Inflammatory and Reactive Lesions



Inflammatory and Reactive Lesions


Syed A. Hoda



FAT NECROSIS

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).


BREAST INFARCT

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).






FIGURE 2.1 Fat Necrosis, Phases. A: Early fat necrosis manifested by a histiocytic and eosinophilic infiltrate, associated with hemorrhage. B: Early organization in fat necrosis. Note focal presence of lymphocytes amid the histiocytic infiltrate. C: Healing fat necrosis. This needle core biopsy specimen obtained from a 1 cm stellate lesion consists of infarcted fat cells, hemorrhage, and a histiocytic reaction. D: Late (organized) fat necrosis: fibrosis and hemosiderin deposition are associated with necrotic fat. This needle core biopsy of a breast mass followed a softball injury 6 weeks earlier.






FIGURE 2.2 Fat Necrosis. A: Needle core biopsy specimen from a mammographically detected mass at the site of a prior lumpectomy for intraductal carcinoma. Fibrosis and granulomatous reaction are evident in the fat necrosis. No foreign body material was found. B: Multinucleated histiocytes with foreign body material are shown in a needle core biopsy specimen from fat necrosis at a prior surgical site.






FIGURE 2.3 Fat Necrosis. A: Coarse calcifications and fibrosis are evident around this focus of long-standing fat necrosis in a needle core biopsy specimen. The section shows “knife scoring” artifact (top right) resulting from damage to the microtome knife caused by the dense calcification. B: Fibrosis is evident around this focus of long-standing fat necrosis in another needle core biopsy specimen. C, D: Lymphocytes and histiocytes in fat necrosis from a 52-year-old woman. E: Calcifications in the lesion shown in (C) and (D).






FIGURE 2.4 Fat Necrosis. Infarcted fat with calcification in a needle core biopsy specimen. Nuclear detail is absent from the fat cells. The lesion was biopsied after calcifications were found on a routine mammogram.






FIGURE 2.5 Invasive Carcinoma in Needle Core Biopsies Simulating Fat Necrosis. A-C: Three examples of invasive lobular carcinoma, all without a history of antecedent trauma or prior needling procedure, are shown. Cursory low-power microscopic examination can misleadingly suggest fat necrosis in each case. Inset in (C) shows estrogen receptor positivity in the malignant cells.

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.







FIGURE 2.6 Infarcted Papilloma. A: A needle core biopsy specimen showing an area of hemorrhage and infarction in a papilloma. B: A sample from the periphery of the lesion with degenerated papillary tissue fragments. C: An area in an excised partially necrotic papilloma showing intact papillary structures. Relatively viable cells are focally evident (top left).






FIGURE 2.7 Infarct with Atypical Cells. This needle core biopsy specimen shows a totally infarcted lesion, possible fat necrosis, and an attached fragment of tissue composed of atypical cells. The latter were cytokeratin-positive (not shown here).


GALACTOCELE

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).







FIGURE 2.8 Galactocele. A cystically dilated gland lined by flattened apocrine-type cells. Cholesterol crystals are present within and outside this galactocele.


DUCT ECTASIA

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).






FIGURE 2.9 Duct Ectasia. A, B: Mammographic density led to a needle core biopsy that demonstrated this dilated duct with a dense, mainly intraluminal, histiocytic reaction. C: Histiocytes with vacuolated, granular cytoplasm have a micropapillary arrangement in this dilated duct in another case. D, E: Ectasia with a solid accumulation of histiocytes and periductal inflammation that mimics clear cell intraductal carcinoma. Residual ductal epithelial cells are highlighted by the cytokeratin immunostain in (D). The histiocytes are cytokeratin-negative. F: Histiocytes with finely granular ceroid pigment (arrow), so-called ochrocytes, are present in the duct lumen, the epithelium, and the surrounding tissue.

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).






FIGURE 2.9 (continued)






FIGURE 2.10 Duct Ectasia and Mastitis. A: This dilated duct with intraluminal histiocytes is surrounded by lymphocytes. Note the histiocytes in the epithelial lining at the perimeter of the duct. B: An intense inflammatory reaction composed of lymphocytes and neutrophils as well as histiocytes involves this duct. Note destruction of the epithelium. C: Transparent calcium oxalate crystals are present in the duct lumen. D: The calcium oxalate crystals glow when viewed with polarized light. E: Calcium oxalate crystals in a needle core biopsy touch preparation. The specimen showed apocrine hyperplasia.






FIGURE 2.10 (continued)

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).






FIGURE 2.11 Duct Ectasia, Late Phases. A: A late-stage lesion sampled by needle core biopsy. There is marked periductal fibrosis with a minimal chronic inflammatory cell infiltrate. B: Duct ectasia with intraluminal multinucleated histiocytes. C: Duct ectasia with mastitis obliterans. A fibrous “polyp” has “obliterated” most of the ductal lumen in this excisional biopsy.

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.






FIGURE 2.12 Duct Ectasia, without Inflammation. The dilated duct is lined by flat epithelium. There is no inflammation. Acellular proteinaceous material fills the duct lumen. Inset shows detail of the epithelial cells lining the dilated duct.

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).


SO-CALLED PLASMA CELL MASTITIS

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.






FIGURE 2.13 So-called Plasma Cell Mastitis. A, B: A needle core biopsy specimen from a patient with a breast mass suspected to be carcinoma. Plasma cells are a prominent element in the reactive cellular infiltrate around the area of necrosis (right).

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.


DIABETIC MASTOPATHY

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).






FIGURE 2.14 Diabetic Mastopathy. A, B: Mature lymphocytes are clustered around a small blood vessel, and prominent myofibroblastic cells are evident in the stroma. The specimen was obtained from a young woman with juvenile-onset diabetes mellitus who presented with a unilateral breast mass. Inset in (B) shows detail of an altered myofibroblast. C: The spindly myofibroblasts are CD34-positive. D: Another case of diabetic mastopathy with the characteristic prominent perivascular and periglandular lymphocytic response amid fibrotic stroma. E: A needle core biopsy showing invasive carcinoma (left) and changes characteristic of diabetic mastopathy in a 38-year-old patient with childhood-onset diabetes mellitus.

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).

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Inflammatory and Reactive Lesions

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