Angiosarcoma is a rare form of sarcoma of vascular origin. It is notorious for its aggressive and relentless progression with frequent local recurrence and distant metastasis.1 Owing to its scarcity and innocuous appearance at an early stage mimicking an ordinary bruise or benign haemangioma, correct diagnosis is often delayed for several months. This problem is compounded further because most patients with angiosarcoma are elderly with frailty and co-morbidity, and prognosis after surgery as the definitive therapy is gloomy. The 5-year overall survival (OS) has been variously reported as 24% to 35%.1 2 When radiotherapy (RT) is given as the main treatment, median survival is only 8 months.3

Almost half (43%) of angiosarcomas originate from the skin of the head and neck.1 2 Compared with truncal and extremity angiosarcoma, the prognosis of cutaneous angiosarcoma (CAS) of the head and neck is even worse. Perez et al2 indicated a greater need for flap or graft reconstruction after tumour extirpation for head and neck CAS (HNCAS), a positive resection margin in 50%, and 5-year OS of 21.5%. Surgery was conventionally regarded as the mainstay of therapy for HNCAS. Because of the poor results and frequent margin involvement (78%),4 a multidisciplinary approach with adjuvant RT has been advocated.

To the best of our knowledge, most articles about HNCAS derived from a Caucasian population. We are not aware of any reported series from ethnic Chinese populations. We therefore conducted this retrospective study of HNCAS in the Chinese patients managed in our hospital over the past two decades. Demographic data, clinicopathological information, modality of treatment, and outcomes were reviewed. The latest approaches to the treatment of this devastating disease are also discussed.

Records of patients with histopathologically verified HNCAS from December 1997 to September 2016 were captured from the head and neck cancer registry of our department. Only Chinese patients were recruited. Patient data were prospectively collected and regularly updated in the registry.

Tumours were classified as a unifocal/localised versus multifocal/diffuse form. Unifocal/localised tumour was characterised by a discrete lesion without macroscopic satellitosis; it was considered operable and potentially curable. If gross satellite lesions were present or the main tumour was too extensive to be removed surgically, it was regarded as a multifocal/diffuse tumour that was probably incurable. Superficial tumours were those confined to the skin and subcutaneous tissue. Conversely, deep tumours were defined as transgression beyond the subcutaneous layer, for example encroaching on the underlying muscle or bone.

If the tumour was resectable, a wide excision with at least a 3-cm margin was performed. The defects were reconstructed by local scalp flap/ skin graft (scalp primary) or submental flap (face primary).5 Neck dissection was performed only in the presence of clinical or radiological evidence of nodal spread. Adjuvant RT was not routinely administered. When disease was deemed inoperable or the patient was unfit for surgery, palliative RT or chemotherapy would be considered.

The OS was calculated from the date of diagnosis to patient death or last follow-up, and is expressed in Kaplan-Meier curve. The data were computed using the SPSS (Windows version 20.0; IBM Corp, Armonk [NY], United States). The principles outlined in the 2013 version of the Declaration of Helsinki have been followed.

A total of 17 patients with HNCAS were identified and managed in our institution from December 1997 to September 2016. Their demographic and clinicopathological information are shown in Table 1. In brief, males predominated and there were only two female patients. Their median age was 81 years (range, 67-92 years). Only one patient had a history of whole-scalp RT for a lateral scalp angiosarcoma more than 10 years ago in another institution. He had a new angiosarcoma on the opposite side of his scalp that was treated in our centre as a second primary angiosarcoma induced by past RT. The median duration from onset of presentation to diagnosis was 4 months (range, 2-33 months).

Patients presented with protean symptoms: bleeding (n=7), pain (n=4), nodule (n=3), ulceration (n=2), pigmentation (n=2), pruritus (n=1), and localised oedema (n=1). One patient presented with an asymptomatic purplish macule but no other symptoms.

The tumours were present in the scalp only (n=11), face only (n=4), or both scalp and face (n=2). No patient had neck CAS. Ten patients had a localised/unifocal tumour. Seven patients were inflicted by multiple/diffuse lesions that were considered inoperable and treated with palliative intent in four. Of the three remaining patients with multiple/diffuse lesions, the tumours were still amenable to potentially curative surgery although two (cases 7 and 15) declined any treatment initially. Deep invasion occurred in two patients. Of the 11 patients whose tumour dimension had been documented, the median diameter was 4 cm (range, 3-13 cm). In the other six patients in whom dimensions were not recorded, there was extensive involvement by the HNCAS.

At the time of diagnosis, the numbers of T1 (≤5 cm) and T2 (>5 cm) diseases were seven and 10, respectively. Regional nodal spread was present in six patients. Only two patients (cases 2 and 3) were found to have distant metastases: lung in one patient, and lung and spine in the other (Table 1). The modalities of therapy were surgery (n=6), surgery + adjuvant RT (n=1), palliative RT (n=5), and palliative chemotherapy (n=3; two of them also received palliative RT following chemotherapy). The remaining two patients (cases 7 and 15) refused any form of treatment initially (Table 2). Incorporating subsequent therapy, surgery, RT and chemotherapy were eventually offered to seven, 10, and five patients, respectively.

Of the seven patients treated surgically, the resection margin was positive in two. Tumour recurred in six of them: four local and two regional recurrences. The median time to relapse was 7.5 months (range, 2-32 months). Overall, 16 patients had died; the causes of death were HNCAS in 12 and inter-current diseases in four (Table 2). One patient (case 15) was still living with the disease 21 months after diagnosis. The median OS was 11.1 months and the longest OS in our series was 42 months (case 6) [Fig 1].

The oncological outcome of this study is obviously far from satisfactory when compared with a reported median survival of 13.4 to 64 months as shown in Table 3,4 6 7 8 9 10 11 12 which summarises the postulated prognosticators. Only those studies performed over the past two decades and that focused on HNCAS with more than 10 cases were included. Patient age, tumour size, tumour differentiation, deep invasion, and margin status showed conflicting results. Of note, RT was the most promising and consistent prognosticator; only one study showed an adverse effect on survival.10 The disparity might well be due to selection bias for RT in a retrospective study—more advanced disease tends to receive adjuvant RT. The evidence lends credence to adjuvant RT for HNCAS. The suboptimal outcome in our study is multifactorial: detainment of diagnosis, inclusion of palliative cases for survival evaluation, advanced age precluding curative treatment, and unpopular adoption of RT or chemotherapy as multimodal therapy. In this series, adjuvant RT was administered to only one patient after surgery, either because others declined RT or wound complications precluded its application.

The diagnosis of HNCAS is often late as early lesions can simulate innocent violaceous macules masquerading as benign dermatological entities (Fig 2). From our experience, the median duration was 4 months prior to diagnostic confirmation with histopathological examination. Three of our patients (cases 7, 15, and 17) had their diagnosis made more than 12 months after onset of disease. The longest delay was 33 months (case 17) and is absolutely not acceptable. Interestingly, HNCAS manifested as pigmented lesions in two patients and thereby misled clinicians in decision making. Increased awareness of this rare disease by primary care clinicians is essential to expedite patient referral. For specialists, a low threshold to biopsy of newly developed purplish skin lesions in the elderly patients is pivotal to an early diagnosis.

In our series, patients who underwent palliative therapy were included in the OS calculation and this might have partially contributed to our poor results. This was echoed by Buschmann et al13 who also included patients with palliative resection in outcome evaluation; their longest survival reported was 36 months. This is similar to our experience where longest survival was 42 months. Conversely, Dettenborn et al10 reported 80 patients with HNCAS treated surgically (44 patients also received postoperative RT) with curative intent and 5-year OS of 54% and median OS of 64 months. Similarly, Suzuki et al12 described their experience of definitive RT as the principal curative treatment for HNCAS; a median OS survival of 31 months was attained. Nonetheless, the results of RT were compromised when palliative cases were incorporated: only 12% of patients survived more than 5 years in one study.14

Our patients were older (median age, 81 years) than those reported in the literature (median age, 63-77 years) [Table 3]. The prognostic significance of age on the outcome of HNCAS is controversial. Patel et al11 reported that patients younger than 70 years fared better with improved locoregional control and relapse-free survival than older patients. Although age is not a confirmed prognostic factor, advanced age often precludes patients from curative therapy due to concomitant chronic diseases or general debility. The elderly patients are also prone to dying of other disease as encountered in this series; four patients died of inter-current illnesses (Table 2). Nonetheless, effective systemic treatments can be well tolerated by some elderly patients with HNCAS. With taxane-based regimens, a response rate of 83% (10 out of 12 patients) was achieved and the progression-free survival was approximately 7 months.15

Surgery is historically the main treatment for HNCAS. The latest approach to optimal management of HNCAS is combined treatment encompassing surgery, RT, or chemotherapy. Adjuvant RT should be liberally offered to maximise the oncological outcomes following surgery. As shown in Table 3, five of six studies support the beneficial role of RT.4 6 7 8 10 11 Guadagnolo et al7 advocated simple resection of the gross tumour to facilitate non-complicated reconstruction and thus expedite RT. Two-staged surgery was discouraged. The resection margin status was not critical to survival if timely adjuvant RT was administered. From their experience, the 5-year OS was 43% and 5-year disease-specific survival was 46%. In a review article, Hwang et al16 also concluded that positive margin was common (64%) but did not impair the ultimate outcome. They recommended that surgeons should not be too obsessive about removing each and every cancer cell if RT was to be pursued.

Definitive treatment with RT and/or chemotherapy has also been reported to be effective for HNCAS.9 Of 17 patients treated in that study, complete and partial responses were accomplished in none and five patients, respectively. The median OS was 26 months. Multimodality treatment in various combinations with surgery, RT, and chemotherapy has been asserted by Patel et al11 to be effective in improving locoregional control, relapse-free survival, and OS. In another study, survival (37 months) following combined therapy (RT and chemotherapy) was better than either modality alone: 23 months for RT and 15 months for chemotherapy.16 Docetaxel is the preferred agent due to its antiangiogenic and radio-sensitising effects.9 Other agents have also been successfully used and include doxorubicin, ifosfamide, bevacizumab, and interleukin-2. Systemic treatment may be used in a neoadjuvant setting, adjuvant setting, and as concurrent treatment with RT.8 17 18 Conversely, RT plus chemotherapy was not shown to have any prognostic value in a meta-analysis by Shin et al.19 Further studies should be carried out to elucidate the benefit of combined modality treatment.

Ip and Lee20 reported a smaller local series of CAS that was not confined to the head and neck. A total of seven patients were enrolled from three clinics of the Social Hygiene Service in Hong Kong. Only six patients had HNCAS. Similarly, poor prognosis was demonstrated in these patients. Our bigger series focusing on HNCAS provides a more updated and detailed strategy for the management of this rare disease in ethnic Chinese.

Our study has some limitations. First, the sample size was small as only 17 patients were included for evaluation. Nevertheless it is the largest series reported in our locality. The study spanned over 19 years (December 1997 to September 2016) and treatment has evolved over this period. Moreover, like many retrospective series, recall bias or selection bias are inherent limitations. Patient symptoms, signs, presentation duration, and criteria for treatment might not be completely accurate.

We present the first report of HNCAS in ethnic Chinese. The oncological outcome is far from satisfactory. A high index of suspicion is mandatory for prompt diagnosis of early disease. Adjuvant RT, as supported by evidence from the literature, is recommended following surgery that should aim at gross tumour extirpation to ensure uneventful reconstruction as well as timely implementation of RT. The benefit and role of systemic treatment in various combinations with surgery or RT require further study.

All authors have disclosed no conflicts of interest.

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