Practical Radiation Oncology (2012) 2, e59–e64
www.practicalradonc.org
Teaching Case
Angiosarcoma of the breast following breast conservation therapy: A case report and review of the literature Sudha B. Mahalingam MD a , Sarah McDonough BS b,⁎ a
Department of Radiation Oncology, TriHealth Hospital, Cincinnati, Ohio E. Kenneth Hatton, MD, Institute for Research and Education, Cincinnati, Ohio
b
Received 22 August 2011; revised 28 September 2011; accepted 17 October 2011
Introduction
Case report
Breast conservation for early-stage breast cancer has become the standard of care in the last 2 decades. As part of breast conservation therapy (BCT), whole breast irradiation following lumpectomy is increasingly used, with many women surviving long term after treatment. Radiation-induced tumors typically occur after a latent period of several years. Sarcomas comprise 12% of these radiation-induced tumors. 1 Among these, fibrosarcomas and chondrosarcomas have been described. Angiosarcomas, however, are rare, comprising only 1% of all soft tissue sarcomas 2; because they are malignant tumors arising from the vascular endothelium, more commonly they involve skin and subcutaneous tissues. Only 8% of angiosarcomas occur in the breast; of these, primary sarcomas are extremely rare. 2 The first case of secondary angiosarcoma of the breast following breast conservation therapy was described in 1987; since then, 221 cases have been reported world wide. 3,4 Few of these cases of secondary angiosarcomas have been reported following postmastectomy chest wall radiation therapy. We describe in this report the clinical course of a patient who developed angiosarcoma of the irradiated breast 8 years following BCT.
A 53-year-old white female was diagnosed with stage 2 (T1c N1M0) infiltrating ductal carcinoma in December 2001 (Fig 1). The tumor was estrogen receptor (ER) and progesterone receptor (PR) positive, and human epidermal growth factor receptor 2 (Her2/neu) was borderline. In addition to being a heavy smoker, she had multiple medical problems including reflex sympathetic dystrophy. This condition required multiple analgesics and interfered with her mobility to the extent that she was in a wheelchair. Following lumpectomy and axillary node dissection, she was recommended systemic chemotherapy which the patient refused. She underwent whole breast irradiation to a dose of 46 Gray (Gy) followed by electron boost to the tumor bed for an additional 14 Gy (Fig 2). In addition, she completed adjuvant hormonal therapy with tamoxifen for 5 years. Her annual mammogram in May 2009 was normal. However, at the time of the mammogram, the patient had noticed a small “pimple” near the inframammary fold. Within a matter of 2 to 3 weeks, she developed multiple lesions covering the entire breast (Figs 3 and 4). Incisional biopsy of the largest lesion established the diagnosis to be a high-grade sarcoma consistent with AS both by morphology as well as immunohistochemistry (Figs 5 and 6). The patient was discussed in a multidisciplinary panel and underwent a metastatic workup with a positron emission tomographic scan. This showed an extensive uptake noted along the outer surface of the left breast involving the skin. There was no uptake within the tissues of the breast. In addition, there was a solitary 1.4-cm left
Conflicts of interest: None. ⁎ Corresponding author. 10498 Montgomery Rd, Ste A, Cincinnati, OH 45242. E-mail address: [email protected] (S. McDonough).
1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2011.10.003
e60
S.B. Mahalingam, S. McDonough
Practical Radiation Oncology: October-December 2012
Figure 3 Biopsy of the largest nodule in the inferior portion of the breast on June 3, 2009.
Figure 1 A 40 magnification of moderately differentiated infiltrating ductal carcinoma; estrogen receptor positive, progesterone receptor positive, and human epidermal growth factor receptor 2 (HER/2neu) 2+.
upper lobe nodule with increased standardized uptake value of 8.2, suggestive of metastasis. There was no lymphadenopathy noted in the axillary, mediastinal, or supraclavicular areas (Figs 7, 8, and 9). She was recommended systemic chemotherapy with weekly Taxol (Bristol-Myers Squibb, New York, NY) with initial partial response that lasted approximately 3 months (Fig 10). Further clinical progression was noted in the same area, as well as in the left axilla. A repeat positron emission tomographic scan in November 2009 showed more disease in the breast parenchyma as well as adjacent lymphatic areas, including internal mammary nodes. The patient deteriorated rapidly and expired in January 2010 about 7 months after her initial diagnosis (Fig 11). What was
Figure 2
Area of left breast treated in 2001.
striking in our patient was the fact that the nodular lesions were confined to the area of treatment throughout the course of the disease, almost outlining the field of irradiation (Fig 12). In addition, the most challenging aspect of her clinical care was the copious serosanguinous drainage from the lesions, which decreased when she started responding to chemotherapy.
Discussion Angiosarcomas arise in the vascular endothelium in the skin and soft tissue. They comprise 1% of all sarcomas; 8% arise in the breast. 2 Breast angiosarcomas can be primary or secondary. Secondary angiosarcomas occur in the irradiated breast or chest wall after a mean latent period of 6 years. 4 Since the first case was reported in 1987, there have been 221 cases reported in the literature. 3,4 With increasing use of BCT, the incidence of angiosarcoma could potentially increase. The published incidence of angiosarcomas following BCT ranges from 0.05% to 1.11%. 5,6 West et al 6 express concern that we may be underestimating the risk of postirradiation angiosarcoma.
Figure 4 Dramatic progression in less than 3 weeks, with nodular lesions covering the left breast within the radiation field.
Practical Radiation Oncology: October-December 2012
Angiosarcoma of the breast
e61
Figure 7 Initial diagnostic positron emission tomographic scan showing uptake confined to the left breast area and solitary in the left lung. Figure 5 Microscopic features showing sheets of poorly differentiated malignant cells with surrounding necrosis; prominent vascular spaces lined by atypical endothelial cells and papillary intraluminal proliferation are present (40).
The tumor registry of TriHealth Hospital was reviewed. From 1996 to 2009 there were 7956 breast cancers diagnosed. Of the 2504 patients who received radiation therapy to the whole breast, we found only 1 other case of secondary angiosarcoma of the breast. There were no occurrences of secondary angiosarcoma in patients having chest wall radiotherapy. Characteristics of both patients are summarized in Table 1. The only other patient with secondary angiosarcoma following radiation therapy was a white female diagnosed
Figure 6 Immunohistochemical staining with CD31, CD34, and factor VIII can be useful in the diagnosis; CD117(c-KIT) may also be helpful. In our patient, CD34 was strongly positive, CD31 and factor VIII were weakly positive, and CD117 was negative. The figure shows CD34 at 40.
with stage 2 right breast cancer at the age of 68. She underwent a lumpectomy in April 2002 followed by whole breast irradiation (50 Gy and 10 Gy boost). In December 2008 the patient presented with bruising and blistering in the area that was irradiated; breast ultrasound showed skin thickening. Ultrasound core biopsy confirmed angiosarcoma. In February 2009 the patient underwent excision of skin lesion, and then a modified mastectomy in April 2009. The patient expired in September 2009. Several possible mechanisms have been explained that lead to the development of angiosarcomas following radiation. In addition to the direct mutagenic effect, indirect effects of radiation causing lymphatic sclerosis and lymphedema are considered significant factors in the causation of postradiation angiosarcomas. 6-9 The possible role of angiogenic tumor factor (vascular endothelial
Figure 8 Positron emission tomography–computed tomography showing intense uptake along the outer surface of the left breast confined to the dermis, with no parenchymal masses in the breast.
e62
S.B. Mahalingam, S. McDonough
Practical Radiation Oncology: October-December 2012
Figure 9 Positron emission tomography–computed tomography showing a solitary nodule in the left lung.
growth factor) may have therapeutic implications for using targeted agents. 4,10-12 Genetic predisposition may also play an important role. 13,14 Clinical characteristics have been well described in the case reports that have been published thus far. The median age at diagnosis has been found to be 70 years, with a range of 36 to 92 years of age. 4,15-17 The 3 largest series have found the median latency period for the development of AS to be 59, 91, and 74 months. 15-17 The volume of the irradiated area, the presence of lymphedema, and the interaction of chemotherapy, as well as properties of the breast tissue, may lead to shorter latency periods for the development of angiosarcomas. 4,16,18 Adverse effects of increasing age have been observed; for each year increase in age at the time of BCT, the latency period has been observed to decrease by 0.5 months. 6 As in our case, the appearance of reddish or purplish nodules or patches, cutaneous or subcutaneous nodules, is often the first manifestation. 15,16,19,20 These can be mistaken for recurrence of the primary breast cancer.
Figure 10
Breast after patient’s third dose of Taxol.
Figure 11 Further clinical progression with increased nodularity and enlargement of left axillary nodes was noted in November 2009; positron emission tomography–computed tomography confirmed clinical findings.
Diffuse skin thickening with erythema may often mimic chronic changes from radiation therapy. Mammography can show skin thickening, 21 although in our patient the mammogram was initiated when she had a solitary lesion in the inframammary fold, and therefore the mammogram, even in retrospect, was normal. Positron emission tomographic scan in our patient showed dramatic involvement of the skin and subcutaneous nodules without any parenchymal tumor in the breast. Incisional or excisional biopsy with immunohistochemistry is essential in the pathologic confirmation of angiosarcoma. Histochemical staining with CD31, CD34, and factor VIII can be helpful. Some angiosarcomas may stain positive for CD117 (c-KIT). This may offer a therapeutic option with
Figure 12 The patient expired 4 weeks after this picture was taken; she was admitted with shortness of breath and was found to have large pleural effusions. She was admitted to Hospice for comfort care.
Practical Radiation Oncology: October-December 2012 Table 1
Angiosarcoma of the breast
Clinical characteristics of 2 patients
Age at Initial radiation diagnosis treatment
Time to Treatment Survival after Clinical develop AS of AS diagnosis of AS presentation
Initial treatment
Adjuvant treatment
54
7.5 y
MRM
None
68
e63
WBI 4600 cGy; E boost 1400 cGy WBI 5000 cGy; E boost 1000 cGy
7y
Weekly Taxol MRM
7 mo
Palpable mass
7 mo
Simple Taxol, Bloody nipple discharge, bruising, mastectomy carboplatin, Abraxane blistering
AS, angiosarcomas, MRM, modified radical mastectomy; WBI, whole breast irradiation.
targeted agents in these tumors which are often nonresponsive to standard chemotherapy agents. Treatment options depend on the extent of involvement. In cases where lesions are limited in extent, mastectomy or wide local excision may be offered, although there is a high propensity for local recurrence. 6 In our patient the lesions were over an extensive area, and therefore mastectomy was not feasible. Hyperfractionated radiation therapy has been used prior to or after surgical removal of the lesions with good local control. The University of Florida has reported on 3 patients with secondary angiosarcoma using fractional doses ranging from 1 Gy to 1.5 Gy, with 2 or 3 daily fractions, to total doses of 30 Gy to 60 Gy. 22 In another report from the same institution, 41 patients with primary as well as secondary angiosarcomas of various sites, including the breast and chest wall, were treated with conventional and hyperfractionated radiation therapy. The best local control and overall survival of patients were found in the group of 18 patients who were treated with radiotherapy 3 times daily when combined with surgery. 23 The University of Florida has also published their experience in 14 patients with secondary angiosarcoma of the breast treated with hyperfractionated radiation therapy combined with surgery. Their patients were treated 3 times a day with 1 Gy, with 4 hours between the fractions. The maximum dose given to the areas of gross disease was 75 Gy, with areas of subclinical disease receiving 45 Gy. Seven patients who received preoperative radiation therapy had complete responses. Nine out of 14 patients are alive with no disease, with follow-up ranging from 36 months to 127 months. They have clearly shown that reirradiation is not only effective but also tolerated with acceptable toxicity. 24 Several chemotherapeutic agents have shown varying degrees of response; anthracyclines, taxanes, and thalidomide are some of the drugs that have shown promise. 4 Our patient did have a partial response for a short period of time. Targeted agents such as bevacizumab, sorafenib, and imatinib are being investigated for use in tumors that express vascular endothelial growth factor and CD117. 4 Prognosis in these tumors is uniformly poor. The median disease-free survival was 1.23 years in one of the larger series reported. 17 Median time to death from diagnosis was reported in one study to be 33.5 months. 16
Conclusions Secondary angiosarcoma of the breast following breast conservation therapy is a potentially fatal complication following curative treatment for breast cancer. Physicians following up breast cancer patients should have a high index of suspicion. Even though these tumors are rapidly progressive, early diagnosis may offer the opportunity for more aggressive multimodality treatment with surgery, hyperfractionated radiation, and chemotherapy.
References 1. Laskin WB, Silverman TA, Enzinger FM. Postradiation soft tissue sarcomas: An analysis of 53 cases. Cancer. 1988;62:2330-2340. 2. Folpe AL, Gowen AM. Malignant vascular tumors. In: Enzinger FM, Weiss SW, eds. Soft tissue tumors. St Louis: Mosby; 1995: 641-677. 3. Body G, Sauvanet E, Calais G, et al. Cutaneous angiosarcoma of the breast following surgery and irradiation of breast adenocarcinoma. [Article in French] J Gynecol Obstet Biol Reprod (Paris). 1987;16: 479-483. 4. Abbott R, Palmieri C. Angiosarcoma of the breast following surgery and radiotherapy for breast cancer. Nat Clin Pract Oncol. 2008;5: 727-736. 5. Marchal C, Weber B, de Lafontan B, et al. Nine breast angiosarcomas after conservative treatment for breast carcinoma: A survey from French comprehensive Cancer Centers. Int J Radiat Oncol Biol Phys. 1999;44:113-119. 6. West JG, Qureshi A, West JE, et al. Risk of angiosarcoma following breast conservation: A clinical alert. Breast J. 2005;11:115-123. 7. Cafiero F, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: Diagnostic and therapeutic implications—two case reports and a review of the literature. Cancer. 1996;77:2496-2502. 8. Karlsson P, Holmberg E, Samuelsson A, Johansson KA, Wallgren A. Soft tissue sarcoma after treatment for breast cancer —a Swedish population-based study. Eur J Cancer. 1998;34:2068-2075. 9. Cozen W, Bernstein L, Wang F, Press MF, Mack TM. The risk of angiosarcoma following primary breast cancer. Br J Cancer. 1999;81:532-536. 10. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56:549-580. 11. Amo Y, Masuzawa M, Hamada Y, Katsuoka K. Expression of vascular endothelial growth factor in a human hemangioma cell line (ISO-HAS). Arch Dermatol Res. 2001;293:296-301. 12. Arbiser JL, Larsson H, Claesson-Welsh L, et al. Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the
e64
13.
14.
15.
16.
17. 18.
S.B. Mahalingam, S. McDonough
VEGF receptors VEGFR-1 and VEGFR-2 in vivo. Am J Pathol. 2000;15:1469-1476. Yap J, Chuba PJ, Thomas R, et al. Sarcoma as a secondary malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys. 2002;52:1231-1237. de Bree E, van Coevorden F, Peterse JL, Russell NS, Rutgers EJ. Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: Genetic predisposition? Eur J Surg Oncol. 2002;28:392-395. Strobbe LJ, Peterse HL, van Tinteren H, Wijnmaalen A, Rutgers EJ. Angiosarcoma of the breast after conservation therapy for invasive cancer, the incidence and outcome. An unforseen sequela. Breast Cancer Res Treat. 1998;47:101-109. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: An analysis of 27 cases. Am J Surg Pathol. 2004;28:781-788. Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the breast. Cancer. 2005;104:2682-2688. Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: Clinicopathologic analysis of 42 cases. Am J Surg Pathol. 2005;29:983-996.
Practical Radiation Oncology: October-December 2012 19. Gherardi G, Rossi S, Perrone S, Scanni A. Angiosarcoma after breast-conserving therapy: Fine-needle aspiration biopsy, immunocytochemistry, and clinicopathologic correlates. Cancer. 2005;105: 145-151. 20. Pendlebury SC, Bilous M, Langlands AO. Sarcomas following radiation therapy for breast cancer: A report of three cases and review of the literature. Int J Radiat Oncol Biol Phys. 1995;31:405-410. 21. Liberman L, Dershaw DD, Kaufman RJ, Rosen PP. Angiosarcoma of the breast. Radiology. 1992;183:649-654. 22. Feigenberg SJ, Mendenhall NP, Reith D, Ward JR, Copeland EM III. Angiosarcoma after breast-conserving therapy: Experience with hyper fractionated radiotherapy. Int J Radiat Oncol Biol Phys. 2002;52:620-626. 23. Scott M, Portnow L, Marcus RB, Mendenhall NP, Mendenhall WM, Indelicato DJ. Radiotherapy for angiosarcoma: The 35-year University of Florida experience. Int J Radiat Oncol Biol Phys. 2010;78:S614. 24. Palta M, Morris CG, Grobmyer SR, Copeland EM III, Mendenhall NP. Angiosarcoma after breast-conserving therapy: Long-term outcomes with hyperfractionated radiotherapy. Cancer. 2010;116: 1872-1878.
www.practicalradonc.org
Teaching Case
Angiosarcoma of the breast following breast conservation therapy: A case report and review of the literature Sudha B. Mahalingam MD a , Sarah McDonough BS b,⁎ a
Department of Radiation Oncology, TriHealth Hospital, Cincinnati, Ohio E. Kenneth Hatton, MD, Institute for Research and Education, Cincinnati, Ohio
b
Received 22 August 2011; revised 28 September 2011; accepted 17 October 2011
Introduction
Case report
Breast conservation for early-stage breast cancer has become the standard of care in the last 2 decades. As part of breast conservation therapy (BCT), whole breast irradiation following lumpectomy is increasingly used, with many women surviving long term after treatment. Radiation-induced tumors typically occur after a latent period of several years. Sarcomas comprise 12% of these radiation-induced tumors. 1 Among these, fibrosarcomas and chondrosarcomas have been described. Angiosarcomas, however, are rare, comprising only 1% of all soft tissue sarcomas 2; because they are malignant tumors arising from the vascular endothelium, more commonly they involve skin and subcutaneous tissues. Only 8% of angiosarcomas occur in the breast; of these, primary sarcomas are extremely rare. 2 The first case of secondary angiosarcoma of the breast following breast conservation therapy was described in 1987; since then, 221 cases have been reported world wide. 3,4 Few of these cases of secondary angiosarcomas have been reported following postmastectomy chest wall radiation therapy. We describe in this report the clinical course of a patient who developed angiosarcoma of the irradiated breast 8 years following BCT.
A 53-year-old white female was diagnosed with stage 2 (T1c N1M0) infiltrating ductal carcinoma in December 2001 (Fig 1). The tumor was estrogen receptor (ER) and progesterone receptor (PR) positive, and human epidermal growth factor receptor 2 (Her2/neu) was borderline. In addition to being a heavy smoker, she had multiple medical problems including reflex sympathetic dystrophy. This condition required multiple analgesics and interfered with her mobility to the extent that she was in a wheelchair. Following lumpectomy and axillary node dissection, she was recommended systemic chemotherapy which the patient refused. She underwent whole breast irradiation to a dose of 46 Gray (Gy) followed by electron boost to the tumor bed for an additional 14 Gy (Fig 2). In addition, she completed adjuvant hormonal therapy with tamoxifen for 5 years. Her annual mammogram in May 2009 was normal. However, at the time of the mammogram, the patient had noticed a small “pimple” near the inframammary fold. Within a matter of 2 to 3 weeks, she developed multiple lesions covering the entire breast (Figs 3 and 4). Incisional biopsy of the largest lesion established the diagnosis to be a high-grade sarcoma consistent with AS both by morphology as well as immunohistochemistry (Figs 5 and 6). The patient was discussed in a multidisciplinary panel and underwent a metastatic workup with a positron emission tomographic scan. This showed an extensive uptake noted along the outer surface of the left breast involving the skin. There was no uptake within the tissues of the breast. In addition, there was a solitary 1.4-cm left
Conflicts of interest: None. ⁎ Corresponding author. 10498 Montgomery Rd, Ste A, Cincinnati, OH 45242. E-mail address: [email protected] (S. McDonough).
1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2011.10.003
e60
S.B. Mahalingam, S. McDonough
Practical Radiation Oncology: October-December 2012
Figure 3 Biopsy of the largest nodule in the inferior portion of the breast on June 3, 2009.
Figure 1 A 40 magnification of moderately differentiated infiltrating ductal carcinoma; estrogen receptor positive, progesterone receptor positive, and human epidermal growth factor receptor 2 (HER/2neu) 2+.
upper lobe nodule with increased standardized uptake value of 8.2, suggestive of metastasis. There was no lymphadenopathy noted in the axillary, mediastinal, or supraclavicular areas (Figs 7, 8, and 9). She was recommended systemic chemotherapy with weekly Taxol (Bristol-Myers Squibb, New York, NY) with initial partial response that lasted approximately 3 months (Fig 10). Further clinical progression was noted in the same area, as well as in the left axilla. A repeat positron emission tomographic scan in November 2009 showed more disease in the breast parenchyma as well as adjacent lymphatic areas, including internal mammary nodes. The patient deteriorated rapidly and expired in January 2010 about 7 months after her initial diagnosis (Fig 11). What was
Figure 2
Area of left breast treated in 2001.
striking in our patient was the fact that the nodular lesions were confined to the area of treatment throughout the course of the disease, almost outlining the field of irradiation (Fig 12). In addition, the most challenging aspect of her clinical care was the copious serosanguinous drainage from the lesions, which decreased when she started responding to chemotherapy.
Discussion Angiosarcomas arise in the vascular endothelium in the skin and soft tissue. They comprise 1% of all sarcomas; 8% arise in the breast. 2 Breast angiosarcomas can be primary or secondary. Secondary angiosarcomas occur in the irradiated breast or chest wall after a mean latent period of 6 years. 4 Since the first case was reported in 1987, there have been 221 cases reported in the literature. 3,4 With increasing use of BCT, the incidence of angiosarcoma could potentially increase. The published incidence of angiosarcomas following BCT ranges from 0.05% to 1.11%. 5,6 West et al 6 express concern that we may be underestimating the risk of postirradiation angiosarcoma.
Figure 4 Dramatic progression in less than 3 weeks, with nodular lesions covering the left breast within the radiation field.
Practical Radiation Oncology: October-December 2012
Angiosarcoma of the breast
e61
Figure 7 Initial diagnostic positron emission tomographic scan showing uptake confined to the left breast area and solitary in the left lung. Figure 5 Microscopic features showing sheets of poorly differentiated malignant cells with surrounding necrosis; prominent vascular spaces lined by atypical endothelial cells and papillary intraluminal proliferation are present (40).
The tumor registry of TriHealth Hospital was reviewed. From 1996 to 2009 there were 7956 breast cancers diagnosed. Of the 2504 patients who received radiation therapy to the whole breast, we found only 1 other case of secondary angiosarcoma of the breast. There were no occurrences of secondary angiosarcoma in patients having chest wall radiotherapy. Characteristics of both patients are summarized in Table 1. The only other patient with secondary angiosarcoma following radiation therapy was a white female diagnosed
Figure 6 Immunohistochemical staining with CD31, CD34, and factor VIII can be useful in the diagnosis; CD117(c-KIT) may also be helpful. In our patient, CD34 was strongly positive, CD31 and factor VIII were weakly positive, and CD117 was negative. The figure shows CD34 at 40.
with stage 2 right breast cancer at the age of 68. She underwent a lumpectomy in April 2002 followed by whole breast irradiation (50 Gy and 10 Gy boost). In December 2008 the patient presented with bruising and blistering in the area that was irradiated; breast ultrasound showed skin thickening. Ultrasound core biopsy confirmed angiosarcoma. In February 2009 the patient underwent excision of skin lesion, and then a modified mastectomy in April 2009. The patient expired in September 2009. Several possible mechanisms have been explained that lead to the development of angiosarcomas following radiation. In addition to the direct mutagenic effect, indirect effects of radiation causing lymphatic sclerosis and lymphedema are considered significant factors in the causation of postradiation angiosarcomas. 6-9 The possible role of angiogenic tumor factor (vascular endothelial
Figure 8 Positron emission tomography–computed tomography showing intense uptake along the outer surface of the left breast confined to the dermis, with no parenchymal masses in the breast.
e62
S.B. Mahalingam, S. McDonough
Practical Radiation Oncology: October-December 2012
Figure 9 Positron emission tomography–computed tomography showing a solitary nodule in the left lung.
growth factor) may have therapeutic implications for using targeted agents. 4,10-12 Genetic predisposition may also play an important role. 13,14 Clinical characteristics have been well described in the case reports that have been published thus far. The median age at diagnosis has been found to be 70 years, with a range of 36 to 92 years of age. 4,15-17 The 3 largest series have found the median latency period for the development of AS to be 59, 91, and 74 months. 15-17 The volume of the irradiated area, the presence of lymphedema, and the interaction of chemotherapy, as well as properties of the breast tissue, may lead to shorter latency periods for the development of angiosarcomas. 4,16,18 Adverse effects of increasing age have been observed; for each year increase in age at the time of BCT, the latency period has been observed to decrease by 0.5 months. 6 As in our case, the appearance of reddish or purplish nodules or patches, cutaneous or subcutaneous nodules, is often the first manifestation. 15,16,19,20 These can be mistaken for recurrence of the primary breast cancer.
Figure 10
Breast after patient’s third dose of Taxol.
Figure 11 Further clinical progression with increased nodularity and enlargement of left axillary nodes was noted in November 2009; positron emission tomography–computed tomography confirmed clinical findings.
Diffuse skin thickening with erythema may often mimic chronic changes from radiation therapy. Mammography can show skin thickening, 21 although in our patient the mammogram was initiated when she had a solitary lesion in the inframammary fold, and therefore the mammogram, even in retrospect, was normal. Positron emission tomographic scan in our patient showed dramatic involvement of the skin and subcutaneous nodules without any parenchymal tumor in the breast. Incisional or excisional biopsy with immunohistochemistry is essential in the pathologic confirmation of angiosarcoma. Histochemical staining with CD31, CD34, and factor VIII can be helpful. Some angiosarcomas may stain positive for CD117 (c-KIT). This may offer a therapeutic option with
Figure 12 The patient expired 4 weeks after this picture was taken; she was admitted with shortness of breath and was found to have large pleural effusions. She was admitted to Hospice for comfort care.
Practical Radiation Oncology: October-December 2012 Table 1
Angiosarcoma of the breast
Clinical characteristics of 2 patients
Age at Initial radiation diagnosis treatment
Time to Treatment Survival after Clinical develop AS of AS diagnosis of AS presentation
Initial treatment
Adjuvant treatment
54
7.5 y
MRM
None
68
e63
WBI 4600 cGy; E boost 1400 cGy WBI 5000 cGy; E boost 1000 cGy
7y
Weekly Taxol MRM
7 mo
Palpable mass
7 mo
Simple Taxol, Bloody nipple discharge, bruising, mastectomy carboplatin, Abraxane blistering
AS, angiosarcomas, MRM, modified radical mastectomy; WBI, whole breast irradiation.
targeted agents in these tumors which are often nonresponsive to standard chemotherapy agents. Treatment options depend on the extent of involvement. In cases where lesions are limited in extent, mastectomy or wide local excision may be offered, although there is a high propensity for local recurrence. 6 In our patient the lesions were over an extensive area, and therefore mastectomy was not feasible. Hyperfractionated radiation therapy has been used prior to or after surgical removal of the lesions with good local control. The University of Florida has reported on 3 patients with secondary angiosarcoma using fractional doses ranging from 1 Gy to 1.5 Gy, with 2 or 3 daily fractions, to total doses of 30 Gy to 60 Gy. 22 In another report from the same institution, 41 patients with primary as well as secondary angiosarcomas of various sites, including the breast and chest wall, were treated with conventional and hyperfractionated radiation therapy. The best local control and overall survival of patients were found in the group of 18 patients who were treated with radiotherapy 3 times daily when combined with surgery. 23 The University of Florida has also published their experience in 14 patients with secondary angiosarcoma of the breast treated with hyperfractionated radiation therapy combined with surgery. Their patients were treated 3 times a day with 1 Gy, with 4 hours between the fractions. The maximum dose given to the areas of gross disease was 75 Gy, with areas of subclinical disease receiving 45 Gy. Seven patients who received preoperative radiation therapy had complete responses. Nine out of 14 patients are alive with no disease, with follow-up ranging from 36 months to 127 months. They have clearly shown that reirradiation is not only effective but also tolerated with acceptable toxicity. 24 Several chemotherapeutic agents have shown varying degrees of response; anthracyclines, taxanes, and thalidomide are some of the drugs that have shown promise. 4 Our patient did have a partial response for a short period of time. Targeted agents such as bevacizumab, sorafenib, and imatinib are being investigated for use in tumors that express vascular endothelial growth factor and CD117. 4 Prognosis in these tumors is uniformly poor. The median disease-free survival was 1.23 years in one of the larger series reported. 17 Median time to death from diagnosis was reported in one study to be 33.5 months. 16
Conclusions Secondary angiosarcoma of the breast following breast conservation therapy is a potentially fatal complication following curative treatment for breast cancer. Physicians following up breast cancer patients should have a high index of suspicion. Even though these tumors are rapidly progressive, early diagnosis may offer the opportunity for more aggressive multimodality treatment with surgery, hyperfractionated radiation, and chemotherapy.
References 1. Laskin WB, Silverman TA, Enzinger FM. Postradiation soft tissue sarcomas: An analysis of 53 cases. Cancer. 1988;62:2330-2340. 2. Folpe AL, Gowen AM. Malignant vascular tumors. In: Enzinger FM, Weiss SW, eds. Soft tissue tumors. St Louis: Mosby; 1995: 641-677. 3. Body G, Sauvanet E, Calais G, et al. Cutaneous angiosarcoma of the breast following surgery and irradiation of breast adenocarcinoma. [Article in French] J Gynecol Obstet Biol Reprod (Paris). 1987;16: 479-483. 4. Abbott R, Palmieri C. Angiosarcoma of the breast following surgery and radiotherapy for breast cancer. Nat Clin Pract Oncol. 2008;5: 727-736. 5. Marchal C, Weber B, de Lafontan B, et al. Nine breast angiosarcomas after conservative treatment for breast carcinoma: A survey from French comprehensive Cancer Centers. Int J Radiat Oncol Biol Phys. 1999;44:113-119. 6. West JG, Qureshi A, West JE, et al. Risk of angiosarcoma following breast conservation: A clinical alert. Breast J. 2005;11:115-123. 7. Cafiero F, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: Diagnostic and therapeutic implications—two case reports and a review of the literature. Cancer. 1996;77:2496-2502. 8. Karlsson P, Holmberg E, Samuelsson A, Johansson KA, Wallgren A. Soft tissue sarcoma after treatment for breast cancer —a Swedish population-based study. Eur J Cancer. 1998;34:2068-2075. 9. Cozen W, Bernstein L, Wang F, Press MF, Mack TM. The risk of angiosarcoma following primary breast cancer. Br J Cancer. 1999;81:532-536. 10. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56:549-580. 11. Amo Y, Masuzawa M, Hamada Y, Katsuoka K. Expression of vascular endothelial growth factor in a human hemangioma cell line (ISO-HAS). Arch Dermatol Res. 2001;293:296-301. 12. Arbiser JL, Larsson H, Claesson-Welsh L, et al. Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the
e64
13.
14.
15.
16.
17. 18.
S.B. Mahalingam, S. McDonough
VEGF receptors VEGFR-1 and VEGFR-2 in vivo. Am J Pathol. 2000;15:1469-1476. Yap J, Chuba PJ, Thomas R, et al. Sarcoma as a secondary malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys. 2002;52:1231-1237. de Bree E, van Coevorden F, Peterse JL, Russell NS, Rutgers EJ. Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: Genetic predisposition? Eur J Surg Oncol. 2002;28:392-395. Strobbe LJ, Peterse HL, van Tinteren H, Wijnmaalen A, Rutgers EJ. Angiosarcoma of the breast after conservation therapy for invasive cancer, the incidence and outcome. An unforseen sequela. Breast Cancer Res Treat. 1998;47:101-109. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: An analysis of 27 cases. Am J Surg Pathol. 2004;28:781-788. Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the breast. Cancer. 2005;104:2682-2688. Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: Clinicopathologic analysis of 42 cases. Am J Surg Pathol. 2005;29:983-996.
Practical Radiation Oncology: October-December 2012 19. Gherardi G, Rossi S, Perrone S, Scanni A. Angiosarcoma after breast-conserving therapy: Fine-needle aspiration biopsy, immunocytochemistry, and clinicopathologic correlates. Cancer. 2005;105: 145-151. 20. Pendlebury SC, Bilous M, Langlands AO. Sarcomas following radiation therapy for breast cancer: A report of three cases and review of the literature. Int J Radiat Oncol Biol Phys. 1995;31:405-410. 21. Liberman L, Dershaw DD, Kaufman RJ, Rosen PP. Angiosarcoma of the breast. Radiology. 1992;183:649-654. 22. Feigenberg SJ, Mendenhall NP, Reith D, Ward JR, Copeland EM III. Angiosarcoma after breast-conserving therapy: Experience with hyper fractionated radiotherapy. Int J Radiat Oncol Biol Phys. 2002;52:620-626. 23. Scott M, Portnow L, Marcus RB, Mendenhall NP, Mendenhall WM, Indelicato DJ. Radiotherapy for angiosarcoma: The 35-year University of Florida experience. Int J Radiat Oncol Biol Phys. 2010;78:S614. 24. Palta M, Morris CG, Grobmyer SR, Copeland EM III, Mendenhall NP. Angiosarcoma after breast-conserving therapy: Long-term outcomes with hyperfractionated radiotherapy. Cancer. 2010;116: 1872-1878.
