Primary breast angiosarcoma – a single institution experience from a tertiary cancer center in South India

Abstract

Introduction:

Primary angiosarcoma of the breast is a rare entity with incidence of less than 0.05% of all malignant breast neoplasms. It occurs in young females without any associated risk factors. The tumor behaves aggressively and has a poor prognosis compared to invasive ductal carcinoma.

Method:

It was a retrospective observational study done at a tertiary cancer center from January 2012 to December 2016. The medical records of patients diagnosed with primary breast angiosarcoma were reviewed for the study. Clinicopathological profile, treatment, and the outcomes were analyzed.

Results:

Four patients were diagnosed with primary breast angiosarcoma out of 2560 breast cancer patients seen over a period of 5 years. Two had metastatic disease at presentation. Among four patients, two underwent surgery of the primary tumor, whereas, all received chemotherapy either as adjuvant or palliative setting. One patient received adjuvant radiation therapy. Three patients received 2nd line and one received 3rd line chemotherapy on disease progression. After a median follow-up of 18 months one patient was surviving on 3rd line chemotherapy with trabectedin. Other three succumbed to disease after progression.

Conclusion:

Due to a small number of this malignancy randomized studies are difficult to perform and optimum treatment strategy still need to be defined.

Introduction

Breast sarcomas are rare and account for less than 1% of all malignant breast neoplasms. Angiosarcoma, fibrosarcoma, and malignant fibrohistiocytoma are the common subtypes included in the sarcomas of the breast [1]. Among all malignant neoplasm of the breast, angiosarcoma represents less than 0.05% and is associated with a poor outcome compared to invasive ductal carcinoma [2,3]. Angiosarcoma of the breast can be divided into primary and secondary subtype. Primary breast angiosarcoma (PBA) do not have any recognizable risk factor, typically occurs within breast parenchyma and commonly seen in women aged between 20 to 40 years. Regional lymph node and distant metastasis are commonly seen in PBA [4,5]. In comparison, secondary breast angiosarcoma (SBA) is usually seen in older age with presumed etiological factors. Common risk factors include prior radiation, mastectomy, and axillary dissection [4,6,7]. Angiosarcoma can also arise due to chronic lymphedema caused by mastectomy or radiation therapy and is termed Sterwart–Treves syndrome [8,9]. Herein, we describe four cases of primary angiosarcoma of the breast from a tertiary cancer centre in South India.

Methods

This was a retrospective observational study of patients diagnosed with primary breast angiosarcoma from January 2012 to December 2016 at our Institute. A total of 2560 patients with breast cancer were seen in the Department of Medical Oncology, out of which 4 (0.15%) were diagnosed as PBA. The medical records of these patients were reviewed to study the clinicopathological profile and treatment outcomes. Patients not on regular follow-up were contacted telephonically to get the accurate survival data. Absence of prior surgery or radiation was imperative for the diagnosis of PBA. Confirmation of diagnosis was made by histology and immunohistochemistry (IHC).

Results

Patient characteristics

The median age of diagnosis was 35 years (range, 25–62 years). One patient was postmenopausal, whereas rest three premenopausal at the time of diagnosis. None of the patients had any co-morbidity or a family history of breast cancer. Average BMI was 25.3  kg   m⁻² .

Clinical presentation and diagnosis

All patients presented with a lump in the breast. One patient had bilateral breast lump as the presenting complaint. The median duration of symptom was 2.5 months (range, 1–6 months). Two patients had skin involvement with reddish purplish coloration and one of these two also had skin ulceration at the time of diagnosis. Axillary lymph node involvement was seen in three patients. Metastasis at presentation was seen in two patients, one with pulmonary metastasis and other having both pulmonary and bony metastasis. Mammography was done for all patients. The common finding was of an ill defined opacity with irregular margins. Focal asymmetry was seen in one patient on mammography, although sonography revealed ill-defined heterogenous mass lesion. Five tumors were BIRADS 4 and one BIRADS 2 on mammography. For establishing the diagnosis of angiosarcoma core needle biopsy was done in all the patients. The clinical characteristics have been listed in Table 1.

Histopathological examination

On microscopic examination, large areas of haemorrhage with hyperchromatic and mitotically active nuclei were seen. Neoplastic cells of epitheloid morphology were present in abundance in the hemorrhagic areas. On IHC, CD31 and Factor VIII positivity was seen in all the patients whereas, CD 34 positivity was seen in one patient. All patients were oestrogen, progesterone negative, as well as HER2 negative. Ki67 was done to see the proliferation rate. The pathological characteristics have been shown in Table 2 and Fig. 1(A–E).

Treatment and outcome

Two patients underwent mastectomy followed by adjuvant chemotherapy with ifosfamide and doxorubicin-based regimen. On pathological examination, margins were positive in one specimen, whereas the other had tumor negative margins. Two patients presented with metastatic disease and started on palliative chemotherapy. Post adjuvant chemotherapy, radiotherapy was given to one patient with node positivity. After a median follow-up of 18 months, all of them had progression of the disease. Two patients with upfront metastasis progressed on first line chemotherapy. Other two who received adjuvant therapy developed metastasis in the lung and liver after a disease-free interval of 9 and 12 months respectively. Three patients received taxane based 2nd line chemotherapy and one received 3rd line chemotherapy in the form of trabectedin. Partial response was seen with trabectedin as the 3rd line with the patient being alive and continuing treatment. Other three succumbed to progressive disease cause of mortality attributed to either pulmonary or hepatic insufficiency. The treatment and outcomes of patients have been shown in Table 3.

Discussion

Primary breast angiosarcoma is a rare tumor with a reported incidence of less than 0.05% of all malignant tumor of the breast. Larger studies with more than 20 cases are limited and based on national database information [10]. The present study reports four cases of primary breast angiosarcoma from a single institution with their treatment and outcomes. The first case of breast angiosarcoma was described by Borrman in 1907 [11]. In our study, the incidence was 0.15% (4 out of 2560). Angiosarcoma of the breast is a distinct clinicopathological entity which carries a poorer prognosis than ductal carcinomas [12]. The median age of PBA is around 40 years [13–15]. Three patients in our study were aged less than 40 years at the time of diagnosis. PBA usually presents with poorly defined breast lump with a rapid growth [16]. In the present study, all presented with a breast lump (one with bilateral breast lump) with a median duration of the symptom being 2.5 months. The differential diagnosis includes fibrosarcoma, myxoid/round cell liposarcomas, phyllodes tumors, malignant fibrous histiocytomas, benign hemangioma and angiomatosis [2]. Sometimes, the benign hemangioma can be difficult to be differentiated from angiosarcoma of the breast. Benign haemangiomas are usually circumscribed tumor usually <2 cm in size. They do not infiltrate the lobules, have fibrous septa and fewer anastomoses which are not complex [17–20].

Mammography and ultrasound of breast do not represent the exact pathological pattern and MRI should be considered which is more likely to reveal the typical malignant signs. MRI characteristically shows hyperintensity on T2 images and a rapid initial intense phase followed by washout [21,22]. Core biopsy is necessary for the accurate pathological diagnosis. There may be excessive bleeding during FNA or core needle biopsy suggesting presence of a highly vascular tumor [23].

The histological subtypes include type I, with vascular channels and scarce papillary endothelial proliferative changes; type II, with papillary endothelial components and type III, having endothelial components with necrosis and hemorrhage. On IHC, CD31, Factor VIII, CD34 and Fli1 positivity confirms the diagnosis [24–27]. Microscopically all patients had epitheloid neoplastic cells in the hemorrhagic background. IHC showed CD31 and Factor VIII positivity in all patients and weak CD34 in one patient.

Angiosarcoma spreads through hematogenous route with the most common site of metastasis being lungs. Lymphatic spread is less commonly seen [28–30]. In the present study, three had pulmonary metastasis one liver metastasis. One patient had both pulmonary and skeletal metastasis at initial presentation.

Surgery is the primary treatment for all resectable tumors. Due to the rarity of this entity, no randomized trial has compared breast conserving surgery with mastectomy. The preferred surgical approach is total mastectomy with or without axillary dissection. Routine use of axillary dissection is debated as most studies have shown axillary lymph node positivity in less than 10% [14,15,22]. Three patients had axillary lymph node involvement which is contrary to previous studies that reported a lesser incidence.

A significant benefit of anthracycline-based chemotherapy in disease-free and overall survival has been documented [31]. Addition of ifosfamide to epirubicin in adjuvant setting showed improvement in survival [32]. In contrast Sher et al., showed no benefit of adjuvant chemotherapy using a combination of anthracycline, taxane, ifosfamide or gemcitabine [33]. In a recent study by Hirata et al., taxane-based regimens showed a survival advantage in metastatic angiosarcoma [34]. Our patients received doxorubicin and ifosfamide-based regimen as 1st line chemotherapy in adjuvant or palliative setting. The disease-free interval in two patients with adjuvant treatment was 9 and 12 months respectively. On progression, three patients received 2nd line taxane-based chemotherapy. One patient got 3rd line chemotherapy in form of trabectedin and showed a partial response after 3 cycles. The patient is still alive and continuing on trabectedin.

The role of radiotherapy in the adjuvant setting is limited to those with microscopically positive margins. Some suggest a role of radiotherapy after mastectomy but the data is based on small retrospective studies from which strong conclusions can’t be drawn [33,35,36]. Two patients in the present study received adjuvant radiotherapy after mastectomy. Both of them had a recurrence in form of lung and liver metastasis and succumbed to disease progression.

Due to the rarity of the disease different prognostic factors need to be established. Tumor size, grade, and resection margin status are the most important prognostic factors at present [13]. Incomplete excision is strongly associated with poor outcome [2,22]. Although tumor size has been correlated with prognosis, there are studies that do not find any association [15,21,22,33]. In our study no correlation could be found between tumor size and prognosis. Most studies have shown margin positivity as a poor prognostic factor, and association with local recurrences and worst survival. Therefore, obtaining a free margin is important and radical surgery should be offered for a better outcome [2,22]. In our series, the tumor with positive margin faired poorer when compared to that with negative margin after surgery (DFS, 9 versus 12 months). Moreover, the poor outcome was with a lower stage. Another important prognostic index is the mitotic or proliferation index. High-grade tumors are associated with higher risk or mortality and thereby poorer prognosis [37,38]. In the present study the only patient alive had the least Ki67% of 20. After 18 months of diagnosis and progression to 1st and 2nd line chemotherapy the patient is still doing well and on 3rd line chemotherapy. Trabectedin has shown a partial response after 3rd cycle and patient is being continued on the same. Trabectedin has been approved by the US FDA as the 2nd line treatment option for unresectable or metastatic liposarcoma and leiomyosarcoma patients who received a prior anthracycline containing regimen. Ongoing trials for the use of trabectedin in other types of sarcoma will provide additional data to support its use outside the FDA recommendations. A randomized phase 3 study comparing doxorubicin and trabectedin as first-line therapy for translocation – related sarcomas showed no significant differences in DFS and OS, with a significantly higher response rate in the doxorubicin arm compared to the trabectedin arm (27% versus 5.9%) [39]. However, more studies are warranted before considering trabectedin as a first line therapy option for STS including angiosarcoma.

In conclusion, primary breast angiosarcoma is a rare type of malignant neoplasm of the breast usually seen in young premenopausal women. Low-grade tumors do better than high-grade ones although the overall outcome remains poor. Due to the rarity of this entity, randomized trials are difficult to happen and the optimal therapeutic approach needs to be established.