Context.—

Inflammatory lesions of the breast are rare but not infrequently pose problems both clinically and morphologically, particularly on needle core biopsies. These lesions range from acute inflammatory conditions to chronic lymphoplasmacytic and lymphohistiocytic to granulomatous inflammatory diseases.

Objective.—

To provide a comprehensive overview of inflammatory lesions of the breast, with etiopathogenesis and clinical, radiologic, and pathologic features as well as differential diagnostic considerations, clinical management, and prognosis.

Data Sources.—

The existing literature in the English language, including original research articles and review articles describing inflammatory lesions of the breast.

Conclusions.—

Inflammatory lesions of the breast are characterized by a wide variety of clinical, radiologic, and morphologic features. The histopathologic differential diagnosis often includes a neoplastic process requiring ancillary studies and correlation with clinical and radiologic findings. Although most specimens display nonspecific findings precluding a definitive pathologic diagnosis, pathologists have a unique opportunity to play a crucial role in identifying key histologic features suggestive of certain entities, such as cystic neutrophilic granulomatous mastitis, immunoglobulin (Ig) G4 mastitis, or squamous metaplasia of lactiferous ducts, in the right clinical and radiologic context, and thereby guiding optimal and timely clinical management. The information presented herein will be helpful to practicing anatomic pathologists and pathology trainees in becoming more familiar with specific morphologic features and overcoming differential diagnostic challenges related to pathology reporting of inflammatory lesions of the breast.

Inflammatory lesions of the breast are less frequently sampled for pathologic evaluation compared with neoplasms but not uncommonly pose problems both clinically and histologically. These lesions range from acute inflammatory conditions to chronic lymphoplasmacytic and lymphohistiocytic to granulomatous inflammatory diseases. Some of these lesions can be particularly difficult to recognize on needle core biopsies. The differential diagnosis often includes a neoplastic process requiring ancillary studies and correlation with clinical-radiologic findings. However, subspecialized breast pathologists and anatomic pathologists practicing breast pathology have a unique opportunity to play a crucial role in identifying key histologic features suggestive of certain entities in the right clinical and radiologic context, and in guiding optimal and timely clinical management. Herein, we provide a comprehensive overview of inflammatory lesions of the breast, with etiopathogenesis; clinical, radiologic, and pathologic features; differential diagnostic considerations; clinical management; and prognosis (Table).

Definition

Acute inflammation, usually due to bacterial infection, occurring during childbirth or the period following childbirth/the lactational period.

Etiopathogenesis

Current evidence suggests that breast milk is not sterile and contains a variety of bacteria constituting the normal breast microbiota.1  Aseptically collected milk contains 103 to 106 bacteria/mL, and breast-fed infants may consume up to 8 billion bacteria daily. Anaerobic and lipophilic bacteria predominate, the most common types being Staphylococcus, Streptococcus, and Pseudomonas.2  Staphylococcal infection is identified in 50% to 70% of cases (predominantly Staphylococcus aureus).3  Rarely, Candida species may infect the nipple skin during lactation. Bacteria may also reside in the ductal and lobular intraluminal secretions. In these anaerobic lipid-rich milieus, bacteria may be introduced via the infant’s oral cavity and skin, the mother’s nipple/areolar skin, or possibly the enteromammary pathway.4  The milk/breast microbiota is thought to be the most likely culprit in the pathogenesis of acute puerperal/lactational inflammatory conditions; however, its role in chronic inflammatory lesions remains unclear. Additional risk factors include first pregnancy, prior history of lactational mastitis, and suboptimal nursing technique.5  The abscesses tend to involve the deep breast parenchyma and are usually associated with Staphylococcus species or, rarely, Streptococcus.4 

Clinical Presentation

Acute/puerperal mastitis affects up to 33% of lactating women, typically develops within 2 to 3 weeks of lactation, and presents with a tender erythematous mass that may be accompanied by fever, draining sinus, and/or nipple discharge. In approximately 1% to 3% of patients, acute mastitis progresses to an abscess, which usually occurs within the first 6 weeks of lactation.

Radiologic Features

Ultrasonographically, mastitis is characterized by ill-defined hyperechogenic and hypoechogenic areas with mild skin thickening, sometimes accompanied by axillary lymphadenopathy. The presence of a multiloculated hypoechoic collection with posterior acoustic enhancement and an echogenic, vascular rim suggests an abscess. Mammography is not usually performed and shows nonspecific findings such as skin thickening and ill-defined areas of increased density in mastitis, and skin thickening, asymmetric density, mass, or distortion in abscess.6 

Pathologic Features

Acute mastitis is not usually biopsied. Surgical specimens are obtained from approximately 15% of abscesses (Figure 1, A and B) and show tissue necrosis or granulation tissue (Figure 1, A) associated with an acute or mixed inflammatory infiltrate (Figure 1, B). Bacteria (gram-positive cocci) may be identified on special stains. At later stages of lactation, fistulas or galactoceles may develop, which usually show chronic inflammation.7  Incision and drainage (I&D) is rarely performed and shows necrosis with acute inflammation, often associated with bacteria.

Management and Prognosis

Treatment is curative and includes antistaphylococcal antibiotics, continuation of lactation, or mechanical expression.8 

Definition

Acute inflammation, due to either noninfectious or infectious causes, not related to pregnancy, childbirth, or lactation.

Etiopathogenesis

The etiology of nonpuerperal mastitis and abscess ranges from noninfectious to infectious agents. Noninfectious causes include endogenous and exogenous noncellular materials. A recently recognized form of relatively common mastitis associated with corynebacteria is cystic neutrophilic granulomatous mastitis (CNGM) (see below). Other infectious organisms such as tuberculous and nontuberculous mycobacteria,912 Bartonella henselae,13 Actinomyces,14 Brucella,15  fungi (including aspergillosis, which may develop in association with implants),16  or parasites1719  are extremely rare in the breast and may be the initial presentation of HIV infection.20 

Clinical Presentation

Clinical symptoms are variable. Some patients show a palpable, tender, painful mass of varying size that may be associated with regional lymphadenopathy (25%), skin erythema, and/or retraction.21  Although tuberculosis of the breast is rare even in endemic regions, it usually affects young women, and rarely men and older women.22  It may present as a mass, ulceration, pain, or abscess without associated systemic or pulmonary symptoms.11,12  Nontuberculous mycobacteria may be associated with silicone implants.10 

Radiologic Features

Mammography and ultrasonography may be unremarkable or show nonspecific findings.21  Magnetic resonance imaging (MRI) shows characteristic nonmasslike enhancements that may be multiple, regional, and separated or contiguous, clustered, and rimlike.21  In tuberculosis, mammographic findings may vary from increased density, mass, and skin thickening to axillary lymphadenopathy23 ; ultrasonography may show a mass, cystic fluid collections, textural change suggestive of inflammatory carcinoma, fistulas, and axillary lymphadenopathy.23 

Pathologic Features

Although nonpuerperal abscess is rare, accounting for less than 1% of breast biopsies, it constitutes approximately 85% of surgically excised breast abscesses (Figure 1, C and D). Morphologic features vary depending on the etiology and may be indistinguishable from those of puerperal mastitis/abscess with a mixed inflammatory infiltrate (Figure 1, C) consisting of lymphocytes, histiocytes, and neutrophils (Figure 1, D). Furthermore, microorganisms may be difficult to culture because of small quantities or prior antimicrobial treatment. DNA or 16s rRNA sequencing technologies may be helpful in some cases.

Tuberculosis

The histologic appearance is similar to tuberculosis in other sites and consists of necrotizing and/or caseating and nonnecrotizing granulomas with epithelioid histiocytes, Langhans-type multinucleated giant cells, eosinophils, lymphocytes, and plasma cells, lacking an overt association with ducts and lobules, but more commonly affecting ducts.12,24  Ziehl-Neelsen special stain, culture, or polymerase chain reaction (PCR) can be used for confirmation of diagnosis.25 

Fungal and Parasitic Infections

Rare cases of aspergillosis (necrotizing granulomas associated with 3- to 12-μm septate hyphae with regular, progressive acute angle [45°] or dichotomous branching, positive on Grocott-Gomori methenamine silver [GMS] and periodic acid–Schiff diastase [PASD] stains), histoplasmosis (caseating granulomas associated with 2- to 4-μm uniform oval narrow-based budding yeasts with eccentric nuclei clustered within the cytoplasm of histiocytes, positive on GMS and PAS), blastomycosis (necrotizing granulomas and abscesses due to 10- to 15-μm broad-based budding yeasts), and cryptococcosis (histiocytes containing 4- to 10-μm narrow-based budding yeasts with a thick capsule that can be identified by mucicarmine and Fontana-Masson stains) have been described. Parasitic infections include filariasis (roundworms, including Wucheria bancrofti, Dirofilaria repens, and Onchocerca volvulus), sparganosis (tapeworm larva of Spirometra genus, forming an eosinophilic tegument surrounding a myxoid matrix of smooth muscle fibers and calcareous bodies), schistosomiasis (parasitic fluke forming calcified ova), and cysticercosis (larval form of Taenia solium with cysts containing viable larvae with a scolex and hooks or calcified dead organisms).1719  Parasitic infections are characterized by necrotizing acute inflammation with prominent eosinophils, sometimes containing degenerating organisms.

Reactions to Noncellular Materials

Exogenous foreign material may be introduced in the breast via biopsy, surgical or cosmetic procedures, or trauma. These materials generally do not directly cause pain or acute inflammation, but increase predisposition to various secondary infections. Metals such as nipple rings may cause allergic-type symptoms and granulomatous inflammation. Biopsy clips may also be associated with chronic inflammation.

Endogenous noncellular materials such as secretions, milk, keratin, or hair may be associated with duct ectasia, ruptured cysts, and galactoceles, and usually form painless masses. In some cases, reactions to keratin or hair present as a painful erythematous mass (see squamous metaplasia of lactiferous ducts [SMOLD] below). Pilonidal sinuses are due to entrapment of hair in the nipple/areolar region. Similar reaction may be seen to exogenous animal hair among individuals with frequent contact with animals, such as sheep shearers or dog groomers.

Management and Prognosis

Treatment may be challenging without identifying a specific etiology, and formation of sinus tracts, skin ulceration, and recurrences are not uncommon.26  Specific treatment and prognosis depend on the etiology.

Definition

CNGM is a specific inflammatory disease with lobulocentric granulomatous inflammation consisting of cystic spaces/lipid vacuoles rimmed by neutrophils and epithelioid histiocytes and sometimes containing gram-positive bacilli (GPB).2733 

Etiopathogenesis

The terms granulomatous mastitis, granulomatous lobular mastitis, and idiopathic granulomatous mastitis have been used synonymously with CNGM. However, more recent microbiologic and histologic evidence suggests that CNGM is a distinct inflammatory condition caused by Corynebacterium species—aerobic, asporogenous, catalase-positive GPB representing part of the endogenous skin flora.28,29,34,35  The most common type of corynebacteria that has been isolated in CNGM is Corynebacterium kroppenstedtii, followed by Corynebacterium amycolatum and Corynebacterium tuberculostearicum.34,35 

Clinical Presentation

CNGM is unilateral in more than 90% of patients and often presents with a mass, nipple/skin retraction, or sinus formation, sometimes with pain, nipple discharge, erythema, or abscess. All patients have been women, with a mean age of 35 years. CNGM is associated with a prior or recent history of pregnancy.2733,35 

Radiologic Features

Ultrasonographic findings includes a hypoechoic mass (>70%), as well as dilated ducts, abscesses, edema, or fluid collection. The most common mammographic abnormalities are masses and asymmetry, which are often suspicious for malignancy.28,31 

Pathologic Features

Macroscopic findings may include solid lesions or masses with abscess cavities. Microscopically (Figure 2, A through D), there is nonnecrotizing lobulocentric granulomatous inflammation (Figure 2, A) consisting of lipid vacuoles rimmed by neutrophils and epithelioid histiocytes (Figure 2, B and C) and containing GPB (Figure 2, D).36  Gram stain and microbiologic cultures do not always identify corynebacteria for various reasons, including prior antibiotic treatment, scarcity of organisms in tissue sections, and requirement of specific culture medium containing 1% polysorbate (Tween) 80 as well as long incubation periods, leading to a greater than 50% false-negative rate in some studies.27,28,31,32,35  Thicker (6-μm) sections for Gram stain have been shown to increase the detection rate from 37% to 58%.33  Less commonly used alternative detection methods include immunostaining using multiple low-specificity antisera, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and 16S rRNA and rpoB gene sequence amplification with PCR.37,38  Despite the strong association between corynebacteria and CNGM, whether the microbiologic finding should be integrated in the diagnostic criteria is currently unclear.36  Nevertheless, varying combinations of histologic features, results of Gram staining, and microbiologic studies can be used to convey the degree of certainty for pathology reporting.36  The characteristic morphology combined with either positive Gram stain or microbiologic cultures would be consistent with CNGM. If the morphology is suggestive but not diagnostic of CNGM, the possibility of this diagnosis may still be raised in the right clinical context, with recommendation for cultures.36 

Management and Prognosis

Clinical management may include observation, lipophilic antibiotics (tetracycline or doxycycline), steroids, I&D, excision, mastectomy, and combined treatment options.27,36  Dosage and duration of antibiotic therapy is unknown, although at least 3 weeks to up to 1 year has been shown to improve clinical outcome in some patients while decreasing the risk of developing resistance. Multidrug-resistant C kroppenstedtii strain has been reported.39  Culture and sensitivity testing have therefore been suggested.32  A systematic review showed that surgery with or without oral steroids achieves an almost 95% complete resolution rate and less than 7% recurrence rate,40  whereas other studies revealed contradictory results.41 

Definition

Inflammatory reaction to keratinaceous debris following abnormal keratin formation and accumulation within the lactiferous sinuses with subsequent rupture. SMOLD is also known as recurrent subareolar abscess, Zuska disease, or periductal mastitis.

Etiopathogenesis

In the normal nipple, the keratinizing squamous epithelium extends 1 to 2 mm into the orifices of lactiferous ducts. Deeper extension leads to keratin accumulation, duct obstruction, dilatation, and rupture, which then results in spillage of keratinaceous debris into the stroma, eliciting an inflammatory response.42  Squamous metaplasia is thought to be related to smoking via vitamin A deficiency or tobacco-related toxins in nipple secretions or inverted nipple triggering periodic retroareolar inflammation and fibrosis.43 

Clinical Presentation

SMOLD usually presents as a painful erythematous subareolar mass mimicking an abscess in adult women and men with a history of smoking.44,45  Because of frequent recurrences and persistent symptoms, patients have been accused of having Munchausen syndrome.46 

Radiologic Features

Imaging is often not helpful and may be technically complicated because of pain. Mammographic density or irregular mass may be present because of inflammation. Fistula tract is not usually visible.47  MRI has been shown to successfully identify abscess cavity and fistula tract.48 

Pathologic Features

The most common specimen is I&D, consisting of fragments of subareolar breast tissue with or without skin and/or subcutaneous fibroadipose tissue (Figure 3, A through D). Histologic findings are nonspecific (Figure 3, A) and include a mixed acute and chronic periductal/stromal inflammatory infiltrate (Figure 3, B and C) and foreign body giant cells associated with keratinaceous debris (Figure 3, D), sometimes with abscess formation.42  Ducts partially lined by squamous epithelium with or without intraluminal keratin may be seen. Excision specimens should be oriented to include the nipple skin and orifice of the involved duct. Sections should be oriented perpendicular to the inked skin surface. Because of multiple prior procedures, squamous metaplasia due to surgery may be difficult to distinguish from a primary lesion. The fistula tract is usually lined by squamous epithelium. Acute inflammatory cells and bacteria are often seen in secondary infections. Both aerobic and anaerobic cultures should be done to exclude an infectious process.

SMOLD is rarely diagnosed in breast core biopsies, accounting for less than 1% of all biopsies. In general, core biopsy is not performed because of pain or may not show diagnostic features; however, location and clinical setting are helpful. In the appropriate clinical context, a thorough search for the presence of keratinaceous debris and squamous metaplasia should be performed and the diagnosis of SMOLD may be suggested to avoid delays in optimal treatment.42 

Management and Prognosis

Initial treatment often includes I&D and antibiotics, the former often aggravating the inflammation and the latter often being ineffective unless there is a secondary infection (usually mixed anaerobes). Because of this suboptimal initial treatment, in many patients SMOLD recurs (hence the term recurrent subareolar abscess) or persists and a single fistula tract opening at the edge of the areola forms.49  Optimal treatment includes excision of the involved duct, wedge resection of the nipple, and cessation of smoking if applicable. Recurrences are uncommon after complete surgical removal of the lesional area. Surgery can achieve a cure rate of 91% and an overall satisfaction rate of 95% in the cosmetic outcome.50 

Definition

Dilatation of large lactiferous ducts with periductal inflammation and fibrosis, also known as plasma cell mastitis or periductal mastitis, although periductal mastitis and duct ectasia have been suggested to represent different entities because of association of smoking only with periductal mastitis.51 

Etiopathogenesis

Duct dilatation may be due to secretory stasis and/or weakening of the walls of large lactiferous sinuses as a result of thinned elastic fibers and diminished contractile properties of myoepithelial cells. Periductal inflammation may be related to extravasated lipids because of duct rupture and/or the breast/milk microbiota. Inflammation subsequently leads to periductal fibrosis with formation of an irregular mass and retraction of the overlying skin.52 

Clinical Presentation

Duct ectasia has been identified in up to 40% of surgical excisions and autopsies from women aged older than 50 years. Most patients are asymptomatic perimenopausal or postmenopausal women. Clinical symptoms may include unilateral or bilateral thick nipple discharge of varying color due to intraluminal inspissated secretions and a painless irregular subareolar mass with or without skin retraction. Duct ectasia may closely mimic carcinoma.52 

Radiologic Features

Mammography may show dilated ducts, an irregular mass, and/or calcifications that are typically large, rod-shaped (casting), linear, and branching (ductal pattern mimicking ductal carcinoma in situ). Ultrasonography reveals subareolar, anechoic, dilated ducts, often filled with fluid or secretions that may be echogenic enough to mimic intraductal malignancy. Movement of particulate matter in secretions is considered diagnostic at real-time ultrasonography.53 

Pathologic Features

Macroscopically, tissue is usually dense, without a discrete mass. Dilated ducts with thick walls and pasty, yellow-brown, intraluminal inspissated debris may be seen. Early lesions are confined to the large subareolar ducts, although an entire mammary segment may be involved at later stages.42  Microscopically (Figure 4, A through D), in early lesions dilated subareolar ducts (Figure 4, A and B) are surrounded by a lymphoplasmacytic infiltrate (Figure 4, C), with or without hemosiderin and hemosiderin-laden macrophages and lipids and lipid-laden macrophages (ochrocytes) (Figure 4, A and D). Well-formed granulomas or giant cells are uncommon. Ductal epithelium may be infiltrated by lymphocytes and histiocytes, the latter sometimes mimicking atypical lobular hyperplasia. Rarely, duct rupture and acute inflammation may lead to fat necrosis, abscess, or fistula formation.42  At later stages, dilated ducts with intraluminal secretions and periductal fibrosis are more prominent, leading to obliteration of the lumens and formation of a ring of epithelial-lined tubular structures, the so-called garland pattern, or 1 or 2 epithelial-lined spaces seen to one side of an obliterated duct.

Management and Prognosis

Duct ectasia is benign and self-limiting, and does not require treatment.

Definition

Inflammatory reaction secondary to injury of fibroadipose and fibroconnective tissue of the breast.

Etiopathogenesis

Injury of breast tissue may be related to a variety of causes, such as ruptured cysts or ducts, autoimmune diseases (lupus mastitis, polyarteritis nodosa, Weber-Christian disease, granulomatous angiopanniculitis), anticoagulation, blunt trauma, pressure, prior biopsy, surgery, or radiation therapy because of postradiation endarteritis obliterans, including 50% of patients following balloon-based brachytherapy.54  No specific cause is identified in 50% of cases.

Clinical Presentation

The mean patient age is 50 years (range, 37–68 years). Clinically, fat necrosis may be asymptomatic or may present as a palpable periareolar mass with or without skin bruising, tenderness, or retraction.55 

Radiologic Features

Ultrasonographic features include either a stellate mass with irregular margins, complex cysts, or oil/lipid cysts.56  Mammography may reveal focal asymmetry, spiculated mass, or eggshell calcifications within lipid cysts, which tend to be clustered, pleomorphic, and linear around a central area of necrotic adipose tissue, mimicking ductal carcinoma in situ.54 

Pathologic Features

Fat necrosis is uncommon, identified in only 0.6% of breast excisions. Macroscopically, early lesions show induration and firmness due to hemorrhage. Later lesions form a mass with a yellow-gray to focally red appearance, often retracting the surrounding tissue. Cystic degeneration with central cavity formation and deposition of calcifications in the cyst wall may be seen. Microscopically (Figure 5, A through D), foamy histiocytes and foreign body–type giant cells (Figure 5, A) surround nonviable adipocytes and lipid vacuoles (Figure 5, B). Cysts lined by foamy histiocytes are common, usually accompanied by a variable lymphoplasmacytic inflammatory infiltrate and hemosiderin deposition. Foamy histiocytes may closely mimic invasive carcinoma (Figure 5, C and D). Later lesions show varying degrees of fibrosis and/or cysts with fibrotic and/or calcified walls.57  Loculated degenerated fat surrounded by fibrosis may persist for months to years. Identification of other histologic findings indicative of a possible cause (eg, radiation atypia, biopsy gel material) may be helpful.57 

Cellular spindled histiocytic pseudotumor is a reactive inflammatory lesion associated with fat necrosis, composed of spindle-shaped histiocytes infiltrating into breast parenchyma and associated with a variable lymphoplasmacytic infiltrate and rare giant cells. Mitoses may be present but are not atypical.58 

Management and Prognosis

Fat necrosis does not require treatment when diagnosed on a core biopsy, except for cases with radiologic-pathologic discordance or imaging features highly suspicious for malignancy.

Definition

Inflammatory reaction consisting of periductal, perilobular, and perivascular lymphocytic infiltrates and dense interlobular stroma, usually in association with autoimmune diseases, also known as diabetic mastopathy, diabetic fibrous mastopathy, or sclerosing lymphocytic lobulitis.

Etiopathogenesis

Most patients have autoimmune diseases such as long-standing insulin-dependent (type 1) diabetes mellitus with microvascular complications (approximately 75%),59  or type 2 diabetes mellitus and Hashimoto thyroiditis (approximately 10%). A subset of patients (approximately 15%) has no known history of diabetes or autoimmune disease.60  Possible hypotheses include inflammatory B-cell response (due to expansion of stromal matrix and accumulation of advanced glycosylation end products as a result of hyperglycemia) and immune response to exogenous insulin.61 

Clinical Presentation

Most patients are premenopausal women, but men may also be affected.60  The usual presentation includes a firm, well-circumscribed or ill-defined palpable unilateral mass, although multiple or bilateral masses, ill-defined nodules, or subtle changes on screening mammography have also been described.

Radiologic Features

Mammographic features may mimic malignancy, with ill-defined masses, architectural distortion, or asymmetric density that may be difficult to evaluate because of dense breasts.62  Ultrasonography usually shows multiple irregular hypoechoic masses with posterior acoustic shadowing.62  MRI findings range from decreased diffuse enhancement to rapid, intense enhancement.63 

Pathologic Features

Macroscopically, dense white masses range in size from 1 to more than 6 cm. Microscopically (Figure 6, A through D), there is a periductal, perilobular, and perivascular lymphocytic infiltrate (mature B cells with a small population of T cells) devoid of germinal centers (Figure 6, A and B) and dense paucicellular interlobular stromal fibrosis (Figure 6, A through C) with a keloidal to glassy appearance. Plasma cells may also be seen.59  The terminal duct–lobular units (TDLUs) may be sparse and atrophic (Figure 6, B and C), with thickened basement membranes. A subset of cases may contain stromal epithelioid fibroblasts, often forming a whorled or nodular growth pattern (Figure 6, C and D). These cells exhibit eosinophilic cytoplasm and bland vesicular oval to round nuclei lacking mitotic activity (Figure 6, D).60 

Management and Prognosis

Lymphocytic mastopathy is benign and requires only routine mammographic surveillance. However, ipsilateral or contralateral recurrences have been reported in some patients who underwent surgical excision.60  In a cohort of 34 cases, 5 (15%) developed recurrence (2 ipsilateral, 3 bilateral). Patients with lymphocytic mastopathy do not have an increased risk of breast cancer or hematolymphoid malignancy.64 

Definition

Immunoglobulin (Ig) G4–related mastitis (IgG4-RM) is an evolving chronic fibroinflammatory condition of the breast that may represent a subtype of organ-specific IgG4-related disease (IgG4-RD). IgG4-RD may involve nearly any organ. The 2020 revised comprehensive diagnostic criteria include (1) clinical-radiologic features with 1 or more organs showing diffuse or localized swelling or a mass or nodule characteristic of IgG4-RD; (2) serologic abnormality with elevated levels of serum IgG4 at greater than 135 mg/dL; and (3) 2 of 3 of the following pathologic findings: (a) dense lymphoplasmacytic infiltrate with fibrosis; (b) the number of IgG4+ plasma cells greater than 10 per high-power field (HPF) and IgG4+:IgG+ plasma cell ratio greater than 40%; and (c) fibrosis, particularly storiform pattern, or obliterative phlebitis.65  The diagnosis of IgG4-RD may be deemed definite (criteria 1–3), probable (criteria 1 and 3), or possible (criteria 1 and 2).65  Per the consensus statement following the 2011 Boston International Symposium, histologic findings highly suggestive of IgG4-RD include 2 or more of the 3 major criteria (lymphoplasmacytic infiltrate, at least focally storiform fibrosis, obliterative phlebitis), whereas an increase in the absolute numbers of IgG4+ plasma cells (10 to >200 per HPF in different organs) and an elevated IgG4+:IgG+ plasma cell ratio of greater than 40% by immunohistochemistry are of secondary importance.66  Other nonspecific minor features include nonobliterative phlebitis and increased numbers of eosinophils.66 

Etiopathogenesis

IgG4-RD may be related to a B-cell–mediated response to an unknown antigen, with CD4+ T-helper cells modulating an immunoglobulin class switch toward IgG4, somatic hypermutation of plasmablasts, or clonal expansion of CD4+ cytotoxic T cells secreting various cytokines in the peripheral blood and organs, including signaling lymphocytic activation molecule F7 (SLAMF7), granzyme A, interleukin 1β (IL-1β), interferon γ (INF-γ), and transforming growth factor β1 (TGF-β1).67  IL-1β, TGF-β, and INF-γ are proinflammatory and may stimulate inflammation and fibrosis. Patients with IgG4-RM have no increased risk for developing breast cancer.

Clinical Presentation

The exact prevalence of IgG4-RM is uncertain because of its rarity, with fewer than 20 reports in the English literature.6872  Although the diagnostic criteria of IgG4-RD were developed without including patients with involvement of rare sites such as the breast, the IgG4-RD criteria have been applied in the reported cases of IgG4-RM. IgG4-RM affects predominantly women, and rarely men.71  IgG4-RM may present as isolated lesions or in synchronous or metachronous association with extramammary (systemic) disease. Clinical presentation includes a unilateral solitary painless mobile mass and less often multiple and/or bilateral masses with or without skin induration. The median age at diagnosis is 51 years (range, 37–84 years). Almost 50% of cases have extramammary involvement.73  Up to 70% of patients with IgG4-RD show approximately 5-fold elevations in serum IgG and IgG4 titers (>140 mg/dL), although this should not be used alone, as IgG4 serum titers may also be increased in patients with other neoplastic and nonneoplastic conditions as well as in the healthy population.74 

Radiologic Features

IgG4-RM usually presents as an ill-defined asymmetric density or a unilateral solitary mass with well-circumscribed or ill-defined margins, which may be suspicious for malignancy.70 

Pathologic Features

Macroscopic findings vary from ill-defined lesions to firm yellow-brown or tan masses, usually lacking hemorrhage or necrosis. Microscopically (Figure 7, A through D), there is a well-defined fibroinflammatory nodule (Figure 7, A) comprising variably hyalinized short fascicles of haphazardly distributed fibroblasts or a vague storiform appearance (Figure 7, B).73  Storiform fibrosis may be focal, subtle, or absent, and obliterative phlebitis is usually absent.72  The TDLUs are surrounded by a lymphoplasmacytic infiltrate and may be atrophic (Figure 7, C). Lymphoid follicles with or without germinal centers are often present (Figure 7, A). Eosinophils and macrophages are variable. IgG4-RM has been reported to show lobulocentric granulomas mimicking granulomatous lobular mastitis.75 

The number of IgG4+ plasma cells is increased (Figure 7, D), with the absolute number per HPF ranging from more than 10 to more than 300 in the published cases of IgG4-RM and the IgG4+:IgG+ plasma cell ratio ranging from more than 40% to 85%.6872  The recommended counting method is the average of 3 microscopic fields at ×40 objective with the highest concentration of IgG4+ plasma cells (hot spots) as well as the ratio.

Management and Prognosis

In patients with other organ involvement as part of IgG4-RD, management and prognosis depend on the systemic disease. Isolated cases of IgG4-RM have been shown to have an excellent response to surgical excision and steroid therapy.69  Spontaneous regression has also been reported.68 

The differential diagnosis of inflammatory lesions of the breast can be challenging and requires clinical-radiologic correlation and ancillary testing, including special stains and immunohistochemical studies (Table). In core biopsies, the most helpful and practical approach would be to first rule out a neoplastic process76,77  and then categorize the inflammatory infiltrate as predominantly acute or mixed without granulomas, or predominantly chronic with or without granulomas (Figures 8 through 10).

Predominantly Acute or Mixed Inflammatory Lesions Without Granulomas

The main differential diagnosis includes puerperal and nonpuerperal mastitis and abscess and SMOLD (Figure 8). In addition to the association with childbirth or the lactational period, puerperal mastitis/abscess should be suspected based on the presence of gram-positive cocci.7  In rare cases, Candida species can be confirmed by special stains (PASD, GMS), although false-negative results may occur. Inflammatory carcinoma is the greatest mimic of puerperal mastitis/abscess. In general, if an erythematous mass fails to respond to antibiotic therapy and/or the characteristic “peau d’orange” appearance of the skin is noted, a biopsy should be performed, which will show parenchymal and dermal lymphatic involvement by invasive carcinoma.

Nonpuerperal mastitis/abscess associated with predominantly acute or mixed inflammation includes infections and noncellular materials. Infectious organisms may be identified by special stains (bacteria, fungi) or thorough morphologic examination (parasites in association with eosinophils). Additionally, clinical history is helpful for recognition for exogenous noncellular materials (metal, animal hair) and endogenous noncellular material (eg, keratin, hair). Of note, secondary infections may also occur in response to foreign material such as nipple rings and hair. Nonpuerperal mastitis and abscess usually involve the deep breast parenchyma without association with the areola, in contrast with SMOLD, which usually presents as a painful erythematous subareolar mass in smokers and showing keratinaceous debris associated with acute inflammation or abscess in earlier stages.47 

Predominantly Chronic Inflammatory Lesions With Granulomas

Similar to other organ sites, granulomatous inflammation of the breast may be due to infectious or noninfectious etiology, usually raising a broad differential diagnosis (Figure 9). Mycobacteria or fungal organisms associated with necrotizing or nonnecrotizing granulomas may be identified by special stains (Ziehl-Neelsen, PASD, GMS), cultures, and/or PCR.25,78  CNGM is characterized by nonnecrotizing lobulocentric granulomas with lipid vacuoles containing GPB (corynebacteria), rimmed by neutrophils and surrounded by a mixed inflammatory infiltrate with scattered giant cells.36 

Foreign body granulomas form in reaction to suture or silicone. Suture material is often readily identified in sections. Silicone particles may mimic lipid vacuoles of CNGM but lack rimming neutrophils and GPB. Granulomatosis with polyangiitis is usually part of systemic disease or may rarely involve the breast alone, and shows necrotizing vasculitis, fat necrosis with mixed inflammation, and occasional granulomas.79  Rheumatoid nodules are characterized by a central area of fibrinoid necrosis with palisading histiocytes, lymphocytes, and plasma cells, and lack GPB.80  Sarcoidosis is a diagnosis of exclusion and shows “naked” nonnecrotizing epithelioid granulomas with multinucleated giant cells and surrounding lymphocytes, sometimes with asteroid bodies (star-shaped cytoplasmic inclusions) and Schaumann bodies (concentrically lamellated calcified nodules) in the multinucleated cells. Rosai-Dorfman disease is a proliferation of S100-positive histiocytes and lymphocytes with characteristic emperipolesis (macrophages engulfing other cells, typically neutrophils).81,82 

Lastly, the term idiopathic granulomatous mastitis has been used as a specific diagnostic entity,83  defined as granulomatous mastitis in which an underlying cause cannot be detected and other forms of granulomatous mastitis have been ruled out.84  However, given that the possibility of false-negative results for ancillary testing or specific diagnostic features for other entities can never be entirely excluded in any given specimen, this term should not be used as a diagnostic category.

Predominantly Chronic Inflammatory Lesions Without Granulomas

This category may be divided into lymphocytic, plasma cell–rich, and histiocytic or giant cell–rich infiltrates (Figure 10). Benign TDLUs entrapped within any of these infiltrates may be distinguished from invasive carcinoma based on the absence of architectural and/or cytologic atypia and/or negative pan-cytokeratin immunohistochemistry.

A lymphocytic inflammatory infiltrate, with or without plasma cells, associated with dense stromal fibrosis is suggestive of lymphocytic mastopathy. In addition, epithelioid fibroblasts may mimic invasive carcinomas with histiocytoid or apocrine morphology or granular cell tumor.57  Immunohistochemistry for pan-cytokeratin, S100, and lymphoid markers is useful for this differential diagnosis. A clinical history of autoimmune conditions would support this diagnosis.60  A periductal lymphocytic infiltrate associated with fibrosis and variably dilated ducts filled with lipid debris indicates duct ectasia.52  Hyaline-vascular–type Castleman disease shows lymphoid follicles with atrophic germinal centers containing vessels (“onion skin” lesions), lymphocytes arranged in layers within expanded mantle zone, fusion of mantle zones with formation of several germinal centers, and interfollicular vascular proliferation with perivascular hyalinization.85  Patients with Sjögren syndrome may develop Sjögren mastitis consisting of lymphocytic infiltrates associated with duct ectasia while lacking stromal fibrosis.86  Low-grade B-cell lymphoma, such as small lymphocytic lymphoma, consists of diffuse infiltrates of neoplastic lymphoid cells not surrounding ducts and would demonstrate a clonal proliferation of B-lymphocytes coexpressing CD5 and CD23.

A plasma cell–rich lymphoplasmacytic infiltrate is identified in IgG4-RM in association with at least focal storiform fibrosis. The differential diagnosis includes Rosai-Dorfman disease, which may show prominent sclerosis and lymphoplasmacytic infiltrate in addition to emperipolesis.81,82  Inflammatory myofibroblastic tumor is a low-grade spindle cell mesenchymal neoplasm associated with a variably prominent lymphoplasmacytic inflammatory infiltrate (but without increased IgG4+ plasma cells) and anaplastic lymphoma kinase expression by immunohistochemistry or rearrangement by in situ hybridization.87,88 

Histiocytic or giant cell–rich inflammatory infiltrates without well-formed granulomas may be seen in various conditions. Fat necrosis shows degenerating fat with lipid-laden macrophages, giant cells, and sometimes neutrophils. It should be differentiated from uncommon types of invasive carcinoma with lipid-rich and histiocytoid morphology such as apocrine carcinoma and invasive lobular carcinoma (Figure 5, C and D). The clinical history of risk factors associated with fat necrosis as well as pan-cytokeratin immunohistochemistry can be helpful. Later stages of SMOLD often show chronic inflammation with foreign body giant cell reaction to keratin and squamous metaplasia in ducts.57  Biopsy site changes involve the prior biopsy site and show giant cell reaction against foreign material, sometimes in association with squamous metaplasia. Epidermal inclusion cyst is lined by keratinizing squamous epithelium, contains keratinaceous debris, and may also lead to mass formation, inflammation, and pain if ruptured.

If a careful morphologic assessment and ancillary studies fail to point to a specific diagnosis in core needle biopsies, a descriptive report may be issued detailing microscopic findings and differential diagnoses based on the combination of clinical, radiologic, and morphologic features. A similar algorithmic approach may be used for surgical specimens, where the possibility of an undersampled specific diagnostic entity is significantly less likely.

Accurate classification of inflammatory lesions of the breast requires integration of clinical, radiologic, and pathologic features, especially on needle core biopsies. Although the radiologic features often overlap, a combination of clinical and morphologic findings and ancillary testing should be used to arrive at the most plausible diagnosis in both the core biopsies and the surgical specimens. Consideration of the clinical and radiologic context and thorough morphologic assessment will ensure accurate diagnosis and avoid misclassification of clinically significant lesions such as CNGM, IgG4-RM, and SMOLD.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.