Mammographic Signs of Systemic Disease 1

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Mammographic Signs of Systemic Disease1 CME FEATURE See www.rsna .org/education /rg_cme.html

LEARNING OBJECTIVES FOR TEST 6 After completing this journal-based CME activity, participants will be able to: ■■Describe

the mammographic changes that occur in the breast vasculature, lymphatic vessels, skin, and parenchyma in various systemic diseases. ■■Discuss

the systemic diseases that can mimic primary breast malignancy at mammography. ■■List

the systemic diseases that are thought to be associated with an increased risk of breast cancer.

Mailan M. Cao, MD • Anne C. Hoyt, MD • Lawrence W. Bassett, MD Although mammography is primarily used for the detection of breast cancer, it can occasionally reveal breast abnormalities related to extramammary disease. Cardiovascular diseases such as congestive heart failure and central venous obstruction may manifest as venous engorgement and breast edema at mammography. Pathologic arterial calcifications seen at mammography can indicate an underlying risk factor for accelerated atherosclerosis such as chronic renal failure. Connective tissue diseases including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis-polymyositis, and systemic scleroderma typically manifest with bilateral axillary lymphadenopathy, and stromal calcifications are also seen in the latter three disease processes. Some diseases such as neurofibromatosis type 1 and filariasis may manifest with pathognomonic findings at mammography, whereas other systemic diseases such as Wegener granulomatosis, sarcoidosis, and amyloidosis can manifest as nonspecific breast masses that are indistinguishable from breast cancer and usually require tissue biopsy for confirmation. Knowledge of the imaging characteristics of various systemic diseases affecting the breast will aid the radiologist in differentiating systemic disease from suspect breast lesions, thereby helping ensure appropriate follow-up. Furthermore, recognition of systemic diseases such as Cowden syndrome that are associated with an increased risk of breast cancer will allow the radiologist to recommend appropriate surveillance. ©

RSNA, 2011 •

Abbreviations: MLO = mediolateral oblique, NF-1 = neurofibromatosis type 1, PXE = pseudoxanthoma elasticum RadioGraphics 2011; 31:1085–1100 • Published online 10.1148/rg.314105205 • Content Code: From the Iris Cantor Center for Breast Imaging, Department of Radiology, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Room 165-47, Los Angeles, CA 90095. Presented as an education exhibit at the 2009 RSNA Annual Meeting. Received September 21, 2010; revision requested November 15 and received January 7, 2011; accepted January 24. For this journal-based CME activity, the authors (M.M.C., A.C.H.), editor, and reviewers have no relevant relationships to disclose. L.W.B. is on the Scientific Advisory Committee of Hologic. Address correspondence to M.M.C. (e-mail: [email protected]). 1


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Mammographic Signs of Systemic Disease Type of Disease

Mammographic Appearance

Inflammatory Rheumatoid arthritis (treated with   gold salts) Systemic lupus erythematosus Dermatomyositis/polymyositis Scleroderma Psoriatic arthritis Wegener granulomatosis Churg-Strauss syndrome Crohn disease

High-density gold deposits within lymph nodes LAD, dystrophic calcifications Dystrophic subcutaneous calcifications, LAD Skin thickening, asymmetric densities, coarse subcutaneous calcifications LAD Ill-defined or irregular high-density mass Increased global breast density, skin thickening Possible abscess due to steroids

Malignant Metastases Lymphoma Leukemia Multiple myeloma/plasmacytoma Radiation-induced changes

Round masses, possible LAD Large circumscribed masses, LAD Irregular mass (chloroma), LAD One or more circumscribed round masses Skin thickening, trabecular thickening

Endocrinopathic Hyperparathyroidism Diabetic mastopathy Lactating adenoma

Vascular calcifications Ill-defined mass or asymmetric densities Circumscribed oval or lobulated mass

Cutaneous Neurofibromatosis Steatocystoma multiplex Necrobiotic xanthogranulomatosis PXE Ehlers-Danlos syndrome

Cutaneous nodules Circumscribed subcutaneous fatty masses Multiple bilateral asymmetric densities Parenchymal, vascular, and skin calcifications Parenchymal calcifications

Infectious Mycobacterium species Parasites

Fungi Viruses

Nodular, diffuse, and sclerosing patterns Filariasis: serpiginous calcifications with or without a mass; schistosomiasis: calcifications with distortion; sparganosis: lobulated mass; echinococcosis: dense, well-circumscribed mass; cutaneous myiasis: ill-defined mass associated with a pair of microcalcifications Actinomyces species: lobulated mass, skin thickening; blastomycosis: circumscribed subcutaneous mass Human immunodeficiency virus: LAD; Epstein-Barr virus: LAD

Cardiovascular Congestive heart failure Superior vena cava obstruction Coronary artery disease

Skin thickening Venous dilatation Arterial calcifications

Other Sarcoidosis Cowden syndrome Amyloidosis

Circumscribed irregular or spiculated masses Variable manifestations (dense or fatty masses) Spiculated mass, microcalcifications, skin thickening

Note.—LAD = lymphadenopathy, PXE = pseudoxanthoma elasticum.


Mammography is primarily used for the detection of breast cancer; occasionally, however, it reveals

evidence of systemic disease. The diseases that can cause breast abnormalities visible at mammography can originate from almost any organ system in the body (Table). Patients with extramammary disease may present for screening mammography

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Figure 1.  Arterial calcifications and left venous engorgement in a 40-year-old woman with end-stage renal disease and left brachiocephalic vein occlusion from an indwelling dialysis catheter. (a) Right and left mediolateral oblique (MLO) mammograms show prominent railroad track arterial calcifications due to renal hyperparathyroidism. (b) Magnified view of the rectangular area in a shows left superficial venous engorgement (*) secondary to occlusion of the left brachiocephalic vein. (c) Coronal noncontrast computed tomographic (CT) scan demonstrates arterial calcifications (arrows) and venous collateral engorgement (*).

stromal changes in systemic disease (breast masses, fat-containing masses, and calcifications).

Vascular Signs Arterial Calcifications with a known diagnosis, and it is the radiologist’s responsibility to determine if mammographic abnormalities are adequately explained by the systemic disease process or if they are suspicious for primary malignancy and therefore warrant tissue diagnosis. When the results of breast biopsy lead to a diagnosis of systemic disease, the breast imager should be familiar with the imaging characteristics of that disease to assess for radiologic-pathologic concordance. In other cases, patients who present for mammography may not be aware of having a systemic condition, and a diagnosis of extramammary disease is made de novo on the basis of mammographic findings. In this article, we discuss the vascular, lymphatic, and cutaneous signs of systemic disease that may be seen at mammography, as well as

Arterial calcifications are one of the most commonly seen markers of systemic disease. At mammography, arterial calcifications appear as curvilinear parallel calcifications, classically described as having a “railroad track” pattern (Fig 1). The prevalence and extent of arterial calcifications increase with age (1). In women under 50 years of age, the presence of arterial calcifications suggests an underlying risk factor for accelerated atherosclerosis such as hypertension or renal osteodystrophy (2,3). The association between breast arterial calcifications and diabetes is uncertain (4–6). Ongoing studies are investigating the usefulness of mammographically visible arterial calcifications as a marker for coronary artery disease; at present, however, published data are ambiguous (7–12).

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Figure 2.  Mondor disease in a 47-year-old woman with a history of left breast trauma who presented with a painful palpable cord in the left breast. (a) Power Doppler US image of the region of the palpable abnormality demonstrates absence of flow within a dilated superficial vein and edema of the surrounding tissues. (b) Concurrent right MLO (left) and craniocaudal (right) mammograms with a skin BB indicating the area of palpable concern demonstrate a linear opacity (arrow) suggestive of a dilated superficial vein.

Venous Engorgement Venous engorgement appears at mammography as thickened and tortuous tubular structures, usually in a superficial location. Bilateral venous engorgement occurs secondary to poor venous return to the heart, as in superior vena cava obstruction or congestive heart failure (13). Less commonly, either of the two aforementioned conditions may affect only one breast. Unilateral venous engorgement more typically occurs with poor venous return at or peripheral to the brachiocephalic–superior vena caval junction (Fig 1). Upper extremity hemodialysis shunts may result in unilateral venous engorgement of the breast due to hyperdynamic venous flow through the upper arm and chest (14). Mondor disease is a superficial thrombophlebitis of the breast. It is usually seen with local trauma to or inflammation of the breast; however, systemic conditions such as hypercoagulability have also been associated with the development of Mondor disease (15). Classically, Mondor disease manifests as focal breast pain with skin erythema over a palpable “cord.” The thrombosed, inflamed vein may be visible at mammography as a tubular structure in the region of pain. Doppler ultrasonography (US) shows an enlarged vein with a central filling defect, lack of compressibility, and absence of intraluminal flow (Fig 2a). Although US is more specific, mammography should also be performed to exclude underlying malignancy as a potential cause of Mondor disease (Fig 2b) (16,17).

Lymphatic Signs Axillary Lymphadenopathy Axillary lymph nodes are often seen on MLO mammograms. Abnormal axillary lymph nodes

are predominantly due to nonspecific reactive hyperplasia, followed by metastases from primary breast malignancy; however, there are a number of systemic processes that can also cause axillary lymphadenopathy. The nonmammary malignancies that most commonly cause axillary lymphadenopathy are lymphoma and leukemia, with metastatic melanoma and ovarian cancer being less common causes. Infectious processes such as tuberculosis (Fig 3), cat-scratch disease, human immunodeficiency virus, and mononucleosis can cause significant axillary lymph node enlargement, as can reactive changes from mastitis or upper extremity infection. Connective tissue diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, dermatomyositis-polymyositis, and systemic scleroderma are associated with bilateral axillary lymphadenopathy. Finally, granulomatous disease, including Wegener granulomatosis and sarcoidosis, occasionally cause axillary lymphadenopathy on breast images (18–22). Although there is significant overlap in the mammographic appearance of normal lymph nodes and pathologic lymph nodes, morphologic clues indicating the presence of disease include loss of the normal fatty hilum, loss of the normal oval or reniform shape, poorly circumscribed margins, and increased size and opacity compared with findings on prior images.

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Figure 3.  Tuberculous lymphadenopathy in a 27-year-old immigrant woman from India who presented with right axillary swelling. (a, b) Right MLO mammogram (magnified view) (a) and coronal CT scan (b) demonstrate multiple enlarged right axillary lymph nodes. (c) US image of the largest right axillary lymph node shows a benign-appearing fatty hilum. Biopsy revealed granuloma consistent with tuberculosis.

Size less than 1.5 cm is an often-reported but highly nonspecific criterion for benignity (23). Shetty and Carpenter (24) propose that axillary lymph nodes that demonstrate at least two abnormal mammographic features and are either palpable or have shown substantial interval enlargement warrant further US evaluation if there is no underlying clinical explanation for axillary adenopathy. US can sometimes be used to help differentiate between reactive and malignant disease entities. Malignant nodes tend to demonstrate an increase in short-axis diameter, leading to rounding of the normal reniform shape; hypoechogenicity of the cortex; asymmetric cortical thickening; eccentric mediastinal compression or displacement; and loss of the normal echogenic outer capsule. Abnormality of only one node in the axillary chain favors malignancy, since metastatic disease tends to affect one node at a time. Alternatively, abnormality of multiple nodes in the chain favors a reac-

tive process because inflammation tends to simultaneously affect all nodes in a given chain (25). Determining when to perform biopsy of axillary lymph nodes can be difficult, given the overlap in appearance of benign and malignant lymphadenopathy. The patient’s clinical status and radiologic findings should both be taken into consideration when deciding whether to perform biopsy of lymph nodes. New lymph nodes without a clear underlying cause should be considered for biopsy, as should those demonstrating worrisome morphologic features. Biopsy should be offered in conjunction with surgical consultation. US-guided core needle biopsy can be performed for lymph nodes that are in an accessible and safe location, taking care to avoid damage to axillary vessels or nerves. If lymphoma or leukemia is suspected, specimens should be placed in saline solution to allow fluorescence-activated cell sorting.

Lymph Nodes with High-Density Foci Lymph nodes containing dense calcifications are usually benign, although microcalcifications in axillary lymph nodes representing metastases from primary breast cancer have been reported on rare occasions (26). Patients who have previously undergone gold salt therapy for rheumatoid arthritis may present with punctate, high-density deposits within normal-sized axillary lymph nodes, since gold salts are known to accumulate

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Figure 4.  Gold deposits from intramuscular gold salt injections in a 75-year-old woman with a long history of rheumatoid arthritis. (a) Right and left MLO mammograms show punctate high-density deposits within axillary lymph nodes. The radiopaque linear marker denotes the location of a skin scar from a previous right breast biopsy, and the incompletely visualized radiopaque circular marker denotes a skin mole. (b) Magnified view of the left axilla more clearly depicts punctate high-density deposits within lymph nodes. (c) Radiograph of the right hand demonstrates surgical fusion of the wrist and arthritis mutilans of the fingers characterized by severe chronic erosions and subluxations of the metacarpophalangeal and proximal interphalangeal joints, classic findings in rheumatoid arthritis.

within lymph nodes (Fig 4) (27,28). A similar mammographic appearance can be seen in patients with large upper-extremity tattoos secondary to deposition of dye pigment within lymph nodes (29). Alternatively, amorphous, peripherally located calcifications in lymph nodes have been described in metastatic thyroid or ovarian cancer due to psammoma body formation (30,31). Coarse intranodal calcifications suggest fat necrosis (32) or granulomatous disease such as sarcoidosis or tuberculosis (33).

Breast Edema Breast edema, although worrisome for inflammatory breast cancer, is also seen in several nonmalignant systemic conditions. Mammographic findings

of breast edema include breast enlargement with increased parenchymal density, trabecular thickening, and skin thickening. Systemic causes of breast edema, such as congestive heart failure (34), more commonly affect both breasts, although the imaging findings may lateralize to the dependent breast if the patient has been recumbent for an extended period of time. Unilateral breast edema may also be caused by capillary leak (eg, in mastitis [35] or postirradiation change [36]), poor lymphatic drainage (eg, with infectious or malignant axillary lymphadenopathy [37]), or increased hydrostatic pressure (eg, in arteriovenous dialysis complications [38,39] or venous obstruction [40]).

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Figure 5.  NF-1 in an 80-yearold woman with multiple superficial neurofibromas over her torso. Right and left MLO mammograms (a) and left craniocaudal mammogram (b) show numerous dense, circumscribed ovoid masses surrounded by lucent halos of air in the axillae (arrowheads in a) and breasts (arrows in b), findings that represent cutaneous neurofibromas.

Cutaneous Signs

Cutaneous abnormalities seen at mammography include skin thickening, nodules, and calcifications. In addition to being a manifestation of breast edema as discussed earlier, skin thickening can be seen in the setting of scleroderma. There are two main forms of scleroderma: localized scleroderma (also known as morphea), which causes fibrosis of the skin only, and systemic scleroderma, which leads to sclerosis of both the skin and noncutaneous organs. Morphea involving the breast can mimic mastitis or inflammatory breast cancer, manifesting in its initial phase as an indurated, erythematous painful lesion on the skin (41,42). With time, the lesion becomes more fibrotic, with central depigmentation and a violaceous border. Mammograms can be normal or can demonstrate unilateral global increased density, and US may show the characteristic skin thickening. Breast magnetic resonance (MR) imaging has been reported to show unilateral skin thickening or replacement of the normal T1-hyperintense subdermal fat signal with T1hypointense signal (43,44). Because there are no specific imaging features that are diagnostic for scleroderma, skin biopsy is ultimately required for definitive diagnosis. Numerous case studies have reported the development of morphea of the breast following radiation therapy, although to our knowledge, no large studies have been performed to examine the association between morphea of the breast and irradiation (45–47). There is ongoing debate concerning the possible

increased risk of breast cancer in patients with systemic scleroderma (48–50). Neurofibromatosis type 1 (NF-1), an autosomal dominant genetic disorder caused by a mutation in the NF-1 tumor suppressor gene, can manifest with multiple rounded neurofibromas of various sizes on the skin of the breast and nippleareolar complex. The neurofibromas will appear mammographically as multiple bilateral, circumscribed skin-based masses (Fig 5) (51,52). One retrospective cohort-based study of 304 patients reported that patients between 40 and 49 years of age with NF-1 have a 5.8% risk of developing breast cancer, compared with a 1.5% risk for the general population. This increased risk emphasizes the importance of breast cancer screening with mammography in this patient population (53). Skin microcalcifications can be seen in a wide variety of systemic diseases, including chronic renal failure, osteoma cutis, Albright hereditary osteodystrophy, and chronic folliculitis. Hypercalcemic states such as hyperparathyroidism, milkalkali syndrome, and hypervitaminosis D may also result in dermal calcification on mammograms. The dermal location of calcifications can be verified with grid placement of a skin marker followed by acquisition of a tangential magnification view (54,55).

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Figure 6.  PXE in a 60-year-old woman with progressive vision loss as well as skin and joint problems. Left MLO mammogram (a) and magnified views (b, c) of the rectangular areas in the top and bottom of a demonstrate dermal calcifications (arrowheads in b), arterial calcifications (arrow), and parenchymal calcifications (* in c), findings that are characteristic of PXE. Physical examination revealed axillary skin thickening.

Pseudoxanthoma elasticum (PXE) is a genetic disorder that causes calcification and fragmentation of the elastic fibers of the skin, vasculature, and choroidal layer of the eye. At mammography, PXE can manifest as breast microcalcifications, dermal calcifications, skin thickening, or vascular calcifications, predominantly involving the axilla (Fig 6). Although none of these findings alone is specific for PXE, a combination of three or more

is suggestive of PXE. The presence of fragmented and mineralized elastic fibers in the middermis at skin biopsy allows definitive diagnosis (56).

Stromal Changes Breast Masses Masses can be seen in a variety of systemic conditions, including metastatic disease, diabetes, pregnancy, amyloidosis, lymphoproliferative disease, histiocytosis, and granulomatous diseases such as sarcoidosis and mycobacterial or fungal infections (Table).

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Figure 7.  Metastatic sarcoma in a 64-year-old woman with a palpable right breast mass. The patient had a history of clear cell sarcoma of the right arm, which had been treated with radiation therapy and axillary lymph node dissection. (a) Right craniocaudal mammogram demonstrates skin thickening due to prior irradiation as well as multiple ovoid masses (arrows), some circumscribed and some partially obscured. (b) US image of the largest mass shows a hypoechoic lesion representing either a single complex mass with thick septa or two adjacent complex masses. A small cystic component with posterior enhancement is seen in the deeper compartment. (c) Fused PET/CT scan shows multiple hypermetabolic foci in the right breast. The results of biopsy confirmed metastatic sarcoma.

Metastatic Disease.—The tumors that most

frequently metastasize to the breast in adults are melanoma, lymphoma, lung carcinoma, ovarian carcinoma, soft-tissue sarcoma (Fig 7), and carcinoid tumor. Metastases to the breast may be difficult to differentiate from primary breast cancer such as invasive ductal carcinoma not otherwise specified, colloid carcinoma, or medullary carcinoma, all of which can manifest as a circumscribed or mostly circumscribed mass. Metastases from nonbreast primary tumor should be suspected when a patient has a known primary tumor and there are multiple bilateral, mostly circumscribed nodules without associated suspect microcalcifications (57). US features of some nonbreast metastases include a circumscribed hypoechogenic mass with normal or enhanced through transmission surrounded by an ill-defined area of echogenic peritumoral edema.

US-guided core needle biopsy and immunohistochemical analysis are usually required for diagnosis. Biopsy specimens obtained in patients with suspected lymphoma should be placed in saline solution rather than formalin. At pathologic analysis, atypical histologic features, periductal and perilobular infiltration without an intraductal component, and multiple lymphatic emboli favor nonmammary metastases (58). Diabetic Mastopathy.—Diabetic mastopathy is

an uncommon condition affecting patients of either gender with long-standing insulin-dependent diabetes mellitus. The hyperglycemic state is thought

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to cause an increase in production and decrease in degradation of collagen, resulting in focal extracellular matrix expansion. Patients present with one or more hard, painless, mobile palpable masses, typically in the subareolar region. At mammography, the breasts usually appear diffusely dense, making visualization of a discrete mass difficult (Fig 8a, 8b). US demonstrates irregular hypoechoic masses with marked posterior acoustic shadowing (Fig 8c). Given the nondiagnostic imaging features, core needle biopsy is usually warranted. Diabetic mastopathy can be self-limited; however, recurrent masses are not uncommon (59,60). Lactating Adenoma.—Contrary to what its

name may suggest, lactating adenoma can occur in antepartum as well as postpartum patients. There is debate as to whether lactating adenomas are distinct neoplastic entities vis-à-vis variants of fibroadenoma, tubular adenoma, or lobular hyperplasia that have changed in response to the hormonal stimulation of pregnancy and lactation. Patients typically present with a painless palpable mass in the third trimester of pregnancy or in the puerperal breast-feeding period. Initial work-up includes US evaluation, which typically (but not reliably) demonstrates benign features such as a homogeneously hypoechoic echotexture with circumscribed margins and posterior enhancement (Fig 9). Mammography is not usually necessary in the pregnant patient, since the presence of a new or enlarging mass at US is sufficient to warrant biopsy. In the lactating postpartum patient, mammography is safe to perform but may be of limited benefit given the density of the lactating breast (61). Core needle biopsy is generally recommended for diagnosis. Lactating adenomas should regress spontaneously after lactation; otherwise, bromocriptine can be used to decrease lesion size (62,63). Amyloidosis.—Amyloidosis is characterized by

insoluble protein deposition within extracellular tissues, primarily involving the heart, kidneys, gastrointestinal tract, skin, peripheral nerves, and lung. Amyloidosis can manifest as a primary systemic process or secondary to inflammatory conditions such as autoimmune disease. Amyloid involvement of the breast is rare and manifests either at clinical examination as a palpable mass or at routine screening mammography as an incidental mass (Fig 10a, 10b). Mammograms usually demonstrate an irregular, sometimes spiculated mass, although various imaging

Figure 8.  Diabetic mastopathy in a 29-year-old woman with long-standing type 1 diabetes mellitus who presented with a nontender palpable mass in the right breast. (a, b) Diagnostic right MLO (a) and craniocaudal (b) mammograms show an irregular, indistinct retroareolar mass at middle depth without calcification, a finding that corresponds to the palpable abnormality. (c) Focused US image demonstrates an irregular and angular hypoechoic mass with posterior acoustic shadowing. Biopsy revealed stromal fibrosis with perivascular infiltration by mature B-cell lymphocytes, findings that are consistent with diabetic mastopathy.

appearances have been reported, including clustered microcalcifications and focal asymmetry. US may reveal an ill-defined hyperechoic mass (Fig 10c). Diagnosis is confirmed with (a) Congo red stain and polarized light or (b) immunohistochemical analysis. Case reports have documented the concurrence of amyloid and primary breast malignancy at tissue biopsy; however, the relationship is uncertain (64,65).

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Cao et al  1095 Figure 9.  Lactating adenoma in a 37-yearold woman in the second trimester of pregnancy who presented with a firm, painless mass in the right breast. Focused color Doppler US image demonstrates a circumscribed, homogeneously hypoechoic oval lesion without hypervascularity. US-guided core needle biopsy revealed hyperplastic secretory cells lining compact lobules and demonstrating extensive secretions, findings that are consistent with lactating adenoma.

Figure 10.  Amyloidosis in a 66-year-old woman with a history of right breast cancer who presented for screening mammography. (a, b) Left MLO mammograms obtained in 2007 (a) and 2009 (b) demonstrate the development of a new irregular mass at middle depth in the lower portion of the breast (circled in b). The smaller area of opacity located more inferiorly was found to represent stable glandular breast tissue. (c) US image shows an irregular hypoechoic lesion with an echogenic halo. Positive Congo red staining of the biopsy specimen was diagnostic for amyloid deposition. (d) Axial chest CT scan (lung window) shows a juxtafissural, lobulated pulmonary nodule in the left upper lobe, a finding that was confirmed at biopsy to represent additional amyloid deposition.

Fat-containing Masses Fat-containing masses in systemic conditions include traumatic oil cysts, galactoceles, steatocystoma multiplex, and Cowden syndrome (multiple hamartoma syndrome). Lipid cysts can be seen in response to a number of traumatic causes, both iatrogenic and noniatrogenic. A bandlike distribution of oil cysts extending along the upper outer to lower inner breast in a patient with a history of a motor vehicle accident is highly suggestive of seat belt injury (66). In a lactating patient, a galactocele may manifest at mammography as a round or oval

circumscribed mass, possibly containing fat. Occasionally, fat-fluid levels can be identified on a 90° lateral view. Correlative US usually shows a round or oval avascular mass containing low-level echoes or an echogenic floating fat layer over a hypo- to anechoic dependent layer. If imaging features are not diagnostic, US-guided needle aspiration may be used for confirmation (67). Steatocystoma multiplex is a rare autosomal dominant disease characterized by hamartomatous malformation of the pilosebaceous duct,

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resulting in multiple small subcutaneous oil cysts that mainly involve the trunk, including the anterior chest and axilla. The oil cysts appear at mammography as small, round, circumscribed fat-density lesions, surrounded by a peripheral high-density rim and lying just deep to the skin (Fig 11). In a patient with multiple palpable yellow or skin-colored nodules on the chest, axilla, and groin and a family history of steatocystoma multiplex, the mammographic findings of peripheral oil cysts are diagnostic for steatocystoma multiplex, and no further work-up is necessary (68). Cowden syndrome, also known as multiple hamartoma syndrome, is a rare autosomal dominant genetic disease caused by mutations in the PTEN tumor suppressor gene. This syndrome is characterized by multiple hamartomatous neoplasms of the skin and mucosa, mammary and thyroid glands, gastrointestinal and genitourinary tracts, and central nervous system. The diagnosis can be difficult to establish because Cowden syndrome is rare and has variable clinical manifestations. The mammographic features of Cowden syndrome are also varied. Case reports have described patients with Cowden syndrome who presented with multiple fibroadenomas, multiple tubular adenomas, multiple lipomatous hamartomas, prepubertal and male gynecomastia, ductal carcinoma in situ, and invasive ductal carcinoma. Recognition of individuals with Cowden syndrome is important because carriers of either gender have an increased risk of thyroid and breast cancer, with women having an increased risk of endometrial cancer (69,70). Women with Cowden syndrome have a reported 25%–50% lifetime risk of developing breast cancer, usually before the age of 50 years. For patients with known Cowden syndrome, the National Comprehensive Cancer Network recommends annual screening with mammography and breast MR imaging starting at age 30–35 years or 5–10 years before the earliest age at which known breast cancer occurred in the family, whichever comes first (71).

Stromal Calcifications Diffuse dystrophic calcifications of the subcutaneous fat that progressively coarsen over time may be seen in collagen vascular diseases such

Figure 11.  Steatocystoma multiplex in a 37-year-old woman with multiple bilateral palpable subcutaneous nodules of the breasts, trunk, groin, and extremities. (a) Left MLO mammogram shows two adjacent round, circumscribed, lucent subcutaneous masses. (b) US image demonstrates circumscribed hypoechoic masses just deep to the dermis. The imaging findings, taken together with physical examination findings, are consistent with steatocystoma multiplex.

as scleroderma, dermatomyositis, and systemic lupus erythematosus. Patients with dermatomyositis may develop bizarre, sheetlike dystrophic calcifications in the subcutaneous tissues that can be localized or extensive (Fig 12). Lupus mastopathy, a rare manifestation of systemic lupus erythematosus, has an early mammographic appearance of thin curvilinear calcifications that, on subsequent images, progressively enlarge and coarsen, mirroring the pathologic evolution of focal panniculitis to maturing fat necrosis of the subcutaneous breast fat (72,73). Parasites occasionally manifest with distinctive calcification patterns at mammography (Table). Filariasis is the most commonly reported parasitic infection of the breast. In general, there are

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Figure 12.  Mixed connective tissue disease characterized by limited systemic sclerosis, severe Raynaud phenomenon, and dermatomyositis in a 37-year-old woman. The patient was referred for evaluation of a palpable abnormality in the right breast with overlying skin ulceration. (a) Right and left MLO mammograms show extensive dense dermal and parenchymal calcifications. (b) US image demonstrates multiple areas of echogenic leading edges with strong posterior acoustic shadowing, findings that are consistent with subcutaneous and parenchymal calcifications. (c) Axial short inversion time inversion-recovery MR image shows diffuse scattered areas of signal void (arrows) representing parenchymal calcifications. No suspicious-looking masses or enhancing foci were identified. (d) Posteroanterior radiographs of the hands demonstrate multifocal soft-tissue calcifications, acro-osteolysis, and soft-tissue thinning at the fingertips.

two forms of the disease: lymphatic and subcutaneous. Lymphatic filariasis is caused by Wuchereria bancrofti and Brugia malayi, which are endemic to tropical regions in Africa and southeast Asia, respectively. In acute lymphatic filariasis, the larvae cause local inflammation and granulomatous lymphangitis, leading to the clinical manifestation of a painless breast mass with overlying peau d’orange and hyperemia of the skin. At mammography, acute infection is typically seen as a circumscribed, hyperdense ovoid mass. A few case reports have described the US appearance of the “filarial dance”—the nonrhythmic, nonpulsatile, rapidly changing movements of organisms within dilated, cystic lymphatic ves-

sels (74). After the parasite dies, mammography will show the characteristic pattern of elongated or tubular calcifications in a spiral or coiled configuration, occasionally with a lucent center. The calcifications may or may not be associated with a mass representing chronic granuloma or dilated lymphatic vessels (75,76). Subcutaneous filariasis is caused by the Loa loa species and is most commonly seen in individuals from the tropical regions of West Africa. If the parasite dies and calcifies in an extended position, mammograms show beaded fine calcifications in a short or long, tubular, nonlinear

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Figure 13.  Subcutaneous filariasis in a 67-year-old immigrant woman from Africa who presented for screening mammography. Right MLO and craniocaudal mammograms (a) and a magnified view of a portion of the craniocaudal mammogram (b) demonstrate multiple serpentine, filamentous calcifications (arrowheads in a), findings that are consistent with Loa loa infection.

configuration (Fig 13). Alternatively, loaiasis can appear as hairlike whorls of calcification (77).


Various systemic diseases can cause abnormalities at mammography. As illustrated in this article, diseases affecting the breast can originate from almost any organ system in the body, and the corresponding mammographic abnormalities can be vascular, lymphatic, cutaneous, or parenchymal in nature. Although some of these diseases have distinctive imaging appearances, others may mimic breast cancer at mammography. It is important that breast imagers be aware of the imaging characteristics of these systemic diseases so as to be able to distinguish them from suspect breast lesions. Knowledge of the mammographic findings of various systemic diseases also gives the radiologist a better sense of the overall health status of the patient. Some systemic diseases, such as Cowden syndrome, are associated with an increased risk of breast cancer, and awareness of these diseases aids the interpreting physician in making follow-up recommendations.

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This journal-based CME activity has been approved for AMA PRA Category 1 Credit . See

Teaching Points

July-August Issue 2011

Mammographic Signs of Systemic Disease Mailan M. Cao, MD • Anne C. Hoyt, MD • Lawrence W. Bassett, MD RadioGraphics 2011; 31:1085–1100 • Published online 10.1148/rg.314105205 • Content Code:

Page 1087 In women under 50 years of age, the presence of arterial calcifications suggests an underlying risk factor for accelerated atherosclerosis such as hypertension or renal osteodystrophy (2,3). Page 1088 In women under 50 years of age, the presence of arterial calcifications suggests an underlying risk factor for accelerated atherosclerosis such as hypertension or renal osteodystrophy (2,3). Page 1090 Unilateral breast edema may also be caused by capillary leak (eg, in mastitis [35] or postirradiation change [36]), poor lymphatic drainage (eg, with infectious or malignant axillary lymphadenopathy [37]), or increased hydrostatic pressure (eg, in arteriovenous dialysis complications [38,39] or venous obstruction [40]). Page 1092 (Table on page 1086) Masses can be seen in a variety of systemic conditions, including metastatic disease, diabetes, pregnancy, amyloidosis, lymphoproliferative disease, histiocytosis, and granulomatous diseases such as sarcoidosis and mycobacterial or fungal infections (Table). Page 1095 Fat-containing masses in systemic conditions include traumatic oil cysts, galactoceles, steatocystoma multiplex, and Cowden syndrome (multiple hamartoma syndrome).

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