ORIGINAL RESEARCH
MRI Findings of Radiation-Associated Angiosarcoma of the Breast (RAS) Sona A. Chikarmane, MD,1* Eva C. Gombos, MD,1,2 Jayender Jagadeesan, PhD,1 Chandrajit Raut, MD, MSc,3,4 and Jyothi P. Jagannathan, MD2 Purpose: To describe the magnetic resonance imaging (MRI) characteristics of radiation-associated breast angiosarcomas (RAS). Materials and Methods: In this Institutional Review board (IRB)-approved retrospective study, 57 women were diagnosed with pathologically confirmed RAS during the study period (January 1999 to May 2013). Seventeen women underwent pretreatment breast MRI (prior to surgical resection or chemotherapy), of which 16 studies were available for review. Imaging features, including all available mammograms, ultrasounds, and breast MRIs, of these patients were evaluated by two radiologists independently and correlated with clinical management and outcomes. Results: The median age of patients at original breast cancer diagnosis was 69.3 years (range 42–84 years), with average time from initial radiation therapy to diagnosis of RAS of 7.3 years (range 5.1–9.5 years). Nine women had mammograms (9/16, 56%) and six had breast ultrasound (US) (6/16, 38%) prior to MRI, which demonstrated nonsuspicious findings in 5/9 mammograms and 3/6 ultrasounds. Four patients had distinct intraparenchymal masses on mammogram and MRI. MRI findings included diffuse T2 high signal skin thickening (16/16, 100%). Nearly half (7/16, 44%) of patients had T2 low signal intensity lesions; all lesions rapidly enhanced on postcontrast T1-weighted imaging. All women underwent surgical resection, with 8/16 (50%) receiving neoadjuvant chemotherapy. Four women died during the study period. Conclusion: Clinical, mammographic, and sonographic findings of RAS are nonspecific and may be occult on conventional breast imaging; MRI findings of RAS include rapidly enhancing dermal and intraparenchymal lesions, some of which are low signal on T2 weighted imaging. J. MAGN. RESON. IMAGING 2015;42:763–770.
B
reast conservation therapy (BCT) is considered the standard of care for treatment of early (stages I and II) breast cancer and consists of lumpectomy and whole-breast irradiation. Radiotherapy (RT) has been associated with the development of secondary soft-tissue sarcomas, with angiosarcoma being the most common.1 Given the increasing use of BCT, the rate of secondary breast angiosarcoma has been reported with more frequency, with 0.9 per 1000 breast cancer incidence.2,3 The latency period of secondary breast angiosarcoma in women after BCT ranges from 2 to 23 years.4 Secondary breast angiosarcomas can be difficult to detect clinically, given that they develop in the background of radiationinduced skin changes and manifest as painless, erythema-
tous, or violaceous cutaneous nodules, which may be attributed to recent trauma.5 Although rare, their occult clinical appearance can subsequently lead to a delay in diagnosis and outcomes are overall poor.4,5 Treatment is surgery, often wide local excision depending on extent of disease, with or without chemotherapy.4 Much is unknown about imaging findings of radiation-associated sarcomas (RAS) in the breast, as the current radiology literature on RAS is in the form of case reports and pictorial reviews,2,3,6–14 many of which describe both primary and secondary breast angiosarcoma cases, or do not pathologically differentiate these entities.2,7,10,14 Given the potential use of breast magnetic resonance imaging (MRI) in the follow-up of women with a personal
View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.24822 Received Aug 12, 2014, Accepted for publication Nov 17, 2014. *Address reprint requests to: S.A.C., Department of Radiology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. E-mail: [email protected] From the 1Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA; 2Department of Imaging, Dana-Farber Cancer Institute/ Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 3Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA; and 4Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
C 2014 Wiley Periodicals, Inc. V 763
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history of breast cancer, in addition to the nonspecific findings of conventional mammography and sonography,14 the initial MRI findings of secondary angiosarcoma may be useful in early detection. The purpose of this study is to describe the breast MRI features of RAS in a cohort of patients with histopathological and clinical correlation.
Materials and Methods Subjects Institutional Review Board approval was obtained for this Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study and requirement for informed consent was waived. All available clinical, radiologic, and pathologic information of 57 patients with secondary, pathologically proven breast angiosarcoma between January 1999 and May 2013 at our institution were reviewed.
Clinical and Histopathologic Features The clinical features of RAS, including age of patient and date of primary breast cancer diagnosis, original breast cancer pathologic diagnosis, time of radiation, time of first presentation of radiationinduced breast angiosarcoma, primary clinical presentation, treatment utilized, and overall outcome were documented. Pathologic features were recorded including mitotic rate, necrosis, and tumor margin. The median age at original breast cancer diagnosis of the study cohort was 69.3 years (range 42–84 years). The original breast cancer diagnosis (n 5 16) included invasive ductal carcinoma (IDC, n 5 13); invasive lobular carcinoma (ILC, n 5 1); invasive carcinoma with mixed lobular and ductal carcinoma (n 5 1); and ductal carcinoma in situ (DCIS, n 5 1). The average time from diagnosis of RAS and initial radiation therapy was 7.3 years (range 5.1–9.5 years). Initial biopsy (predefinite treatment) demonstrated angiosarcoma (n 5 14), atypical postradiation vascular proliferation (APRVP) (n 5 1), and dedifferentiated round cell tumor (n 5 1). Both APRVP and dedifferentiated round cell tumor were classified as angiosarcoma after definitive surgery.
MRI Protocol The current breast MRI protocol at our institution includes prone imaging on either a GE Signa 1.5T, GE 3T HDX (General Electric Medical Systems, Milwaukee, WI), or a Siemens Trio 3T (Siemens Medical, Wendell, NC) scanner, using a dedicated breast surface coil (16 channel Siemens, 8 channel GE, or 7 channel InVivo, Orlando, FL). Sequences include a 3-plane localizing sequence, axial fat-suppressed T2W FSE or T2 STIR sequence, and axial fast spoiled gradient T1W nonfat-suppressed sequence before contrast administration. Dynamic T1W fat-suppressed 3D fast spoiled gradient echo (3D FSPGR) sequences are then performed before and four times following intravenous administration of contrast (0.1 mmol/kg, Magnevist, Berlex, NJ) in the axial plane. A T1W 3D FSPGR delayed postcontrast sequence is acquired in the sagittal plane. Prior to 2010, dynamic images were acquired in either the sagittal or the axial plane, with delayed imaging performed in the orthogonal plane. Postprocessing, including subtrac764
tion axial images, maximum intensity projections (MIP), and computer-aided diagnosis (CADSTREAM), is routinely employed.
Image and Data Analysis Two radiologists with 8 and 13 years of experience (E.G. and J.P.) independently reviewed all available imaging studies, including mammograms, ultrasounds, and MRIs (baseline and follow-up); all the imaging findings of the different modalities (mammograms, ultrasounds, and MRIs) were reviewed concurrently. The following MRI features of pathologically proven RAS were recorded: location, T1 and T2 signal intensity compared with skeletal muscle, degree and homogeneity of enhancement, and infiltration into adjacent structures.
Results Clinical and Histopathological Findings Fifty-seven women were diagnosed with pathologyconfirmed RAS during the study period. Of these 57 women, seventeen (29.8%) underwent pretreatment contrast-enhanced breast MRI examinations (prior to surgical resection or chemotherapy). Sixteen breast MRI studies were available for review and comprise the study cohort. The indication for pretreatment MRI included assessing extent of disease after skin biopsy (n 5 13) and work-up of clinical skin findings (ecchymoses) without known histopathologic diagnosis (n 5 3). Imaging Findings Among these 16 women, nine women underwent pre-MRI mammogram (9/16, 56.2%), which were available for review, as part of their imaging work-up. Five (5/9, 55.6%) were found to have expected skin thickening and posttreatment changes, and were therefore mammographically occult. The remaining four (4/9) were found to have underlying masses mammographically. Six women underwent pre-MRI ultrasound (6/16), of which three demonstrated expected skin thickening and nonspecific posttreatment and clinical follow-up was recommended; the remaining three were found to have underlying irregular masses on both ultrasound and mammogram. Findings on T2-Weighted Sequences On MRI, all cases demonstrated diffuse T2 hyperintense skin thickening (n 5 16). Within the diffusely T2 hyperintense skin thickening, the signal intensity of discrete lesions varied. Seven out of 16 cases demonstrated T2 low signal (hypointense) lesions within diffusely T2 hyperintense skin thickening. Five (5/16) demonstrated T2 heterogeneous intensity and four (4/16) were T2 hyperintense. Findings on T1-Weighted Sequences On postcontrast T1-weighted imaging, all cutaneous and intraparenchymal masses demonstrated rapid initial and washout delayed enhancement kinetics. Four major patterns of contrast enhancement on postcontrast T1-weighted imaging Volume 42, No. 3
Chikarmane et al.: MRI Findings of RAS
FIGURE 1: An 82-year-old female with history of left breast invasive ductal carcinoma, status post lumpectomy, and radiation treatment who presented with bruising around her nipple 5 years after radiation treatment. Initial mammogram (not shown) was reported as normal. Skin punch biopsy revealed RAS. Presurgical MRI revealed diffuse, nonmass hypointensity within skin on T2weighted imaging (a, arrow), which appeared isointense on T1-weighted imaging (b, arrow), and rapidly enhanced on dynamic postcontrast imaging (c, arrow). No discrete cutaneous or intraparenchymal masses were present. Subsequent mastectomy was performed and the patient has been disease free.
were observed during image analysis. These patterns included diffuse, heterogeneous persistent skin enhancement without discrete cutaneous masses (n 5 7, 7/16) (Fig. 1a–c); diffuse, heterogeneous persistent skin enhancement with discrete cutaneous masses (n 5 6, 6/16) (Fig. 2a–c); multifocal small masses without diffuse skin enhancement (n 5 2, 2/16) (Fig. 3a,b); and single discrete focus of enhancement (n 5 1, 1/16) (Fig. 4a,b). Out of the 16 cases, 10 (10/16) demonstrated disease in a quadrant away from the original lumpectomy site on MRI. No abnormal enhancement was seen at the lumpectomy sites in the 16 cases. Of the 16 cases, four demonstrated irregular, intraparenchymal masses in addition to skin involvement on MRI (Fig. 5a–c), all four of which were demonstrated on mammography and three were seen on ultrasound. The nipple asymmetrically enhanced and was pathologically involved in eight cases (8/16) (Fig. 2a–c). Imaging findings may be found in Table 1. Treatment and Outcome Eight women underwent surgical management without chemotherapy. Surgical management after diagnosis included
initial surgical excision with subsequent radical mastectomy with chest wall resection (n 5 2); mastectomy with subsequent chest wall resection (n 5 1); mastectomy only (n 5 4); and radical mastectomy with chest wall resection (n 5 1). Neoadjuvant chemotherapy was administered to eight of the 16 women; chemotherapy regimens included taxol only (n 5 1), paclitaxil only (n 5 2), gemcitabine only (n 5 1), gemcitabine and docetaxil (n 5 1), gemcitabine and paclitaxil (n 5 2), and gemcitabine, paclitaxil and bevacizumab (n 5 1). Of these eight women, seven underwent radical mastectomy with chest wall resection. The remaining patient had surgical excision without further surgical treatment, given that she was a poor surgical candidate for other reasons; she is currently on gemcitabine palliative maintenance therapy without evidence of recurrence or metastases to date. Of the 16 women, four developed recurrence within the chest wall in an average of 7 months (range: 3 months to 1.5 years) after initial resection. Six (6/16) developed local or metastatic disease including within the lungs (n 5 2), lung and bone (n 5 1), liver (n 5 1), contralateral breast (n 5 1), and axillary lymph node (n 5 1). The average
FIGURE 2: A 75-year-old female with history of left breast invasive ductal carcinoma, status post lumpectomy, and radiation treatment who presented with violaceous skin lesion at level of nipple 8 years after radiation treatment. No mammogram or ultrasound was available for review. Skin punch biopsy revealed RAS. Premastectomy MRI demonstrated diffuse heterogeneous skin enhancement with a discrete cutaneous mass involving the nipple-areolar complex. The mass appears heterogeneous on T2weighted imaging (a, arrow), T1 hypointense (b, arrow), and rapidly enhanced on postcontrast imaging (c, arrow).
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FIGURE 3: A 54-year-old female with history of invasive ductal carcinoma, status post neoadjuvant chemotherapy, lumpectomy, and radiation treatment 7 years prior who presented with bruising in the left breast. Skin punch biopsy revealed RAS involving dermis and subcutaneous tissue. Pretreatment MRI demonstrated multifocal T2 hyperintense small masses (a) which rapidly enhanced on postcontrast imaging without diffuse skin enhancement (b). The patient underwent presurgical chemotherapy with taxol before radical mastectomy and chest wall resection. She is currently disease free.
time to metastatic disease from angiosarcoma diagnosis was 5.5 months (range 2–5 months). Four women died during the study period. Three of these four women had intraparenchymal masses on presentation (3/4). Two of the four women who died had metastatic disease (lung and bones (n 5 1) and liver (n 5 1)) in addition to intraparenchymal masses.
Discussion Radiation-associated secondary breast angiosarcoma is a rare but important clinical entity whose MRI characteristics have been previously described only in case reports.1,3,4,6,8–13 Our study provides the largest cohort of pretreatment breast MRIs of biopsy-proven radiation-associated angiosarcomas to date, and sheds light on the entity’s imaging characteristics. Secondary angiosarcoma is clinically and pathologically distinct from primary angiosarcoma; secondary RAS arises within the skin of previously irradiated breast tissue, with variable invasion in the underlying parenchyma.2,5,15,16 This differs from primary angiosarcoma,
FIGURE 4: A 66-year-old female with history of invasive ductal and lobular carcinoma of left breast, status post lumpectomy, and radiation therapy 7 years prior who presented with left breast violaceous skin lesion. Pretreatment breast MRI revealed a T1 isointense (a), T2 heterogeneous (not shown) focus which rapidly enhanced on dynamic postcontrast imaging (b, arrow) within the skin; skin punch biopsy revealed RAS. The patient underwent presurgical chemotherapy with taxol and gemcitabine before radical mastectomy and chest wall resection. She is currently disease free.
which tends to arise in the breast parenchyma, with variable involvement of skin. Secondary angiosarcoma in the pre-BCT era was most often seen in patients with mastectomy and axillary dissection, and associated with the occurrence of lymphedema.4 Mammographic and sonographic findings of secondary breast angiosarcoma can be nonsuspicious, with expected posttreatment changes, which may lead to delays in diagnosis and treatment. Of the nine patients who underwent preMRI mammograms available for review, over half had expected skin thickening with postradiation and lumpectomy changes. The remaining four patients were found to have underlying masses on mammogram, but these women were also the only four who demonstrated intraparenchymal masses on subsequent breast MRI. Sonographic findings of secondary breast angiosarcoma are similar to those seen at mammography, as half the women who underwent breast ultrasound were found to have nonspecific skin thickening and posttreatment changes. Given the postradiation changes of skin thickening, predominately dermal lesions may be particularly difficult to delineate on ultrasound.
FIGURE 5: A 60-year-old woman with history of left breast invasive ductal carcinoma status post lumpectomy and radiation 8 years prior who presented with increased edema around surgical scar. No mammograms or ultrasounds were available for review. Skin punch biopsy revealed RAS. Presurgical MRI revealed T2 heterogeneous irregular intraparenchymal mass (a, arrow), which was T1 hypointense (b, arrow) and enhanced rapidly on dynamic postcontrast imaging (c, arrow). The patient underwent neoadjuvant chemotherapy with paclitaxil and gemcitabine before radical mastectomy and chest wall resection. She is currently disease free.
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Volume 42, No. 3
Age at diagnosis
67
75
54
84
60
68
64
42
67
66
75
#
1
September 2015
2
3
4
5
6
7
8
9
10
11
IDC
IDLC
IDC
IDC
IDC
IDC
IDC
IDC
IDC
DCIS
IDC
Original breast cancer
8.4
7.6
6.3
5.1
7.4
9.5
8.1
8.7
7.1
7.1
7.2
Time after radiation (years)
Heterogeneous
Heterogeneous
Hypointense
Heterogeneous
Hypointense
Hypointense
Heterogeneous
Hypointense
Hyperintense
Hyperintense
Hypointense
T2 signal
Diffuse, heterogeneous skin enhancement with discrete masses
Single focus of enhancement
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Multifocal small masses without diffuse skin enhancement
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Distribution of enhancement
Radical chest wall resection and mastectomy Radical chest wall resection and mastectomy Radical chest wall resection and mastectomy Mastectomy
Mastectomy
Radical chest wall resection and mastectomy
Yes
Yes
No
Yes
No
No
Mastectomy
Radical chest wall resection and mastectomy
No
No
Mastectomy
Yes
Mastectomy
Radical chest wall resection and mastectomy
No
No
Treatment
Discrete intraparenchymal masses
TABLE 1. Characteristics and Findings of Patients with Radiation Associated Breast Angiosarcoma (RAS)
Yes
Yes
No
No
Yes
Yes
No
Yes
No
No
Yes
Yes
No
No
Yes
Yes
Yes
No
No
No
No
No
Mets
Chemo?
Alive
Alive
Alive
Deceased
Deceased
Alive
Alive
Deceased
Alive
Deceased
Alive
Outcome
Chikarmane et al.: MRI Findings of RAS
767
768
82
75
82
82
66
12
13
14
15
16
IDC
IDC
IDC
ILC
IDC
Original breast cancer
5.8
5.7
9.3
7.2
5.3
Time after radiation (years)
Hypointense
Heterogeneous
Hyperintense
Hyperintense
Hypointense
T2 signal
Multifocal small masses without diffuse skin enhancement
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Distribution of enhancement
Treatment
Mastectomy
Radical chest wall resection and mastectomy Radical chest wall resection and mastectomy Surgical excision
Radical chest wall resection and mastectomy
Discrete intraparenchymal masses No
No
No
No
No
No
No
No
Yes
No
No
Yes
Yes
No
Mets
No
Chemo?
IDC 5 invasive ductal carcinoma; IDLC 5 invasive ductal and lobular carcinoma; ILC 5 invasive lobular carcinoma; Mets 5 metastases; Chemo 5 chemotherapy.
Age at diagnosis
#
TABLE 1: Continued
Alive
Alive
Alive
Alive
Alive
Outcome
Journal of Magnetic Resonance Imaging
Volume 42, No. 3
Chikarmane et al.: MRI Findings of RAS
Our study demonstrates the important role MRI plays in the diagnosis and determination of disease extent in patients diagnosed with radiation-associated breast angiosarcoma. All cases with indeterminate mammographic and sonographic features demonstrated suspicious features on MRI. The vast majority of patients were found to have diffuse heterogeneous skin enhancement with or without cutaneous, enhancing masses. In addition, one-quarter were found to have intraparenchymal involvement as demonstrated by irregular masses. The breadth of these MRI findings confirm the variation in imaging appearances which have only been described in the case report literature; for example, Sanders et al described small (
MRI Findings of Radiation-Associated Angiosarcoma of the Breast (RAS) Sona A. Chikarmane, MD,1* Eva C. Gombos, MD,1,2 Jayender Jagadeesan, PhD,1 Chandrajit Raut, MD, MSc,3,4 and Jyothi P. Jagannathan, MD2 Purpose: To describe the magnetic resonance imaging (MRI) characteristics of radiation-associated breast angiosarcomas (RAS). Materials and Methods: In this Institutional Review board (IRB)-approved retrospective study, 57 women were diagnosed with pathologically confirmed RAS during the study period (January 1999 to May 2013). Seventeen women underwent pretreatment breast MRI (prior to surgical resection or chemotherapy), of which 16 studies were available for review. Imaging features, including all available mammograms, ultrasounds, and breast MRIs, of these patients were evaluated by two radiologists independently and correlated with clinical management and outcomes. Results: The median age of patients at original breast cancer diagnosis was 69.3 years (range 42–84 years), with average time from initial radiation therapy to diagnosis of RAS of 7.3 years (range 5.1–9.5 years). Nine women had mammograms (9/16, 56%) and six had breast ultrasound (US) (6/16, 38%) prior to MRI, which demonstrated nonsuspicious findings in 5/9 mammograms and 3/6 ultrasounds. Four patients had distinct intraparenchymal masses on mammogram and MRI. MRI findings included diffuse T2 high signal skin thickening (16/16, 100%). Nearly half (7/16, 44%) of patients had T2 low signal intensity lesions; all lesions rapidly enhanced on postcontrast T1-weighted imaging. All women underwent surgical resection, with 8/16 (50%) receiving neoadjuvant chemotherapy. Four women died during the study period. Conclusion: Clinical, mammographic, and sonographic findings of RAS are nonspecific and may be occult on conventional breast imaging; MRI findings of RAS include rapidly enhancing dermal and intraparenchymal lesions, some of which are low signal on T2 weighted imaging. J. MAGN. RESON. IMAGING 2015;42:763–770.
B
reast conservation therapy (BCT) is considered the standard of care for treatment of early (stages I and II) breast cancer and consists of lumpectomy and whole-breast irradiation. Radiotherapy (RT) has been associated with the development of secondary soft-tissue sarcomas, with angiosarcoma being the most common.1 Given the increasing use of BCT, the rate of secondary breast angiosarcoma has been reported with more frequency, with 0.9 per 1000 breast cancer incidence.2,3 The latency period of secondary breast angiosarcoma in women after BCT ranges from 2 to 23 years.4 Secondary breast angiosarcomas can be difficult to detect clinically, given that they develop in the background of radiationinduced skin changes and manifest as painless, erythema-
tous, or violaceous cutaneous nodules, which may be attributed to recent trauma.5 Although rare, their occult clinical appearance can subsequently lead to a delay in diagnosis and outcomes are overall poor.4,5 Treatment is surgery, often wide local excision depending on extent of disease, with or without chemotherapy.4 Much is unknown about imaging findings of radiation-associated sarcomas (RAS) in the breast, as the current radiology literature on RAS is in the form of case reports and pictorial reviews,2,3,6–14 many of which describe both primary and secondary breast angiosarcoma cases, or do not pathologically differentiate these entities.2,7,10,14 Given the potential use of breast magnetic resonance imaging (MRI) in the follow-up of women with a personal
View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.24822 Received Aug 12, 2014, Accepted for publication Nov 17, 2014. *Address reprint requests to: S.A.C., Department of Radiology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. E-mail: [email protected] From the 1Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA; 2Department of Imaging, Dana-Farber Cancer Institute/ Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 3Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA; and 4Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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history of breast cancer, in addition to the nonspecific findings of conventional mammography and sonography,14 the initial MRI findings of secondary angiosarcoma may be useful in early detection. The purpose of this study is to describe the breast MRI features of RAS in a cohort of patients with histopathological and clinical correlation.
Materials and Methods Subjects Institutional Review Board approval was obtained for this Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study and requirement for informed consent was waived. All available clinical, radiologic, and pathologic information of 57 patients with secondary, pathologically proven breast angiosarcoma between January 1999 and May 2013 at our institution were reviewed.
Clinical and Histopathologic Features The clinical features of RAS, including age of patient and date of primary breast cancer diagnosis, original breast cancer pathologic diagnosis, time of radiation, time of first presentation of radiationinduced breast angiosarcoma, primary clinical presentation, treatment utilized, and overall outcome were documented. Pathologic features were recorded including mitotic rate, necrosis, and tumor margin. The median age at original breast cancer diagnosis of the study cohort was 69.3 years (range 42–84 years). The original breast cancer diagnosis (n 5 16) included invasive ductal carcinoma (IDC, n 5 13); invasive lobular carcinoma (ILC, n 5 1); invasive carcinoma with mixed lobular and ductal carcinoma (n 5 1); and ductal carcinoma in situ (DCIS, n 5 1). The average time from diagnosis of RAS and initial radiation therapy was 7.3 years (range 5.1–9.5 years). Initial biopsy (predefinite treatment) demonstrated angiosarcoma (n 5 14), atypical postradiation vascular proliferation (APRVP) (n 5 1), and dedifferentiated round cell tumor (n 5 1). Both APRVP and dedifferentiated round cell tumor were classified as angiosarcoma after definitive surgery.
MRI Protocol The current breast MRI protocol at our institution includes prone imaging on either a GE Signa 1.5T, GE 3T HDX (General Electric Medical Systems, Milwaukee, WI), or a Siemens Trio 3T (Siemens Medical, Wendell, NC) scanner, using a dedicated breast surface coil (16 channel Siemens, 8 channel GE, or 7 channel InVivo, Orlando, FL). Sequences include a 3-plane localizing sequence, axial fat-suppressed T2W FSE or T2 STIR sequence, and axial fast spoiled gradient T1W nonfat-suppressed sequence before contrast administration. Dynamic T1W fat-suppressed 3D fast spoiled gradient echo (3D FSPGR) sequences are then performed before and four times following intravenous administration of contrast (0.1 mmol/kg, Magnevist, Berlex, NJ) in the axial plane. A T1W 3D FSPGR delayed postcontrast sequence is acquired in the sagittal plane. Prior to 2010, dynamic images were acquired in either the sagittal or the axial plane, with delayed imaging performed in the orthogonal plane. Postprocessing, including subtrac764
tion axial images, maximum intensity projections (MIP), and computer-aided diagnosis (CADSTREAM), is routinely employed.
Image and Data Analysis Two radiologists with 8 and 13 years of experience (E.G. and J.P.) independently reviewed all available imaging studies, including mammograms, ultrasounds, and MRIs (baseline and follow-up); all the imaging findings of the different modalities (mammograms, ultrasounds, and MRIs) were reviewed concurrently. The following MRI features of pathologically proven RAS were recorded: location, T1 and T2 signal intensity compared with skeletal muscle, degree and homogeneity of enhancement, and infiltration into adjacent structures.
Results Clinical and Histopathological Findings Fifty-seven women were diagnosed with pathologyconfirmed RAS during the study period. Of these 57 women, seventeen (29.8%) underwent pretreatment contrast-enhanced breast MRI examinations (prior to surgical resection or chemotherapy). Sixteen breast MRI studies were available for review and comprise the study cohort. The indication for pretreatment MRI included assessing extent of disease after skin biopsy (n 5 13) and work-up of clinical skin findings (ecchymoses) without known histopathologic diagnosis (n 5 3). Imaging Findings Among these 16 women, nine women underwent pre-MRI mammogram (9/16, 56.2%), which were available for review, as part of their imaging work-up. Five (5/9, 55.6%) were found to have expected skin thickening and posttreatment changes, and were therefore mammographically occult. The remaining four (4/9) were found to have underlying masses mammographically. Six women underwent pre-MRI ultrasound (6/16), of which three demonstrated expected skin thickening and nonspecific posttreatment and clinical follow-up was recommended; the remaining three were found to have underlying irregular masses on both ultrasound and mammogram. Findings on T2-Weighted Sequences On MRI, all cases demonstrated diffuse T2 hyperintense skin thickening (n 5 16). Within the diffusely T2 hyperintense skin thickening, the signal intensity of discrete lesions varied. Seven out of 16 cases demonstrated T2 low signal (hypointense) lesions within diffusely T2 hyperintense skin thickening. Five (5/16) demonstrated T2 heterogeneous intensity and four (4/16) were T2 hyperintense. Findings on T1-Weighted Sequences On postcontrast T1-weighted imaging, all cutaneous and intraparenchymal masses demonstrated rapid initial and washout delayed enhancement kinetics. Four major patterns of contrast enhancement on postcontrast T1-weighted imaging Volume 42, No. 3
Chikarmane et al.: MRI Findings of RAS
FIGURE 1: An 82-year-old female with history of left breast invasive ductal carcinoma, status post lumpectomy, and radiation treatment who presented with bruising around her nipple 5 years after radiation treatment. Initial mammogram (not shown) was reported as normal. Skin punch biopsy revealed RAS. Presurgical MRI revealed diffuse, nonmass hypointensity within skin on T2weighted imaging (a, arrow), which appeared isointense on T1-weighted imaging (b, arrow), and rapidly enhanced on dynamic postcontrast imaging (c, arrow). No discrete cutaneous or intraparenchymal masses were present. Subsequent mastectomy was performed and the patient has been disease free.
were observed during image analysis. These patterns included diffuse, heterogeneous persistent skin enhancement without discrete cutaneous masses (n 5 7, 7/16) (Fig. 1a–c); diffuse, heterogeneous persistent skin enhancement with discrete cutaneous masses (n 5 6, 6/16) (Fig. 2a–c); multifocal small masses without diffuse skin enhancement (n 5 2, 2/16) (Fig. 3a,b); and single discrete focus of enhancement (n 5 1, 1/16) (Fig. 4a,b). Out of the 16 cases, 10 (10/16) demonstrated disease in a quadrant away from the original lumpectomy site on MRI. No abnormal enhancement was seen at the lumpectomy sites in the 16 cases. Of the 16 cases, four demonstrated irregular, intraparenchymal masses in addition to skin involvement on MRI (Fig. 5a–c), all four of which were demonstrated on mammography and three were seen on ultrasound. The nipple asymmetrically enhanced and was pathologically involved in eight cases (8/16) (Fig. 2a–c). Imaging findings may be found in Table 1. Treatment and Outcome Eight women underwent surgical management without chemotherapy. Surgical management after diagnosis included
initial surgical excision with subsequent radical mastectomy with chest wall resection (n 5 2); mastectomy with subsequent chest wall resection (n 5 1); mastectomy only (n 5 4); and radical mastectomy with chest wall resection (n 5 1). Neoadjuvant chemotherapy was administered to eight of the 16 women; chemotherapy regimens included taxol only (n 5 1), paclitaxil only (n 5 2), gemcitabine only (n 5 1), gemcitabine and docetaxil (n 5 1), gemcitabine and paclitaxil (n 5 2), and gemcitabine, paclitaxil and bevacizumab (n 5 1). Of these eight women, seven underwent radical mastectomy with chest wall resection. The remaining patient had surgical excision without further surgical treatment, given that she was a poor surgical candidate for other reasons; she is currently on gemcitabine palliative maintenance therapy without evidence of recurrence or metastases to date. Of the 16 women, four developed recurrence within the chest wall in an average of 7 months (range: 3 months to 1.5 years) after initial resection. Six (6/16) developed local or metastatic disease including within the lungs (n 5 2), lung and bone (n 5 1), liver (n 5 1), contralateral breast (n 5 1), and axillary lymph node (n 5 1). The average
FIGURE 2: A 75-year-old female with history of left breast invasive ductal carcinoma, status post lumpectomy, and radiation treatment who presented with violaceous skin lesion at level of nipple 8 years after radiation treatment. No mammogram or ultrasound was available for review. Skin punch biopsy revealed RAS. Premastectomy MRI demonstrated diffuse heterogeneous skin enhancement with a discrete cutaneous mass involving the nipple-areolar complex. The mass appears heterogeneous on T2weighted imaging (a, arrow), T1 hypointense (b, arrow), and rapidly enhanced on postcontrast imaging (c, arrow).
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FIGURE 3: A 54-year-old female with history of invasive ductal carcinoma, status post neoadjuvant chemotherapy, lumpectomy, and radiation treatment 7 years prior who presented with bruising in the left breast. Skin punch biopsy revealed RAS involving dermis and subcutaneous tissue. Pretreatment MRI demonstrated multifocal T2 hyperintense small masses (a) which rapidly enhanced on postcontrast imaging without diffuse skin enhancement (b). The patient underwent presurgical chemotherapy with taxol before radical mastectomy and chest wall resection. She is currently disease free.
time to metastatic disease from angiosarcoma diagnosis was 5.5 months (range 2–5 months). Four women died during the study period. Three of these four women had intraparenchymal masses on presentation (3/4). Two of the four women who died had metastatic disease (lung and bones (n 5 1) and liver (n 5 1)) in addition to intraparenchymal masses.
Discussion Radiation-associated secondary breast angiosarcoma is a rare but important clinical entity whose MRI characteristics have been previously described only in case reports.1,3,4,6,8–13 Our study provides the largest cohort of pretreatment breast MRIs of biopsy-proven radiation-associated angiosarcomas to date, and sheds light on the entity’s imaging characteristics. Secondary angiosarcoma is clinically and pathologically distinct from primary angiosarcoma; secondary RAS arises within the skin of previously irradiated breast tissue, with variable invasion in the underlying parenchyma.2,5,15,16 This differs from primary angiosarcoma,
FIGURE 4: A 66-year-old female with history of invasive ductal and lobular carcinoma of left breast, status post lumpectomy, and radiation therapy 7 years prior who presented with left breast violaceous skin lesion. Pretreatment breast MRI revealed a T1 isointense (a), T2 heterogeneous (not shown) focus which rapidly enhanced on dynamic postcontrast imaging (b, arrow) within the skin; skin punch biopsy revealed RAS. The patient underwent presurgical chemotherapy with taxol and gemcitabine before radical mastectomy and chest wall resection. She is currently disease free.
which tends to arise in the breast parenchyma, with variable involvement of skin. Secondary angiosarcoma in the pre-BCT era was most often seen in patients with mastectomy and axillary dissection, and associated with the occurrence of lymphedema.4 Mammographic and sonographic findings of secondary breast angiosarcoma can be nonsuspicious, with expected posttreatment changes, which may lead to delays in diagnosis and treatment. Of the nine patients who underwent preMRI mammograms available for review, over half had expected skin thickening with postradiation and lumpectomy changes. The remaining four patients were found to have underlying masses on mammogram, but these women were also the only four who demonstrated intraparenchymal masses on subsequent breast MRI. Sonographic findings of secondary breast angiosarcoma are similar to those seen at mammography, as half the women who underwent breast ultrasound were found to have nonspecific skin thickening and posttreatment changes. Given the postradiation changes of skin thickening, predominately dermal lesions may be particularly difficult to delineate on ultrasound.
FIGURE 5: A 60-year-old woman with history of left breast invasive ductal carcinoma status post lumpectomy and radiation 8 years prior who presented with increased edema around surgical scar. No mammograms or ultrasounds were available for review. Skin punch biopsy revealed RAS. Presurgical MRI revealed T2 heterogeneous irregular intraparenchymal mass (a, arrow), which was T1 hypointense (b, arrow) and enhanced rapidly on dynamic postcontrast imaging (c, arrow). The patient underwent neoadjuvant chemotherapy with paclitaxil and gemcitabine before radical mastectomy and chest wall resection. She is currently disease free.
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Volume 42, No. 3
Age at diagnosis
67
75
54
84
60
68
64
42
67
66
75
#
1
September 2015
2
3
4
5
6
7
8
9
10
11
IDC
IDLC
IDC
IDC
IDC
IDC
IDC
IDC
IDC
DCIS
IDC
Original breast cancer
8.4
7.6
6.3
5.1
7.4
9.5
8.1
8.7
7.1
7.1
7.2
Time after radiation (years)
Heterogeneous
Heterogeneous
Hypointense
Heterogeneous
Hypointense
Hypointense
Heterogeneous
Hypointense
Hyperintense
Hyperintense
Hypointense
T2 signal
Diffuse, heterogeneous skin enhancement with discrete masses
Single focus of enhancement
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Multifocal small masses without diffuse skin enhancement
Diffuse, heterogeneous skin enhancement with discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Distribution of enhancement
Radical chest wall resection and mastectomy Radical chest wall resection and mastectomy Radical chest wall resection and mastectomy Mastectomy
Mastectomy
Radical chest wall resection and mastectomy
Yes
Yes
No
Yes
No
No
Mastectomy
Radical chest wall resection and mastectomy
No
No
Mastectomy
Yes
Mastectomy
Radical chest wall resection and mastectomy
No
No
Treatment
Discrete intraparenchymal masses
TABLE 1. Characteristics and Findings of Patients with Radiation Associated Breast Angiosarcoma (RAS)
Yes
Yes
No
No
Yes
Yes
No
Yes
No
No
Yes
Yes
No
No
Yes
Yes
Yes
No
No
No
No
No
Mets
Chemo?
Alive
Alive
Alive
Deceased
Deceased
Alive
Alive
Deceased
Alive
Deceased
Alive
Outcome
Chikarmane et al.: MRI Findings of RAS
767
768
82
75
82
82
66
12
13
14
15
16
IDC
IDC
IDC
ILC
IDC
Original breast cancer
5.8
5.7
9.3
7.2
5.3
Time after radiation (years)
Hypointense
Heterogeneous
Hyperintense
Hyperintense
Hypointense
T2 signal
Multifocal small masses without diffuse skin enhancement
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Diffuse, heterogeneous skin enhancement; no discrete masses
Distribution of enhancement
Treatment
Mastectomy
Radical chest wall resection and mastectomy Radical chest wall resection and mastectomy Surgical excision
Radical chest wall resection and mastectomy
Discrete intraparenchymal masses No
No
No
No
No
No
No
No
Yes
No
No
Yes
Yes
No
Mets
No
Chemo?
IDC 5 invasive ductal carcinoma; IDLC 5 invasive ductal and lobular carcinoma; ILC 5 invasive lobular carcinoma; Mets 5 metastases; Chemo 5 chemotherapy.
Age at diagnosis
#
TABLE 1: Continued
Alive
Alive
Alive
Alive
Alive
Outcome
Journal of Magnetic Resonance Imaging
Volume 42, No. 3
Chikarmane et al.: MRI Findings of RAS
Our study demonstrates the important role MRI plays in the diagnosis and determination of disease extent in patients diagnosed with radiation-associated breast angiosarcoma. All cases with indeterminate mammographic and sonographic features demonstrated suspicious features on MRI. The vast majority of patients were found to have diffuse heterogeneous skin enhancement with or without cutaneous, enhancing masses. In addition, one-quarter were found to have intraparenchymal involvement as demonstrated by irregular masses. The breadth of these MRI findings confirm the variation in imaging appearances which have only been described in the case report literature; for example, Sanders et al described small (
