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Education Primary angiosarcoma of the breast: a case report with a review of the literature
The Breast (2002) 11, 175–178 r 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/brst.2001.0395, available online at http://www.idealibrary.com on
EDUCATION
Primary angiosarcoma of the breast: a case report with a review of the literature T. Saleem, D. O’Driscoll, G. C. Wishart and A. J. Marker Departments of Histopathology, Radiology and Surgery, Addenbrooke’s NHS Trust, Hills Road, Cambridge, CB2 2QQ, UK S U M M A R Y . Primary angiosarcoma of the breast is a rare malignant mammary neoplasm. Once regarded as uniformly fatal, it is now recognized as a group of morphologically heterogeneous neoplasms in which histological grade is prognostically significant. This report describes a new case of primary angiosarcoma of the breast, and reviews the literature with regards to its diagnosis and management. In the reporting of angiosarcoma of the breast, the location of the tumour, whether in the skin or the breast proper, should be specified. Histological grading is important as it carries significance regarding the prognosis and any possible further therapy. The clinical context should be appreciated, and we should be aware that non-malignant vascular lesions can also occur in an irradiated breast. The procedure of choice in primary breast angiosarcoma is simple mastectomy without lymphadenectomy but also, in tumours of higher grade, adjuvant chemotherapy may be indicated. r 2002 Elsevier Science Ltd. All rights reserved.
quadrant of the right breast enhanced avidly, with washout, consistent with a malignant tumour. The margins were not well defined, but there was nothing to suggest chest wall involvement on MRM. A screen for metastatic disease, including FBC, LFTs and a CT scan of the chest and abdomen were negative. The patient underwent a simple mastectomy. Macroscopically, the cut surface of the mastectomy specimen showed a 2.0 cm haemorrhagic lesion within the breast proper that was present 2.3 cm from the resection margin. Microscopically, the lesion measured 19 mm and was composed of intricate vascular channels that surrounded and invaded breast lobules (Figs 1 and 2). The vascular channels were lined by cells with pleomorphic, vesicular nuclei (Fig. 3), and they also infiltrated the fat. Numerous mitoses were noted. In areas, there was endothelial tufting. ‘Blood lakes’, solid sarcomatous areas, and areas of necrosis were not present. Immunohistochemistry, performed on the needle core biopsy, showed the tumour cells to be positive for CD31, CD34 and factor VIII, confirming the endothelial differentiation. Representative sections from the remaining breast tissue showed benign fibrocystic changes. The final diagnosis was primary angiosarcoma of the breast, histological grade 2.
CASE REPORT A 38-year-old premenopausal woman presented complaining of a painless lump in the right breast. She had previously borne two children, conceived by in vitro fertilization. There was no past medical history of note. On examination, there was a non-tender, mobile lump in the upper-outer quadrant of the right breast, also with some nodularity in the left breast. There was no axillary lymphadenopathy. Mammography of the right breast showed an asymmetrical density in the upper-outer quadrant, and on ultrasound scan there was an area of subtle, ill-defined heterogeneity. Ultrasound and mammography of the left breast failed to demonstrate any abnormality. Needle core biopsy was performed under ultrasound guidance, and histological examination showed an angiosarcoma, grade 2.1 Biopsy of the left breast showed only fibrocystic changes and no evidence of neoplasia. On subsequent magnetic resonance mammography (MRM), the lesion in the upper-outer Address correspondence to: Dr A. J. Marker, Department of Histopathology, Box 235, Addenbrooke’s NHS Trust, Hills Road, Cambridge, CB2 2QQ, UK. Tel.: +44 (0) 1223 217169; Fax: +44 (0) 1223 216980; E-mail: [email protected] Received: 19 January 2001 Revised: 13 August 2001 Accepted: 17 August 2001
175
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The Breast
Fig. 1 Angiosarcoma of the breast: at low power, tumour is seen within the breast (haematoxylin and eosin, 2 magnification).
Fig. 3 Angiosarcoma of the breast: a broader vascular channel is seen, lined by pleomorphic endothelial-type cells (haematoxylin and eosin, 40 magnification).
angiosarcomas tend to differ in grade with respect to primary angiosarcomas, as will be discussed later. In Donnell et al.’s series of 40 cases of primary angiosarcoma arising in the breast,1 the age at presentation ranged from 16 to 69 years, with a mean of 34 years. The manner of presentation was usually as a painless mass, clinically felt either to be carcinoma or benign breast disease. Occasionally however, the tumour presented as a bulky haemorrhagic mass, suggesting a vascular neoplasm. Diagnosis Fig. 2 Angiosarcoma of the breast: narrow vascular channels lined by atypical endothelial cells are infiltrating a breast lobule (haematoxylin and eosin, 20 magnification).
The patient made a good recovery and received postoperative radiotherapy with adjuvant chemotherapy.
DISCUSSION One of the forms of mammary sarcoma is angiosarcoma. Secondary angiosarcomas can arise following radiotherapy in breast cancer patients who have had a mastectomy (Stewart-Treves syndrome). These tend to involve the skin of the breast,2 and occasionally arise in the scar.3 By definition, primary angiosarcoma does not have any such antecedent. Grading of angiosarcoma has been shown to carry prognostic significance. Secondary
Liberman et al. a reviewed the radiological findings of 29 women with biopsy-proven mammary angiosarcoma.4 Mammographical findings, available in 21 cases, included a solitary uncalcified mass in 11 (52%) patients, a mass with calcifications in two (10%), and a mass associated with skin thickening in one (5%); no mammographic findings were present in seven (33%) patients. In Donnell et al.’s series,1 macroscopic appearances ranged from poorly defined areas of thickening or induration to soft and haemorrhagic lesions. Tumour sizes varied from 2 cm to 11 cm, the average being 5.3 cm. Criteria that feature in the grading of angiosarcoma are endothelial tufting and papillary formations, solidspindle cell foci, mitoses, presence of ‘blood lakes’ and the presence of necrosis. Hyperchromasia was present in angiosarcomas of all grades. Necrosis, blood lakes and solid-spindle cell foci were seen only in grade 3 tumours. Endothelial tufting was present in grade 2 and grade 3 tumours but was said to be more prominent in grade 3
Primary angiosarcoma tumours. Mitoses were most numerous in grade 3 tumours, and present predominantly in papillary areas in grade 2 tumours. Histological grading was performed on the overall series, and 13 cases were designated as grade 1, six as grade 2 and 20 as grade 3. As regards prognosis, 12 of 13 of patients with grade 1 tumours were alive after an average of 5 years, with 10 patients without evidence of recurrent tumour; the patient who had died had been treated only by local excision and developed recurrence with subsequent metastasis. Two of the six patients with grade 2 tumours died of metastatic angiosarcoma; one patient died of colonic carcinoma 8 years after treatment of the angiosarcoma. The remaining three patients were alive without evidence of disease after an average of 4 years. Of the patients with grade 3 tumours, 14 of 18 died of metastatic disease; two were alive with metastatic disease developing 6 and 7 months after mastectomy; two remained disease-free 11 years and 5 years after mastectomy with adjuvant chemotherapy. Earlier, Chen et a1.5 reviewed the literature on 87 cases of mammary angiosarcoma and in many respects, such as age and clinical presentation, patients were not dissimilar to those of Donnell et al. Most deaths occurred as a result of haematogenous dissemination of angiosarcoma and the commonest sites for metastasis were, in order of frequency, lung, skin and subcutaneous tissue, bone, liver, brain and ovary. Lymph node metastasis was uncommon among these cases, but correlation with histological grade was not addressed specifically. The differential diagnosis of angiosarcoma of the breast includes both benign and malignant neoplasms. The main malignant differential is an epithelial neoplasm, such as infiltrating ductal carcinoma of the breast. This should be positive for cytokeratin and negative for vascular markers. Benign differentials are haemangioma and pseudoangiomatous hyperplasia, both of which can be difficult to distinguish from grade 1 angiosarcomas, as was shown in Rosen et al.’s series of 63 cases,6 where of 25 grade 1 angiosarcomas, three had initially been misinterpreted as a haemangioma. A point to help in the distinction is that haemangiomas tend to only grow around lobules rather than within them, hence the designation peri-lobular haemangioma. Pseudoangiomatous hyperplasia, unlike angiosarcoma, should not infiltrate fat and also the cells, believed to be myofibroblastic in nature, are negative for CD31 but are positive for CD34.7 ‘Atypical vascular lesions’ which have been reported to occur in the skin and in the breast after irradiation are discussed later. Adequate sampling of angiosarcomas is necessary as an admixture of patterns might be seen and grade 3 foci
177
can be surrounded by areas of grade 1 morphology.7 The histological features of post-irradiation angiosarcoma differ from those of primary angiosarcoma in that in the former tumours tend to be of higher grade, with areas of solid epithelioid or solid spindle cell foci.2 Further, architecture notwithstanding, the malignant cells tend to be poorly differentiated with nuclei that are vesicular, exhibiting mitotic activity and showing prominent nucleoli. In Fineberg and Rosen’s report,2 three patients with post-irradiation angiosarcoma had a time interval from radiotherapy to diagnosis of 3.5 years, 3.7 years and 5.25 years. The authors state that post-irradiation angiosarcomas must be distinguished from non-malignant vascular lesions that can arise in the breast in the same clinical setting, describing these as ‘atypical vascular lesions’ (AVL). Four cases were reported, three occurring in the skin and one in the breast. Histologically they showed chronic inflammation, hyperchromatic endothelial cells, relative circumscription, projection of stroma into the lumen of the lesion and, most importantly, a lack of marked cytological atypia. There was no evidence that these AVLs evolved into angiosarcoma; one of these patients had undergone local excision of multiple cutaneous lesions and remained well after 10 years of follow-up.
Therapy Perhaps it ought to be mentioned here, if only cursorily, that it is in the context of cystosarcoma phyllodes that a sarcoma in the breast can more commonly be encountered. In these circumstances, the mainstay of therapy is deemed to be wide local excision of the primary lesion (and recurrent lesions), with neither lymphadenectomy nor adjuvant chemoradiation believed to add any significant benefit.8 It is recognized that angiosarcoma is a particularly aggressive form of breast sarcoma.9 It has been stated that simple mastectomy is the procedure of choice and axillary dissection is not recommended.10 In addition, some reports of primary breast angiosarcoma suggest that adjuvant chemotherapy can result in long-term survival for some patients.9,10 In the latter study, Silverman et al. analysed all reports of chemotherapy for breast angiosarcoma (which included Donnell and Rosen’s group1) and the authors noted that of the more poorly differentiated tumours, the proportion of patients treated with adjuvant chemotherapy who remained relapse-free was statistically superior to the proportion for those not treated (29.2% vs 4.4%; Po0.05). Parenthetically, they observed that welldifferentiated tumours derived little appreciable benefit
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The Breast
from chemotherapy. Whether this ultimately impacted on survival was not discernible from the data.
Acknowledgements We would like to thank Chris Burton for his assistance with the illustrations.
References 1. Donnell R M, Rosen P P, Lieberman P H et al. Angiosarcoma and other vascular tumours of the breast. Pathologic analysis as a guide to prognosis. Am J Surg Path 1981; 5: 629–642. 2. Fineberg S, Rosen P P. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Path 1994; 102: 757–763.
3. Hamels J, Blondiau P, Mirgaux M. Cutaneous angiosarcoma arising in a mastectomy scar after therapeutic irradiation. Bull Cancer 1981; 68: 353–356. 4. Liberman L, Dershaw D D, Kaufman R J et al. Angiosarcoma of the breast. Radiology 1992; 183: 649–654. 5. Chen K T K, Dale D, Kirkegaard D D et al. Angiosarcoma of the breast. Cancer 1980; 46: 368–371. 6. Rosen P P, Kimmel M, Ernsberger D. Mammary angiosarcoma, the prognostic significance of tumor differentiation. Cancer 1988; 62: 2145–2151. 7. Elston C W, Ellis I O, Pinder S E. The Breast 3rd ed. Churchill Livingstone, 1998: pp. 436–442. 8. Geisler D P, Boyle M J, Malner K F et al. Phyllodes tumours of the breast. Am Surg 2000; 66: 360–365. 9. Rosner D. Angiosarcoma of the breast: long-term survival following adjuvant chemotherapy. J Surg Oncol 1988; 39: 90–95. 10. Silverman L R, Deligdisch L, Mandeli J, Greenspan E M. Chemotherapy for angiosarcoma of the breast: case report of 30 year survival and analysis of the literature. Cancer Invest 1994; 12: 145–155.
EDUCATION
Primary angiosarcoma of the breast: a case report with a review of the literature T. Saleem, D. O’Driscoll, G. C. Wishart and A. J. Marker Departments of Histopathology, Radiology and Surgery, Addenbrooke’s NHS Trust, Hills Road, Cambridge, CB2 2QQ, UK S U M M A R Y . Primary angiosarcoma of the breast is a rare malignant mammary neoplasm. Once regarded as uniformly fatal, it is now recognized as a group of morphologically heterogeneous neoplasms in which histological grade is prognostically significant. This report describes a new case of primary angiosarcoma of the breast, and reviews the literature with regards to its diagnosis and management. In the reporting of angiosarcoma of the breast, the location of the tumour, whether in the skin or the breast proper, should be specified. Histological grading is important as it carries significance regarding the prognosis and any possible further therapy. The clinical context should be appreciated, and we should be aware that non-malignant vascular lesions can also occur in an irradiated breast. The procedure of choice in primary breast angiosarcoma is simple mastectomy without lymphadenectomy but also, in tumours of higher grade, adjuvant chemotherapy may be indicated. r 2002 Elsevier Science Ltd. All rights reserved.
quadrant of the right breast enhanced avidly, with washout, consistent with a malignant tumour. The margins were not well defined, but there was nothing to suggest chest wall involvement on MRM. A screen for metastatic disease, including FBC, LFTs and a CT scan of the chest and abdomen were negative. The patient underwent a simple mastectomy. Macroscopically, the cut surface of the mastectomy specimen showed a 2.0 cm haemorrhagic lesion within the breast proper that was present 2.3 cm from the resection margin. Microscopically, the lesion measured 19 mm and was composed of intricate vascular channels that surrounded and invaded breast lobules (Figs 1 and 2). The vascular channels were lined by cells with pleomorphic, vesicular nuclei (Fig. 3), and they also infiltrated the fat. Numerous mitoses were noted. In areas, there was endothelial tufting. ‘Blood lakes’, solid sarcomatous areas, and areas of necrosis were not present. Immunohistochemistry, performed on the needle core biopsy, showed the tumour cells to be positive for CD31, CD34 and factor VIII, confirming the endothelial differentiation. Representative sections from the remaining breast tissue showed benign fibrocystic changes. The final diagnosis was primary angiosarcoma of the breast, histological grade 2.
CASE REPORT A 38-year-old premenopausal woman presented complaining of a painless lump in the right breast. She had previously borne two children, conceived by in vitro fertilization. There was no past medical history of note. On examination, there was a non-tender, mobile lump in the upper-outer quadrant of the right breast, also with some nodularity in the left breast. There was no axillary lymphadenopathy. Mammography of the right breast showed an asymmetrical density in the upper-outer quadrant, and on ultrasound scan there was an area of subtle, ill-defined heterogeneity. Ultrasound and mammography of the left breast failed to demonstrate any abnormality. Needle core biopsy was performed under ultrasound guidance, and histological examination showed an angiosarcoma, grade 2.1 Biopsy of the left breast showed only fibrocystic changes and no evidence of neoplasia. On subsequent magnetic resonance mammography (MRM), the lesion in the upper-outer Address correspondence to: Dr A. J. Marker, Department of Histopathology, Box 235, Addenbrooke’s NHS Trust, Hills Road, Cambridge, CB2 2QQ, UK. Tel.: +44 (0) 1223 217169; Fax: +44 (0) 1223 216980; E-mail: [email protected] Received: 19 January 2001 Revised: 13 August 2001 Accepted: 17 August 2001
175
176
The Breast
Fig. 1 Angiosarcoma of the breast: at low power, tumour is seen within the breast (haematoxylin and eosin, 2 magnification).
Fig. 3 Angiosarcoma of the breast: a broader vascular channel is seen, lined by pleomorphic endothelial-type cells (haematoxylin and eosin, 40 magnification).
angiosarcomas tend to differ in grade with respect to primary angiosarcomas, as will be discussed later. In Donnell et al.’s series of 40 cases of primary angiosarcoma arising in the breast,1 the age at presentation ranged from 16 to 69 years, with a mean of 34 years. The manner of presentation was usually as a painless mass, clinically felt either to be carcinoma or benign breast disease. Occasionally however, the tumour presented as a bulky haemorrhagic mass, suggesting a vascular neoplasm. Diagnosis Fig. 2 Angiosarcoma of the breast: narrow vascular channels lined by atypical endothelial cells are infiltrating a breast lobule (haematoxylin and eosin, 20 magnification).
The patient made a good recovery and received postoperative radiotherapy with adjuvant chemotherapy.
DISCUSSION One of the forms of mammary sarcoma is angiosarcoma. Secondary angiosarcomas can arise following radiotherapy in breast cancer patients who have had a mastectomy (Stewart-Treves syndrome). These tend to involve the skin of the breast,2 and occasionally arise in the scar.3 By definition, primary angiosarcoma does not have any such antecedent. Grading of angiosarcoma has been shown to carry prognostic significance. Secondary
Liberman et al. a reviewed the radiological findings of 29 women with biopsy-proven mammary angiosarcoma.4 Mammographical findings, available in 21 cases, included a solitary uncalcified mass in 11 (52%) patients, a mass with calcifications in two (10%), and a mass associated with skin thickening in one (5%); no mammographic findings were present in seven (33%) patients. In Donnell et al.’s series,1 macroscopic appearances ranged from poorly defined areas of thickening or induration to soft and haemorrhagic lesions. Tumour sizes varied from 2 cm to 11 cm, the average being 5.3 cm. Criteria that feature in the grading of angiosarcoma are endothelial tufting and papillary formations, solidspindle cell foci, mitoses, presence of ‘blood lakes’ and the presence of necrosis. Hyperchromasia was present in angiosarcomas of all grades. Necrosis, blood lakes and solid-spindle cell foci were seen only in grade 3 tumours. Endothelial tufting was present in grade 2 and grade 3 tumours but was said to be more prominent in grade 3
Primary angiosarcoma tumours. Mitoses were most numerous in grade 3 tumours, and present predominantly in papillary areas in grade 2 tumours. Histological grading was performed on the overall series, and 13 cases were designated as grade 1, six as grade 2 and 20 as grade 3. As regards prognosis, 12 of 13 of patients with grade 1 tumours were alive after an average of 5 years, with 10 patients without evidence of recurrent tumour; the patient who had died had been treated only by local excision and developed recurrence with subsequent metastasis. Two of the six patients with grade 2 tumours died of metastatic angiosarcoma; one patient died of colonic carcinoma 8 years after treatment of the angiosarcoma. The remaining three patients were alive without evidence of disease after an average of 4 years. Of the patients with grade 3 tumours, 14 of 18 died of metastatic disease; two were alive with metastatic disease developing 6 and 7 months after mastectomy; two remained disease-free 11 years and 5 years after mastectomy with adjuvant chemotherapy. Earlier, Chen et a1.5 reviewed the literature on 87 cases of mammary angiosarcoma and in many respects, such as age and clinical presentation, patients were not dissimilar to those of Donnell et al. Most deaths occurred as a result of haematogenous dissemination of angiosarcoma and the commonest sites for metastasis were, in order of frequency, lung, skin and subcutaneous tissue, bone, liver, brain and ovary. Lymph node metastasis was uncommon among these cases, but correlation with histological grade was not addressed specifically. The differential diagnosis of angiosarcoma of the breast includes both benign and malignant neoplasms. The main malignant differential is an epithelial neoplasm, such as infiltrating ductal carcinoma of the breast. This should be positive for cytokeratin and negative for vascular markers. Benign differentials are haemangioma and pseudoangiomatous hyperplasia, both of which can be difficult to distinguish from grade 1 angiosarcomas, as was shown in Rosen et al.’s series of 63 cases,6 where of 25 grade 1 angiosarcomas, three had initially been misinterpreted as a haemangioma. A point to help in the distinction is that haemangiomas tend to only grow around lobules rather than within them, hence the designation peri-lobular haemangioma. Pseudoangiomatous hyperplasia, unlike angiosarcoma, should not infiltrate fat and also the cells, believed to be myofibroblastic in nature, are negative for CD31 but are positive for CD34.7 ‘Atypical vascular lesions’ which have been reported to occur in the skin and in the breast after irradiation are discussed later. Adequate sampling of angiosarcomas is necessary as an admixture of patterns might be seen and grade 3 foci
177
can be surrounded by areas of grade 1 morphology.7 The histological features of post-irradiation angiosarcoma differ from those of primary angiosarcoma in that in the former tumours tend to be of higher grade, with areas of solid epithelioid or solid spindle cell foci.2 Further, architecture notwithstanding, the malignant cells tend to be poorly differentiated with nuclei that are vesicular, exhibiting mitotic activity and showing prominent nucleoli. In Fineberg and Rosen’s report,2 three patients with post-irradiation angiosarcoma had a time interval from radiotherapy to diagnosis of 3.5 years, 3.7 years and 5.25 years. The authors state that post-irradiation angiosarcomas must be distinguished from non-malignant vascular lesions that can arise in the breast in the same clinical setting, describing these as ‘atypical vascular lesions’ (AVL). Four cases were reported, three occurring in the skin and one in the breast. Histologically they showed chronic inflammation, hyperchromatic endothelial cells, relative circumscription, projection of stroma into the lumen of the lesion and, most importantly, a lack of marked cytological atypia. There was no evidence that these AVLs evolved into angiosarcoma; one of these patients had undergone local excision of multiple cutaneous lesions and remained well after 10 years of follow-up.
Therapy Perhaps it ought to be mentioned here, if only cursorily, that it is in the context of cystosarcoma phyllodes that a sarcoma in the breast can more commonly be encountered. In these circumstances, the mainstay of therapy is deemed to be wide local excision of the primary lesion (and recurrent lesions), with neither lymphadenectomy nor adjuvant chemoradiation believed to add any significant benefit.8 It is recognized that angiosarcoma is a particularly aggressive form of breast sarcoma.9 It has been stated that simple mastectomy is the procedure of choice and axillary dissection is not recommended.10 In addition, some reports of primary breast angiosarcoma suggest that adjuvant chemotherapy can result in long-term survival for some patients.9,10 In the latter study, Silverman et al. analysed all reports of chemotherapy for breast angiosarcoma (which included Donnell and Rosen’s group1) and the authors noted that of the more poorly differentiated tumours, the proportion of patients treated with adjuvant chemotherapy who remained relapse-free was statistically superior to the proportion for those not treated (29.2% vs 4.4%; Po0.05). Parenthetically, they observed that welldifferentiated tumours derived little appreciable benefit
178
The Breast
from chemotherapy. Whether this ultimately impacted on survival was not discernible from the data.
Acknowledgements We would like to thank Chris Burton for his assistance with the illustrations.
References 1. Donnell R M, Rosen P P, Lieberman P H et al. Angiosarcoma and other vascular tumours of the breast. Pathologic analysis as a guide to prognosis. Am J Surg Path 1981; 5: 629–642. 2. Fineberg S, Rosen P P. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Path 1994; 102: 757–763.
3. Hamels J, Blondiau P, Mirgaux M. Cutaneous angiosarcoma arising in a mastectomy scar after therapeutic irradiation. Bull Cancer 1981; 68: 353–356. 4. Liberman L, Dershaw D D, Kaufman R J et al. Angiosarcoma of the breast. Radiology 1992; 183: 649–654. 5. Chen K T K, Dale D, Kirkegaard D D et al. Angiosarcoma of the breast. Cancer 1980; 46: 368–371. 6. Rosen P P, Kimmel M, Ernsberger D. Mammary angiosarcoma, the prognostic significance of tumor differentiation. Cancer 1988; 62: 2145–2151. 7. Elston C W, Ellis I O, Pinder S E. The Breast 3rd ed. Churchill Livingstone, 1998: pp. 436–442. 8. Geisler D P, Boyle M J, Malner K F et al. Phyllodes tumours of the breast. Am Surg 2000; 66: 360–365. 9. Rosner D. Angiosarcoma of the breast: long-term survival following adjuvant chemotherapy. J Surg Oncol 1988; 39: 90–95. 10. Silverman L R, Deligdisch L, Mandeli J, Greenspan E M. Chemotherapy for angiosarcoma of the breast: case report of 30 year survival and analysis of the literature. Cancer Invest 1994; 12: 145–155.