Clinical Pathophysiology and Research Highlights of Cardiac Angiosarcoma: Obligation for Immunogenetic Profiling to Understand Their Growth Pattern and Tailor Therapies

Abstract

Cardiac angiosarcoma is the most common malignant tumor of the heart. The typical clinical profile is a young male with 30–50 years of age. Due to varied clinical presentation, it can disguise common cardiovascular disorders, such as pericarditis, congestive cardiac failure, and angina. This can delay the diagnosis, thus allowing the tumor to progress to the advanced stage by the time it is detected. Depending on tumor grade and size, a combination of surgery, chemotherapy, and radiation is advocated. Despite aggressive management, these tumors have a propensity to recur, advance, and metastasize, thereby underscoring the treatment resistance commonly encountered with these tumors. Resultantly, most of the patients are more prone to have shorter survival time, worse clinical outcomes, and grave prognosis. Research efforts should be directed toward decoding the inherent immune-genetic traits of these aggressive tumors so that their rapid progression can be extensively repressed. So, we propounded basic and clinical research studies to grasp the genetic makeup of these tumors so that crafting novel therapeutic modalities for improving prognosis and survival interval in these malignant tumors can materialize.

1. Introduction

As compared to the past, when cardiac tumors were mostly diagnosed following postmortem analysis, current advancements in imaging and surgical techniques have empowered us to diagnose and manage them with modest success. The reported prevalence of primary cardiac tumors is estimated to be around 0.0017–0.0028% [1,2]. According to a recent systematic review and meta-analysis, the prevalence of heart transplantation, short-term mortality (6 months), and long-term mortality (5 years) in all cardiac tumors was estimated to be 2.45%, 5.9%, and 2.55%, respectively [3]. Cardiac tumors are classified as benign, malignant, and metastatic [1,2]. The mortality rate of all cardiac tumors, benign cardiac tumors, and malignant cardiac tumors was around 2.55%, 0.79%, and 14.77%, respectively [3]. Primary cardiac tumors are classified as benign (75%) and malignant (25%) [1,4]. Myxoma (50%) and rhabdomyoma (20%) are the most common benign tumors, whereas sarcoma (20%) and lymphoma are mainstream malignant tumors of the heart [4]. Among sarcomas, angiosarcoma, Kaposi sarcoma, rhabdomyosarcoma, leiomyosarcoma, intimal sarcoma, and osteosarcoma are the notable ones [4].

The most common type of sarcoma is cardiac angiosarcoma, which primarily originates from the blood vessels of the heart [4]. The traditional age of presentation of angiosarcoma is roughly 30–50 years. Although various reports indicate that males are twice as likely to develop this tumor as compared to females, the underlying reason for these gender differences is currently obscure, although it can be speculated to be linked to hormonal imbalances [5,6]. In a population-based retrospective study, the prevalence of cardiac angiosarcoma was shown to be predominant in whites as compared to other races [7]. Cardiac angiosarcoma can emanate from the right heart, left heart, or pulmonary artery [8]. Right-sided angiosarcomas are bulky, exophytic, infiltrative, and aggressive, whereas left-sided are more circumscribed, less bulky, and less infiltrative and have decreased metastatic potential [9]. Although the exact cause is unknown, the relationship between some risk factors and the onset of soft tissue angiosarcoma was ascertained based on prior clinical studies. Some of the common etiologies speculated to trigger the onset of cardiac angiosarcoma are radiation therapy, environmental carcinogens (vinyl chloride, thorium dioxide, and chronic arsenic ingestion and Anabolic steroids), lymphedema, immunosuppression, and genetic syndromes (Neurofibromatosis NF-1, Maffucci syndrome, bilateral retinoblastoma, Ollier Disease, Xeroderma pigmentosa, and Klippel–Trenaunay syndrome) [10,11,12,13]. With most breast cancer patients receiving radiation therapy, the risk of post-radiation angiosarcoma has been rising at an increasing rate, with the malignant transformation unfolding after a latency period of 6–8.9 years [14,15]. A relevant occupational history, along with the duration and intensity of exposure to the aforementioned environmental carcinogens, should be thoroughly evaluated in all the patients [16]. Genetic predisposition to the development of angiosarcoma was seen in some genetic syndromes, and it has been hypothesized that aberrations in the angiogenic pathways and tumor suppressor genes might be alleged to have caused its causation [10]. Research should be directed toward delineating the genetic mutations that heighten the propensity of developing cardiac angiosarcoma.

Right-sided angiosarcomas are notorious for metastasizing early and invade tissues extensively as compared to left-sided and pulmonary sarcomas [8]. A combination of surgical resection and chemotherapy is the first line of therapy for right- and left-sided angiosarcomas [8]. However, radiation therapy is preferable in pulmonary angiosarcomas due to their less proximity to the cardiac tissues [8]. Even though the current literature does not pinpoint specific etiological factors that can trigger the conception of cardiac angiosarcoma, few clinical researchers speculated that genetic susceptibility, radiation, chronic lymphedema, and environmental carcinogens are partially to be blamed [10]. Its clinical presentation is quite enigmatic, and patients might present with clinical symptoms that might mimic various cardiac disorders, including pericarditis, congestive heart failure, angina pectoris, aortic/mitral/pulmonary valve stenosis coronary artery spasm, giant cell arteritis, cardiomyopathy [hypertrophic, restrictive, and dilated], and Kawasaki disease. Consequently, the spectrum of clinical presentation can range from chest pain, dyspnea, pulmonary venous hypertension, peripheral edema, fever, malaise, arthralgia, rash, fatigue, weight loss, hepatic dysfunction, Raynaud phenomenon, elevated ESR [Erythrocyte Sedimentation Rate], hyperglobulinemia, hemolytic anemia, and elevated white cell count thrombocytopenia to polycythemia [1,4]. As the tumor progresses, some of the complications that can be expected include obstructive shock, cardiac tamponade, systemic embolization, supraventricular arrhythmias, ventricular arrhythmias, heart blocks, and acute respiratory syndrome [5,6]. A high degree of clinical suspicion is warranted, and patients should be evaluated with a combination of ultrasonography, cardiac MRI [Magnetic Resonance Imaging], and cardiac CT [Computed Tomography] scan to rule out or confirm the presence of cardiac masses [1]. Any appearance of cardiac masses should be pertinently followed by surgical intervention, intraoperative frozen section, and histological examination to verify the diagnosis of angiosarcoma [5]. It is important to recognize the fact that endomyocardial biopsy and transbronchial biopsy will rarely be successful in confirming the diagnosis of angiosarcoma [17,18]. As the diagnosis of cardiac angiosarcoma is confirmed, the future course of action is contingent upon the presence of a tumor localized in the heart, local advancement, and distant metastasis. The low-grade tumor, which is confined to the heart, usually resolves through complete surgical resection, although some clinicians recommend preventive chemotherapy and close clinical follow-up to prevent future recurrences [19]. However, locally advanced tumor necessitates the implementation of radical surgical resection in combination with adjuvant chemotherapy and radiation [5,6]. In aggressive and metastatic tumors, combination chemotherapy with or without radiation would be a front-line therapy for prolonging the symptom-free survival time, although the patient is vulnerable to chemotherapy side effects with resultant mortality and morbidity [19,20,21,22,23]. With it being a near-fatal disease, the average survival time from the time of diagnosis is around 6–11 months, although some studies report as long as 26.6 months after positive histological diagnosis [24,25,26]. The survival of angiosarcoma is dependent upon prognostic factors such as tumor size and local tumor invasion [25].

2. Assimilating the Idiosyncratic Growth Traits of Cardiac Angiosarcoma Entails Excavating into Its Immunogenetic Profile

The clinical presentation, growth pattern, treatment response, and clinical remission rate of cardiac angiosarcoma are quite variable, as seen in the clinical cases reported in the literature. Despite adhering to the treatment protocols and timely intervention, some patients have complete regression while others experience early recurrence and metastasis.

There were instances where patients with complete clinical remission for several years presented with recurrent or metastatic tumors elsewhere, thus underscoring the presumption that these patients would require close clinical monitoring even after complete surgical removal and histological confirmation of negative cancer cells from the tumor bed. A lot of case reports published over the past several years paint a very grim picture of angiosarcoma, with most patients experiencing early metastatic spread, higher tumor complications, higher morbidity, and early mortality. Due to its cryptic aggressive growth pattern and higher mortality, it is recognized as one of the most daunting primary cardiac malignancies, which should be managed with due diligence and close monitoring. Most cases of cardiac angiosarcoma clinically present themselves in late stages due to their non-specific presentation, thus mimicking most common cardiovascular disorders and delaying the diagnosis. Lack of specific therapy, tumor recurrence, the unfolding of metastasis even after complete surgical resection, and a poor response to chemotherapy/radiation are some of the common clinical traits of cardiac angiosarcoma that make it one of the most unreliable, puzzling, and recalcitrant cardiac malignancies. Due to these aforementioned reasons, achieving favorable clinical outcomes and longer patient survival rates is next to impossible with these cardiac malignancies.

In most cases, the growth pattern of the angiosarcoma is primarily dependent upon its inherent genetic expression, which provides the necessary drive for its aggressive growth pattern. Consequently, exploration to ascertain the genetic makeup and immunological markers of these intractable tumor tissues might unravel molecular targets, which might be the lurking and tangible catalysts for setting in motion pertinent downstream signaling events for sparking extravagant growth patterns typically perceived in these tumors. These molecular targets can be further investigated in basic and clinical research studies to decipher their clinical significance and evaluate their relationship to growth patterns witnessed in these malignancies. Over and above that, they might form the structural basis for future clinical trials. On top of everything, these new targets can form the molecular basis for crafting tailor-made therapies that can be administered in these patients to arrest the exorbitant growth of these tumors, thus enkindling improvement in survival outcomes, longer symptom-free intervals, and favorable prognoses. In this review, we briefly discuss the histology of cardiac angiosarcomas, summarizing their morphology and pathological findings. We also present a case series of a few important cardiac angiosarcoma cases reported in the literature to highlight their unusual presentation and metastasis and bring forward the treatment modalities that were utilized and their survival rates. Lastly, a section of future research is also included where we discuss the immunogenetic profile of these cardiac tumors, which can form the springboard for crafting tailor-made therapies for these recalcitrant and aggressive tumors.

3. Pathological Hallmarks of Cardiac Angiosarcoma

3.1. Macroscopic Appearance

The common site of origin is the right atrium, but less commonly, it can be located in the left atrium, right ventricle, and left ventricle [27]. The average size of the tumor is approximately 5.9–7.2 cm (range: 1.5–17 cm) [27,28,29,30]. The gross appearance of cardiac angiosarcoma tends to attract attention by impersonating different morphological forms, although some commonalities between them cannot be ruled out. It can stick out as an intramural mass, completely replacing the right atrial wall and protruding into the atrial lumen as an irregular or nodular outline [25,31]. Alternatively, it can assume cauliflower or sunray appearance with foci of blood splattered all over [27,31,32,33]. Sometimes, it can present as a solitary mass confined to the pericardial membrane while sparing the right atrial chamber [34]. The tumor catches the eye as a red-brown papillary neoplasm with hemorrhagic, necrotic, and tan-brown solid areas interspersed within the tumor [25,27,28].

3.2. Microscopic Appearance

Histological biopsy of cardiac angiosarcoma is confirmatory. Studies indicate that the transesophageal-guided endomyocardial biopsy of tumors is rarely sufficient for histological diagnosis, as it has a low diagnostic yield [17,35,36,37]. Some clinicians tried transbronchial biopsy, but it did not have a good success rate for the diagnosis of angiosarcoma [18]. However, surgical intervention, incisional biopsy, and intraoperative frozen sections will have higher diagnostic accuracy for the diagnosis of angiosarcoma [35,36]. It is important to keep in mind that the biopsy of these tumors can be problematic, with an increased risk of hemorrhage due to their high vascularity and tissue adhesions [38].

Histologically, the tumor can be classified as spindle cell (most common), epithelioid, and biphasic [25,27,28]. In an immunohistochemical and grading study of 24 primary cardiac sarcomas, angiosarcoma presented itself as an anastomosing microvasculature studded by malignant cells with some of them overhanging into the luminal space of the vessels [25,27,30]. These cancerous endothelial cells have a microscopically specific appearance with pale eosinophilic cytoplasm, hyperchromatic nuclei, and an abundance of mitotic figures [39]. Interspersed between these tumor cells are thick-walled capillaries with eye-catching pericytes [39]. Moreover, almost all the angiosarcomas diagnosed belonged to histological grades II or III [25,29,30]. Another prominent histological characteristic of angiosarcoma cancer cells is the increased predominance of mitotic activity, with an average of 6–32 mitoses per 10 HPF [high power field] [25,28,30]. On top of that, a frequent finding unique to all cardiac angiosarcomas in most clinical studies is the appearance of tumor necrosis [25,27,28].

4. Case Summaries

As angiosarcomas have non-specific and varied presentation, we compiled a list of interesting angiosarcoma cases that have been documented in the literature in a table format. In each case, we presented the details including, age/sex, symptoms, primary site, metastasis, ultrasonography, CT/MRI imaging, treatment, and prognosis (

Table 1. Clinical case series of Cardiac Angiosarcoma.

Case	Age/Sex	Primary Site	Symptoms	Metastasis	USG/Angiography	CT Scan/MRI	Treatment	Prognosis	Reference
1	26-year-old male	Right ventricle	Left hemithorax heaviness, and mild dyspnea	NIL	Immobile nonhomogeneous lobulated mass in the right ventricle (RV) apex	MRI: Round intracavitary mass in the RV apex with well-defined borders, isointense in T1 weighted image, hyperintense in T2 weighted image	Median sternotomy (MS) followed by full pericardiotomy	No recurrence after discharge	[40]
2	58-year-old male	Left atrium	Shortness of breath and bradycardia	Inferior vena cava	NIL	MRI: An 8.8 × 6.4 cm × 6.6 cm mass affecting primarily the left atrium, with extension into the right atrium, pericardium, circumflex coronary artery, and IVC	Three-dimensional conformal radiation and docetaxel	Poor prognosis. The patient died 16 months after radiotherapy	[23]
3	49-year-old male	Right atrium	Dyspnea and cyanosis	NIL	Mass in the right atrium moving into tricuspid valve during diastole	NIL	Surgical resection with postoperative radiation	Good. No signs of tumor recurrence or metastasis 36 months after surgery	[41]
4	45-old-female	Left atrium	Confusion and left side weakness	Brain	NIL	CT/MRI: Multiple cerebral lesions with cerebral edema	Radiation was offered but was not administered.	Declining clinical course with death within three weeks	[42]
5	17-year-old female	Pericardium	Dry cough, dyspnea, and periodic fever	NIL	Moderate amount of pericardial fluid with constrictive pericarditis	No metastasis	Pericardiectomy with postoperative docetaxel	Poor. Died within two weeks of discharge secondary to respiratory failure	[43]
6	64-year-old male	Right coronary artery	Chest pain dyspnea	Right atrium, brain, spleen, adrenal, and bone	Massive pericardial effusion with cardiac tamponade	CT scan: Mass in the mediastinum. Left heart catheterization: Hypervascular tumor from RCA to acute margin of the heart	Surgical resection with postoperative paclitaxel	The patient succumbed within 5 months of diagnosis due to extensive metastasis.	[44]
7	31-year-old male	Pericardium	Shortness of breath, orthopnea, and hemodynamic compromise	Mediastinum,	Large pericardial effusion	CT scan: Large homogeneous mass within pericardium and mediastinum infiltrating big vessels and right atrium. Pulmonary embolism of RPA	Repeated pericardiocentesis. Chemotherapy with vincristine, ifosfamide, doxorubicin, and etoposide did not evince a favorable tumor response. Following this, treatment with paclitaxel and pazopanib was initiated.	Patient improved clinically after a paclitaxel and pazopanib > 10 months follow-up revealed that the patient was resuming everyday activities.	[45]
8	20-year-old male	Pericardium	Epistaxis, hemoptysis, malaise, pain in right hip, epigastrium, bilateral pleural effusions and peripheral edema, and weakness of the left arm, left hemiplegia.	Lungs, liver, and brain	Right carotid angiography: Large mass in the right posterior parietal region	NIL	Thoracotomy, repeated thoracocentesis, and pericardiocentesis	The patient rapidly deteriorated and died 5 months within the onset of illness	[46]
9	41-old female with intrapapillary breast carcinoma treated with lumpectomy and radiotherapy	Pericardium	Progressive dyspnea, orthopnea, cough, repeated pleural, and pericardial effusions	Pleural and right atrium	Preserved left ventricular ejection fraction, diastolic dysfunction, bilateral pleural effusions, and evidence of effusive-constrictive pericarditis	Hemorrhagic pericardial fluid with mass in the right atrium	Open chest pericardiectomy. Paclitaxel for palliative therapy	Grave prognosis due to tumor not amenable to complete resection	[47]
10	20-year-old women	Chest pain, back pain, fever, and malaise	Pericardium and right atrium	Lung and left atrium	Massive and bloody pericardial effusion.	MRI: Massive bilateral pleural effusion, mass in the right atrium	Pericardiocentesis, open heart surgery. The right atrium is removed and replaced with a Gore-tex sheet. Palliative chemotherapy with cyclophosphamide, doxorubicin and decarbazine	Poor prognosis. The patient died within 2 months of chemotherapy.	[48]
11	65-year-old male	Transferred from another hospital for intracardiac mass. A 6-month history of dyspnea, asthenia and PAF. Nausea, vomiting, weight loss, asthenia, and dizziness	Right atrium	NIL	Large immobile mass in the right atrium attached to the inter-atrial septum. Mild TR. The right atrium is severely dilated, and RV is small.	NIL	NIL	Patient died a few hours after ultrasonography	[49]
12	63-year-old female	Atrial fibrillation with a rapid ventricular response. Palpitation, asthenia, dry cough, and fever.	Inter-atrial septum	NIL	Inhomogeneous sessile mass originating from the inter-atrial septum and occupying 70% of the left atrial cavity. The tumor invaded the right upper pulmonary vein.	Nil	Complete excision of the tumor and reconstruction of the left atrium, pulmonary vein and pericardium is performed.	Grave prognosis. The patient expired 8 days after surgery due to respiratory failure.	[49]
13	28-year-old male	Low back pain in sternocostal and lumbro-sacral regions.	Right atrium	Lung and bone	TTE = Ill-defined hypoechoic mass attached to the lateral wall of the right atrium.	Cardiac MRI: Right atrial tumor with multiple pulmonary lesions. Enhanced MRI: Arterial heterogeneous enhancement. PET CT: Increased FDG uptake with pulmonary and bone metastasis	Palliative chemotherapy with epirubicin, ifosfamide, and pembrolizumab. Palliative radiotherapy (20 Gy/5 f) at the sites of the 10th vertebra.	Repeat CMRI and chest CT showed significant regression of the tumor and pulmonary metastases. Now, the patient continues chemotherapy and immunotherapy	[50]
14	35-year-old female	Right atrium	Occipital headache, cough, chills, slurred speech, and nystagmus.	Midbrain, lungs, ovaries, uterus, spleen, liver, thyroid gland, kidney, and lymph nodes.	NIL	NIL	NIL	Patient died after a lumbar puncture. Autopsy: Mass in the right atrium, with tumor deposits in the pulmonary trunk, ascending aorta, and pericardium.	[51]
15	44-year-old male	Left atrium.	Shortness of breath, chest pain, and fatigue.	NIL	TTE = Mass in the left atrium with extensive pericardial effusion.	Chest CT: Infiltrating, spreading tumor that invades the pericardial cavity, pericardium, and left lung hilum. Chest MRI: Large tumor (5.3 × 4.9 × 5.0 cm), heterogeneously hypointense on pre-contrast T1W and T2W images, developed from the posterior left atrial wall and attached to the posterior mitral valve leaflet and the left lung hilum	Mediastinal endoscopic surgery: Complete removal of the tumor with the right atrium. Postoperative chemotherapy	The patient made a remarkable recovery after >1 month of intensive treatment (adjuvant chemotherapy) and is still living a healthy life with his family, without signs of metastasis, 6 months postoperatively.	[52]

).

5. Treatment

The treatment plan for angiosarcoma is based on the presence of tumor-free margins or tumor-positive margins. Additionally, patient management varies depending on the presence of a locally advanced tumor or, else, distance metastasis. A combination of surgical resection, chemotherapy, radiation, anti-molecule therapy, and targeted therapy based on immunohistochemical analysis are currently adapted treatment modalities based on the pertinent clinical scenario. Cardiac transplantation and enrollment in the clinical trials are made depending upon the clinical severity of patients. A summary of the treatment plan is presented in Figure 1.

5.1. Surgery

The overall 5-year survival rate of cardiac angiosarcoma is roughly 31%, with higher chances of survival in tumors with superficial invasion and negative microscopic surgical margins [53]. Wide resection of tumor margins supplemented with some palliative procedure to restore cardiac output would be an ideal surgical intervention for angiosarcomas of the heart [54].

It is important to understand that the end purpose of surgical intervention in cardiac angiosarcoma is to achieve tumor-free surgical margins, which is the pivotal prognostic factor that has a major impact on the ultimate clinical outcomes [55]. In most instances, accomplishing this objective is far-fetched due to the operation of multiple factors, including aggressive local invasion, deferred diagnosis, and tumor abutting vascular endothelial cells, provoking early metastasis [55]. Due to the aforementioned factors, most patients present with advanced clinical stage and positive tumor margins, thereby precluding complete surgical resection and bringing on shorter survival rates and worse prognosis in these patients [25,27,55]. There are no relatively safe margins that can be taken into consideration during surgical resection of cardiac angiosarcoma [56]. Even though tissues at the surgical margins are macroscopically normal, complete surgical resection of these tumors will yield R0 stage (No residual tumor) in roughly 50% of cases, according to multiple studies [56,57,58]. As a result, despite complete surgical resection, most of these cardiac tumors necessitate revision surgery to remove the recurrent tumor [56].

In a clinicopathological study of 24 patients with cardiac angiosarcoma spanning from 1994 to 2006 in the Methodist Hospital of Houston, complete surgical resection was possible only in 22.7% of cases, while the rest, 77.3% of cases, had incomplete resection due to tumor overrunning into the surrounding tissues [27]. In a clinical study between 1980 and 1997, where 91 patients with primary cardiac tumors were subjected to surgical intervention, 66% of the patients required re-resection for excising the residual tumor load, and all the patients succumbed due to tumor complications, metastasis or complications of therapy within 3 months of primary surgery [54]. On that account, the median survival rates of patients with complete surgical remission and incomplete surgical excision are 17–25 months and 5–6 months, respectively [29,55,57]. The mean survival rate of angiosarcoma patients undergoing surgery and those without surgery is approximately 14.3 months vs 3.8 months [59].

Due to their aggressive growth traits and metastatic potential, malignant cardiac tumors command the supplementation of surgical therapy with potent adjuvant therapy (chemotherapy or radiation) to promote optimal clinical outcomes, better prognosis, enhanced patient outcomes, and longer patient survival of up to 3 years [41,54,55,60,61]. Interestingly, while some studies showed encouraging results with post-surgical adjuvant therapy, others demonstrated no change in the prognosis and survival interval of cardiac angiosarcomas. In a study involving the analysis of 10 cardiac angiosarcoma cases, the patients randomized to receive adjuvant therapy following surgery had better survival as compared to those who did not [28]. Equivalently, in patients with cardiac angiosarcoma who underwent extensive surgical resection, starting postoperative doxorubicin therapy was beneficial for modulating the natural progression of these tumors so that long tumor-free survival times and better prognosis were final outcomes [62]. In contrast, despite comprehensive treatment regimens, the overall survival of patients with malignant sarcomas is very low and patient demise can be ascribed to therapy complications, recurrent tumor, or metastasis [54,63]. According to the experience of managing malignant cardiac tumors at the University of Minnesota, extensive surgical resection complemented with chemoradiotherapy did not yield promising results, with mean survival time being 5 months after surgical intervention, and 26% of these tumors had already been metastasized by the time of diagnosis [64]. According to Burke, A.P. et al., some of the prognostic factors that are associated with better survival rate using univariate analysis in cardiac angiosarcomas include tumor location on the left side of the heart, absence of necrosis, no metastasis, low mitosis, complete surgical resection, primary cardiac tumors other than angiosarcoma, and chemoradiation therapy [62,65]. Likewise, other prognostic factors of angiosarcoma included in the literature are tumor grade, tumor necrosis, and mitotic rate [26,30,65]. In a population-based retrospective diagnostic study, tumor size and chemotherapy were considered to be important prognostic factors for cancer-specific survival of cardiac angiosarcomas [66]. In practical terms, progression-free survival time is less in angiosarcoma (5 months) as compared to other primary cardiac sarcomas, namely malignant fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, and synoviosarcoma (17 months) [57,62].

5.2. Chemotherapy

The treatment options for cardiac angiosarcoma include surgery, chemotherapy, and radiotherapy, either alone or in combination, based on clinical stage and patient profile [55]. Clinical studies employing the utilization of chemoradiation therapy and surgery either alone or in combination in the treatment of angiosarcomas have yielded mixed results [10]. Paclitaxel is effective in the treatment of angiosarcomas due to its inherent tendency to retrogress VEGF [vascular endothelial growth factor]-induced neovascularization [67]. It is administered intravenously in 4-week cycles and has been found to have a substantial clinical benefit with respect to the modest prolongation of progression-free survival rate in angiosarcoma [68]. In a clinical study where they administered weekly paclitaxel therapy to 30 patients of visceral angiosarcoma (involving liver, kidney, small bowel, breast, skin, bone, and head and neck) between 2005 and 2006, the progression-free survival rate at 4 months was 45%, while the overall survival of these patients was roughly 8 months [68]. With weekly paclitaxel therapy proving modest improvement in the patient-free survival of visceral angiosarcoma, it would be prudent to gauge its clinical efficacy in locally advanced and metastatic cardiac angiosarcoma. In unresectable or metastatic angiosarcomas where weekly paclitaxel was administered, the non-progression of tumor growth was evidenced in 78% of cases, while complete histological responses were noted only in 10% of cases [69]. In some instances, pericardial involvement along with multiple lung metastases responded completely with single therapy paclitaxel even without co-administration of radiotherapy [70]. In a case report by Hata, A. et al., they present a case of right atrial angiosarcoma with multiple lung nodules, which had remarkedly responded with combination therapy with paclitaxel and carboplatin [20]. In a case report by Suderman, D. et al., where a cardiac angiosarcoma patient presented with a cardiac mass under the esophagus infiltrating pericardium, left atrium, left ventricle, inter-atrial septum, circumflex coronary artery, and inferior vena, delivering a combination of radiation therapy and docetaxel afforded a progression-free survival of 16 months [23]. A 14-year prospective study on the clinical features and treatment outcomes of angiosarcoma revealed that progression-free survival with paclitaxel is between 2.8–6.8 months, whereas, with a doxorubicin-based regimen, it is 3.7–5.4 months [53]. In a case study by Barreto, L. et al., cardiac epithelioid angiosarcoma presenting with painful skin lesions on both hands treated with liposomal doxorubicin brought about complete tumor regression. Surprisingly, this exemplary treatment response translated into 48 months of progression-free survival upon follow-up, thus emphasizing the clinical efficacy of systemic chemotherapy in prolonging the patient’s lifespan [71]. Doxorubicin and ifosfamide were considered for neoadjuvant therapy before surgery because they tend to downsize the tumor burden and clear the cancer cells from the tumor margins, henceforth increasing the chances of complete surgical resection in these tumors [9,72]. In some studies, the application of neoadjuvant chemotherapy has yielded encouraging results by increasing the survival rate in cardiac angiosarcomas. Retrospective analysis revealed that neoadjuvant chemotherapy in right-sided cardiac sarcomas was instrumental in doubling the survival time (20 months versus 9.5 months) [73]. On top of that, following neoadjuvant chemotherapy, the survival interval in cardiac angiosarcoma patients undergoing R0 and R1 resection is 56 months and 9.5 months, respectively [73]. Alternatively, this regimen can be used as an adjuvant chemotherapy in metastatic disease with better chances of survival in patients with R0 resection as compared to R1 resection [72]. In a case report by Yadav, U. et al., a clinical case of right-sided angiosarcoma with pericardial metastasis treated with six rounds of doxorubicin + ifosfamide chemotherapy responded with a 50% reduction in the tumor burden; despite this, she developed cardiopulmonary failure and was ultimately transferred to hospice care [74]. In soft tissue sarcomas, the combination of gemcitabine + docetaxel was superior as compared to gemcitabine alone, with higher progression-free survival (6.2 months vs. 3 months) and increased medial overall survival (17.9 months vs. 11.5 months) [75]. There are currently few clinical trials that are currently underwork to still test the efficacy of gemicitabina + docetaxel combination in soft tissue and bone sarcomas, results of which might shed light on their clinical efficacy on progression-free survival and tumor recurrence [76,77]. These findings might be projected and added to the treatment protocols of cardiac angiosarcoma, thus providing a ray of hope for these recalcitrant malignancies.

In a few case reports, locally advanced primary cardiac angiosarcoma treated with 3D-conformal or standard fractionated radiation therapy in combination with docetaxel (25 mg/m²) granted a mild-moderate response, with tumor progression gridlocked for 12 months [22,23]. In other instances where the tumor was initially unresectable due to its incursion of surrounding tissues and vasculature, precedent paclitaxel (80 mg/m²) and radiotherapy (60 Gy in 30 fractions) were instrumental in substantial tumor shrinking and facilitated surgical resection [78].

5.3. Radiation Therapy

In most instances, radiation therapy is given in combination with chemotherapy, thus being used as a palliative therapy in locally advanced and metastatic cardiac angiosarcomas. However, few clinical reports published utilized radiotherapy as a primary therapeutic intervention or used it as an alternative when tumor response to chemotherapy is suboptimal. In a case report by Rhomberg, W. et al., a 65-year-old patient with primary cardiac angiosarcoma of the right atrium and liver metastasis was initially treated with combination chemotherapy (fosfamide, epirubicin, and dacarbizine) [79]. Even after five cycles of chemotherapy, the patient developed additional pulmonary metastasis with no regression of the primary tumor [79]. Subsequently, razoxane 125 mg twice daily (Radiosensizer) along with 30 Gy radiation was delivered, which resulted in the sub-total remission of the primary tumor but with no improvement in metastatic cancer after 5 months of therapy [79]. In another report, cardiac angiosarcoma of the pericardium extending into the right ventricle and coronary vessels treated with carbon-ion radiotherapy (64 Gy) over 4 weeks gave rise to substantial therapeutic benefit by shrinking the tumor mass by 86% [80]. Thereafter, the patient was given recombinant interleukin-2 (IL-2) therapy for the next 1.5 years, with the patient showing no regrowth, recurrence, or metastasis upon following up with CT scans [80]. These studies emphasize the effectiveness of radiation therapy either alone or as adjuvant therapy, which should be considered on a case-by-case basis in these cardiac malignancies.

5.4. Cardiac Transplantation

As a last resort, few clinicians have adopted cardiac transplantation after surgical excision of cardiac angiosarcoma as long as tumor-free margins are achieved. Consideration of cardiac transplantation in cardiac angiosarcoma is a decision that is taken after careful forethought and after a thorough scrutiny of various factors, including patient age, risk factor profile, risk of recurrences, economic feasibility, availability of matching donors and graft rejection. In a case report by Andrei, V. et. al., a young patient presenting with left-sided angiosarcoma managed with surgery and chemoradiation experienced tumor recurrences in the subsequent follow-up. Eventually, cardiac transplantation was performed, and follow-up was complicated with pericardial tamponade and cardiogenic shock, which are resultantly managed with veno-arterial extracorporeal membrane oxygenation until the patient regained near-normal left ventricular function [81]. Thus, even after cardiac transplantation, patients need to be closely monitored for any complications, and the success rate depends on the patient’s ability to accept the transplanted tissues. Consequently, it is a therapeutic option that is offered to very few patients after explaining all the pros and cons of the procedure. Although some clinical centers reported a 100% survival rate post-transplantation, other studies revealed shortened survival rates secondary to failure to achieve tumor-free margins, tumor recurrence, multiple metastases, and adjuvant therapy-induced tumor growth [82,83,84,85].

5.5. Antiangiogenic, Tyrosine Kinase Inhibitor Therapy, and Targeted Therapies Based on Immunogenetic Studies

Since VEGF is implicated in the angiogenesis and instigation of metastasis with the dislodging of tumor cells into the systemic vessels, efforts expended in blocking this molecule have yielded encouraging results so far in the recently conducted clinical trials [86,87]. In a single-arm, phase II trial, 32 angiosarcoma patients, out of which nine had tumors localized in the visceral organs, including the heart, were administered bevacizumab (VEGF antibody) 15 mg/kg IV infusions, with 50% of the patients exhibiting a stable response in locally advanced and metastatic tumors [88]. Bevacizumab, given in combination with chemotherapy and radiotherapy, also yielded complete responses in angiosarcomas [89,90]. Tyrosine kinase inhibitors, which can potentially inhibit the VEGF-mediated signaling pathways, have been tested in clinical trials [91]. In a multi-arm clinical trial, soratenib (tyrosine kinase inhibitor) was given to 145 angiosarcoma patients, and it gave rise to median overall survival and progression-free survival of 14.3 and 3.2 months, respectively, suggesting that it might be a viable candidate for usage either as solo or adjunctive therapy in cardiac angiosarcomas [92]. In some cases, whole genome sequencing of primary cardiac angiosarcoma revealed gene mutations, which can be used as a foundational basis for delivering targeted therapies. In a case report by Zhrebker, L. et al., whole genome sequencing of postmortem cardiac angiosarcoma tumor indicated the overexpression of novel KDR [kinase insert domain receptor] mutation (G68iR), as well as high-level amplification of chromosome 1q encompassing MDM4 (negative modulator of P53 or P53 binding protein) [93]. Based on these findings, clinicians concluded that specific KDR [kinase insert domain receptor] inhibitors would be a better strategy for supplementing the therapeutic regimens for effectively tackling prolific KDR [kinase insert domain receptor] activation in these tumors [93]. Furthermore, some of gene amplifications recognized upon genome sequencing of angiosarcoma include DNMT3A [DNA (cytosine-5)-methyltransferase 3A], POT1 [Protection of Telomeres 1], N-RAS [NRAS Proto-Oncogene, GTPase], KRAS [KRAS Proto-Oncogene, GTPase], KIT [KIT proto-oncogene, receptor tyrosine kinase], KDR [kinase insert domain receptor], PLGC1 [Phospholipase C, gamma 1] and PDL1 [programmed death-ligand-1] [94,95,96,97]. Acknowledging these genetic aberrations will be helpful in crafting tailor-made therapies for effectively treating resistant and metastatic cardiac angiosarcomas, thus giving us an opportunity to increase progression-free survival and optimize clinical outcomes in these patients.

6. Future Research

Despite the administration of combination therapy, various factors, including advanced tumor stage, age, patient clinical profile, response to therapy, and side effects of therapy, might affect treatment outcomes, thus substantially increasing the risk of mortality and morbidity in these patients. In most cases, the survival rate of the patients is very low (weeks to months), thus drastically reducing the life expectancy of these patients. This warrants pertinent research to unmask the molecular characterization and genetic abnormalities of these angiosarcomas, which might unravel cryptic signaling molecules that might overrule their tumor growth and metastatic potential [Figure 2] [97]. Molecular cytogenetic analysis of 10 cardiac angiosarcoma cases by Leduc, C. et al. unmasked a multitude of aberrations, including trisomy (Single chromosome gain) of chromosomes 4, 8, 11, 17, and 20, a gain of the long arm of chromosome 1 (1q+) and homozygous deletion of CDKN2 [cyclin-dependent kinase inhibitor 2A] [28]. Likewise, additional chromosomal changes noted include trisomy 5, deletion of the short arm of 7, alterations of chromosomes 8.20 and 22, and loss of chromosome Y [11]. Additionally, immunohistochemical analysis unveiled that most of the cardiac angiosarcomas showed immunoreactivity to cytokeratin, Factor VIII antigen, smooth muscle actin, Ki-67 [nuclear protein], WT-1 [Wilms’s tumor gene], P53 [tumor suppressor gene], EMA [epithelial membrane antigen 31], ERG [ETS-related gene], FLI-1 [Friend leukemia integration 1 transcription factor], CD31 [cluster of differentiation 31] and CD34 [cluster of differentiation 34] [25,27,28,29,30]. Out of these, CD31 is the most common and hallmark criterion that is symbolic of cardiac angiosarcoma [10]. Idiosyncratically, cardiac angiosarcomas were precisely identified using diffuse and intense cytoplasmic staining of Wilms tumor gene (WT-1) with immunohistochemistry, a feature that assists in differentiating it from primary cardiac tumors such as synovial sarcoma, leiomyosarcoma, and other unclassified sarcomas [25]. Human angiosarcomas predominantly express galactin (GAL-3), which affords anti-apoptotic attributes to the cancer cells via upregulation of MAPK and downregulation of Bad expression [98]. Resultantly, small molecule compounds inhibiting GAL-3 expression might potentiate the therapeutic efficacy, as well as increase the vulnerability to the cytotoxic effects of anticancer regimens on angiosarcoma cell lines [98]. According to Itakura, E. et al., the immunohistochemical expression of VEGF-A [vascular endothelial growth factor-A] (94%), VEGF-C [cVascular endothelial growth factor-C] (12%), VEGFR-1 [vascular endothelial growth factor receptor 1] (94%), VEGFR-2 [vascular endothelial growth factor receptor 2] (65%), and VEGFR-3 [vascular endothelial growth factor receptor 3] (79%) were noticed in these cardiac angiosarcomas [99]. Specifically, the heightened presence of VEGF-C [vascular endothelial growth factor-C] in cardiac angiosarcomas will provide them the required impetus for rapid growth and increase their proclivity to lymphatic metastasis [99]. Over and above, these tumors were distinguished by the nuclear staining of P53 [tumor suppressor gene] and Ki67 [nuclear protein], a feature that marks the highly proliferating nature of these tumors and serves to distinguish them from benign malignancies [25]. It is vitally important to know that endothelial cells harboring tumor cells have a predominant expression of CD31 [Cluster of differentiation 31], CD34 [Cluster of differentiation 34] and factor VIII antigen as compared to normal adjoining endothelial cells [30]. In a study by Urbini, M. et al., the molecular characterization of cardiac angiosarcomas revealed the alteration of multiple genes including POT1 [Protection of Telomeres 1], KDR [kinase inserts domain receptors], PLCG1 [Phospholipase C, gamma 1], TP53 [tumor suppressor gene], CDKN2A/B [cyclin dependent kinase inhibitor 2A], KRAS [KRAS Proto-Oncogene, GTPase], NRAS [NRAS Proto-Oncogene, GTPase], KMT2D [Lysine-specific methyltransferase 2D], CIC [Capicua transcriptional repressor] FLT4 [Fms-related receptor tyrosine kinase 4], and MYC [proto-oncogene] [97,100,101,102]. The activation of P53 [tumor suppressor gene] and KRAS has been demonstrated in young males with primary cardiac angiosarcomas [103]. Animal studies have disclosed that RAS activation in the tumors ignites angiogenesis via the increased expression of VEGF [vascular endothelial growth factor] and MMP [matrix metalloproteinase], the inhibition of tissue inhibitor of MMP [matrix metalloproteinase], and the stimulation of PI3 [Phosphoinositide 3] kinase [104]. Increased PI3 [Phosphoinositide 3], MMP [matrix metalloproteinase], and VEGF [vascular endothelial growth factor] production is detrimental as they provoke tumor proliferation, degradation of basement membrane components (Laminin, collagen type IV, fibronectin, and heparan sulfate proteoglycan) and escape of cancer cells into systemic circulation, respectively [105,106,107].

The underlying and intrinsic signaling mechanisms that foster incessant proliferation, persistent angiogenesis, and endless survival of angiosarcoma cancer cells are PI3K [Phosphoinositide 3-kinases]/AKT [Protein Kinase b]/PLCG1 [Phospholipase C, gamma 1]/PKC [Protein Kinase C], and RAS [proto-oncogene] pathways [97]. The tumor growth and their aggressive behavior can be subdued with a drug regimen including monoclonal antibodies, tyrosine kinase inhibitors, RAF [rapidly accelerated fibrosarcoma] inhibitors, PKC [Protein Kinase C] inhibitors, and P13K [Phosphoinositide 3-kinases]/mTOR [mammalian target of rapamycin] inhibitors, either alone or in combination [97]. All the abovementioned crucial information can be carefully capitalized for crafting novel diagnostic and therapeutic modalities, thus enabling us to promptly diagnose and competently manage these recalcitrant metastatic tumors [97]. Along with it, this information can form the springboard upon which novel blood-based biomarkers can be devised. The expeditious diagnosis of cardiac angiosarcomas is imperative not only from a treatment perspective but also for recruitment to the currently active clinical trials so that these patients can take advantage of the latest advancements in the therapeutic modalities of cardiac malignancies. Moreover, this approach can be harnessed to design and deliver patient-centric therapy based on their inherent molecular/genetic aberrations [97]. Basic science and clinical research studies assessing the potency of these patient-centric therapies are warranted before launching multi-centered clinical trials. Once these designed diagnostic and patient-centric therapeutic interventions demonstrate efficacy in the clinical trials, they can be brought to the primary care clinics for earlier diagnosis and effectual management of these cardiac tumors. Fruitful efforts in this regard might be the stepping stones for boosting tumor regression, reversal of tumor progression, improved patient quality of life, longer patient survival, and favorable prognosis in these cardiac malignancies.

7. Conclusions

Despite their rarity, primary cardiac angiosarcomas should remain high on the differentials list for young male patients with non-specific presentations. Echocardiogram is the preferred initial imaging modality. Diagnosis is confirmed on cardiac CT or MRI. PET scans can be utilized for staging. Definitive diagnosis relies on the surgical incisional biopsy and examination of pathology with immunohistochemistry. Surgery is the mainstay treatment modality, although chemoradiotherapy and immunotherapy are beneficial. Recently, whole genome sequencing of the tumor specimens revealed varied genetic mutations, which can form a basis for delivering tailor-made targeted therapies for modest increases in survival and clinical outcomes. Overall, unusual presentation, delayed diagnosis, aggressive growth, and metastasis are some of the factors that give rise to grave prognosis in these patients. Research studies and clinical trials are warranted for harnessing novel modalities of treatment that might provide a ray of hope for the future.