Primary angiosarcoma of the breast: a literature review

Introduction

Angiosarcoma of the breast is a high-grade malignant soft tissue tumor, and it can be classified into a primary form with no known precursor and a secondary form, secondary breast angiosarcoma (SBA), with a history of primary breast diseases followed by radiotherapies (1). Primary angiosarcoma of the breast (PBA) is a malignant vascular tumor originating in the breast parenchyma. And it is a very rare disease that accounts for only 0.04% of all malignant breast tumors, with a difficult diagnosis and poor prognosis (2). PBA is difficult to study due to the low disease incidence and geographically dispersed patient populations, which resulted in considerable unmet therapeutic requirements for people with uncommon malignancies. There is little evidence of a comprehensive and systematic approach to the treatment and management of PBA. Also, PBA is easily misdiagnosed due to the rarity of the disease, the similarity of other benign diseases, and the non-specific imaging findings. Accurately diagnosing PBA is essential prior to initiating treatment. Furthermore, the existing evidence to inform clinical practice is predominantly derived from retrospective studies, database reviews, and case reports. Most of the retrospective studies included limited patients and mixed with the other diseases. Moreover, the current reported reviews about PBA are limited and were provided with limited evidence. For a greater comprehension of the disease and to evaluate evidence-based practices for the treatment of PBA, we systematically reviewed the published literature in the English language. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-16/rc).

Methods

The study flow of the search diagram is illustrated in Figure 1. For this narrative review, an extensive literature search was conducted in MEDLINE (via PubMed) and Cochrane in September 2023 (Table 1). The search strategy and data analysis methods were established prior to commencing the study. Searches were restricted to English-language publications and covered works published from 1975 onward, following the first description of primary angiosarcoma in 1976 (3). The search used the keywords “primary angiosarcoma of the breast”, “primary mammary angiosarcoma”, “angiosarcoma and breast”, and “breast angiosarcoma with no radiation exposure”. Identical articles and abstracts were identified to avoid duplication. Publications from the same institution were examined, the results from both searches were merged, and duplicate entries were eliminated. Articles with no available full text or insufficient information, research of different diseases, review articles, comment articles, and articles in different languages were excluded.

Figure 1 Search diagram.

Results

A total of 255 studies or reports were identified through the implementation of the strategy predefined in the study protocol. A total of 137 studies were incorporated into the review, encompassing 1,888 patients. A notable deficiency persists in the current body of literature due to the absence of substantial evidence to inform the management of PBA. We classified and evaluated the 137 original articles in accordance with the hierarchical levels of scientific evidence as described in Table 2 by Hadorn et al. (4). The PBA patients (n=1,888) were separated into subgroups, along with their critical clinical data based on levels: (I) level 1 evidence. We found no prospective, randomized trials exclusive to PBA. Only one randomized controlled trial with mixed diseases which concentrated in all kinds of angiosarcoma (9 PBA patients included) has been conducted so far (2,5). (II) Level 3 evidence (Table 3). Thirty-six articles involving 1,759 patients with PBA are included, of which 11 articles are exclusive to PBA, including 395 patients (3). (III) Level 5 evidence (Table 4). One hundred articles involving 120 PBA patients were included. No level 2, level 4, level 6, or level 7 evidence was discovered.

Epidemiology and etiology

Angiosarcoma of the breast accounts for 1% of all breast tumors that occur in the soft tissues. It originates from the interconnected breast tissues and may spread to the skin above it (142). PBA is an extremely rare and heterogeneous disease that is not related to radiation exposure. Only around 20% of the mammary angiosarcomas are primary angiosarcomas, accounting for about 0.04% of all breast malignancies and 8% of breast sarcomas (27,143,144). PBA is typical of young age, compared to the SBA, which manifests suddenly and has a median onset age ranging from 30 to 50 years (34). PBA almost exclusively affects female patients, four well-documented male patients which were extremely rare were reported in the literature so far (66,130,145,146). Given the rarity of PBA, risk factors are difficult to elucidate. It is plausible that the alteration of lymphatic drainage of the breast contributes to the development of angiosarcoma in the breast (147). According to the retrospective database research by Friedrich et al., black and Asian/Pacific Islander patients were more likely to have primary angiosarcoma (34). The incidence of certain diseases varied by race and ethnicity due to genetic factors and dietary and lifestyle differences. There still exists uncertainty about other factors contributing to the development of PBA.

Genomic features

Numerous studies demonstrated that c-MYC amplification was a recurrent genetic alteration in SBA but not in PBA or atypical vascular lesions (AVL), indicating that PBA and SBA have genetically distinct pathogenetic mechanisms (7,12,148,149). Wei et al. compared the differentially expressed genes (DEGs) between PBA and SBA. Out of these instances, 13 were downregulated (PGM5, IQCA1, CETP, WASF3, GCOM1, CTLA4, SLR2, MYC, RELN, UNC5A, CMBL, ICOS, CDCA7L) and five were upregulated (SERPINE1, TGM2, BNC2, LXN, and BAMBI) in PBA and the related protein-protein interaction networks of these DEGs identified the most outstanding genes including MYC, FOXP3 and SERPINE1, suggesting the potential to serve as therapeutic targets as well new biomarkers for the diagnosis and prognosis between PBA and SBA (150). Gennaro et al. found that vascular endothelial growth factor receptor (VEGFR) expression is significantly correlated with low- and intermediate-grade breast angiosarcoma, and VEGFR was also significantly more frequent in patients with PBA and younger patients, therefore suggesting anti-angiogenic treatment may represent a novel therapeutic approach in VEGFR-positive cases of this rare and aggressive disease (33,151). Teruyama et al. reported a PBA case with repeated resection and recurrence over 15 years. Germline mutations linked to malignancy were identified through a comprehensive genetic mutation analysis conducted throughout the progression of the disease. Notable mutations identified included single nucleotide polymorphisms in the tumor protein p53 (TP53), kinase insert domain receptor (KDR), and fibroblast growth factor receptor 4 (FGFR4). PBA is an aggressive disease and has a high chance of local recurrence and metastasis. Although many metastasized tumors had been reported to inherit driver gene mutations from the primary tumor, this particular case did not exhibit any driver gene mutations associated with angiosarcoma that had been previously documented (53). There was clear evidence of genetic heterogeneity among PBA; therefore, additional research is required to determine the oncogenic trigger events that are distinct to this subset of tumors.

Clinical presentation and diagnosis

Patient with PBA usually presents a rapidly growing painless and palpable mass in a relatively larger size. PBA usually manifests with bluish, reddish, violaceous, or black skin discoloration, yet the discoloration may be mistaken for bruising, leading to a delayed diagnosis (143,152-155). Angiosarcoma is characterized by its highly aggressive nature, frequent multicentric presentation, which may indicate localized metastasis or locoregional dissemination, and its propensity for distant metastasis. Mammography and ultrasound often lead to misdiagnosis since the image findings are non-specific and because of the dense breast parenchyma (92). In comparison, magnetic resonance imaging (MRI) with dynamic contrast enhancement is more informative. PBA typically exhibits moderate intensity on T1-weighted images and high intensity on T2-weighted images on MRI. Angiosarcomas of low-grade exhibit progressive enlargement. High-grade angiosarcomas are characterized by frequent visualization of large draining vessels and rapid enhancement and discharge. In conjunction with numerous unenhanced regions within the tumor, these results may be indicative of angiosarcoma (108,142,156,157). Three grades of angiosarcoma were described (2). Multiple grades may exist in the same tumor; therefore, a complete excision and careful histologic evaluation are needed to accurately determine the tumor grade (152). Histologically, the PBA is often composed of well-formed vascular spaces and appears deceptively benign. Consequently, the accurate diagnosis of breast angiosarcoma poses a frequent challenge in clinical practice. The lesions were misdiagnosed as hemangioma, lymphangioma, hematoma, or dysplasia. Percutaneous biopsy frequently yields a false negative conclusion (92,158). Immunohistochemical staining for CD31, CD34, vascular markers factor VIII, and Fli-1 is a valuable technique in the identification and localization of specific proteins or antigens within tissue samples (69,159,160). A clear clinical history in conjunction with clinical, radiological and pathological findings is essential for establishing an early and accurate diagnosis.

Treatment

Complete surgical excision is the gold standard treatment for patients with PBA. However, there is no compelling evidence for us to make a conclusive recommendation on the total mastectomy or breast-conserving treatment. Patients with smaller tumors may benefit from wide local excision surgery (10,11,67). Only isolated cases are reported to have lymphatic spread and the PBA is thought to be hematogenous metastasis (136). Presently, the necessity of axillary nodal dissection is unknown, and the node dissection is controversial unless clinically positive nodes are identified (14,161). Regardless of the rarity of PBA, there is no international consensus on the role of neoadjuvant, adjuvant chemotherapy, and radiotherapy. McClelland et al. conducted a database review and concluded adjuvant therapies are not associated with improved survival, except for the possible role of adjuvant chemotherapy in large primary tumors (24). A meta-analysis of patients treated with doxorubicin and a randomized trial of epirubicin plus ifosfamide exhibited longer disease-free survival and overall survival (OS) (162). Survival may be enhanced and locoregional control could benefit from hyperfractionated radiotherapy (161,163,164). Also, as was mentioned in the above paragraph on ‘genomic features’, several genes provide the potential to serve as therapeutic targets to improve the prognosis. Further investigations, preferably prospective clinical studies are needed.

Prognosis

The median OS was 38 months and the 1-, 3- and 5-year OS with PBA was 80%, 39%, and 25%, respectively (17). The incidence of distant metastasis was considerable, affecting around 60% of the patients. Skin, lungs, liver, and bones emerged as the most frequent sites of metastasis (19). The prognosis of PBA, like the other types of sarcomas, is proposed to be related to the tumor size, the tumor grade, and the resection margin status (69). The most frequently discussed and controversial prognostic factor is grade. It was believed that the histologic grade of the tumor in PBA played a pivotal role in predicting (10,67) patients’ prognosis (35,152,153). Regardless of grade, PBA demonstrated a high propensity for metastasis and a high risk of tumor-related mortality. Nascimento et al. proposed that there was no correlation between the histologic grade of the tumors and the probability of distal metastasis, local recurrence, or mortality in their series, which contradicts previous findings (19).

Conclusions

PBA is a rare breast neoplasm that impacts the younger females, and it is characterized by its challenging diagnostic criteria and unfavorable prognosis. This review of PBA evaluated the epidemiology, etiology, genomic features, clinical presentations, diagnosis, treatment, and prognosis for this rare disease. No published articles presented evidence exclusive to PBA at levels 1 or 2. Thus, no adequate evidence is available to guide clinicians. Complete surgical excision continues to be the principal approach in managing PBA. Regrettably, the exact role of adjuvant and neoadjuvant chemotherapy and radiotherapy is still unknown. Adjuvant therapies could be offered for residual microscopic diseases after surgery. This review emphasizes the necessity for additional meticulously designed studies to educate the management and efficiently direct the treatment of PBA.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-16/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-16/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-16/coif). M.T. receives grants or contracts from Celltrion, Pfizer, and Eisai. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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