Angiosarcoma of the Heart

Corresponding Author

Angiosarcoma is a malignant endothelial cell tumor of lymphatic or vascular origin with aggressive progression, high metastatic capability, and local recurrence rate. This malignancy represents <1% of all soft tissue sarcomas. It originates from vascular endothelium featured by a variable degree of cellular atypia and progresses along vascular structures, such as vessels, cavernous spaces, and sinusoidal cavities. The tumor may form solid masses, nodules, poorly differentiated vessels, or amorphous structures. The histopathological identification may pose a challenge for the differential diagnosis of further vascular tumors (i.e., hemangiomas), but the aggressive form can resemble even epithelial carcinomas (1).

Due to the endothelial origin, angiosarcomas develop throughout the body. The cutaneous form is the most common, mainly involving the head and neck region and representing more than one-half of all angiosarcomas but <0.1% of all malignancies of the same region. It occurs more frequently in male subjects, with a reported median age of the sixth decade of life. Angiosarcoma primarily spreads hematogenously, and lungs are the primary target of metastases; however, liver, bone, and lymph node secondary infiltrates are common. The site of origin is often uncertain at the time of diagnosis, and multiorgan infiltration challenges all therapeutic attempts. Previous radiation therapy and chronic lymphoedema are risk factors of the disease, although familial syndromes and environmental toxins can also initiate the malignant transformation (2).

Primary cardiac tumors have an autopsy incidence <0.5%, and 75% of them are benign. The most common cardiac malignancy is represented by sarcomas, with 21% angiosarcomas, 17% synovial sarcomas, 10% malignant fibrous histiocytomas, and 10% intimal sarcomas (3). The first identified heart tumor by Realdo Columbus dates back to the 16th century, although the first scientific report emerged only in 1934. Primary cardiac angiosarcomas are featured by an aggressive infiltration of the myocardial wall and adjacent structures or intracardiac cavities. Predominantly, the right side of the heart is involved in the disease, especially the right atrium, and a pericardial extension is often observed (Figure 1). The right coronary artery is commonly infiltrated or surrounded, making surgical debulking hazardous (Figure 2), although in some cases, the origin of malignancy was located in the coronary artery itself (4). Patients suffering from cardiac angiosarcoma are younger than those having other primary organ origins; the cardiac mean age at diagnosis measured 50 years without gender predominance in a 25-year retrospective review reported by the Cleveland Clinic (3).

Figure 1.

Cardiac Angiosarcoma Is Mobilized With Adherent Pericardium

Figure 2.

Total Right Atrial Free Wall Resection

The arrow indicates the marked right coronary artery to avoid incidental injury at structural bovine pericardial patch reconstruction.

In this issue of JACC: Case Reports, Jex et al. (5) document the case of a 30-year-old man who presented with palpitations, fever, and pleuritic chest pain with complaints of an acute reduction in exercise tolerance. His medical history was unremarkable. The differential diagnosis included the novel coronavirus (SARS-CoV-2) infection, other viral or bacterial pneumonia, and venous pulmonary embolism. D-dimer levels were elevated, and computed tomographic pulmonary angiogram revealed a voluminous soft tissue mass in the mediastinum. Transthoracic echocardiogram and cardiac magnetic resonance scan demonstrated a large right atrial mass filling >90% of the chamber lumen. Furthermore, the mass invaded the right atrial wall, the atrioventricular groove, basal right ventricular free wall segment, and anterior tricuspid valve leaflet and has limited the inferior caval inflow. A concomitant moderate pericardial effusion was detected. Heterogeneous signal intensity was detected on T₁ and T₂ weighted images, and on early and late gadolinium enhancement imaging, first-pass perfusion imaging demonstrated heterogeneous enhancement with increased marginal and reduced core perfusion of the mass. These features were strongly suggestive of a cardiac angiosarcoma, and fluorodeoxyglucose–positron emission tomography revealed a moderate uptake within the tumor and additional chest wall lymph node positivity and pelvic bone involvement.

Results of a trans-jugular core biopsy confirmed CD34 and ERG-positive spindle cell angiosarcoma of the heart. The highly vascular mass was supplied from the right coronary artery and had already compressed the supplying vessel. Due to widespread metastasis, a curative treatment was not possible but de bulking surgery was performed. The free wall of the right atrium was reconstructed after an extensive resection, and the distal right coronary was grafted. The patient underwent doxorubicin palliative chemotherapy and radiotherapy for pelvic metastases. Despite all therapeutic efforts, the patient passed away 4 months after the initial diagnosis.

In the introduced case (5), the nonspecific initial presentation of this life-threatening disease is well demonstrated; later on, the logical pathway of diagnostic sequence guides us through the pitfalls of decision-making.

Both symptomatic and conventional diagnostic modalities, including chest radiography and echocardiography, may provide a hint regarding cardiac angiosarcoma, revealing a dominantly right heart involvement in terms of mass location, right-sided diastolic dysfunction, and cardiac tamponade. The differential diagnosis has a broad spectrum starting from myxoma to thrombus, metastasis, lymphoma, and rhabdomyosarcoma. Chest radiography shows asymmetric cardiomegaly; computed tomography imaging demonstrates a highly vascular right-sided mass involving the chamber cavity, mainly with an irregular contour. On T₁ weighted magnetic resonance images, cardiac angiosarcomas are isointense; on T₂ weighted samples, they are hyperintense. They may show lobulated, “cauliflower” configuration, and a “sunray” effect has been described on contrast-enhanced magnetic resonance imaging in cases of pericardial involvement. On T₁ weighted gradient echo sequences, a hypointense layer with phase shift features the hemorrhage within the mass caused by its highly vascular nature. On steady-state free precession images, angiosarcomas are hyperintense in contrast to normal myocardium. Alteration of high and low signal intensities refers to hemorrhages and necroses within the conglomerate (2). 18-fluorodeoxyglugose–positron emission tomography can effectively reveal active uptake within the tumor tissue and signal lymph node positivity or distant metastases.

In addition, the level of uptake in primary tumor enables following up the response to neoadjuvant chemotherapy. Transesophageal echocardiography has 97% sensitivity in detecting cardiac masses; in addition to the extent and shape of tumor, mobility and attachment to the surroundings can be reliably assessed. Coronary angiography and ventriculography can reveal the blood supply and location of the neoplasm, and invasive access enables the most definitive diagnostic modality, histopathologic sampling (4).

The masses appear dark red to tawny macroscopically (Figure 3), with infiltrative lobulated borders that may imperceptibly merge with the endocardial surface. The most common cytomorphology is represented by spindle cells (Figure 4), but pure epithelioid and biphasic forms containing both spindle cell and epithelioid features are known. ERG is the most sensitive vascular marker with diffuse immunoreactivity; FLI-1 is at least focally present in angiosarcoma samples, just as CD31 positivity. Immunoreactivity for CD34 features the lowest sensitivity compared with other vascular markers. Several recurrent cytogenetic aberrations are identified in these tumor samples, including trisomies in chromosomes 4, 8, 11, 17, and 20 and homozygous deletion of CDKN2 (6).

Figure 3.

Typical Macroscopic Appearance of a Tawny Colored Cardiac Angiosarcoma

En bloc resection with infiltrated pericardium.

Figure 4.

Spindle and Atypical Cells With Blood-Filled Vascular Channels at 20× Power of Magnification

Complete surgical resection of cardiac angiosarcoma is often impossible, if it is detected at an advanced stage. However, right-sided cardiac sarcomas with R0 resection show a significantly better median and 5-year survival than patients with R1 resection (median: 27 months vs. 4 months; 5 years: 36% vs. 0%). Achieving R0 resection in right-sided cardiac sarcomas varies between 38% and 42% in the literature, although >80% of patients have some degree of metastatic disease at the initial diagnosis. Conversely, left-sided cardiac sarcomas may lead to early heart failure in the disease process; they are more circumscribed and less infiltrative, as they exhibit better overall survival and metastasize later (7). The right-sided version often requires a complete resection of the right atrial free wall and an atrioventricular groove debridement. The vicinity or process involvement of the right coronary artery poses a technical challenge. The right coronary may require patching or bypass grafting, although with intact vascular walls and debrided atrioventricular groove, a patch inclusion into the right atrial cavity may offer a suitable operative solution. Resection of left-sided sarcomas, especially left atrial sarcomas, is facilitated by a cardiac autotransplantation procedure. Nevertheless, if the tumor extends too far into the pulmonary veins to allow a complete resection without including a pneumonectomy, the patient should not be considered for operation. Combined cardiac autotransplantations with pneumonectomies are less successful, with a mortality rate >50% due to bleeding into the pneumonectomy space, multiple transfusions, unilateral pulmonary edema, and right heart failure (7).

The Houston Methodist Heart Center demonstrated that neoadjuvant chemotherapy with doxorubicin hydrochloride and ifosfamide facilitates cytoreduction effectively and eliminates microscopic fingers of disease invading the surrounding tissues. Patients receive 6 cycles of chemotherapy before proceeding to surgery. If an optimal response is not achieved, alternative regimens are considered such as gemcitabine and docetaxel. Overall median survival for right-side sarcoma measures 20 months in their experience. Median survival after receiving neoadjuvant chemotherapy is double that of without (20 months vs. 9.5 months). Patients with R0 resection have a significantly longer median overall survival (53.5 months vs. 9.5 months). Additional radiotherapy application is often debated; it is mainly utilized if a localized tumor is present outside the heart or further cardiac resection is not possible (8).

Finally, we emphasize the utmost importance of thorough and generous resection of atrial “myxomas”; hence, one sample in our experience was later histologically diagnosed as interstitial sarcoma, and the sufficient resection has saved the patient’s life.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.