Angiosarcomas are complex soft-tissue sarcomas that are aggressive often based on malignant endothelial origin involving blood and lymph vessels. Approximately 2 % of soft tissue sarcomas and 5 % of cutaneous sarcomas are diagnosed as angiosarcomas [1]. The incidence of angiosarcoma has risen over the last several decades with a higher prevalence in older Caucasian males with average age at diagnosis of 65–70 [1, 2]. The prognosis of these tumors is poor with a reported 5-year survival rate of less than 40%.

Current treatment includes surgery with wide-field radiotherapy; however, the tumor tends to invade tissue and is often prone to incomplete excision [3]. Studies have reported success with a combined-modality approach of surgical resection followed by postoperative radiation therapy and/or chemotherapy [4]. A recent retrospective study evaluated survival outcomes of 55 patients with angiosarcoma of the face and scalp treated with either single modality or multimodality therapy with surgery, radiation and/or chemotherapy [5]. Patients who underwent multimodality treatment had significantly favorable local regional control (20% vs 11%; P = .04), recurrence-free survival (19% vs 10%; P = .02) and higher overall survival (46% vs 16%; P = .04) when compared with patients treated with single modality treatment [5]. Even after optimal local-regional treatment, patients are still at risk for the development of distant metastases [1–3] Doxorubicin-based regimens, taxanes and ifosfamide as single agents or in combination regimens are used to treat metastatic angiosarcoma with PFS ranging from a median of 3.7 to 9.5 months. One study reported an overall survival with weekly paclitaxel of 7.6 months [2].

The immune system is critical in cancer control and progression, and appropriate modulation of the immune system may provide an effective therapeutic option for sarcoma. Early observations in patients with renal transplant showed that patients developed Kaposi’s sarcoma at a higher rate than the control population implying that the immune system can play a role in the natural history of this disease [6]. In addition, in a study by Penn and colleagues evaluating 8191 patients that had both organ allografts and immunosuppression they found that 1.7% of patients developed sarcoma, a higher incidence of sarcoma compared to the general population [7]. Results of an adjuvant immunotherapy for pediatric sarcomas suggested that overall survival in these patients was increased, although a double blind study was not carried out [8]. This finding suggested a role for the immune system in regulating sarcoma outgrowth. The recent success of immune checkpoint inhibitors that target either PD-1 or PD-L1 in treatment of melanoma, non-small cell lung, renal and bladder carcinomas suggests that immunotherapy might play an important role in sarcoma therapy.

Here we describe a 63-year-old man with refractory metastatic cutaneous angiosarcoma who obtained an ongoing major partial response with the PD-1 inhibitor pembrolizumab after failure of surgery and chemotherapy to control his disease.

Angiosarcoma treatment often includes combined radical surgical excision and radiotherapy. However, over 60% of patients ultimately develop distant metastases. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is an unmet clinical need for more effective therapies to induce durable responses. In the last 2 years, the advent of immunotherapy has provided a promising alternative for classical cytotoxic chemotherapy. Sensitivity to immunotherapy is thought to be secondary to higher DNA mutation rates, for example those found in melanoma and non-small cell lung cancer. While in comparison the mutation rate in acute leukemia is low. The genetic aberrations involved in the development of angiosarcoma are still poorly understood. Until recently, most of the genetic alterations were identified mostly in secondary but not in primary angiosarcomas. The most frequent chromosomal abnormalities were on chromosome 8q, 10p and 5q [9]. Additonally, MYC amplification is a recurrent genetic mutation in secondary angiosarcoma. Recently, Shon and his colleagues confirmed the presence of both MYC amplification and MYC overexpression in a minority of primary angiosarcomas [10]. In their study, by IHC analysis, MYC overexpression was present in 9 of 38 (24%) cases. Six of the nine positive cases were from the head and neck region [10]. Therefore, in comparison to other tumor types, angiosarcoma would appear to have an intermediate mutation frequency.

The anti-CTLA4 antibody ipilimumab has been given to six patients with synovial sarcoma without a response [11]. Current data using PD-1 inhibitors for the treatment of sarcoma is limited. PD-1 and PD-L1 expression has been reported in a variety of sarcomas, although the limited number of angiosarcomas tested have been negative for this marker. One study reviewed PD-1 and PD-L1 expression in 105 patients with multiple subtypes of sarcoma and found that intratumoral infiltration of PD-1 positive lymphocytes was seen in 65% of cases and PD-L1 tumor expression in 58% [12]. PD-1 and PD-L1 expression was correlated with higher tumor grade, advanced stage of disease, presence of metastasis, and poor clinical outcome [12]. Another study evaluated various subtypes of soft tissue in 50 sarcoma patients, and pathologic expression revealed lower levels of PD-L1 expression on tumor cells and infiltrating lymphocytes (12% and 30%, respectively) [13]. In this study, there was no association between clinical features and overall survival with PD-L1 expression in tumor or immune infiltrates. The authors proposed that the reason for the differing results could be due to the small heterogeneous cohort and the use of a differing PD-L1 assay in these studies.

Despite the lack of a large clinical trial data showing definitive efficacy in sarcomas, there is data from smaller trials that show that immunotherapy has activity against certain sarcomas. Tawbi and colleagues evaluated the use of pembrolizumab in soft tissue sarcoma and bone sarcoma in a phase II study [14]. Five of the 76 patients had a partial response after 20 weeks of treatment suggesting that the use of PD-1 and PD-L1 blockade does show efficacy in the treatment of sarcomas and may provide a viable treatment option for patients [14]. Another retrospective analysis included 23 metastatic soft tissue sarcoma or bone sarcoma patients treated with nivolumab [15]. Thirteen of these patients also received concomitant treatment with the tyrosine kinase inhibitor, pazopanib. Patients had baseline imaging and then restaging imaging after 6 cycles of treatment and 9/23 patients were found to have clinical benefit, with either a partial response or stable disease [15].

Our patient also has an underlying history of indolent CLL for which he never received treatment. Although there is no evidence that patients with an underlying B cell lymphoproliferative disorder respond better to treatment with PD-1 and PD-LI inhibitors, given the increased number of B cells and their potential regulation of CD8 T cells, it is possible that this may have contributed to his response and warrants further evaluation. This case report demonstrates a clear response of angiosarcoma to a PD-1 inhibitor and the potential for the use of these inhibitors in this disease.