Mammary fat necrosis may occasionally result from incidental trauma; however, presently, the most common causes are previous needling procedures (such as fine needle aspiration or needle core biopsy), surgery, and radiation therapy (1,2). Patients with fat necrosis typically present with a painless superficial mass, occasionally associated with retraction or dimpling of the overlying skin. Any part of the breast may be affected. At presentation, the typically solitary mass spans approximately 2 cm. Fat necrosis in the male breast is usually traumatic in origin and has been diagnosed on needle core biopsy (3). Hemorrhagic and fat necrosis of subcutaneous and breast tissue, occasionally progressing to gangrenous necrosis, has been associated with warfarin (Coumadin) anticoagulant treatment (4); however, with better therapeutic monitoring, this iatrogenic complication is now less common (5).

The clinical and radiologic problem of distinguishing fat necrosis from recurrent carcinoma is especially difficult in patients who have undergone breast-conserving surgery and various modalities of radiation therapy (6,7,8). Mammography of fat necrosis usually reveals a spiculated mass that may contain irregular, punctate, or coarse calcifications (9,10). Less frequently, the lesion appears as an “oil cyst”, that is, a circumscribed, oil-filled, partly calcified cyst (11). Both patterns may coexist in a single lesion. Ultrasonography and magnetic resonance imaging (MRI) features of fat necrosis are also variable and may be indistinguishable from carcinoma (10).

The initial histologic change in fat necrosis is adipocyte injury (diminished size, fine vacuolization, and dropout) associated with a neutrophilic infiltrate (Fig. 2.1). Further evolution of the lesion is marked by the progressive appearance of histiocytes, eosinophils, lymphocytes, and plasma cells with deposition of hemosiderin (Fig. 2.2). Some histiocytes that accompany fat necrosis can simulate lipoblasts. Unlike lipoblasts, histiocytes are of relatively uniform size with fine intracytoplasmic vacuoles that do not indent the generally round nucleus. A giant cell granulomatous reaction may develop over time (Fig. 2.3). Fibrosis develops peripherally, demarcating the region of necrotic fat, cellular debris, and calcifications (Fig. 2.4). In late lesions, the reactive inflammatory components are replaced by fibroplasia, which evolves into a dense scar. An exaggerated histiocytic response to fat necrosis may take the form of a “cellular spindled histiocytic pseudotumor” (12) (arguably, an innovative term for inflammatory pseudotumor), wherein the mitotically active histiocytic spindle cell proliferation has the potential to be mistaken for spindle cell neoplasm, such as metaplastic carcinoma. Reactive squamous metaplasia may develop in the epithelium of ducts and lobules in the vicinity of fat necrosis. Loculated necrotic fat, with dystrophic calcification, may persist for many years (Fig. 2.5). Among patients who develop fat necrosis after radiotherapy, the characteristic histopathologic effects of radiation on epithelial, stromal, and vascular tissues can be identified in the native mammary tissue.

Needle core biopsy is required in all instances wherein clinical and radiologic diagnosis of fat necrosis is uncertain. Careful microscopic examination is warranted in every needle core biopsy of fat necrosis as the process may mask a histologically subtle invasive carcinoma. The use of epithelial (cytokeratin) and histiocytic (CD11c, CD68, and CD163) immunostains can be helpful in this regard.

Erdheim-Chester disease, an extremely infrequent xanthomatous form of non-Langerhans cell histiocytosis of uncertain etiology, rarely involves the breast (13,14,15). Histologically, the disease can be mistaken for fat necrosis, especially if the initial clinical manifestation is a breast mass (13). Typically, there are synchronous cutaneous, osseous, and orbital lesions that are characterized by infiltrates of histiocytes, Touton-type giant cells (with wreath-like arrangement of nuclei at the perimeter of the giant cell), plasma cells, and infrequent epithelioid granulomata. The lesional histiocytes are immunoreactive for CD68, but are negative for S-100 protein, CD1a, and cytokeratins (13). The disease may simply be interpreted as a benign histiocytic proliferation on needle core biopsy—unless the clinical setting is known and Touton-type giant cells are recognized (14).

The most frequent form of breast infarct occurs during pregnancy or in the postpartum period. The lesion usually presents as a solitary, discrete, firm mass that can clinically suggest carcinoma. Pain and tenderness are sometimes reported. Hemorrhage and ischemic degeneration with little or no inflammatory cell infiltrate characterize the histologic appearance of


early lesions. Later stages feature fully developed coagulative necrosis (i.e., infarct). Bilateral multifocal mammary infarcts involving lactational breast tissue have been reported (16).

Infarction can occur spontaneously in fibroadenomas (17,18,19) and in benign proliferative lesions. Foci of necrosis may be found in florid sclerosing adenosis, usually during pregnancy, when the epithelium in sclerosing adenosis may also exhibit pronounced hyperplasia, mitotic activity, and cytologic atypia. The latter feature can be striking in fine needle aspirates of breast infarcts (20,21).

Papillomas are susceptible to partial or complete infarction, especially those that occur in major lactiferous ducts. Infarction can occur in papillomas at any age, but tends to be more frequent in postmenopausal women, and there is no known association with pregnancy. Bloody nipple discharge is the most frequent sign of an infarcted papilloma. Acute infarcts in a papilloma exhibit ischemic degeneration progressing to coagulative necrosis. Despite progressive loss of cytologic detail, the architectural integrity of the papilloma is usually maintained (Fig. 2.6). At a late stage, fragmentation of infarcted portions of the papilloma occurs. Occasionally, an infarcted papilloma is reduced to an inflammatory polyp consisting mainly of granulation tissue with little or no epithelium. Chronic ischemia and healing of infarcts are marked by fibrosis that may cause sclerosing entrapment of residual epithelium, producing a pattern that could be mistaken for carcinoma (22). Squamous metaplasia sometimes develops in the proliferating reparative epithelium within an infarcted papilloma (23,24). Calcifications eventually appear in the infarcted papilloma.

Infarcted carcinoma can be distinguished from infarction of a benign lesion if there is residual viable in situ or invasive carcinoma (25). In such cases, one can display the “ghost” architecture of the lesion upon reticulin staining. In some instances, immunoreactivity for cytokeratin and myoepithelial markers, especially p63, is surprisingly well preserved. When this occurs, it may be possible to “resurrect” the structure of the original lesion to a considerable degree. If a papillary structure can be demonstrated in this circumstance, the lesion was probably a papilloma rather than a papillary carcinoma because infarcts occur considerably more often in benign papillary tumors than in papillary carcinomas.

Excisional biopsy is usually necessary for the diagnosis of a mammary infarct, although the findings in a needle core biopsy specimen may be suggestive of the lesion. In most cases, recognition of the underlying condition hinges on finding a residual histologically viable (i.e., uninfarcted) component. As noted earlier, a reticulin stain and a p63 immunostain may be useful. Rarely, the diagnosis of a totally infarcted lesion remains enigmatic (Fig. 2.7).

Before diagnosing a breast infarct, particularly on the basis of a needle core biopsy sampling, it is prudent to exclude the presence of a centrally necrotizing carcinoma of the breast. These carcinomas typically harbor a large central acellular zone (26). Clinical and radiologic correlation is helpful in this regard.

A galactocele is a cystically dilated major duct, typically filled with degenerated milky contents. The lesion is most commonly encountered in younger women who are either pregnant or lactating. At presentation, the lesion typically spans about 2 cm; however, much larger lesions (>5 cm) have been described (27). Mammography reveals a circumscribed density that, in many instances, has a characteristic appearance with two zones demarcated by a “fluid level” (28). The two zones consist of the upper, lighter lipid-containing components over the lower, heavier water-based constituents of the fluid. Comparable differences in echogenicity are observed on ultrasound examination.

Clinically, the firm and usually painless lesion may suggest carcinoma. Necrotic cells and debris, accompanied by inflammatory cells, are present in a fine needle aspiration-derived cytology preparation (29,30). Viable cells with reactive hyperchromatic nuclei may be present and could be mistaken for carcinoma. Excisional biopsy is diagnostic and provides adequate therapy if the lesion does not resolve after the aspiration of cyst contents.

Histologically, a galactocele is composed of a cyst, or an aggregate of cysts, which are lined by simple cuboidal epithelium. The cysts contain milky inspissated secretions in the form of soft caseous material. Intact cysts are encompassed by a variably thick fibrous wall with little or no inflammatory reaction. Leakage from a cyst elicits a chronic inflammatory cell reaction that may be accompanied by fat necrosis and a xanthogranulomatous reaction (31). Peri-implant galactocele formation has been described after breast augmentation procedures (32). In this setting, a galactocele has been reported to develop after a needle core biopsy procedure (33).

Duct ectasia (i.e., dilatation) is usually encountered in the breasts of premenopausal women as a localized reaction to inspissated secretions in larger ducts (34). The earliest symptom of the disease is spontaneous, intermittent, mainly watery nipple discharge. Upon disease progression, subareolar induration may lead to the formation of a mass. Nipple retraction and inversion is generally associated with periductal fibrosis and contracture. In some cases, squamous metaplasia of the terminal lactiferous duct epithelium results in obstruction that contributes to ductal dilatation, and could eventually lead to the formation of lactiferous duct fistulas (35,36). The mammographic abnormalities include microcalcifications, spiculated masses, and lobulated partially smooth masses, and can rarely simulate carcinoma (37).

The composition of the intraluminal contents in duct ectasia is variable, ranging from eosinophilic (granular or amorphous) proteinaceous material to an admixture of lipid-containing histiocytic cells and desquamated duct epithelial cells. Cholesterol crystals and calcifications may be found amid such debris (Fig. 2.8). Histiocytes that contain ceroid pigment have been termed ochrocytes by Davies (38). Foam cells (histiocytes with finely vacuolated cytoplasm) may be found within ductal lumina, in the epithelial-myoepithelial layer of ducts, and in periductal tissues (Fig. 2.9). The presence of neutrophils, lymphocytes, and plasma cells within the ducts indicates a more intense inflammatory reaction (Fig. 2.10). Disruption of ectatic ducts is accompanied by discharge of stasis material (including cholesterol crystals) in periductal tissue, causing periductal inflammation. Deposition of cholesterol crystals is the predominant finding in needle core biopsies of mass-forming lesions (“cholesteroloma”) (39,40). Plasma cells and granulomata are inconspicuous features of duct ectasia.

Calcium oxalate crystals may be found when stasis occurs in a duct with apocrine epithelium (Fig. 2.10).

Histiocytes with clear or “foamy” cytoplasm positioned in ductal epithelia can be confused with pagetoid carcinoma cells. In most instances, the distinction is made with ease on the basis of bland nuclear cytology of these cells, and the associated inflammatory and reactive features, of duct ectasia. The histiocytic phenotype of foam cells can be confirmed by CD68 (KP1) immunoreactivity. These cells are negative for cytoplasmic cytokeratin and actin, but may display misleading surface cytokeratin staining from the cell membranes of contiguous epithelial cells or weak reactivity for adsorbed antigens such as gross cystic disease fluid protein-15 (GCDFP-15) (41).

In advanced cases of duct ectasia, the development of periductal fibrosis and hyperelastosis, often with a lamellar distribution, leads to mural thickening (Fig. 2.11). The inflammatory reaction is less conspicuous, and the ducts are encased in thickened laminated layers of fibrous and elastic tissue (42). The duct lumen can become widely dilated, or even partially obliterated—so-called “mastitis obliterans”
(Fig. 2.12). In some instances, the periductal reactive process includes proliferating granulation tissue and hyperelastosis that can narrow, and even occlude, ducts (43,44). The affected ducts may eventually be reduced to a fibrous scar. Remnants of persisting epithelium may proliferate to form secondary glands within such sclerotic ducts.

The diagnosis of primary “histiocytoid” breast carcinoma should be considered in cases wherein minimally atypical histiocyte-like cells proliferate with neither admixed inflammatory cell infiltrate nor ductal disruption. Use of epithelial (cytokeratin) and histiocytic (CD68) immunostains can be helpful in confirming the diagnosis (45).

The disease process known as plasma cell mastitis (PCM) is an extreme form of periductal mastitis that features a prominent plasma cell reaction to retained secretions in ducts. In the early phases of PCM, patients experience the acute onset of redness, pain, and thick nipple discharge. After the inflammatory symptoms subside, the skin may remain edematous over the lesional mass. The latter may span several centimeters. Nipple discharge is usually persistent, and nipple retraction is observed in most patients. The ipsilateral axillary lymph nodes are often enlarged. In all its phases, PCM can be clinically (and radiologically) difficult to distinguish from mammary carcinoma.

PCM is characterized by a marked, diffuse plasma cell infiltrate surrounding ducts as well as lobules. The lesion is associated with variably hyperplastic ductal epithelium (Fig. 2.13). Foci of PCM, which grossly appear to be xanthomatous and necrotic, histologically correspond to histiocytic and granulomatous reaction to the desquamated epithelium and lipid material. Lymphocytes and neutrophils are variably present. Neither periductal fibrosis nor obliterative intraductal proliferation of granulation tissue are features of PCM. Hyperplastic epithelial cells, which may appear to be highly atypical, can be mistaken for carcinoma in a needle core biopsy sample. Plasmacytoma and myeloma should be considered in the differential diagnosis in cases of overwhelming plasma cell infiltration. It is possible for some cases of exuberant duct ectasia to be mistaken for PCM, and vice versa.

The occurrence of tumor-forming stromal proliferations in patients with diabetes mellitus is referred to as diabetic mastopathy (DM) (46). The initial clinical symptom is a palpable, firm-to-hard mass that may suggest carcinoma. The histopathologic alterations are not entirely specific for insulin-dependent diabetes mellitus (47,48,49), and similar lesions have been reported in patients with autoimmune diseases who did not have diabetes (50,51).

With rare exceptions (52), DM has been limited to females. In six series, the mean age of patients at the time of biopsy varied from 36 to 57 years, with a range of 20 to 77 years (48). Most DM patients with type I insulin-dependent diabetes
mellitus are younger than 30 years, and the interval between the onset of diabetes and detection of the breast lesion is about 20 years. Bilateral lesions have been present in nearly 50% of the cases. Most of the DM patients have had complications of juvenile-onset diabetes, with diabetic retinopathy being reported in many instances.

The mammogram in DM often reveals localized, increased density or a heterogeneous parenchymal pattern, but no specific features have been associated with this condition (53,54). The mammographic appearance of the mass can resemble a fibroadenoma or carcinoma (50,55). An irregular hypoechoic mass with variable acoustic shadowing is found on sonographic examination. Ultrasound guidance is the preferred modality for performing a needle core biopsy procedure (53). Breast density associated with DM could obscure a coexistent lesion such as carcinoma, a setting in which MRI may be useful (56,57). Spontaneous regression and clinical disappearance of DM has been described (58).

The lesional tissue of DM consists of collagenous stroma with keloidal features and a variably increased number of stromal cells when compared with the surrounding breast tissue. Polygonal epithelioid cells are found dispersed in the collagen among the spindly stromal cells in most, but not all, cases. The stromal cells are myofibroblasts with variable fibroblastic and myoid differentiation (Fig. 2.14). Multinucleated stromal giant cells and mitotic activity are not part of this proliferative
process. Rarely, CD10-positive atypical myofibroblastic cells may be present (59). Mature perivascular, periductal, and perilobular lymphocytes are clustered throughout the lesion. Few, if any, plasma cells or neutrophils are present in the infiltrates. Lymphoid follicles with germinal centers are rare. When studied by immunohistochemistry, the lymphocytes have a B-cell phenotype. The polymerase chain reaction detected no Ig heavy-chain gene rearrangements in tissue samples from six patients with DM (60).