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Cellular Spindled Histiocytic Pseudotumor: A Benign Mimic of Spindle Cell Neoplasia of the Breast.

Cellular spindled histiocytic pseudotumor (CSHPT) is a nonneoplastic proliferation of spindled histiocytes likely representing an exuberant manifestation of mammary fat necrosis. As fat necrosis is common (accounting for almost 3% of all breast lesions (1)) and can show significant radiologic overlap with other breast lesions, including carcinoma, it is frequently biopsied. Recognition of CSHPT is important for the pathologist, as it represents a potential histologic mimic of other spindle cell lesions of the breast, both benign and malignant.

FAT NECROSIS

Mammary fat necrosis is a benign, nonsuppurative inflammatory process of adipose tissue that most commonly affects women of perimenopausal age and occurs most commonly after accidental trauma, followed by surgery with or without postoperative radiation therapy. (1,2) Less common causes include post-breast reconstruction, post-fat grafting, infection, duct ectasia, and rarely autoimmune disease. (3) This process often presents as a palpable mass identified via self or clinical examination with or without a prior history of antecedent trauma to the affected area. It can also present with other, often concerning, findings such as nipple retraction and ipsilateral axillary lymphadenopathy. (1)

Mammographically, mammary fat necrosis can manifest in a variety of patterns, most commonly as oil cysts with dystrophic ("eggshell") calcifications. (3) However, it can also present as a spiculated area of increased opacity with associated distortion, closely mimicking invasive mammary carcinoma. Ultrasonographically, fat necrosis commonly presents as increased echogenicity of the subcutaneous tissues, supporting benignity based on the very low percentage of hyperechoic cancers. However, it can also often present as a hypoechoic mass with posterior acoustic shadowing or as a complex, solid/cystic mass with heterogeneous echotexture. (4) Magnetic resonance imaging (MRI) can be a useful adjunct when fat suppression sequences are used in order to distinguish fatty lesions from enhancing lesions on Tl-weighted MRI. (3,4) Overall, the constellation of sometimes worrisome clinical and radiographic features often necessitates core biopsy.

In straightforward cases of mammary fat necrosis, the histopathology is characterized by a destruction of adipocytes leading to cytoplasmic vacuoles containing necrotic lipid material and gross cystic degeneration, followed by an influx of chronic inflammatory cells including numerous histiocytes, lymphocytes, plasma cells, and multinucleated giant cells. Phagocytosis of necrotic adipocytes results in sheets of foamy (lipid-laden) macrophages, which later undergo fibrosis with peripheral dystrophic calcifications, the latter correlating with the "eggshell" calcifications seen on mammography. (1,5,6)

CELLULAR SPINDLED HISTIOCYTIC PSEUDOTUMOR

The term cellular spindled histiocytic pseudotumor (CSHPT) was first introduced by Sciallis and colleagues (7) to describe a series of breast masses comprising a moderately cellular proliferation of spindled histiocytes arranged into short fascicles and often surrounded by areas of mammary fat necrosis. The spindled histiocytes often infiltrated into surrounding breast parenchyma, leading to entrapment of normal mammary ducts (Figure 1, A through C). A variably dense chronic inflammatory cell infiltrate may be prominent, comprising lymphocytes and plasma cells, and there are often scattered multinucleated giant cells (Figure 1, D and E). Cytologically, the spindled cells contain moderately abundant pale eosinophilic cytoplasm and slightly irregular grooved nuclei with fine chromatin and indistinct nucleoli. Conspicuous mitotic activity is often present, but atypical mitotic figures are not typically identified. Conventional features of fat necrosis are often seen at the periphery of the lesion (Figure 1, F). However, it is important to be aware that focal fat necrosis can also be seen at the periphery of malignant lesions with spiculated fibrosis as well. The sometimes highly infiltrative border raises concern for a carcinoma with histiocytic cytomorphologic features or a metaplastic carcinoma, and adjunctive immunohistochemistry is critical in the distinction.

The spindled cells in CSHPT are strongly positive for markers of histiocytic differentiation (Figure 2, A and B), including CD163, CD11c, and CD68. Of these, CD68 often shows the strongest staining, but given that it is a marker of lysosomes rather than true histiocytic lineage, it is much less specific with regard to entities in the morphologic differential diagnosis than CD163. Granular cytoplasmic expression of CD31 (Figure 2, C), similar to that described in other histiocytic lesions, is often seen, (8) as well as focal positivity for CD34 (Figure 2, D). Importantly, the constituent spindled cells are negative for keratins and other epithelial markers (Figure 2, E), including OSCAR, AE1/AE3, CAM 5.2, cytokeratin 5/6, and p63, and they are also negative for S100 protein (Figure 2, F). Because of the histiocytic nature of the CSHPT, special stains for microorganisms are often performed, but staining results are negative. Moreover, in the event a tissue culture is performed, there is no growth of acid-fast bacilli or fungi. Growth of Staphylococcus epidermidis may be seen in rare cases; however, the significance of this otherwise commensal organism as it pertains to fat necrosis is unknown. (7)

Radiographically, CSHPTs were found to be suggestive of malignancy (59%), benign (29%), or indeterminate (12%). (7) Sciallis et al (7) followed up 18 patients (mean follow-up, 37 months) and found all patients to be alive without disease. In their series, 6 of 18 patients underwent a subsequent surgical excision that revealed only uncomplicated fat necrosis.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical mesenchymal proliferations in the breast includes a spectrum of benign, malignant, and inflammatory conditions. Herein, we describe entities worthy of diagnostic consideration and exclusion before diagnosis of CSHPT.

Metaplastic Carcinoma

Spindled cell metaplastic carcinoma (Figure 3, A and B) is a primary diagnostic consideration for spindle cell lesions of the breast. It often presents as a circumscribed lesion, shows variable degrees of cellularity, and typically demonstrates a short fascicular or vaguely storiform architecture. Cytologically, these tumors tend to be mitotically active with a moderate to high degree of nuclear atypia with large, irregular nuclei containing coarse chromatin with variably prominent nucleoli, (9,10) whereas CSHPT typically exhibits a much lower degree of cytologic atypia.

Identifying a conventional invasive carcinoma or ductal carcinoma in situ can be very helpful to support a diagnosis of metaplastic carcinoma, though these components are not always present despite extensive sampling. (11) Both metaplastic carcinoma and CSHPT may show entrapped benign elements and infiltrative borders.

Immunohistochemical stains show that the constituent cells of spindle cell metaplastic carcinoma commonly express smooth muscle actin (SMA), MNF116, cytokeratin AE1/AE3, p63, and/or cytokeratin 5/6, though the distribution of each may be focal or patchy. (12)

Extranodal Rosai-Dorfman Disease

Extranodal Rosai-Dorfman disease (Figure 3, C and D) is a nonneoplastic chronic inflammatory process of unknown etiology that often involves multiple sites, including the skin and soft tissue of the extremities, trunk, and head and neck sites. Rare cases have been reported in the breast and may be unilateral or bilateral. (13)

Histologic features of Rosai-Dorfman disease include clusters and sheets of large, spindled, and epithelioid histiocytes containing abundant finely vacuolated cytoplasm and round, vesicular nuclei, with associated lymphoplasmacytic inflammation. Emperipolesis of inflammatory cells is often identified. Multinucleated giant cells are generally not a feature. The histiocytes in Rosai-Dorfman disease are positive for S100 protein in addition to CD68 and CD163, but negative for CD1a. (6) The diffuse, strong expression of S100 protein is an important diagnostic feature, particularly in cases that are not otherwise morphologically classic, and helps distinguishes it from CSHPT.

Inflammatory Myofibroblastic Tumor

Inflammatory myofibroblast tumor (IMT) of the breast is a rare proliferation with pathologic features that are similar to IMTs of other anatomic sites. As in other sites, it is often challenging to determine if a given tumor is reactive or neoplastic, though a large subset of tumors exhibit alterations of the ALK receptor gene at chromosome band 2p23, suggesting a neoplastic etiology in many cases. Ultimately, the diagnostic entity may consist of lesions with similar histology derived from distinct etiologies (both reactive and neoplastic). Of note, most of the reported cases of IMT of the breast have not had a preceding history of a procedure such as breast fine-needle aspiration or biopsy, which helps to exclude a postiatrogenic inflammatory pseudotumor. (14)

Inflammatory myofibroblastic tumors tend to be circumscribed lesions that can range significantly in size. (15) As in other sites, histologic features include haphazardly arranged spindled cells, edema, and mixed acute and chronic (lymphoplasmacytic) inflammation (Figure 3, E and F). Like CSHPT, the spindled cells typically lack significant cytologic atypia or mitotic activity, though in some cases the nuclei can be quite large with prominent nucleoli, and mitotic activity can occasionally be brisk. (14) In contrast to CSHPT, the constituent cells in IMT demonstrate a myofibroblastic immunophenotype, including a distinct membranous expression pattern of SMA, though nonspecific staining with keratins and CD68 may occur. (16) In the limited number of mammary IMTs reported, keratin expression does not appear to be as robust as in IMTs reported in other sites such as the bladder.

Silicone Granuloma

Rupture of silicone breast implants is an uncommon complication of breast implant surgery, with macroscopic leakage identified in 3% of explants. (17) Rupture of implants or injection of silicone materials allows for dispersion of silicone into the surrounding tissues and lymph nodes, inducing a foreign body reaction (Figure 3, G and H). In cases of ruptured implant, a fibrous capsule may form around the implant. If silicone disperses farther into the surrounding tissue or lymph nodes, it may form a so-called silicone granuloma, which appears as numerous cystic spaces and vacuolated histiocytes partially filled with amorphous, refractile, nonpolarizing material. (18,19)

Immunohistochemically, the tissue histiocytes containing silicone materials will express markers of histiocytic lineage including CD163 and CD68, (19) and therefore its distinction from CSHPT relies on the clinical knowledge of silicone implants combined with the morphology. Most helpful in distinguishing these entities is the presence of refractile material within cystic spaces and histiocytic vacuoles. Compared to CSHPT, the cystic spaces in silicone granulomas often show a much wider variability in size. Furthermore, silicone granulomas tend to be paucicellular, and certainly hypocellular in comparison to CSHPT.

Desmoid-type Fibromatosis

Mammary desmoid-type fibromatosis is a locally aggressive mesenchymal neoplasm lacking metastatic potential that affects a broad age range, with a mean age of 43 years. (20) Histologically, it is characterized by dissecting, long, sweeping fascicles of uniform myofibroblasts with frequent entrapment of benign mammary ducts (Figure 3, I and J). (21) The spindled cell proliferation displays an even cellularity, and linear ectatic small vessels of similar caliber are evenly distributed throughout the lesion between fascicles. Mild cellular atypia can be seen, with nuclear enlargement and small but conspicuous nucleoli. Local recurrence may occur and rarely may be years after diagnosis. (20) Immunohistochemically, fibromatosis is negative for cytokeratins and CD34, (22) though it does demonstrate nuclear b-catenin accumulation in upwards of 80% of cases, a result of alterations of the APC/b-catenin pathway. (23) Prominent cytoplasmic b-catenin staining can make interpretation of nuclear accumulation challenging, especially when the nuclear positivity is of similar intensity to that seen in the cytoplasm, but a lack of nuclear positivity should result in distinct pale basophilic nuclei highlighted by the counterstain. However, b-catenin staining is rarely needed to distinguish it from CSHPT, since desmoid-type fibromatosis is not a histiocyte-rich proliferation.

Histiocytoid Lobular Carcinoma

Histiocytoid lobular carcinoma is an uncommon variant of invasive lobular carcinoma, the most common special type of invasive mammary carcinoma. (9) These tumors are composed of small cells with abundant pale, granular cytoplasm with central or eccentrically placed nuclei, arranged in small aggregates or single file linear patterns (Figure 3, K and L). A background of lobular neoplasia may also be present, the cells of which may demonstrate conventional, histiocytoid, or apocrine cytology. (24) Nuclei lack the grooved, folded, or reniform shapes of true histiocytes, and instead share the more rounded nuclei with smooth nuclear contours and occasionally prominent nucleoli of typical lobular carcinoma. Immunohistochemical stains easily adjudicate this differential diagnosis, with cytokeratins showing positivity in histiocytoid lobular carcinoma and histiocyte markers CD68 and CD163 showing negativity, (25) while the converse is true in CSHPT.

Mammary-type Myofibroblastoma

Mammary myofibroblastoma is a benign tumor that presents as a slow-growing nodule in men and women. Classically, myofibroblastoma consists of short fascicles of spindled cells with ovoid nuclei, with associated dense "wire-like" collagen and adipose tissue (Figure 3, M and N). Variants may demonstrate increased adipocytic, fibrous, or myxoid stroma, as well as myoid or epithelioid differentiation. The constituent cells in myofibroblastoma show frequent coexpression of a muscle marker (desmin, SMA, or calponin) with frequent expression of CD34. Estrogen receptor and progesterone receptor are also usually positive. Immunohistochemical studies may also show loss or aberrant staining of retinoblastoma (Rb) protein, a reflection of the loss of 13q14. (26)

Low-Grade Fibromatosis-like Spindle Cell Carcinoma

Fibromatosis-like spindle cell carcinoma (FLSCC) is typically seen in postmenopausal women as a rapidly enlarging mass. Like fibromatosis, FLSCC shows sweeping fascicles of bland spindled cells with finger-like infiltration into the surrounding breast parenchyma (Figure 3, O through R). Similar to both fibromatosis and CSHPT, entrapment of benign ductal elements may be seen. Additionally, as with other metaplastic carcinomas, a focal malignant epithelial component can be present that may be glandular or squamous. (27) Similar to other metaplastic carcinomas, multiple cytokeratins, including high-molecular-weight cytokeratins (such as antibodies to CK 5/6, 34BE12) and p63 (Figure 3, S and T), may be necessary to demonstrate immunoreactivity to support a diagnosis of carcinoma. (28)

CONCLUSIONS

Cellular spindled histiocytic pseudotumor is a rare, benign entity that is likely an exuberant form of fat necrosis. The high cellularity and spindled nature creates a diagnostic dilemma, for which the differential diagnosis includes a wide spectrum of epithelial neoplasms, mesenchymal neoplasms, and histiocytic proliferations. With careful analysis for sometimes sparse areas of conventional fat necrosis, combined with a small panel of immunohistochemical stains, a diagnosis of CSHPT can usually be rendered in a core biopsy. Knowledge of this entity is critical to avoid misdiagnosis, as many of the entities in the differential diagnosis demonstrate malignant potential and/or that risk for recurrence, thus requiring radically different treatment modalities.

References

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Ellen G. East, MD; Cody S. Carter, MD; Andrew P. Sciallis, MD

Accepted for publication August 6, 2019.

From the Department of Pathology, Michigan Medicine, Ann Arbor.

This original work was funded by the University of Michigan Department of Pathology, Division of Anatomic Pathology. The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the New Frontiers in Pathology meeting; September 27-29, 2018; Ann Arbor, Michigan.

Corresponding author: Ellen G. East, MD, Department of Pathology, Michigan Medicine, 2800 Plymouth Rd, Bldg 35, Ann Arbor, Ml 48109 (email: ellengeast@gmail.com).

Caption: Figure 1. Cellular spindled histiocytic pseudotumor (CSHPT) is composed of a densely cellular spindled cell proliferation (A) that may infiltrate into the surrounding mammary parenchyma (B). CSHPT shows a vaguely fascicular growth pattern with associated lymphoplasmacytic inflammation (C and D). The spindled cells contain moderately abundant pale eosinophilic cytoplasm and show mild nuclear atypia, often with intermixed multinucleated giant cells (E). The background breast parenchyma shows areas of fat necrosis, which are particularly accentuated at the periphery of the lesion (F) (hematoxylin-eosin, original magnifications X20 [A and F], X40 [B], X100 [C and D], and X200 [E]).

Caption: Figure 2. Immunohistochemical findings in cellular spindled histiocytic pseudotumor (CSHPT). The spindled cell component of CSHPT is diffusely positive for CD68 (A) and to a lesser extent for CD163 (B). CD31 shows granular cytoplasmic staining (C), while CD34 shows focal weak staining (D). Cytokeratin cocktail (AE1/AE3 and CAM 5.2) shows negativity (E). S100 protein also shows negativity (F) (original magnification X400 [A through F]).

Caption: Figure 3. Differential diagnosis of cellular spindled histiocytic pseudotumor (CSHPT). Metaplastic carcinoma shows a vaguely fascicular growth pattern (A), but exhibits a greater degree of cytologic atypia than CSHPT (B). Extranodal Rosai-Dorfman disease also consists of a spindled and/or epithelioid histiocytic proliferation with chronic inflammation (C), with more abundant foamy histiocytes than CSHPT (D). Inflammatory myofibroblastic tumor often shows a myxedematous stroma as shown (E) and elongated spindled cells with tapered, amphophilic cytoplasmic processes (F). Silicone granuloma may show large cystlike spaces (G) and vacuolated cells containing refractile, nonpolarizable material (H) in addition to areas resembling CSHPT. Desmoid-type fibromatosis consists of long, sweeping fascicles (I) composed of elongated spindled cells with tapered, amphophilic to pale eosinophilic cytoplasm and vesicular nuclei with pinpoint nucleoli (J). It lacks the level of inflammation and histiocytic reaction seen in CSHPT. The "histiocytoid variant" of invasive lobular carcinoma shows small aggregates and cords (K) of bland epithelial cells with abundant pale cytoplasm and central to eccentric nuclei resembling histiocytes; it is usually not as cellular as CSHPT and contains a less prominent inflammatory cell infiltrate (L). Mammary-type myofibroblastoma is a cellular myofibroblastic proliferation with fascicular architecture and collagen bundles (M), with bland cytologic features (N). Low-grade " fibromatosis-like" metaplastic carcinoma may have a similar cellularity to CSHPT and is characterized by an infiltrative proliferation of spindle cells resembling myofibroblasts and histiocytes (O) bearing close resemblance to desmoid-type fibromatosis (P); however, the neoplastic cells in low-grade "fibromatosis-like" metaplastic carcinoma tend to have more nuclear hyperchromasia (Q) and lack histiocytoid nuclei (R); the cells in low-grade "fibromatosis-like" metaplastic carcinoma are usually positive for keratins (S) and/or p63 (T) (hematoxylin-eosin, original magnifications X40 [A, C, E, G, I, and K], X200 [B, D, and N], X400 [F, H, J, L, Q, and R], and X100 [M, O, and P]; cytokeratin cocktail of AE1/AE3 and CAM 5.2, original magnification X200 [S]; original magnification X200 [T]).
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Author:East, Ellen G.; Carter, Cody S.; Sciallis, Andrew P.
Publication:Archives of Pathology & Laboratory Medicine
Date:Dec 1, 2019
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