Current Problems in Diagnostic Radiology ] (2015) ]]]–]]]

Current Problems in Diagnostic Radiology

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Metastatic Disease to the Breast From Extramammary Malignancies:A Multimodality Pictorial Review

Dorothy A. Sippo, MD, MPHa,n,1, Kopal Kulkarni, MDa, Philip Di Carlo, MDa, Bonmyong Lee, MDa,David Eisner, MDa, Ashley Cimino-Mathews, MDb, Susan C. Harvey, MDa

a Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MDb Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD

This pictorial review demonstrates imaging features of extramammary malignancies metastatic to the breast seen with multiple modalities, includingmammography, ultrasound, computed tomography (CT), positron emission tomography, and magnetic resonance imaging. Although rare, metastases tothe breast may have a distinct imaging appearance from the appearance of primary breast cancers. They are important to identify because they can mimicbenign breast disease and their treatment differs from that of primary breast cancer. Metastatic disease to the breast most commonly appears as a singleround or oval mass with circumscribed margins. Sonographically it is usually hypoechoic, and with CT or magnetic resonance imaging it usuallyenhances. In contrast with primary breast cancer, breast metastases do not demonstrate spiculated margins and rarely have associated calcifications.A variety of clinical presentations of breast metastases are reviewed, including presentation with a palpable mass, detection at screening mammography,and detection with CT or positron emission tomography.

& 2015 Mosby, Inc. All rights reserved.

Introduction

Although metastases to the breast are rare, in 12%-31% of cases inwhich they were diagnosed, they have been reported as the firstfinding leading to a diagnosis of an extramammary cancer.1,2 Meta-static lesions typically appear distinct from primary breast cancer; yetthey can present a diagnostic dilemma as they may resemble benignbreast lesions. Metastases are important to identify, as they require adifferent treatment approach from that of primary breast cancer.Extramammary metastases to the breast are uncommon in clinicalseries, accounting for 1%-2% of all instances of malignancy in thebreast.3 The most frequent source of primary solid-organ malignancyis melanoma.1 Other primary sources arise from the blood (leukemiaor lymphoma), lung, ovary, gastrointestinal tract (gastric and carcinoidtumors), kidneys, thyroid, head and neck, as well as sarcoma (Fig 1).

Extramammary breast metastasis occurs predominantly inwomen, based on 2 large case series,1,4 85%-92% of the time. Inmen, the pathology is often melanoma or lung cancer.4 Patientsusually have a known history of cancer (Fig 2). In a study byWilliams et al,1 among patients with a history of cancer, roughlyhalf already had known metastatic disease. When identified, mostmetastatic lesions present as a single mass in one breast, mostfrequently detected on physical examination, followed by detec-tion with screening mammography.1

x.doi.org/10.1067/j.cpradiol.2015.07.00188/& 2015 Mosby, Inc. All rights reserved.

int requests: Dorothy A. Sippo, MD, MPH, 318 Fourth St, Union City, NJ

ail address: dsippo@post.harvard.edu (D.A. Sippo).urrent institution: Department of Radiology, Massachusetts Generall, Boston, MA.

Overall, the prognosis is poor for patients diagnosed withbreast metastases, with a reported median survival time of 10months from the time of detection.1 Cases where the onlyevidence of disease was within the breast and those with neuro-endocrine primary were associated with better survival rates.1

Treatment is tailored to the individual patient and depends on thetype of primary cancer and extent of disease identified. In rarecases of the breast being the only site of metastatic disease, orminimal disease outside the breast, wide local surgical excision isan option. Williams et al1 did report that patients who underwentsurgical excision of breast metastases had a significantly longermedian survival of 15.5 months with surgery, compared with8.1 months without surgery. The possibility was raised of aselection bias with healthier patients undergoing surgery.1

Extramammary metastasis to the breast can occur via hema-togenous or lymphatic routes. Reviewing our cases of breastmetastases, we found hematogenous spread to be more commonthan lymphatic spread. In the case of hematogenous spread, themetastasis often occurs in the upper outer quadrant superficiallywhere there is ample vascularity (Fig 3).5 Lymphatic spreadappears as diffuse subcutaneous edema, trabecular thickening,and skin thickening without an underlying primary mass (Fig 4).The tumor obstructs the lymphatics, causing lymphedema andpossibly associated lymphadenopathy. Lymphatic metastaticspread may mimic inflammatory breast cancer.5

Mammographic Findings

Metastatic disease to the breast can be detected on screeningmammography (Fig 5). It can also be identified with diagno-

Fig. 1. A 67-year-old woman with a history of retroperitoneal leiomyosarcoma, status post resection, who presented with a palpable mass. Core needle biopsy revealedmetastatic leiomyosarcoma. (A) Right mammogram, craniocaudal projection. Circumscribed oval high-density mass is identified at the palpable lump along the inner breast,middle depth (arrow). (B) Grayscale ultrasound image of the right breast. Corresponding circumscribed oval hypoechoic mass.

Fig. 2. A 76-year-old man with a history of left renal cell cancer, status post cryoablation 7 years before. He underwent PET/CT to evaluate response to chemotherapy forsquamous cell carcinoma of the lung. (A) Noncontrast CT revealed a new oval 1-cm mass in the posterior right breast (arrow). (B) PET demonstrated this mass to behypermetabolic (arrow). (C) Right mammogram, mediolateral oblique projection, demonstrates an oval high-density mass in the posterior breast (arrow). The nipple ismarked with a ball bearing (BB). (D) Color Doppler ultrasound image of the right breast demonstrates an oval circumscribed hypoechoic mass with peripheral vascularity.Core needle biopsy of this mass revealed it to be a renal cell carcinoma metastasis. (Color version of figure is available online.)

Fig. 3. A 65-year-old woman with a history of lung cancer, presenting with a tender palpable lump in the left breast, above the nipple. (A and B) Left mammogram,craniocaudal and mediolateral oblique projections. Round high-density mass is seen at the palpable lump, noted by the triangular skin marker. (C and D) Grayscale and colorDoppler ultrasound images of the left breast. Complex solid and cystic mass with increased vascularity corresponds to the mammographic mass. This was proven to bemetastatic squamous cell carcinoma from a primary lung cancer. (Color version of figure is available online.)

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stic mammography, performed to evaluate a palpable mass(Fig 6). On mammography, in both the screening and diagnosticsettings, the most common finding is a single mass (Fig 7),although multiple masses may also be seen (Fig 8).1 Similar toprimary breast cancer, the most common location for a metastasisis the upper outer quadrant. The masses often are round or oval in

shape with circumscribed or microlobulated margins and noassociated calcifications.6,7 An exception that may demonstrateassociated calcifications is metastatic ovarian cancer.8,9

Unlike primary breast cancer, breast metastases do not dem-onstrate spiculated margins. This is because they do not causethe desmoplastic reaction, which occurs with invasive ductal

Fig. 4. A 53-year-old woman with lymphatic metastasis of lung adenocarcinoma toher right breast. Noncontrast CT demonstrates skin thickening and trabecularthickening.

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carcinoma. For this same reason, the mammographic size of abreast metastasis is usually similar to the size of the mass palpatedon physical examination. In contrast, invasive ductal carcinomatends to feel larger on palpation than the mammographic size of

Fig. 5. A 74-year-old woman with a history of B-cell lymphoma in remission. (A) Rretroareolar asymmetry (arrow) in the right breast. (B) Color Doppler and grayscale ultrbehind the right nipple. (C) Histologic examination of the core needle biopsy reveals shbenign breast lobules and ducts (H&E, 200� ). (D) Immunohistochemistry reveals theselarge B-cell lymphoma. H&E, hematoxylin and eosin. (Color version of figure is availabl

Fig. 6. A 48-year-old woman with history of high-grade serous ovarian adenocarcinomadiagnostic mammogram, mediolateral oblique view, demonstrates an asymmetry in th(B) Color Doppler ultrasound image of the left breast. Irregular mass with heterogenemetastatic ovarian cancer with core needle biopsy. (C) Grayscale ultrasound image of thwas later proven to be metastatic ovarian cancer with fine needle aspiration. (D) Histoglands with a micropapillary appearance (H&E, 400� ) with abundant lymphovascular in(D: 400� ) and WT1 (not shown), supporting a diagnosis of metastatic ovarian carcino

the mass due to the fibrous connective tissue proliferation thatsurrounds the carcinoma. Metastases typically are not associatedwith skin or nipple retraction, which can be seen with primarybreast cancer, again owing to the lack of desmoplastic reaction.6

Due to the masking effect of dense breast tissue, metastases maynot be visible with mammography and may be identified only withultrasound imaging.

Sonographic Findings

Ultrasound is integral to the evaluation of all palpable breastmasses and, therefore, plays a key role in the diagnosis ofmetastatic lesions, which commonly present as palpable lumps(Fig 9). Most masses are round or oval and hypoechoic. Margins

outine screening mammogram, mediolateral oblique projection, demonstrated aasound images demonstrated a corresponding hypervascular oval hypoechoic masseets of basophilic cells with high nuclear-to-cytoplasmic ratios infiltrating aroundatypical cells to label for CD20 (200� ), supporting a diagnosis of metastatic diffusee online.)

presenting with a new hard palpable mass in her lower inner left breast. (A) Lefte posterior lower breast (arrow) underlying the triangular palpable skin marker.ous echo pattern is identified at the palpable lump. This was later proven to bee right axilla. Morphologically abnormal lymph node with loss of fatty hilum. Thislogic examination of the core needle biopsy revealed infiltrating nests of atypicalvasion. (E) The malignant glands were positive by immunohistochemistry for Pax8ma. H&E, hematoxylin and eosin. (Color version of figure is available online.)

Fig. 7. Melanoma metastasis to the breast. (A) Mammogram, craniocaudal projection and (B) spot compression view. Single round mass with microlobulated margins is seenin the posterior outer breast (circle).

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are most commonly circumscribed, but can also be microlobulatedor indistinct. Posterior acoustic enhancement is common (Fig 10)and posterior acoustic shadowing is rarely seen. This is in contrastwith the sonographic appearance of primary breast cancer, wherean irregular mass, with margins that are not circumscribed, andposterior acoustic shadowing are most typical. Evaluation ofmetastatic masses with color Doppler can demonstrate variablevascularity. The vascularity of the metastasis tends to reflect thatof the primary malignancy with metastatic melanoma, renal cellcarcinoma, carcinoid tumors, and sarcomas tending to be hyper-vascular (Fig 11).7

Fig. 8. Lung adenocarcinoma metastatic to the breast. (A and B) Mammogram, bilatera(circles).

Metastases can mimic benign breast lesions. When they appearas hypoechoic oval circumscribed masses, they can resemblefibroadenomas. Metastases may be anechoic and round, mimick-ing benign cysts. Color Doppler evaluation to identify internalvascularity and increasing the gain to identify internal echoes mayhelp distinguish a metastatic mass from a cyst. In a postmeno-pausal woman a new apparent cyst should be carefully evaluated,to exclude the possibility of both primary breast cancer (mucinouscarcinomas can have a cystic appearance) and the rare instance ofmetastasis (Fig 12). One should especially consider the possibilityof metastasis in an older patient or a patient with a known history

l mediolateral oblique projections. Multiple round masses are seen in both breasts

Fig. 9. A 52-year-old woman presenting with palpable right axillary lymphadenopathy. She underwent resection of a right upper extremity melanoma 10 years before.(A) Right mammogram, craniocaudal projection. Grouped fine pleomorphic calcifications are present (circle). Core needle biopsy revealed DCIS. (B and C) Grayscaleultrasound images of the right breast. Irregular masses with heterogeneous echotexture are demonstrated at the 9:30-10:00 axes. Core needle biopsy of one of these massesrevealed metastatic melanoma. (D) Photograph of the core needle biopsy specimens, which demonstrate dark pigmentation that can be seen with melanoma. (E) Grayscaleultrasound image of the right axilla. Enlarged irregular mass representing metastatic melanoma to a lymph node. (F) Postcontrast T1-weighted fat-saturated breast MRimage and (G) superimposed computer-aided detection color map illustrate enlarged right axillary lymph nodes and multiple masses in the posterior right outer breast,representing metastatic melanoma and DCIS, respectively. Red represents washout delayed phase kinetics, green plateau, and blue persistent. (H) PET image shows one ofthe right breast masses and axillary lymphadenopathy to have striking FDG uptake. MR, magnetic resonance; DCIS, ductal carcinoma in situ. (Color version of figure isavailable online.)

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of cancer. One should consider confirming the true nature of anapparent new cyst with cyst aspiration, followed by core biopsy ifthe finding does not resolve with attempted aspiration.

Although metastatic masses are frequently hypoechoic, their echopattern can be variable, including heterogeneous, anechoic, or evenhyperechoic. Most hyperechoic masses are benign, containing fat,

Fig. 10. Lung adenocarcinoma metastatic to the breast. Grayscale ultrasound imageof the breast demonstrates a hypoechoic, oval mass with posterior acousticenhancement.

Fig. 11. Melanoma metastatic to the breast. Color Doppler image of the breastdemonstrates a hypoechoic, irregular mass with peripheral internal vascularity.(Color version of figure is available online.)

Fig. 12. Melanoma metastatic to the breast. (A) Grayscale ultrasound image of the breast demonstrates what appears to be a new cyst. (B) Further evaluation with the gainincreased demonstrates this to be a hypoechoic mass that was recommended for biopsy.

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such as harmartomas, lipomas, and fat necrosis. All of these wouldappear as radiolucent, fat-containing masses on mammography.However, metastasis may occasionally present as a hyperechoic mass(Fig 13D).10 The sonographic features of leukemia within the breastare not well described in the literature, yet we demonstrate a case ofleukemia that is hyperechoic. A case series by Yang et al11 describedleukemia as being hypoechoic. Biopsy is warranted for a new hyper-echoic mass when there is a history of cancer, presence of internalvascularity, or no mammographic radiolucent correlate.

Fig. 13. A 31-year-old woman with T-cell acute lymphoblastic leukemia, status post bo(A) A contrast-enhanced chest CT scan, obtained in the hospital to evaluate a pleural effmammography projections reveal a corresponding high-density round mass (arrows).usually a benign finding, but requiring biopsy given the history of leukemia and interleukemia. (E) Subsequent PET demonstrates the mass (arrow) to be mildly FDG avid. (F) Hcells characterized by hyperchromatic nuclei, nuclear molding, high nuclear-to-cytoplasmalignant cells were positive by immunohistochemistry for CKit (200� ), supporting aMLO, mediolateral oblique. (Color version of figure is available online.)

Computed Tomography Findings

Breast metastases may be incidentally identified with com-puted tomography (CT) imaging, as it is commonly performed formany indications, including staging and follow-up of neoplasticdisease. CT shows a round or oval well-defined mass, often withcircumscribed margins (Figs 13A and 14A). The mass typicallyenhances (Fig 15A), mirroring the internal vascularity seen withultrasound color Doppler evaluation (Fig 15B).7

ne marrow transplantation 2 years before, presenting with graft vs host disease.usion, demonstrated a new left breast mass (arrow). (B) CC and (C) MLO diagnostic(D) Grayscale ultrasound image demonstrates a corresponding hyperechoic mass,val development of the mass. Core needle biopsy revealed involvement by acuteistologic examination of the core needle biopsy specimen reveals sheets of atypicalmic ratios, scattered nucleoli, and abundant mitotic figures (H&E, 200� ). (G) Thediagnosis of acute leukemia. CC, cranio-caudal view; H&E, hematoxylin and eosin;

Fig. 14. A 66-year-old woman with a history of left breast DCIS treated with lumpectomy and radiation therapy. She underwent a staging PET/CT for a recent diagnosis oflung adenocarcinoma that demonstrated a mass in the left breast. (A) CT scan of the chest without contrast demonstrates a 6-mm oval mass in the left breast (arrow). (B) PETdemonstrates the mass (arrow) to be mildly FDG avid. (C) Diagnostic mammography ML projection reveals a corresponding round microlobulated equal-density mass in thesuperficial upper breast (arrow). Postlumpectomy changes are also present in the upper breast. (D) Grayscale ultrasound image reveals the mass to be hypoechoic andmicrolobulated. Ultrasound-guided core needle biopsy revealed metastatic pulmonary adenocarcinoma. The CT, mammogram, and ultrasound images also demonstrateoverlying skin thickening. (E) Histologic examination of the skin reveals small nests of adenocarcinoma infiltrating within the skin dermis and involving the dermallymphatics (H&E, 400� ). (F) The atypical cells are positive by immunohistochemistry for TTF1 (400� ), supporting a diagnosis of metastatic pulmonary adenocarcinoma.ML, mediolateral; H&E, hematoxylin and eosin. (Color version of figure is available online.)

Fig. 15. A 55-year-old woman with history of locally invasive renal cell carcinoma, status post nephrectomy 6 years earlier, currently in remission. (A) Annual follow-uparterial phase CT scan demonstrates an enhancing 6-mm oval left breast mass (arrow). (B) Color Doppler ultrasound image shows a corresponding hypervascular isoechoicoval mass. Small isoechoic lesions can be difficult to identify with ultrasound. Correlation with additional imaging for location, size, and shape, as well color Dopplerevaluation, can facilitate lesion identification. (C) MRI post-contrast subtraction image demonstrates an enhancing oval mass (arrow). (D) Histologic examination of the coreneedle biopsy reveals nests of bland cells with abundant clear cytoplasm and minimal nuclear atypia, accompanied by a delicate capillary vasculature (H&E, 200� ). Thehistologic features are characteristic of clear cell renal cell carcinoma. H&E, hematoxylin and eosin; MRI, magnetic resonance imaging. (Color version of figure is availableonline.)

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Positron Emission Tomography Findings

Positron emission tomography (PET) is another common toolfor monitoring neoplastic disease progression and response totherapy that can show metastatic disease to the breast (Fig 13E).PET can be combined with CT to provide both functional andanatomical information. Fluorodeoxyglucose (FDG) uptake withinbreast tissue varies with age, breast density, time of menstrualcycle, and menopausal status, as well as use of hormone replace-ment therapy.12,13 Extramammary metastasis to the breast candemonstrate avid FDG uptake (Fig 9H). The FDG uptake of thebreast metastasis usually mirrors that of the primary tumor.12

A breast mass identified with PET/CT should prompt dedicatedbreast imaging with diagnostic mammography and breast ultra-sound (Fig 14B).

Magnetic Resonance Imaging Findings

With magnetic resonance imaging, extramammary metastasisusually appears as a round or oval circumscribed mass. The mass istypically isointense to normal breast parenchyma on both T1- andT2-weighted images, with homogeneous enhancement on post-contrast images (Fig 15C). The enhancement commonly demon-strates rapid initial phase followed by variable delayed phasekinetics. Surov et al7 reported metastases to the breast to morecommonly exhibit plateau and washout delayed phase kinetics.

Conclusions

Across multiple imaging modalities, extramammary metastasesto the breast have distinct imaging features. In contrast withprimary breast cancer, they commonly present as round or ovalcircumscribed masses and are typically not associated with calci-fications. This may lead to their being mistaken for benign breastlesions, such as fibroadenomas and cysts. Although rare, it is

important to diagnose metastases to the breast because theirtreatment approach differs from that of primary breast cancer.

Acknowledgments

We would like to acknowledge Shirley Yang, MD, for reviewingthe PET portion of this article.

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