemorrhage have not been reported.

The classic type of myofibroblastoma is devoid of mammary ducts and lobules. The border of the tumor is usually circumscribed, and compressed breast parenchyma forms a peripheral pseudocapsule. A few examples incorporate adipocytes or small collections of glandular tissue into the periphery of the mass, a phenomenon that indicates invasion of surrounding parenchyma. Two distinctive histologic features are bundles of slender, bipolar, uniform spindle cells typically arranged in short fascicles, and intervening broad bands of hyalinized collagen (Fig. 20.13). The spindle cells have bland, ovoid to spindly nuclei with dispersed chromatin and small nucleoli. Nuclear grooves may be present (62). The cytoplasm is typically pale and eosinophilic, and cell borders are indistinct. Mitotic figures are sparse or undetectable. Multinucleated cells are uncommon, and pleomorphic nuclei, which are believed to represent a degenerative phenomenon are encountered only rarely (63,64). Nuclear palisading can create Verocay-like bodies, which would bring to mind the diagnosis of schwannoma (62,65). Rarely, adipocytes are dispersed separately or in small groups throughout the tumor, and certain myofibroblastomas have foci of leiomyomatous or cartilaginous differentiation (51,63,66). One can sometimes
identify a perivascular lymphoplasmacytic infiltrate. Most tumors possess many mast cells.

The histologic features of certain myofibroblastomas deviate from those of the classic type. These variant forms exhibit a spectrum of histologic appearances. A single variant pattern may dominate in a tumor, or several variant patterns may be mixed. In the collagenized or fibrous myofibroblastoma, the spindle cells are distributed in collagenous stroma (Fig. 20.14). The broad, deeply eosinophilic fibrous bands that are so prominent in a classic myofibroblastoma are absent or greatly reduced in number. Irregular slit-like spaces are formed between tumor cells. The stroma is reminiscent of PASH, and some of these tumors have a fascicular structure.

The epithelioid variant of myofibroblastoma features medium to large polygonal or epithelioid cells arranged in alveolar groups (Fig. 20.15). Nuclei are round to oval and may be
eccentrically located. Mild to moderate nuclear pleomorphism can be seen, and scattered binucleated and multinucleated cells are not uncommon (67,68). Mitotic activity is absent or minimal. Epithelioid areas may be mixed with classic elements, or they can constitute the predominant growth pattern. The term epithelioid variant is used arbitrarily for tumors in which more than 50% of the lesion has this histologic pattern. The epithelioid cells in an epithelioid myofibroblastoma with sclerotic stroma can have a linear growth pattern that resembles the appearance of invasive lobular carcinoma. In contrast to invasive carcinoma, epithelioid myofibroblastoma usually has well-circumscribed borders. Rare tumors composed of large cells with abundant glassy cytoplasm and vesicular nuclei have been referred to as a “deciduoid-like” variant (69).

A cellular variant of myofibroblastoma features a dense proliferation of spindle-shaped neoplastic myofibroblasts. Collagenous bands may be absent in some parts of the lesion. These tumors tend to have infiltrative borders. Rarely, cellular and collagenous or fibrous growth patterns are combined in a single tumor.

The infiltrative variant of myofibroblastoma is characterized by invasive growth (Fig. 20.16). One finds bundles of
relatively evenly dispersed spindle, ovoid, and epithelioid cells embedded in collagenous stroma interspersed with fat, mammary stroma, ducts, and lobules. The classic and other foregoing variants of myofibroblastoma ordinarily consist almost entirely of lesional tissue. One sometimes finds small collections of glandular tissue entrapped at the periphery of a typical myofibroblastoma, but commonplace myofibroblastomas do not demonstrate either the abundance or the diffuse distribution of mammary tissues seen in the infiltrative types of myofibroblastoma. Certain infiltrative myofibroblastomas exhibit a peculiar tendency for the neoplastic myofibroblasts to be oriented around blood vessels.

Myxoid myofibroblastomas consist of sparse spindle cells distributed in the myxoid stroma (Fig. 20.17). This variety
of myofibroblastoma often exhibits an infiltrative manner of growth. Certain tumors classified as mucinosis may represent myxoid myofibroblastomas. Magro et al. (70) described a myofibroblastoma with extensive myxedematous stromal change.

Rarely, myofibroblastomas contain abundant fat suggestive of a lipomatous element. The term lipomatous myofibroblastoma has been suggested for this type of lesion (Fig. 20.18) (71,72). An example of a pericytoma-like myofibroblastoma has been described (73).

Most myofibroblastomas, including the epithelioid variety, are immunoreactive for vimentin, desmin, calponin, SMA, muscle actin, CD10, CD34, bcl-2, and CD99. The tumors usually stain for vimentin diffusely, whereas the other markers can show variable reactivity. The tumors do not stain for cytokeratin or factor VIII, and they stain for S-100 protein only rarely and weakly. Myofibroblasts exhibiting overt smooth muscle differentiation are strongly immunoreactive for desmin and variably reactive for actin, SMA, and h-caldesmon. The myofibroblasts often stain for ER, PR, and androgen receptor (AR), although the reactivity can be variable. Fluorescence in situ hybridization studies demonstrated a monoallelic loss of the FOXO1/13q14 locus in one case (65), but another tumor did not show this alteration (68).

Myofibroblastoma must be considered in the differential diagnosis of spindle cell mammary tumors. Sarcoma and metaplastic carcinoma typically display greater cellularity, atypia, and mitotic activity than do myofibroblastomas, and sarcomas and metaplastic carcinomas often exhibit distinctive histologic features. Fasciitis and fibromatosis, which also contain myofibroblasts, tend to be stellate invasive lesions. Plump myoid cells and the inflammatory reaction of fasciitis are not seen in a myofibroblastoma. Fibromatosis exhibits abundant collagen and spindle cells arranged in broad bands rather than in short fascicles. Spindle cell lipomas commonly occur in males and sometimes may be well circumscribed. They have more abundant adipose tissue than myofibroblastomas; however, the distinction between spindle cell lipoma and myofibroblastoma (particularly the lipomatous variant) by light microscopy can be difficult (57). Molecular analysis indicates that both lesions often show loss of genes located on 13q (65,74,75,76,77,78). These findings suggest that the two lesions may represent related entities rather than distinct lesions. The report of a tumor showing intermixed, distinct regions of spindle cell lipoma within a myofibroblastoma adds support to this suggestion (79).

The epithelioid variant of myofibroblastoma can mimic an invasive carcinoma such as pleomorphic lobular carcinoma or apocrine carcinoma (67,68,80). The distinction can be particularly problematic in the setting of a NCB. Morphologic features that suggest the diagnosis of epithelioid myofibroblastoma include a well-circumscribed, pushing border; absent or minimal mitotic activity; associated spindle cells with typical myofibroblastic morphology; lack of glandular elements within the tumor; and dense collagenized stroma.

An excision of the mass provides adequate treatment for virtually all patients, although large lesions in men have necessitated mastectomies. Complete excision is recommended when a myofibroblastoma is identified in a NCB sample. Re-excision may be considered if a myofibroblastoma is present at the margin of an excision specimen. Recurrences have not been reported after follow-up periods of 3 to 126 months after complete excision.

Granular cell tumors are derived from the Schwann cells of peripheral nerves. These tumors occur throughout the body, and approximately 5% arise in the breast (81).

Granular cell tumor of the breast (GCTB) typically affects women between the ages of 30 and 50 years, but it has been described in adolescents and elderly women. The patients’ ages range from 14 to 77 years. About 10% of GCTBs occur in males. In several studies, the majority of patients have been African-American, and Papalas et al. (82) reported a younger average age at presentation for African-Americans (41 years) than Caucasians (54 years).

Most patients present with a firm or hard painless mass. The left and right breasts are affected equally. GCTB may arise in any part of the breast including the axillary tail and in a subcutaneous location. Superficial lesions may cause skin retraction, and nipple inversion has been reported with subareolar tumors. In one woman, the hyperplastic skin and the underlying nests of tumor cells created a polypoid mass likened to a mulberry protruding from the breast (83). Large tumors and those that arise deep in the breast may adhere to the pectoral fascia or invade the pectoral muscle and partially encase the ribs (84). GCTB usually occurs as a solitary unilateral mass, but rare instances of multiple and bilateral tumors have been reported (85,86). Patients who have multiple granular cell tumors at various sites may have one or more lesions in the breast (82,86,87). The publication by Brown et al. (88) presents clinical, radiologic, and pathologic details of 91 cases of GCTB published between 1989 and 2008.

On mammography, GCTB is difficult to distinguish from carcinoma. GCTB typically forms a stellate mass, but circumscribed lesions occur occasionally (85,89). The mass usually has a dense core and lacks calcifications. Mammography has detected nonpalpable GCTB (90). Ultrasound often shows a solid mass with indistinct margins and posterior shadowing suggestive of carcinoma. The findings using MRI can overlap with those of carcinoma.

Granular cell tumors as large as 9 cm have been reported, but the typical example spans 2 cm or less. The mass consists of white, gray, yellow, or tan tissue, which feels firm or hard. Many tumors appear well circumscribed, but occasional examples have ill-defined infiltrative borders.

The histologic and immunohistochemical features of mammary granular cell tumors duplicate those of extramammary granular cell tumors. The tumor consists of compact nests or sheets of cells containing eosinophilic cytoplasmic granules (Fig. 20.19). The cells vary from polygonal to spindly, and the cell borders appear well defined. The nuclei are round to slightly oval. They contain open chromatin and prominent nucleoli. In some cases, a modest amount of nuclear pleomorphism, occasional multinucleated cells, and rare mitoses may be found. These features should not be interpreted as evidence of malignancy. Easily seen granules usually fill the cytoplasm; however, in some lesions, the cytoplasm displays vacuolization and clearing. The cytoplasmic granules are PAS-positive and diastase-resistant. Variable amounts of collagenous stroma are present. The neoplastic cells may surround ducts and lobules and incorporate them into the mass, and these cells may penetrate into the lobules. When the neoplastic cells invade the dermis, the overlying epidermis may demonstrate pseudoepitheliomatous hyperplasia (83,84). Small nerve bundles are sometimes seen in the tumor or in close association with its peripheral extensions.

Mammary granular cell tumors typically stain for S-100 protein, carcinoembryonic antigen (CEA), and AR, and most stain for vimentin. GCTB does not stain for cytokeratin, GCDFP-15, ER, PR, or myoglobin. The cytoplasmic granules in these tumors are Luxol fast blue-positive, an observation that suggests that they contain myelin.

The differential diagnosis of GCTB includes histiocytic lesions, mammary carcinoma, and metastatic neoplasms. The superficial resemblance between the cells of GCTB and histiocytes can lead to confusion with a granulomatous inflammatory reaction or a histiocytic tumor. GCTB does not stain for histiocyte-associated antigens such as α1-antitrypsin, α1-antichymotrypsin, and muramidase, but reactivity for CD68 (KP-1) has been described in GCTB (91).

GCTB can closely resemble an invasive apocrine carcinoma. The presence of carcinoma in situ, often of the comedo type, as well as cytologic pleomorphism usually serve to identify apocrine carcinoma, but NCB specimens may not demonstrate these findings. In such situations, a confident diagnosis requires the analysis of the results of immunohistochemical staining. GCTB shows strong, diffuse immunoreactivity for S-100 protein and CEA; however, these results do not distinguish GCTB from mammary carcinoma, because some carcinomas are also S-100- and CEA-positive. A positive reaction for vimentin supports the diagnosis of GCTB, because few carcinomas express this protein. GCTB is negative for cytokeratin, GCDFP-15, ER, and PR. Apocrine carcinomas stain for epithelial markers such as cytokeratin, they often stain for epithelial membrane antigen (EMA), and they typically express AR.

GCTB must also be distinguished from metastatic neoplasms that have oncocytic or clear cell features such as renal carcinoma and malignant melanoma and from alveolar soft part sarcoma. Details of the clinical history and the results of immunohistochemical staining will establish the primary site in most cases.

NCB represents an accurate method for rendering a diagnosis of GCTB. Among the cases collated by Brown et al. (88), correct diagnosis was made in all NCB specimens.

Benign GCTB is treated by wide excision. Local recurrence may occur after incomplete excision, but it is sometimes difficult to distinguish recurrences from asynchronous multifocal
lesions. Most patients with positive or close margins do not experience recurrence of their tumors.

Fewer than 1% of all granular cell tumors, including mammary lesions, are malignant. Criteria of malignancy proposed for extramammary granular cell tumors include a diameter greater than 5 cm, necrosis, spindling of the cells, nuclear pleomorphism, vesicular chromatin, prominent nucleoli, high nuclear-to-cytoplasmic ratio, increased mitotic activity (more than 2 mitotic figures per 10 HPF at 200X magnification), and the presence of metastatic foci.

Both locoregional and distant metastatic spread from GCTB have been described (92). Metastases in the breast and axillary lymph nodes from extramammary granular cell tumors have also been reported (93,94). In some instances, it may not be possible to distinguish between multifocal benign granular cell tumors and metastatic malignant granular cell tumor.

Benign neural neoplasms commonly found in the soft tissues at various sites rarely occur in the breast. Benign nerve sheath tumors of the breast have been reported, usually diagnosed as schwannomas or as “neurilemomas.” Many of these tumors occupied the mammary subcutaneous tissue (95); however,
parenchymal lesions have also been described, and a schwannoma originating in the chest wall presented as a mass in the breast (96). The age range at diagnosis is 6 to 83 years, with most patients in their fourth to sixth decade of life. Although most patients have been female, benign neural neoplasms have arisen in the male breast (97).

Mammary schwannomas account for less than 3% of all schwannomas (98). Two publications (98,99) list clinical and pathologic findings of 23 cases described prior to 2007. A typical schwannoma presents as a painless, well-defined mass, which may have grown slowly (96,100) or remained stable for as long as 25 years (101). Two reports (100,102) illustrate exophytic tumors. Schwannomas involve the right breast more commonly than the left (98). The lateral quadrants, especially the superior lateral quadrant, seem like favored sites, but reports describe examples in all regions of the breast. One report (103) describes the case of a patient with two schwannomas of one breast.