Granulomatous diseases of the breast and axilla: radiological findings with pathological correlation
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This article reviews our experience and describes the literature findings of granulomatous diseases of the breast and axilla.
After approval of the Institutional Review Board was obtained, the surgical pathological records from January 2000 to January 2017 were searched for the keyword granulomatous. Clinical, imaging and histology findings were reviewed by both a fellowship-trained radiologist and a breast-imaging consultant radiologist, reviewing 127 patients (age range, 32–86 years; 126 women and 1 man).
Most common causes of granulomatous lesions of the breast and axilla included silicone granulomas 33% (n = 42), fat necrosis 29% (n = 37) and suture granulomas 11% (n = 14). In 16% (n = 20), no cause could be found and clinical history was consistent with idiopathic granulomatous mastitis. Other granulomatous aetiologies included granulomatous infections, sarcoidosis and Sjögren’s syndrome. Causes of axillary granulomatous disease were similar to the breast; however, a case of cat-scratch disease was found that only involved the axillary lymph nodes. They can have a variable appearance on imaging and may mimic malignancy with irregular masses seen on mammography, ultrasound and magnetic resonance imaging. Fistulas to the skin and nipple retraction can suggest chronicity and a granulomatous aetiology. Combination of clinical history, laboratory and imaging findings can be diagnostic.
Granulomatous processes of the breast are rare. The diagnosis can, however, be made if there is relevant history (prior trauma, silicone breast implants, lactation), laboratory (systemic or infectious processes) and imaging findings (fistula, nipple retraction). Recognising these entities is important for establishing pathological concordance after biopsy and for preventing unnecessary treatment.
Breast granulomatous are rare but can mimic breast carcinoma on imaging
Imaging with clinical and laboratory findings can correctly diagnosis specific granulomatous breast diseases
Recognition of the imaging findings allows appropriate pathological concordance and treatment
KeywordsBreast Granulomatous mastitis Mammography MRI Ultrasonography
With Institutional Review Board approval, a search of the surgical pathology records of approximately 17,000 breast biopsies performed at our institution from 1 January 2000 to 1 January 2017 yielded 127 patients (age range, 32–86 years; 126 women and 1 men) with granulomatous disease of the breast, and their imaging results were available for review by both a fellowship-trained radiologist and breast-imaging consultant radiologist. The search found records of 42 silicone granulomas, 37 fat necrosis, 20 idiopathic granulomatous mastitis, 14 suture granulomas, 1 Corynebacterium, 1 Mycobacterium fortuitum infection, 2 sarcoidosis and 1 Sjögren’s syndrome. Additionally, nine cases of granulomatous lymphadenitis where found: six of which were secondary to granulomatous causes involving the breast (for example, silicone granuloma), one was idiopathic and one patient was diagnosed with cat-scratch disease.
Most breast infections are bacterial and are usually secondary to skin contamination, with most infections resolving without sequela. Specialised stains are occasionally necessary for specific diagnosis, including Gram, periodic acid-Schiff and Ziehl-Neelsen stains. Overall, chronic infections with granulomatous reactions are rare and a high index of clinical suspicion is necessary.
Clinically patients present with a painful and/or palpable breast mass, often with axillary lymphadenopathy. A discharging sinus tract can be seen if treatment is delayed. The subareolar regions may be relatively spared. Reactive lymphadenopathy may be present in up to 15% of cases.
Imaging features are variable depending on type of infection, but are unable to reliably separate based solely on imaging. Bacterial infections (Corynebacterium, etc.) often present as an erythematous, inflamed breast with skin thickening and complex cystic mass on ultrasound. An irregular hypoechoic mass or vague ill-defined hypoechoic mass with increased vascularity on Doppler evaluation can also be seen. Fungal infections (blastomycosis, cryptococcosis, histoplasmosis, actinomycosis) usually present as a lobulated, irregular or well-defined complex cystic mass sonographically. Less common parasitic infections (filarial, schistosomiasis, sparganosis, echinococcosis) can present with calcifications with or without a mass mammographically.
Mycobacterium infections (tuberculous, atypical) present with axillary lymphadenopathy, skin thickening or ill-defined mass, often with sinus tracts and fistulae. Mammographically, tuberculosis can manifest as an ill-defined or irregular mass resembling cancer; however, skin bulging and sinus tracts can suggest tuberculous infection and large, dense, calcified axillary lymph nodes can also be a clue to tuberculous infection.
On MRI, the most frequent finding was focal or diffuse asymmetrical signal intensity changes without significant mass effect. Nodular lesions can also be seen with hypointense T1 regions and hyperintense T2 regions. Dynamic contrast-enhanced MRI can show mass-like enhancement, ring-like enhancement and/or nodular enhancement, while time-intensity curves can vary.
The granulomas can show caseating “cheesy” necrosis, and occasionally acid-fast bacilli are found within the central portion of the granuloma [1, 2]. Caseous necrosis is often encountered in tuberculosis infections but can also be caused by syphilis and certain fungi. A similar appearance can be associated with histoplasmosis, cryptococcosis and coccidioidomycosis.
Foreign bodies and traumatic causes
Foreign body granuloma arises from reaction to any foreign materials that cannot be broken down, such as silicone, suture material, wood, gunpowder, plastic sewing needle and paraffin. Alternatively, traumatic granulomas originate from any procedure or injury resulting in fat necrosis. The granulomas that form around fat necrosis are the result of difficulty removing the necrotic fat because of its large size [3, 4, 5, 6].
Silicone for breast augmentation was initially injected directly into the breast. This procedure was performed in the United States until it was prohibited in the 1970s because of reports of lymphadenopathy, infection, granulomatous masses and fibrosis.
Silicone implants were introduced in the 1960s with the theory that the barrier shell would reduce the complications of direct silicone injection. Unfortunately, the shells used in these early implants were semi-porous and allowed small amounts of silicone gel to “bleed” without implant rupture. These early implants were also prone to rupture with increasing age, and when they rupture result in large amounts of extracapsular silicone . The complications of this free silicone were indistinguishable from those of direct silicone injection .
Patients may present with pain, soreness or swelling in the affected breast, change in breast size or shape, lumps in the affected breast or softening or hardening of the affected breast. Silicone granulomas may present distant from the implant site; primarily, the ipsilateral chest wall and axillary lymph nodes are involved. Ductal extension, with silicone being discharged from the nipple, and pectoralis muscle extension have also been reported [9, 10].
Ultrasonography shows a “snowstorm” appearance with well-defined echogenicity anteriorly and dirty posterior acoustic shadowing. The lymph nodes may also be echogenic with dirty shadowing.
Dual-energy CT can perform material decomposition, identifying intracapsular and extracapsular rupture and extracapsular silicone .
MRI shows low T1-signal and high T2-signal foci separate from the implant and high-signal foci on silicone-sensitive sequences. Enhancement may be noted if active inflammation or granulomas are present.
Most cases of fat necrosis occur postoperatively or after radiation therapy. The condition is typically asymptomatic; however, when it is symptomatic, 97% of patients present with a palpable abnormality. This is usually within a periareolar or superficial location. In a few cases, bruising and tenderness (26%), skin tethering or dimpling (14%) or nipple retraction (9%) occur. Palpable breast abnormalities that are associated with fat necrosis may enlarge, remain unchanged, regress or resolve [12, 13].
On sonography, the appearance of fat necrosis ranges from a solid hypoechoic mass with posterior acoustic shadowing to complex intracystic masses that evolve over time (Fig. 5). The other common sonographic finding is an area of increased echogenicity in the subcutaneous tissue with or without small cysts and architectural distortion.
MRI shows a wide spectrum of appearances depending on the amount of inflammatory reaction, liquefied fat and the degree of fibrosis. The necrotic central fat is isointense or slightly lower signal on saturated T1-weighted images than the remaining fat in the breast. The “Black hole” sign of fat necrosis had been described with marked hypointensity on STIR images when compared with surrounding fat. The surrounding fibrosis shows enhancement on post-gadolinium images; the enhancement being most marked in the early stages of fat necrosis and decreasing with time. The enhancement may be thin, thick, irregular or spiculated and may mimic malignancy. Kinetic analysis is of little help in granulomatous fat necrosis as the full spectrum of enhancement patterns can be seen (Fig. 5).
CT findings of fat necrosis are not well described but tend to correspond with MRI findings with central fat and peripheral enhancement if contrast is given. The fibrosis has attenuation values similar to fibroglandular tissue or linear densities resembling fibrous bands. Calcifications occasionally are seen on CT .
Histologically, fat necrosis within the breast occurs when there is vacuolisation and saponification of the remnants of the necrotic fat, which become surrounded by lipid-laden macrophages, multinucleated giant cells and acute inflammatory cells. Fibrosis develops, enclosing the area of necrotic fat and cellular debris [12, 13, 15] (Fig. 5).
Sjögren’s syndrome is an autoimmune disease typically affecting the salivary glands and often presents with dry eyes and mouth. Non-glandular manifestations are reported and are likely related to lymphocytic infiltration vasculitis. There is a female preponderance for Sjögren’s syndrome, and the incidence in the general population is 0.1–0.6%. There is a bimodal age distribution; peaks occur between 20 and 30 years and between 50 and 55 years. Those affected by Sjögren’s syndrome have a 5% increased risk for development of lymphoma, 18.9 times higher than that in the general population .
Granulomas of unknown cause
Idiopathic granulomatous mastitis
As the name suggests, the cause of idiopathic granulomatous mastitis is unknown. This condition is more common in pregnant and lactating women and in patients with hyperprolactinaemia and may be related to increased ductal secretions. These increased ductal secretions may lead to damaged ductal epithelium with glandular secretions leaking into the connective tissue of the breast stroma. This process results in a chemical mastitis .
Mammography shows variable features, ranging from normal-appearing in patients with dense breast tissue to discrete masses. There is often focal or regional asymmetry, solitary mass or masses, skin thickening, skin or nipple retraction and axillary lymphadenopathy. The affected breast is larger than the contralateral breast and calcifications are exceedingly rare. The mammographic appearance can be indistinguishable from invasive or inflammatory breast cancer.
On ultrasonography, multiple contiguous hypoechoic masses have been considered suggestive of the disease with skin fistulae common in advanced cases. Posterior acoustic enhancement and shadowing have both been described. Doppler imaging demonstrates increased vascularity and in advanced cases fluid collections and cavities can be seen. Ultrasound is useful in documenting sinus tracts and in the evaluation of any enlarged axillary reactive lymph nodes.
MRI is indicated to assess the extent of disease and in assessment of the contralateral breast. It is best reserved for advanced, aggressive or refractory disease and can be used to assess disease progression or regression over time. The MRI findings are variable depending on the severity of the inflammation, with both heterogeneous ill-defined masses and non-mass enhancement being described . Idiopathic granulomatous mastitis demonstrates marked parenchymal enhancement most often with progressive or plateau kinetics. There are often areas of increase T2 signal representing fluid collections. The involved parenchyma demonstrates restricted diffusion with ADC valves consistently lower than seen in normal breast parenchyma .
On histopathologic examination, non-caseating granulomatous inflammation is centred on lobules. Common end-stage features of idiopathic granulomatous mastitis are fat necrosis, abscess formation and fibrosis [22, 26, 27].
The aetiology of sarcoidosis is unknown, and usually the lungs, lymph nodes, skin, spleen, and liver are involved. Breast involvement is rare, occurring in less than 1% of patients with systemic sarcoidosis.
Mammary lesions are usually detected after the diagnosis of sarcoidosis has already been well established, and only rarely does sarcoidosis present initially as a breast disease. Like sarcoidosis elsewhere, it usually affects women in their 20s and 30s and can manifest as a firm, hard mass mimicking breast cancer or lymphadenopathy. In 20% of reported cases of sarcoidosis of the breast, the initial presentation is a breast mass. The characteristic clinical finding is a non-tender, mobile breast mass with other organ involvement and an increased level of angiotensin-converting enzyme [3, 4, 5, 28].
Irregular, hypoechoic masses with indistinct margins are the most common finding on ultrasonography.
Increased uptake on positron emission tomography can cause sarcoidosis to be mistaken for metastatic breast carcinoma (Fig. 9). It is important for clinicians and radiologists to be aware that imaging findings and systemic manifestations of sarcoidosis can be confused with those of metastatic breast cancer [29, 30].
Gross pathological findings consist of firm to hard, tan tissue that may have well-defined or indistinct borders and can measure up to 5 cm in diameter. Microscopic examination shows epithelioid granulomas with multinucleated giant cells. The lesions classically do not have caseous necrosis or calcification, and fat necrosis is not found in the surrounding breast. Associated lymphocytes and fibrosis are often present. Not all non-necrotising granulomas are sarcoidosis; however, other causes of non-necrotising granulomas need to be excluded. The diagnosis requires exclusion of these other causes and often clinical evidence of sarcoidosis elsewhere. Stains and cultures for bacteria, mycobacteria and fungus should be negative. These studies are indicated even in patients with previously diagnosed sarcoidosis, because secondary infections can develop, especially in patients who have had corticosteroid treatment.
Axillary lymph nodes
The causes of granulomas within axillary lymph nodes are similar to the causes of granulomas within the breast parenchyma. Lymph node granulomas are often classified into infectious or non-infectious causes.
Non-infectious causes of granulomatous lymphadenitis include sarcoidosis, berylliosis and sarcoid-like reaction, and these are rarely associated with abscesses or necrosis . Infectious granulomatous lymphadenitis can be further categorised as suppurative or non-suppurative. Suppurative infections are associated with central abscesses, necrosis and granulomas and include tularaemia, cat-scratch disease, yersiniosis and lymphogranuloma venereum.
Patients present with tenderness, erythema, swelling and abscess formation. Alternatively, non-suppurative infectious granulomatous lymphadenitis shows no signs of inflammation and results in “cold” abscesses. Causes of non-suppurative infections include tuberculous, atypical mycobacterium, toxoplasmosis, syphilis, brucellosis or various fungal infections .
Although granulomatous lymphadenitis of the axilla has multiple causes, only a few specifically have a preference for the axilla and typically spare the breast parenchyma. Cat-scratch disease, or cat-scratch fever, is one of those processes. It is caused by a bacterial infection and most commonly occurs in children after a cat scratches or bites an arm . It has worldwide distribution and has been described in all areas of North America. In northern temperate zones, it occurs more often from August through October, usually in humid, warm locales. There are an estimated 22,000 new cases of cat-scratch disease per year in the United States .
Cat-scratch disease is usually limited to one side of the body and commonly presents as tender, swollen lymph nodes near the site of the bite or scratch. Regional lymphadenopathy occurs 1–3 weeks after inoculation. A vesicle or an erythematous papule may form at the site of initial infection, and regional lymphadenopathy (85%), axillary lymphadenopathy (27%), and fever, headache and malaise (77%) often develop. It may take 7–14 days before symptoms appear, and most cases are self-limited, resolving within 1 month with or without treatment. The lymphadenopathy may, however, persist for several months after the other symptoms have disappeared .
Cat-scratch disease is characterised by granulomatous inflammation on histological examination of the lymph nodes. Breast parenchymal involvement occurs less commonly; when it does, it presents as a palpable mass with enlarged lymph nodes within the axilla in 38% of patients .
Clinical and imaging findings of granulomatous processes of the breast and axilla
• Aspiration demonstrating bacterial, fungal or parasitic infection
• Mammo: serpiginous calcifications seen with parasitic infection
• US/MRI: lymphadenopathy, skin thickening, ill-defined mass, often with sinus tracts and fistulae
• History of trauma
• Mammo: lipid cysts or dystrophic calcifications
• US/MRI/CT: fat seen within the centre of mass
• Prior surgery
• Mammo: Suture knots seen on mammography
• Breast implants
• Mammo: high-density silicone on mammography
• US: snow storm on US
• MRI: high-signal on silicone-sensitive sequences
• CT: dual-energy CT identifying silicone
• Rheumatoid: cutaneous rheumatoid nodules, RF, ANA
• GPA: ANCA
• Sjögren’s syndrome: dry eyes and mouth, Anti-Ro/SSA, Anti-La/SSB
• Mammo: bilateral ill-defined or irregular masses
• US: Bilateral irregular hypoechoic masses
• ACE elevated, hypercalcaemia or hypercalciuria
• Lungs, skin or lymph nodes, less common eyes, liver, heart & brain
• Mammo/US: bilateral masses, asymmetry or architectural distortion
• [18F]-FDG-PET: Increased uptake
• Pregnant or lactating
• Subareolar or entire breast
• Affected breast larger, with pain, erythema, swelling or axillary lymphadenopathy
• Cultures negative
• Mammo/US: solitary mass, skin thickening and nipple retraction
• MRI: marked parenchymal enhancement with sterile micro-abscesses
• Similar aetiologies to breast
• Infectious vs non-infectious
• Cat bite or scratch to arm
• Mammo/US: lymph nodes enlarged and round
• Fistula to skin
Granulomatous breast disease commonly presents with a unilateral breast mass, and axillary lymphadenopathy can be seen. Fistula formation can suggest a granulomatous cause—either infectious or idiopathic granulomatous mastitis. Mammographic findings include asymmetric density or an ill-defined mass. Sonographic findings commonly demonstrate an irregular hypoechoic mass or masses with specific findings for granulomas, including: the “snowstorm” appearance seen with extracapsular silicone; ill-defined confluent hypoechoic areas with marked vascularity and sinus tracts to the skin, as well as adjacent fluid collections, seen with Mycobacterium infections and idiopathic granulomatous mastitis; circumscribed hypoechoic masses with or without surrounding hyperechogenicity, which can be found with fat necrosis. MRI is beneficial in evaluation of the extent of disease and may demonstrate peripheral enhancement and abscess formation as the granuloma tries to wall-off the inciting antigen.
Recognising these entities is important for establishing pathological concordance after biopsy and for preventing unnecessary treatment.
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