Angiosarcomas

Angiosarcomas are rare tumors of endovascular origin that are found in all organs of the body (1). Approximately 8 percent of angiosarcomas arise in the breast. Primary breast angiosarcomas occur most commonly in women between the ages of 20-40 years, and typically present as an ill-defined breast mass.

Secondary angiosarcomas usually occur in older women years following the treatment of breast cancer. They can arise in the lymphedemateous upper extremity years following radical mastectomy and irradiation, a condition first described by Stewart and Treves in 1947(2). Secondary angiosarcomas can also arise in the chest wall following mastectomy and irradiation, or in the breast following breast-conserving therapy.

Details on a Breast Angiosarcoma

The first case of post-irradiation angiosarcoma of the breast was reported by Body in 1987. Since that time approximately 100 cases have been reported(3). Angiosarcoma following breast conservation usually presents with skin changes that are often confused with post-irradiation skin changes or other benign conditions such as infection or trauma. Diagnostic delays are common, and this may contribute to their extremely poor prognosis. Recurrence rates approach 70 percent and 2-year disease-free survival ranges from zero to 35 percent in various reported series(4-8).

Breast Angiosarcoma Prevalence

The two largest reported studies estimate the prevalence to range from 0.05 percent to 0.16 percent(6,7).The higher prevalence occurred in the Dutch series which was restricted to patients followed more than five years and who received irradiation.

The Dutch also estimated that the 5-year mortality was 15 percent and subtracted the estimated non-survivors from their denominator. The differences in methods of determining the denominator accounts in large part for the differences in prevalence reported in the two series. The prevalence reported in our series was 1.11% using the Dutch criteria.

Age

The age range for the reported cases of angiosarcomas following breast conservation is 36 to 91-years-old. The average reported age is 65-years-old.

Latency

The latency period from completion of irradiation until detection of angiosarcoma ranges from 18 to 204 months with a median latency period of 71 months. Only four of the reported 116 cases had a latency period of less than 36 months.

Etiology

Exposure to irradiation is generally recognized as a risk factor for developing soft tissue sarcomas. Although controversial, recent evidence suggests that exposure to irradiation is a risk factor for developing angiosarcoma. A recent review of SEER data demonstrated a 16-fold increased relative risk of angiosarcoma of the breast and chest wall following irradiation of the primary breast cancer(9). The Dutch study noted a 3,200-fold increased relative risk for angiosarcoma following breast irradiation as compared to the risk of primary angiosarcoma in the general population(6).

Exposure to chronic lymphedema is also a risk factor(10,11). In 1947 Stewart and Treves described the first series of cases of angiosarcoma arising in a lymphedematous extremity following mastectomy and chest wall irradiation(2). The Stewart-Treves syndrome accounts for 90 percent of the reported cases of angiosarcoma associated with chronic lymphedema. The remaining 10 percent arise in association with either primary lymphedema or lymphedema secondary to lymphadenectomy or infection. A single case has been reported of an angiosarcoma arising in a lymphedematous breast following lumpectomy for the treatment of cancer, but having had neither irradiation nor lymphadenectomy(12).

The association between breast lymphedema and angiosarcoma of the breast is inconsistent. Less than half of the reported cases of post-irradiation angiosarcoma were associated the clinically evident breast edema, and none of our four cases had obvious breast edema.

The data on genetic risk factors and other risk factors such as environmental and exposure to chemotherapeutic agents are limited. In a recent report, E.De Bree describes a case of bilateral angiosarcomas after conservative therapy, and provides a good discussion of the potential contribution of genetic predisposition to the development of post-irradiation angiosarcoma(13). Our case no. 5 was positive for Br Ca II.

Clinical Presentation

By far the most common presenting finding of post-irradiation angiosarcoma are skin changes. They can appear as focal, macular lesions or as ill-defined patches of skin discoloration ranging in color from red to blue to purple.

Focal, elevated skin nodules, papules and vesicles are also common. They can be single or multiple, and can be associated with an explosive growth pattern.

Another common presenting finding is skin hemorrhage which is often attributed to minor trauma. Skin erythema, another common early finding, is often confused with infection. The initial presenting findings can also be confused with post-irradiation changes. Less common presenting findings include eczematoid changes, ulcerations, bloody nipple discharge and non-pigmented macules.

Most patients present with a combination of the above- described features. In approximately 10 percent of the cases a mass lesion is the dominant presenting clinical feature, but in most of these cases skin changes will be obvious. Although pain is not commonly reported in the literature, 3 of our 5 patients presented with pain prior to the onset of skin changes.

Ancillary Diagnostic Aids

Ancillary diagnostic aids such as mammography and ultrasound are usually either negative or non-specific, and thus are of limited diagnostic value. There is limited experience in the literature with MRI, but the few reported cases and our own experience with two cases suggest that contrast enhanced MRI does have a role in early detection(14,15).

Making the Diagnosis

There is consensus in the literature that the best was to make an accurate diagnosis of post-irradiation angiosarcoma is to do a generous open biopsy. This is understandable since angiosarcomas can have low grade changes at their margins that can be easily confused with post-irradiation changes. We have adopted a liberal approach to doing skin punch biopsies on subtle skin changes in post-irradiated breast. If the biopsy is not diagnostic, we proceed to an generous open biopsy(17).

Making the diagnosis of post-irradiation angiosarcoma can be difficult. High grade angiosarcomas can be easily confused with other malignant tumors such as recurrent andenocarcinoma, lymphoma, and melanoma. Low grade angiosarcomas can be easily confused with atypical vascular lesions (18,19).

The lesions are often multifocal with transitional changes at the margins so that generous tissue sampling is indicated. Various tumor markers such as Factor VIII-associated antigen and CD31 and CD34 when positive can be helpful in establishing the diagnosis of angiosarcoma, and cytokeratin when positive confirms the diagnosis of recurrent breast carcinoma (1,4).

Natural History and Prognosis

The natural history of post-irradiation angiosarcoma is dismal. The Dutch report the best results with a two-year disease free survival of 35 percent (6). Their favourable results may in part be related to their aggressive approach to early detection and diagnosis. Two-thirds of their patients presented to the clinic early because of skin changes or palpable masses, and in 15 of 21 patients the diagnosis was made within one month of presentation.

Treatment

Standard treatment for post-irradiation angiosarcoma is total mastectomy which is usually followed by latissimus flap closure. Regional lymph node metastasis are rare. In the absence of clinically evident metastatic disease routine axillary dissection is not indicated. Even with what appear to be adequate margins, rates of recurrence and mortality are high. Thus, in addition to wide excision, consideration should be given to adjuvant treatments.

A recent report from Florida suggests that hyperfractionated irradiation may decrease rates of local recurrence (4,16). We have had limited experience with this modality. Hyperfractionated irradiation was used in three of our cases (Case no. 3,4,5) with mixed results. At the present time we believe that hyperfractionated irradiation should be used in all but the most favorable clinical situations (i.e. well differentiated small tumors with wide resection margins).

In locally advanced cases we recommend hyperfractionated therapy be given prior to surgical resection. There is limited data on value of chemotherapy. We have seen a partial response to adriamycin in one patient (case no. 1), and a complete response to taxol in a second case (case no. 3). We believe that hyperthermia, interleukin-2, and anti-angiogenesis therapy, are experimental and should be limited to protocol settings.

CONCLUSIONS

As the number of patients receiving breast conservation increase, it is inevitable that more cases of post-irradiation angiosarcoma will be diagnosed. Our review of the literature suggests that early detection and aggressive treatment could lead to improved outcomes. Our results also lead us to consider the withholding of irradiation treatments to elderly women with early staged breast cancer. There is an urgent need to obtain more information on this rare but highly aggressive tumor. Hopefully, in the future a national database will be established that will provide this information. In the meantime we hope that this web-page will help clinicians to better understand and more effectively treat this challenging tumor.

Breast Angiosarcoma Case Histories:

Case No. 1 :

Our first case was a 68 year asymptomatic female. She had been on premarin for 10 years and had a 35 pack-year history. Screening mammogram revealed a 12 mm ill-defined density at 6 o’clock in the left breast. Partial mastectomy and axillary dissection revealed a 1.6×1.2x.9 cm infiltrating ductal carcinoma with clear margins on re-excision. 16 axillary lymph nodes were negative. The tumor was E.R. positive with a low S-phase and a DNA index of 1.

Her post-operative course was associated central breast redness that resolved spontaneously. Radiation therapy consisted of 6040 cGy in 33 fractions over 64 days (5,000cGy whole breast and 1,000 cGy boost). A re-review of all radiation data revealed no unusual deviations from standard techniques.

She was given a course of tamoxifen, which was well tolerated. In 1992 she developed lower extremity pain and weakness and was found to have spinal cord neuroma which was successfully removed. In April of 1995 she was seen in routine follow-up, and was noted to what looked like bruising in upper inner left breast which the patient attributed to mammogram done a few months previously. She stated she had pain and bruising following the recent mammogram, but her symptoms were improving by the time of her office visit.

One month later the skin hemorrhage was stable, but there was an increase in skin thickening and a new macular rash was noted. A full thickness skin biopsy was positive for angiosarcoma (cytokeratin negative and positive for vinentin and factor VIII). The patient initially refused surgery, and the tumor grew rapidly with extension of multiple red macular and papular nodules to the infra- mammary fold.

On 6/30/95 a left mastectomy was preformed with a latissimus flap closure. The breast specimen contained an extensive high-grade tumor. The margins were grossly cleared, but there was microscopic extension to the skin margins. Multiple parenchymal breast nodules extended to within millimeters of the deep margin. The patient refused additional surgery and was not given post-op irradiation.

On 10/18/95 multiple recurrent skin nodules were noted, and biopsy was positive for recurrent chest wall angiosarcoma. She had a 75% reduction of visible tumor in response to here initial course of adriamycin, but then experienced an explosive growth of chest wall recurrent tumor. Her major symptom was chest wall and back pain which were readily controlled with oral narcotics. She expired on 7/11/96 and autopsy was refused.

Case No 2:

Our second case was an asymptomatic 76-year-old female. Her sister died 10 years earlier of breast cancer and the patient had mild hypertension. Screening mammogram (10/30/89) was noted to have multiple “moles” and also revealed a 1.8 cm density medial to the right nipple and a suspicious axillary lymph node. Partial mastectomy and axillary node dissection revealed a 1.3 cm infiltrating ductal carcinoma with clear margins. One of 13 nodes was positive. Both E.R. and P.R. were strongly positive. DNA was anuploid and S-phase was high.

Post-operative she had an axillary seroma which responded to repeat aspirations. She was started on tamoxifen which caused fatigue and nausea. The dose was reduced to 10 mg per day. She was given a course of radiation therapy which included 5040 cGy to the med/lat tangential right breast and a 1440 cGy electron boost, AP to the right breast for a total dose to the primary tumor of 6480 cGy.

She remained essentially asymptomatic until 9/10/99 when she was seen for her routine follow- Up. Her history at that time was progressive ill-defined pain in the right breast for the past several months. She also gave a one month history of skin thickening and bruising in the upper inner right breast, which she attributed to minor trauma.

On physical examination she had a 3-4 cm. patch of skin thickening with skin hemorrhage, and the diagnosis of angiosarcoma was suspected. Skin punch biopsy revealed an atypical lymphocytic infiltrate with the suggestion of viral inclusions. Second opinion of the biopsy was interpreted as atypical lymphoreticular infiltrate suggestive of Ki-1 lymphoproliverative disorder. The lesion grew rapidly. Open biopsy was recommended but refused. Core biopsy was suggestive of angiosarcoma and positive for CD-1 and CD-34.

On 3/25/00 a right mastectomy and latissimus flap closure was performed. By the time of surgery the skin lesion had increased to approximately 10 cm. in diameter. The mastectomy specimen revealed an 8 cm high-grade angiosarcoma. Margins were described as clear. Her post-op course was uneventful. She was not given post-operative chemotherapy or irradiation. She did well until October of 1990 when she had a stroke. Chest X-ray revealed metastatic nodules. She died on Nov.8, 2000. Permission for autopsy was not granted.

Case No. 3:

Our third case was a 67 year asymptomatic female whose screening mammogram revealed a cluster of calcifications with an associated density. She had a history of hypertension; a 30 year pack history, and used premarin. Open biopsy at another institution revealed a 4 mm infiltrating ductal carcinoma with positive margins. The tumor was poorly differentiated and had positive E.R. and P.R. receptors. Re-excision biopsy and axillary dissection was performed at our institution on 10/29/93 . There was a small residual tumor, but margins were cleared and all 19 nodes were negative.

Post-operative course was uneventful except for transient wound erythema that responded to a short course of antibiotics. She was given a standard course of tamoxifen. She received a standard course of radiation therapy: 5040 Gyc with a 1000Gyc boost. Except for mild erythema of the breast, she tolerated the radiation well.

She continued to do well until 11/5/02 when she presented to clinic for routine follow-up with a 2-3 month history of ill-defined central left breast pain. She was unaware of any skin changes, but on examination had a 5 mm. elevated dark nodule.There was no palpable breast mass. A skin punch biopsy was interpreted as an atypical vascular lesion, although it did stain positive for CD 31. Open biopsy revealed a 7 cm. high-grade angiosarcoma.

A mastectomy was performed ( 12/18/02 ) with latissimus flap closure. There were scattered foci of angiosarcoma within the breast parenchyma, but the margins were clear. Five weeks post-operatively she was healing well.

The patient was encouraged to undergo post-operative hyperfractionated irradiation therapy, but she refused. She was seen in the office on 6/2/03 for routine follow-up. She was noted to have dermal nodules, skin thickening with mild erythema, and an ill-defined induration in the chest wall adjacent to the margins of the latissimus flap.

An MRI revealed contrast enhancement in the areas of induration and nodule formation, which was considered suspicious for malignancy. Skin punch biopsy was positive for angiosarcoma. She was started on a course of hyperfractionated irradiation. Over the next few weeks the visible skin lesion resolved but the deep induration persisted.

Radiation treatment consisted of five electron fields using a 25 cm cone. Three fields were treated a one time and two the next time. She was treated three times a day; treatments were spaced out 4 hours apart and fraction per treatment were 100 rads. A 12 MEV electron beam was used to treat the area which was decided upon because of the depth of the tumor on MRI scan. She tolerated the treatments well.

Two weeks following the completion of irradiation a wide excision of all irradiated skin, tram flap, and the anterior pectoralis muscle was performed (specimen measured 45 x 37 cm). The right breast along with a pectoralis muscle was mobilized extensively and shifted to the left to cover approximately 35% of the defect. The posterior skin along with the latissimus muscle was also obilized medially. Skin from the lower abdomen and from the lower neck were also mobilized and advanced forward. After extensive mobilization there was still a 22 x 20 cm. defect that was closed with split thickness skin graft.

Microscopic analysis of the resected specimen revealed residual angiosarcoma in the muscle, but with widely cleared skin margins. She returned to the operating room where the pectoralis major and minor muscle were removed along with the previous split thickness skin grafts. The previously mobilized right breast was mobilized further to the left, and a tram flap was mobilized to cover the remaining defect. Thus the entire defect was closed with vascularized myocutaneous flaps. Microscopic evaluation of the resected muscle showed no residual angiosarcoma.

Post-operatively she did will except for fatigue, but was discharged in good spirits on the fourth p.o. day. On the second day at home she developed shortness of breast and tachycardia. She was found to have a myocardial infarction with mild congestive heart failure. She was treated medically and did well. She developed edge necrosis of her tram flap and required aggressive wound management. 35 days after placement of the tram flap she was returned to the operating room for debridement. She was found to have an area of focal induration at the wound edge. It was biopsied and was positive for recurrent angiosarcoma.

Over the next three weeks she had an explosive recurrence over the chest wall with a rapidly enlarging right axillary lymph node. There was no evidence of systemic disease. She was started on a course of taxol. She had a dramatic response and within one month all visible tumor had resolved. She remained essentially asymptomatic for 6 months at which time she developed acute onset of shortness of breath. She was found to have a malignant pleural effusion and soon there after developed skin recurrences. She was given supportive care and died within one month of her third recurrence.

Case No. 4:

Our fourth case was a 79 year asymptomatic female whose screening mammogram revealed two small foci of calcification in the upper outer quadrant of her right breast. She had been previously treated with prednisone for polymalgica rheumatica. Medications also included premarin, synthroid, and timoptic eye drops for glaucoma. She had a 23 year pack history and was a social drinker.

Physical exam revealed a vague ridge in the area of mammographic concern, and a FNA was atypical. Biopsy revealed a 1.3 x .4 cm infiltrating ductal carcinoma with associated DCIS. Re- excision partial mastectomy and axillary dissection was performed on 1/29/92 . There was a small focus of residual cancer with sections of skin showing areas of tumor involvement within the deep dermal tissue and subcutaneous fat. Margins were clear and 15 axillary lymph nodes were negative. The tumor was diploid with low S-phase and a DNA index of 0.99.; the tumor was E.R. positive and P.R. negative.

Her post-op course was complicated by a recurrent axillary seroma that required multiple aspirations over the next several months, but resolved completely. She was placed on a 5 year course of tamoxifen which she completed and tolerated well.

She received a course of radiation therapy, with 4,500 Gyc to the whole breast and 1,400 Gyc boost. The radiation therapy was well tolerated except for a small area of moist desquamation at the boost site which resolved spontaneously. She did well until 1998 when she developed atrial fibrillation and was started on coumadin.

On 11/19/02 she was seen for routine follow up at which time she was asymptomatic. On physical examination she had a slightly elevated 1 cm escar in the inferior aspect of the right breast and associated ill-defined deep breast ridge. Open biopsy was recommended, but refused. Core biopsy was non-diagnostic. She missed her next appointment and was seen 17 week later at which time the escar had grown to a 3 cm dark nodule with extensive surrounding ecchymosis. Skin punch biopsy was positive for angiosarcoma.

MRI revealed diffuse edema of the retro-areolar region and of the lower half of the right breast. The MRI also revealed a 6 cm heterogeneously enhancing mass and extenstive skin edema.

Mastectomy was performed with a wide excision of areas of ecchymosis followed by latissimus 13 flap closure. Pathology revealed a 4 cm. high-grade angiosarcoma with extension into the surrounding parenchyma, with extensive hemorrhage. Margins were clear. Post-operatively she did remarkably well, but was slow to gain strength.

After six months of recuperation she consented to a course of hyperfractionated irradiation which was relatively well tolerated. She was treated to the right and lateral chest wall to an area encompassing her mastectomy reconstruction scars by IMRT techniques employing a 6 MV linear accelerator. A total of 6 fields were used, 120 cGy given b.i.d. for a total of 30 fractions calculated at the 100% isodose center for total dose of 3,600 cGy to the right anterior and right lateral chest wall. Concurrently the right posterior surgical scars were treated with an apposition 6 mev electrons, 10 x 300 cGy calculated at the 90% isodose level for a 3,000 cGy dose. (treatment: 10/16/03-11/14/03). She is currently asymptomatic with no evidence of residual disease ( 01/25/05 ).

Case No. 5:

Our fifth case was a 29 years old when a screening mammogram revealed a cluster of calcification in the left breast. She was asymptomatic, but had a strong family history (3 sisters and a maternal aunt diagnosed in their 20’s and 30’s). Recent genetic testing was positive for the Br Ca II gene mutation. DCIS was found on open biopsy. A left modified radical mastectomy and right subcutaneous mastectomy was performed 4/28/89 (pathology report not available for review and number of nodes removed not known). She subsequently underwent a tram-flam reconstruction on the Left and placement of a tissue expander on the right

She had numerous reconstruction procedures in both breasts which included exchange of implants and construction of a nipple on the left.

In October of 2000 she developed a palpable mass in 12 o’clock position of the right breast. Mammogram and ultra-sound were suspicious. FNA was positive. Mastectomy and sentinel node biopsy were performed with placement of a tissue expander. She was found to have an 1.8 cm. poorly differentiated infiltrating ductal cancer. Five lymph nodes were negative and the margins were considered clear (although invasion into the muscle was note on microscopic examination. The post-operative course was uneventful. No post-operative irradiation was given. She was given a course of CMF which she tolerated well.

She had recurrent episodes of fluid collections on the right which required multiple aspiration. During this time period she had right nipple reconstruction. See was seen in routine follow up in May of 2003. At that time she was asymptomatic. However pictures of the right breast do show the first hint of color change below the breast that was not appreciated at the time . By Nov. 03 she developed clinically evident erythema below right reconstructed breast. Low grade infection was suspected and she was started on a course of antibiotics. There was no clinical response to the antibiotics. Culture and cytology of the peri-implant fluid was negative.

The inframammary erythema progressed while on antiobiotics. Skin punch biopsies showed atypical vascular changes. PET-scan showed bilaterally enlarged axillary lymph nodes suspicious for metastatic disease. Bilateral axillary lymph node biopsies were performed as well as full thickness biopsy of inframammary skin lesion. Lymph nodes showed only reactive hyperplasia. The skin lesion was diagnosed as low grade angiosarcoma. This diagnosis was confirmed by Dr. Sharon Weiss at Emory University .

Because of the extensive skin involvement it was elected to start treatment with a course of taxol. She tolerated her chemo well and there was some regression of the skin lesions. A Pet-Ct scan done after the initial treatment with taxon demonstrated reduction in size of the axillary lymph nodes. However, subsequent Pet-ct demonstrated enlargement of the axillary lymph nodes which was interpreted as possible tumor recurrence (I suspect that the lymph nodes are benign. I also suspect that there is an element of lymphatic obstruction that may have contributed to her risk of developing angiosarcoma).

Following her course of taxol she was given a course of hyperfractionated irradiation which she tolerated well, but it was associated with extensive skin changes. She was initially scheduled for wide resection with TRAM flap closure, but has postponed surgery. Her radiation changes are resolving rapidly and she is currently asymptomatic and a course of cisplatin (02/01/05).

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