Primary Pericardial Angiosarcoma Demonstrating Initial Response Followed by Progression on First‐Line Chemotherapy: A Case Report

ABSTRACT

Primary pericardial angiosarcoma is an exceedingly rare and highly aggressive malignancy arising from pericardial endothelial cells, with a reported median survival of approximately 7 months. Owing to its non‐specific clinical presentation, diagnosis is frequently delayed, particularly in tuberculosis‐endemic regions, where symptoms may be attributed to tuberculous pericarditis. We report the case of a 25‐year‐old Nepalese male who presented with a six‐month history of progressively worsening dyspnea (MMRC grade 1 to 4) and an ECOG performance status of 3. Initial evaluation revealed a large pericardial effusion and a right atrial mass measuring 4.5 × 3.7 × 3.2 cm on MDCT. Based on trace Mycobacterium tuberculosis detection on sputum GeneXpert with indeterminate rifampicin resistance, the patient was initially diagnosed and treated as tuberculous pericarditis. However, symptoms persisted despite 2 weeks of antitubercular therapy. Subsequent pericardiocentesis yielded hemorrhagic fluid; repeat sputum and pericardial fluid testing were negative for tuberculosis, and pericardial fluid cytology was inconclusive for malignancy. Due to persistent diagnostic uncertainty, the patient underwent median sternotomy with creation of a bilateral pleuropericardial window. Histopathological examination revealed high‐grade angiosarcoma, with immunohistochemistry positive for CD31, CD34, and ERG, and a Ki‐67 proliferation index of 30%. Baseline systemic staging showed no definite evidence of distant metastasis. The patient received first‐line chemotherapy with ifosfamide and epirubicin. After 3 cycles, remarkable clinical improvement was observed, including improvement in ECOG performance status from 3 to 1, complete resolution of the pericardial effusion, and a 65% reduction in tumor volume. However, following completion of 6 cycles, MDCT demonstrated disease progression with new left para‐aortic deposits measuring 5.6 × 2.6 cm. Second‐line chemotherapy with nab‐paclitaxel and gemcitabine was subsequently initiated, with planned response assessment after 3 cycles. This case highlights the significant diagnostic challenges of pericardial angiosarcoma in tuberculosis‐endemic regions and underscores the need to consider malignant etiologies in patients with hemorrhagic pericardial effusion and cardiac masses. Although substantial initial responses to chemotherapy may occur, the disease remains highly aggressive with a high risk of progression. Early histopathological diagnosis and timely initiation of adaptive, multimodal treatment strategies are critical to optimizing clinical outcomes.

Key Clinical Message

Primary pericardial angiosarcoma is a rare, highly aggressive tumor that is often misdiagnosed as tuberculous pericarditis in endemic regions. In patients presenting with hemorrhagic pericardial effusion accompanied by a cardiac or pericardial mass, infectious and malignant causes should be investigated simultaneously. Early tissue diagnosis is essential, as prompt initiation of systemic therapy may provide temporary clinical benefit despite the tumor's aggressive behavior and high risk of progression.

Abbreviations

ATT

Antitubercular Therapy

ECOG

Eastern Cooperative Oncology Group

IE

Ifosfamide‐Epirubicin

IVC

Inferior Vena Cava

LVEF

Left Ventricular Ejection Fraction

MDCT

Multidetector Computed Tomography

MMRC

Modified Medical Research Council

MTB

Mycobacterium Tuberculosis

SEER

Surveillance, Epidemiology, and End Results

1. Background

Primary cardiac tumors are rare entities, with an incidence of 0.001%–0.03% in autopsy series, of which approximately 25% are malignant [1]. Angiosarcoma represents the most common primary cardiac malignancy, accounting for 30% of all malignant cardiac tumors [2, 3]. Primary pericardial angiosarcoma, arising from pericardial endothelial cells, is particularly rare and carries an abysmal prognosis [4, 5, 6].

The clinical presentation of pericardial angiosarcoma is typically nonspecific, with patients presenting with dyspnea, chest pain, pericardial effusion, and cardiac tamponade [7]. These symptoms often lead to misdiagnosis, particularly in tuberculosis‐endemic regions where pericardial involvement may be attributed to tuberculous pericarditis [5, 6]. Data from the Surveillance, Epidemiology, and End Results (SEER) database indicates a median disease‐specific survival of 7.22 months with a five‐year survival rate of only 10.2% [8].

The aggressive nature of pericardial angiosarcoma, combined with its propensity for early metastasis and local infiltration, presents significant therapeutic challenges [6, 7, 8]. Current treatment strategies involve multimodal approaches including surgery, chemotherapy, and radiotherapy, though optimal sequencing remains undefined [1, 6]. We present a case that illustrates both the diagnostic challenges and the complex treatment course of this rare malignancy.

2. Case Presentation

2.1. Clinical History and Examination

A 25‐year‐old Nepalese male presented to Shahid Gangalal National Heart Centre with a six‐month history of progressive dyspnea. The patient initially experienced exertional dyspnea (MMRC Grade 1), which progressively worsened to MMRC Grade 4, ultimately resulting in dyspnea at rest and orthopnea. His ECOG performance status at presentation was 3. Associated symptoms included a non‐productive cough. The patient had no significant past medical history, no known allergies, and no history of tobacco or alcohol use. Family history was unremarkable for cardiovascular or oncologic conditions.

Physical examination revealed tachypnea with a respiratory rate of 24 breaths per minute, blood pressure of 110/70 mmHg, and a regular pulse of 96 beats per minute. Jugular venous pressure was elevated. Cardiac examination revealed muffled heart sounds with no audible murmurs. Bilateral basal crepitations were present on lung auscultation.

2.2. Diagnostic Assessment

2.2.1. Initial Investigations

Laboratory investigations showed hemoglobin 11.2 g/dL, total leukocyte count 8500/mm³; platelet count 320,000/mm³, and normal renal and liver function tests. Chest radiography demonstrated cardiomegaly with a cardiothoracic ratio of 0.65. The electrocardiogram showed sinus rhythm with intermittent junctional rhythm and low‐voltage QRS complexes.

2.2.2. Imaging Studies

Transthoracic echocardiography revealed a large circumferential pericardial effusion with evidence of early tamponade physiology, along with a heterogeneous mass in the right atrium, with LVEF preserved at 60%.

Contrast‐enhanced MDCT of the chest/abdomen/pelvis demonstrated a lobulated, heterogeneously enhancing soft tissue mass measuring 4.5 × 3.7 × 3.2 cm in the inferolateral right atrium at the junction of the inferior vena cava. The mass showed post‐contrast enhancement with intralesional vascularity. Additional findings included a large pericardial effusion (28 mm thickness), bilateral pleural effusions, subsegmental atelectasis, and mild ascites (Figure 1A,B).

FIGURE 1.

Pre‐treatment multidetector computed tomography. (A) Axial view demonstrates a lobulated soft‐tissue mass in the inferolateral right atrium with large pericardial and bilateral pleural effusions. (B) The coronal view shows the mass at the inferior vena cava junction with post‐contrast enhancement and intralesional vascularity.

2.2.3. Diagnostic Procedures

At the first presentation, the GeneXpert sputum test detected trace Mycobacterium tuberculosis with indeterminate rifampicin resistance, and the patient was initiated on ATT with isoniazid, rifampicin, pyrazinamide, and ethambutol. However, despite 2 weeks of ATT, the patient's symptoms persisted, and emergency pericardiocentesis was performed, draining 850 mL of hemorrhagic fluid. Repeat sputum testing and pericardial fluid analysis for Mycobacterium tuberculosis were negative. Pericardial fluid was also evaluated for malignancy, including cytology; however, cytology did not establish malignancy.

Given the lack of clinical improvement and diagnostic uncertainty, the patient underwent exploratory median sternotomy with creation of bilateral pleuropericardial windows. Intraoperative findings included hemorrhagic pericardial effusion and multiple pericardial nodules with evidence of pericardial thickening (Figure 2). Biopsy specimens were obtained from the pericardial nodules.

FIGURE 2.

Intraoperative photographs during median sternotomy showing creation of a bilateral pleuropericardial window with hemorrhagic pericardial effusion and nodular pericardial thickening; biopsy was obtained from pericardial nodules.

2.3. Histopathological Diagnosis

Histopathological examination revealed irregular, anastomosing vascular channels lined by atypical endothelial cells, with a highly infiltrative architecture and poor demarcation from surrounding tissue (Figure 3A). Higher magnification demonstrated vascular structures lined by cells with pleomorphic, hyperchromatic, plump, spindle‐shaped nuclei and scant cytoplasm, consistent with high‐grade angiosarcoma (Figure 3B).

FIGURE 3.

Histopathological and immunohistochemical findings. (A) Irregular anastomosing vascular channels lined by atypical endothelial cells (Hematoxylin and eosin, ×100). (B) Vascular structures lined by atypical cells with pleomorphic, hyperchromatic, plump, spindle‐shaped nuclei and scant cytoplasm, consistent with high‐grade angiosarcoma (Hematoxylin and eosin, ×400). (C) Immunohistochemical stains show tumor cells positive for CD34, CD31, ERG, and Ki‐67 proliferation index of 30%.

Immunohistochemical analysis demonstrated strong diffuse positivity of tumor cells for endothelial markers CD31, CD34, and ERG, confirming vascular differentiation. The Ki‐67 proliferation index was approximately 30%, indicating high proliferative activity (Figure 3C).

Additional immunostains were performed to evaluate key differential diagnoses, including WT‐1, calretinin, claudin, SALL4, S100, cytokeratin, p63, HHV‐8, and TFE3; all were negative, and INI‐1 expression was retained. These findings excluded mesothelial, epithelial, melanocytic, germ cell, epithelioid sarcoma, and HHV‐8–associated vascular neoplasms.

No tumor‐specific biomarker is currently established to guide systemic therapy selection in primary pericardial angiosarcoma; management is generally extrapolated from soft‐tissue sarcoma practice. Taken together, the morphological features and immunophenotypic profile confirm the diagnosis of high‐grade primary pericardial angiosarcoma.

2.4. Baseline Staging

Systemic staging was performed using contrast‐enhanced CT of the chest, abdomen, and pelvis with additional cranial imaging and cardiac MRI, which did not demonstrate definite distant metastases at baseline prior to initiation of chemotherapy. PET‐CT was not performed due to limited accessibility and cost constraints, as well as the urgency to initiate treatment without delay.

3. Treatment

3.1. First‐Line Chemotherapy

Following confirmation of the diagnosis, the patient was transferred to Kathmandu Cancer Center for specialized oncologic management. After a multidisciplinary team discussion, chemotherapy was initiated on a three‐weekly regimen. The protocol included ifosfamide at 1800 mg/m² administered intravenously on days 1 through 3, epirubicin at 75 mg/m² administered intravenously on day 2, and mesna given for uroprotection according to the standard protocol. Anthracycline‐based therapy remains a guideline‐supported first‐line approach for advanced high‐grade soft tissue sarcoma and is commonly extrapolated to cardiac/pericardial sarcomas.

3.2. Response Assessment After Three Cycles

Following 3 cycles of chemotherapy, a comprehensive response evaluation was performed.

3.2.1. Clinical Response

The patient demonstrated remarkable functional improvement with ECOG performance status improving from 3 to 1. Dyspnea improved from MMRC Grade 4 to Grade 1, with complete resolution of orthopnea. The patient could resume light daily activities with a significantly improved quality of life. No grade 3 or 4 toxicities were observed.

3.2.2. Radiological Response

MDCT chest showed a significant decrease in tumor burden, with the right atrial mass reducing from 4.5 × 3.7 × 3.2 cm to approximately 2.0 × 0.9 cm, representing a substantial reduction in tumor volume. Complete resolution of pericardial and bilateral pleural effusions was achieved. Residual hypo vascular pericardial thickening (maximum 15 mm) was noted along the outer wall of the right atrium, consistent with post‐treatment fibrosis (Figure 4A,B).

FIGURE 4.

Post‐treatment MDCT after 3 cycles of IE chemotherapy (A) Axial view shows a significant reduction in tumor size with resolution of pericardial effusion. (B) Coronal view demonstrates decreased mass size and resolved pleural effusions with residual hypovascular pericardial thickening.

3.3. Completion of First‐Line Therapy and Disease Progression

Given the excellent initial response, a decision was made to complete 6 cycles of IE chemotherapy, with plans for subsequent surgical evaluation for pericardial stripping and resection of any residual mass. The patient completed all 6 cycles without significant toxicity. However, the response evaluation with MDCT demonstrated disease progression. Imaging revealed a new heterogeneously enhancing solid lesion measuring 5.6 × 2.6 cm in the left para‐aortic region, abutting the aortic arch posteriorly and the left pulmonary artery trunk inferiorly. Two adjacent sub‐centimeter deposits were also identified and associated with nodular pericardial enhancement. Persistent hypodense pericardial thickening measuring 16 mm was noted along the right atrium, causing indentation of the atrial wall. In addition, minimal left pleural effusion with lingular atelectasis was observed. No evidence of distant metastases was detected on the performed imaging (Figure 5A,B).

FIGURE 5.

MDCT showing disease progression after completion of 6 cycles of IE chemotherapy (A) Axial view demonstrates a new heterogeneously enhancing left para‐aortic lesion with adjacent deposits and persistent pericardial thickening. (B) Coronal view shows the lesion abutting the aortic arch/left pulmonary artery region with persistent right atrial/pericardial thickening.

3.4. Second‐Line Chemotherapy

In view of the disease progression, surgical intervention was deferred, and the patient was started on a second‐line chemotherapy regimen administered every 3 weeks. The treatment protocol included gemcitabine at 850 mg/m², given intravenously on days 1 and 8, and nab‐paclitaxel at 200 mg/m², administered intravenously on day 2. Gemcitabine has demonstrated activity in advanced angiosarcoma, and nab‐paclitaxel plus gemcitabine has shown activity in pretreated soft tissue sarcoma.

3.5. Current Status and Follow‐Up

The patient is currently receiving second‐line chemotherapy with good tolerance. The treatment plan includes completion of 3 cycles followed by response assessment with MDCT. Depending on the response, the multidisciplinary team will reconsider surgical options or alternative therapeutic strategies, including radiotherapy or enrollment in clinical trials. The patient maintains ECOG performance status 1–2 with adequate organ function.

4. Discussion

This case highlights several important aspects of the diagnosis and management of primary pericardial angiosarcoma. Foremost, it underscores the significant diagnostic challenges encountered in tuberculosis‐endemic regions, where pericardial involvement is frequently attributed to tuberculous pericarditis, often resulting in delayed recognition of malignancy [5, 6]. In our patient, an initial sputum GeneXpert result reporting “trace” Mycobacterium tuberculosis led to the initiation of antitubercular therapy. However, persistent symptoms and the presence of a right atrial–pericardial mass necessitated diagnostic reassessment. The subsequent finding of hemorrhagic pericardial effusion, negative repeat tuberculosis testing, and non‐diagnostic cytology emphasized that when hemorrhagic pericardial effusion coexists with a cardiac or pericardial mass, infectious and malignant etiologies should be evaluated concurrently, with early tissue diagnosis prioritized.

The Xpert MTB/RIF Ultra assay includes a “trace” category, reflecting an extremely low bacillary burden. Such results may represent nonviable mycobacterial DNA or, less commonly, laboratory contamination. World Health Organization guidance indicates that “trace” results may be considered bacteriological confirmation in selected high‐risk populations, but interpretation must be guided by clinical and radiologic correlation. In this case, the discordance between the initial sputum “trace” result and subsequent negative testing, combined with imaging features suspicious for malignancy, reinforced the need for early histopathological confirmation rather than continued empiric therapy [9, 10].

The initial response to ifosfamide–epirubicin chemotherapy in our patient was notable, with a substantial reduction in tumor volume, complete resolution of pericardial effusion, and improvement in ECOG performance status from 3 to 1. This degree of response appears more pronounced than that reported in many contemporary series of cardiac or pericardial angiosarcoma, where advanced disease, early progression, and limited treatment response are common [5, 6, 8] Nevertheless, disease progression after 6 cycles of chemotherapy in our patient highlights the aggressive biological behavior of this malignancy and the potential for rapid relapse despite an initial favorable response. Existing literature similarly emphasizes the poor prognosis associated with cardiac and pericardial angiosarcomas, with frequent presentation at locally advanced or metastatic stages [5, 6].

The selection of anthracycline‐based chemotherapy as first‐line treatment was consistent with current guideline‐supported management of advanced high‐grade soft tissue sarcoma and is commonly extrapolated to cardiac and pericardial sarcomas, particularly in patients with adequate organ function who require rapid symptomatic improvement [11]. Following disease progression, second‐line therapy with gemcitabine and nab‐paclitaxel was initiated based on evidence supporting gemcitabine activity in advanced angiosarcoma and phase I/II data demonstrating efficacy of this combination in pretreated soft tissue sarcoma [12, 13]. Because primary pericardial angiosarcoma is extremely rare, data on its management are limited. However, this case demonstrates that systemic therapy can provide meaningful clinical benefit, even if the response is often temporary.

The role and timing of surgical intervention in pericardial angiosarcoma remain controversial. While complete surgical resection offers the best chance for prolonged survival, extensive local infiltration at diagnosis frequently precludes curative surgery [1]. In such cases, surgical procedures are often limited to diagnostic or palliative interventions, as was necessary in our patient.

Several important learning points emerge from this case: (1) a high index of suspicion for malignancy is essential in patients presenting with hemorrhagic pericardial effusion, even in tuberculosis‐endemic regions; (2) “trace” GeneXpert results should be interpreted in clinical context, particularly when treatment response is lacking or imaging reveals a mass lesion; (3) early tissue diagnosis should be prioritized when diagnostic uncertainty persists; and (4) despite significant initial chemotherapy response, close monitoring for progression is essential. The limitations of this report include its single‐case nature and limited follow‐up duration. A longer follow‐up will be required to assess response to second‐line therapy and overall survival. Future research should focus on identifying predictive biomarkers of treatment response, exploring molecularly targeted therapies, and establishing optimal multimodal treatment strategies through collaborative efforts, given the rarity of this malignancy.

5. Conclusion

Primary pericardial angiosarcoma continues to pose a major therapeutic challenge despite advances in multimodal cancer treatment. Although substantial initial responses to systemic chemotherapy may be achieved, as seen in this case, disease progression is common and may occur rapidly. Early recognition, along with adaptive treatment strategies that incorporate sequential systemic therapies and prompt multidisciplinary evaluation, is essential to optimize outcomes in this highly aggressive malignancy.

Author Contributions

Ujjwal Kumar Thakur: conceptualization, formal analysis, methodology, project administration, visualization, writing – original draft, writing – review and editing. Akash Subedi: conceptualization, formal analysis, visualization, writing – original draft, writing – review and editing. Rheecha Joshi: conceptualization, formal analysis, methodology, resources, software, supervision, validation, visualization, writing – review and editing. Sunita Dhanchha: conceptualization, formal analysis, investigation, methodology, validation, writing – review and editing. Sumit Yadav: conceptualization, formal analysis, investigation, methodology, validation, writing – review and editing. Binaya Pangyani: conceptualization, formal analysis, investigation, methodology, validation, visualization, writing – review and editing. Ajaya Acharya: formal analysis, methodology, writing – review and editing. Punam KC: formal analysis, methodology, writing – review and editing. Sunil Shrestha: data curation, formal analysis, investigation, methodology, project administration, supervision, writing – review and editing. Gerim Prasai: data curation, formal analysis, methodology, supervision, writing – original draft, writing – review and editing. Abish Adhikari: investigation, methodology, project administration, supervision, writing – original draft, writing – review and editing. Anjani Kumar Jha: project administration, resources, supervision, validation, writing – review and editing. Subhas Pandit: methodology, project administration, resources, software, supervision, validation, writing – review and editing. Simit Sapkota: project administration, resources, software, supervision, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

This case report was exempted from formal ethical review as per institutional guidelines for case reports. Written informed consent was obtained from the patient to publish this case report and accompanying images.

Consent

Written informed consent was obtained from the patient to publish this case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

All data generated or analyzed during this study are included in this published article.