Angiosarcoma (AS) is a rare soft tissue neoplasm (incidence: circa 0.2/100.000)1,2 of vascular or lymphatic origin, accounting for 1–2 % of all sarcomas and pursuing an aggressive behavior, with an overall 5-year survival of 30 % and a median overall survival of 33 months. It shows a predilection for skin of head and neck in elderly patients, with a peak incidence in the seventh decade and a slight female predominance.25 Other common sites of involvement are represented by extremities and breast, where it mainly occurs as a complication of previous radiotherapy (RT) in patients with breast cancer. It can develop indeed either sporadically as a primary angiosarcoma (pAS) or following radiation or chronic lymphedema, which is referred to as secondary AS (sAS).6 However, virtually any anatomic site can be affected, including liver, heart, bone, spleen and viscera, where it is associated with a worse clinical outcome compared with AS of either skin or breast.2,7 It is worth noting that AS from different locations has demonstrated a significant biological heterogeneity impacting clinical and prognostic features; hence the issue of AS should be better addressed with a specific focus upon the site of origin.3,5

In the thyroid gland, primary mesenchymal tumors are rather uncommon, comprising 0––3 % of all malignancies.8,9 Vascular entities predominate, representing 13 % of all mesenchymal tumors, and ranging from hemangiomas to epithelioid hemangioendothelioma and AS, which outnumbers the others.9, 10, 11 In large studies on thyroid mesenchymal tumors, AS was the most frequent sarcoma, accounting for 20.4 %.9 The existence of bona-fide thyroid angiosarcoma (TAS) has been questioned for many years owing to the strict resemblance to the angiomatoid variant of thyroid anaplastic carcinoma (AC).12 Furthermore, the distinction between TAS and AC has been considered merely academic by many authors, due to their similar prognosis and treatment.13 Nevertheless, TAS has been ultimately recognized as a pure entity with distinct endothelial origin, and newer insights about its pathogenesis and genetic profile hopefully warrant more specific and effective treatments.14, 15, 16

Herein we draw an updated outline of the topic by providing the most relevant information gained by a thorough review of the literature. We also cover the clinical, epidemiological and morphological aspects, along with molecular and therapeutic advancements.

TAS is a rare tumor with a predominant incidence in goitrous alpine regions of Northern Italy, Austria and Switzerland.17, 18 where it used to represent 10–20 % of thyroid malignancies before the introduction of iodized salt.16 It currently accounts for 2–10 % of thyroid neoplasms in these areas19, 20, 21 and it is strongly associated with long-standing goiter due to iodine deficiency. It has been postulated that inveterate goiter possibly undergoes malignant transformation due to recurrent intra-nodular hemorrhages and infarctions, which lead to prominent endothelial proliferation.22 TAS usually affects elderly patients, with a peak incidence in the seventh decade (mean age of 66, range 21–89) and a slight female predilection (F:M = 1.4:1).17,19, 20

Notwithstanding the high prevalence in alpine regions, TAS represents the most frequent thyroid sarcoma regardless of the geographical location. Indeed, several cases of TAS affecting patients in non–Alpine regions have been reported, suggesting the existence of additional etiological factors.15,19,23, 24, 25, 26, 27 but most of them represent cases of secondary thyroid angiosarcoma due to radiation exposure (iatrogenic or occupational) or vinyl chloride exposure.30, 31, 32, 33 The link between AS and radiation may be related to the stasis of lymphatic channels due to fibrosis.28 Exposure to vinyl chloride is a known risk factor for AS of the liver, in conjunction with arsenic and thorium dioxide (Thorotrast).29,31 Accordingly, Rhomberg et al. documented long-lasting occupational exposure (median 31 years) to vinyl chloride and other polymeric materials in 41.6 % of cases of examined TAS.32 The same authors reported 2 further cases of TAS which were previously exposed to vinyl chloride for 9 and 30 years respectively.33

From a clinical standpoint, TAS usually manifests as a rapidly growing bulky mass in the neck, often in the context of a longstanding goiter. Its development is associated with non-specific local symptoms such as dyspnea, dysphagia, neck pain, hemoptysis and hoarseness, along with systemic alterations with weight loss, anemia, asthenia and night sweats.17,23 Distant metastases can yield unexpected hemorrhagic events such as intestinal bleeding, pleural effusion and intracerebral hemorrhage, since they recapitulate the high vascularity of the primary tumor.23,34, 35 In a case with metastasis infiltrating the bone marrow, the clinical picture was marked by severe anemia and splenomegaly.

The relationship between hyperthyroidism/hypothyroidism and TAS is unclear. The association between TAS and hyperthyroidism has been reported in some cases.36, 37, 38, 39 Although possibly representing a stochastic event, some authors assume that hyperthyroidism could be related to increased functional activity of the gland following hypervascularity which promotes TAS growth.38 On the other hand, cases of TAS with concomitant hypothyroidism are reported anecdotally.32,40 Of note, exceptional cases of TAS arising in well-differentiated thyroid carcinomas have also been reported.39,41

By ultrasonography, TAS frequently presents as hypoechoic nodules with inhomogeneous texture and calcifications, features that overlap in appearance with regressive infarcted nodules. Thyroid scan reveals a cold nodule in the majority of cases.17,42 Like its extra-thyroidal counterpart, the clinical behavior is highly aggressive. In most cases the prognosis is dismal, with frequent infiltration of adjacent organs and early metastases to lungs, cervical lymph nodes, viscera and bones.23 Death often occurs within a few months, because of hemorrhages or bulky effect of the tumor.43 However, the outcome crucially depends upon tumor size, extrathyroidal extension, distant metastases at diagnosis and angioinvasion, which were identified as predictive features of a more aggressive outcome.44 Kaur et al. reported the prognostic data of a series of 48 TASs in which the rate of survivors with no evidence of disease was only 20.8 % (medium follow-up of 39.2 months).17 Nevertheless, the number of long-survivors in TAS series reported in literature is not negligible, such cases being mainly characterized by localized disease at the time of surgery, undergoing total thyroidectomy with or without adjuvant therapy (Table 1). Interestingly, there seems to be a higher prevalence of long survival in non-endemic goiter areas.10,19,24,29, 30,33,40,45, 46 Therefore, some authors suggest that it could be of worth to further investigate a possible correlation between biological aggressiveness of TAS and iodine-deficiency.29

On gross examination, TAS manifests as a large mass (mostly ≥5 cm in size), sometimes encapsulated, showing cystic areas with extensive hemorrhage and necrosis and usually lying within an adenomatous goiter.17,23,47, 48

The histology of TAS is marked by a sharp predominance of epithelioid morphology, characterized by pleomorphic cells with abundant eosinophilic cytoplasm and large nuclei with vesicular chromatin and prominent nucleoli25 (Fig. 1). Neoplastic cells depict a wide range of architectural patterns, which span from anastomosing vascular channels with cleft-like spaces to the commonest arrangement of solid growth in sheets and cords with scant intervening stroma, closely resembling carcinoma25,44 (Fig. 1). A good clue to the vascular nature of the tumor is the presence of occasional intracytoplasmic vacuoles filled with erythrocytes49 (Fig. 1). Among other possible patterns of growth, a pseudopapillary architecture with papillae projecting into vascular lumens can also be encountered.19,44,47,50 In addition, some cases of TAS feature a typical sarcomatous appearance characterized by irregular fascicles of spindle to ovoid cells51 (Fig. 1). Cells are usually embedded in varying amounts of hemorrhagic and fibrotic stroma with areas of necrosis, engulfing inflammatory cells and hemosiderin-laden macrophages. Mitotic figures are easy to find, with frequent atypical mitoses. The presence of vascular emboli is not infrequent and correlates with worse behavior.44

By immunohistochemistry, CD31 represents the most sensitive and specific marker of endothelial differentiation and supports the diagnosis.17,45 Other vascular markers such as ERG and factor VIII-related antigen are also frequently positive, whereas CD34 expression is variable14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 (Fig. 2). Of note, cytokeratin (CK) expression is not uncommon, especially in the context of epithelioid morphology15, 16, 17, 18, 19, 20, 21, 22, 23, 24 (Fig. 2). Markers of thyroidal differentiation such as PAX8, TTF-1, thyroglobulin (TG) and thyroperoxidase (TPO) are consistently negative.17 Immunohistochemical expression of VEGF/VEGFR2 and VEGF-C/VEFGR-3, which are deeply involved in angiogenesis, was observed in a series of ASs of the scalp, although this finding has never been ascertained in the thyroidal counterpart.53

The overlapping features with angiomatoid AC made the recognition of TAS controversial for long time, although nowadays stable criteria have now been developed to warrant their distinction51 (Table 2). Notably, vascular markers and CK cannot aid in the differential diagnosis, since their expression can be found in both entities. On the other hand, markers of thyroidal differentiation such as PAX8, TTF-1 and TG commonly show variable positivity in angiomatoid AC, but they are consistently negative in TAS.51,54 Accordingly, an analysis by radioactive in situ hybridization (ISH), aiming to compare TG mRNA expression in AC versus AS, recorded weak but consistent levels of TG expression in all ACs. In contrast, the analysis failed to find any level of transcripts in AS, thus supporting the hypothesis that these entities are unrelated.54

An angiosarcoma-like appearance can rarely occur in medullary carcinoma (MC), featuring clefts and pseudo-follicles filled with erythrocytes and lined by cells with occasional intracytoplasmic vacuoles. Nevertheless, the neoplastic cells are characterized by ovoid nuclei with mixed fine and coarse (i.e., ‘salt and pepper’) chromatin and inconspicuous nucleoli. By immunohistochemistry, they are positive for synaptophysin, chromogranin A and calcitonin, in the absence of endothelial marker expression.55

Lastly, another potential diagnostic pitfall is represented by the so called “worrisome histologic alterations following fine needle aspiration of the thyroid” (WHAFFT), which can be encountered in resection specimens. In this condition, vascular spaces are lined by mildly atypical and plump endothelial cells, resembling well-differentiated vascular tumors. The absence of anastomosing vascular growth is a useful clue to distinguish WHAFFT from TAS.42

Notwithstanding the pivotal role of Fine Needle Aspiration Cytology (FNAC) in the investigation of thyroid nodules, the diagnostic criteria for the diagnosis of mesenchymal tumors are blurry.56 However, when adopted as a screening tool, FNAC ensures a correct diagnosis of TAS in about 20 % of cases; the remaining cases are reported as inconclusive or nonspecific malignancy.17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 On the other hand, according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), TAS was classified as malignant (VI) in the few cases reported in the literature.44,56 Overall, AS is usually hypocellular with atypical cells either singularly dispersed or arranged in small clusters, lying in a hemorrhagic background with necrotic spots and inflammatory cells.57 Sometimes cells are organized in acinar structures which give the false appearance of glandular differentiation.58, 59 Some authors argue that samples with cystic changes and few cells should raise suspicion for the possibility of TAS in the presence of aggressive clinical presentation.57 Cytomorphology of TAS reveals the presence of epithelioid and pleomorphic elements with dense eosinophilic cytoplasm, but their shape can range from spindled to plasmacytoid.17,56 Nuclei are enlarged and hyperchromatic, often eccentric, with an irregular nuclear membrane. The chromatin is coarse, and prominent nucleoli are often seen.29,56, 57,59 Intracytoplasmic vacuoles with lumina formation filled with erythrocytes or neutrophils are a typical finding although they can be absent.56, 57,59 Mitotic figures are usually found.56 Other possible findings are represented by hyaline globules and bi- or multinucleated elements. Immunohistochemistry basically replicates the features observed by histopathological examination56, 57,59 and it is pivotal for differentiating TAS from AC, since the latter reveals overlapping cytologic features.29,60 It is also worth considering that regressive nodules in long-standing goiters can yield misleading findings by FNAC. Indeed, they can show low cellularity with a hemorrhagic background, as well as plump endothelial cells with nuclear atypia and prominent nucleoli – findings which can easily raise concern for malignancy. Nevertheless, the degree and extent of nuclear atypia in benign infarcted nodules fall short of angiosarcoma.42

The cytomorphology of cells in AS can sometimes reveal a plasmacytoid appearance with eccentric nuclei, which can be misdiagnosed for MC.55 However, MC has smaller cells that reveal a granular quality of chromatin and lack a prominent nucleolus.59

The differential diagnosis includes several entities such as metastatic carcinoma, melanoma and large cell or anaplastic lymphoma. However, all these tumors can be easily ruled out by the absence of vascular markers expression by immunohistochemistry.59

The genetic landscape of AS has been only partially elucidated, and some studies have shown marked variability according to the site of origin.61 Table 3 summarizes the molecular features of AS, as well as their possible role in the pathogenesis of this tumor and in targeted treatments.

Regarding the molecular profile of TAS, very few results have been collected to date, and they mainly stem from studies of comparison between TAS and AC (Table 3). Overall, AC seems to bear a significantly higher tumor mutational burden (TMB) than TAS.8,51 In addition, mutations in TP53 and TERT have been detected by next-generation sequencing (NGS) in only AC samples, while pTASs were devoid of such molecular features. The few genetic alterations found in pTASs were present as single events involving HRAS, MAP2K1 and PIK3CA genes.51 Albeit not providing any relevant information about the molecular background of TAS, the importance of these data hinge upon the confirmation that TAS and AC are genetically distinct.

Another study, performing massive parallel sequencing on 34 samples of ASs from several sites, failed to demonstrate any relevant genetic event in the only case of TAS available. Finally, an isolated case of secondary TAS, arising in a 62-year-old man with prior irradiation of the neck region, was confirmed to harbour p.G382D and p.Y165C mutations in the MUTYH gene by NGS analysis.10 Of note, MUTYH mutation has been described in other post-radiation sarcomas.62

A few studies aimed to analyze p53 expression in TASs and determine its correlation with outcome, but they did not yield any significant results about possible prognostic implications.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 On the other hand, immunohistochemical p53 overexpression has been found in 50 % of cases of either pAS or sAS of other sites, and it was associated with a worse disease-free survival.63

Overall, recurrent genetic aberrations have been mainly identified in sAS, while pAS has shown complex structural and numerical alterations. Notably, 50–100 % of sASs seem to harbor high level amplification of MYC at locus 8q24.21, which plays a crucial role in its pathogenesis.64,65 Another consistent molecular alteration in sAS is represented by the amplification of FLT4, which encodes VEGFR-3 and is always concomitant with MYC amplification.65 Mutation in KDR (encoding VEGFR-2) was the first genetic alteration to be detected in AS, and it was initially observed in 10 % of either breast pAS or sASs.66 Importantly, the activating mutation in KDR represents a rationale for the use of drugs inhibiting VEGF/VEGFR pathway. Another study identified concomitant driver mutations in PTPRB and PLCG1 in radiation-associated ASs. Both genes are deeply related to angiogenesis.67

Among other molecular alterations with therapeutic relevance, mutation in PIK3CA and alteration of the MAP kinase pathway have been found in both pAS and sAS of several sites, prompting a possible therapeutic approach with PIK3alpha inhibitors and MAPK inhibitors, respectively.63,68