Cytological Diagnosis of Primary Cardiac Angiosarcoma Presenting With Multiple Serous Effusions: A Case Report With Cell Block

ABSTRACT

Primary cardiac angiosarcoma (PCAS) is the most aggressive primary malignant cardiac tumor. Owing to the nonspecific nature of clinical symptoms, early detection, diagnosis, and treatment remain challenging. The tumor is characterized by high malignancy, a propensity for early metastasis, and an overall poor prognosis. We report a 42‐year‐old female presenting with abdominal distension and exertional dyspnea for 1 month, found to have a cardiac space‐occupying lesion and multiple serous effusions on imaging. The final diagnosis of PCAS was established by combining cytomorphological analysis of the pleural effusion (showing pleomorphic tumor cells with marked atypia), cell block (CB) preparation, and immunocytochemical (ICC) staining. Next‐generation sequencing (NGS) of the CB specimen identified a missense mutation in MSH2 (c.14C>A, p.Pro5Gln) with a variant allele frequency (VAF) of 48%, confirming the feasibility of CB as an alternative specimen for molecular testing. The patient received chemotherapy combined with radiotherapy and remained in stable clinical condition. Cytopathology offers a valuable diagnostic approach for patients with primary cardiac tumors in whom histological sampling cannot be obtained, and molecular testing using CB specimens can provide additional insights into the genetic profile of such rare tumors.

1. Introduction

PCAS is extremely rare, only 25% are malignant, of which angiosarcomas are the most frequent [1]. Derived from endothelial cells with unclear etiology, PCAS most commonly originates in the right atrium, particularly involving the pericardium [2]. It is highly invasive, with a propensity for local infiltration and widespread metastasis [3]. Diagnosis remains challenging due to the absence of disease‐specific clinical features [4]. We present a case of a 42‐year‐old female patient with PCAS presenting with abdominal distension and exertional dyspnea, who was diagnosed via pleural effusion cytology, CB and ICC staining. This study aims to explore the utility of cytopathology in establishing a pathological diagnosis for patients ineligible for histological sampling.

2. Case Report

A 42‐year‐old female patient was admitted to the Department of Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, in October 2025, presenting with a 1‐month history of abdominal distension accompanied by exertional dyspnea. The reporting of this study conforms to the Case Report (CARE) guidelines [5]. The patient was in good health previously, had no allergies, and no family genetic disease history. Respiratory exam showed dull percussion at bilateral lung bases and diminished bilateral air entry, and abdominal exam unremarkable.

Echocardiography detected a hypoechoic‐to‐isoechoic space‐occupying lesion at the top of the right atrium near the interatrial septum. Contrast‐enhanced chest computed tomography (CT) revealed pleural and pericardial effusions and a space‐occupying lesion in the right middle mediastinum (between the left and right atria), with ill‐defined boundaries. Positron emission tomography/computed tomography (PET/CT) demonstrated space‐occupying lesions in the right posterior pericardium and interatrial sulcus, with increased fluorodeoxyglucose (FDG) uptake.

FFPE (Formalin‐Fixed Paraffin‐Embedded) cell blocks were prepared from bloody turbid pleural effusion specimens. ICC staining was subsequently performed on a Ventana automated staining platform. The tumor cells were present in clusters or scattered singly, with increased cell size, eccentric nuclei, and coarse chromatin. The cytoplasm can be finely vacuolated. Tumor cells demonstrate malignant cytologic features including anisonucleosis, irregular nuclear borders, increased nuclear‐cytoplasmic (N/C) ratios with small to prominent nucleoli (Figure 1A). In the CB, tumor cells were arranged in nested and clustered patterns. They exhibited marked cellular atypia, with large, hyperchromatic nuclei containing prominent nucleoli. Typical mitotic figures were observed (Figure 1B). ICC staining demonstrated diffusely and strongly positive for CD31, CD34, ERG, Vimentin and focal positivity for FLI‐1, coupled with a Ki‐67 proliferation index of approximately 50%. The tumor cells were negative for epithelial antigen (EA), calretinin, D2‐40, TTF‐1, NapsinA, P40, CD56, Syn, S100, MelanA, MyoD1, Myogenin, Human herpesvirus 8 (HHV8), TFE3, FOSB. Partial ICC staining is shown in Figure 2A–F.

FIGURE 1.

(A) Pleural effusion: Tumor cells arranged in clusters and scattered distribution with marked atypia (original magnification ×400). (B) Cell block showing tumor cell morphology (H&E, original magnification ×200).

FIGURE 2.

Immunocytochemical staining of the cell block. Tumor cells are positive for CD31 (A), CD34 (B), ERG (C), and Ki‐67 (D) with a high proliferative index and negative for EA (E) and D2‐40 (F) (original magnification ×200).

NGS of CB specimen identified a missense mutation, c.14C>A, in the MSH2 gene, with a variant allele frequency (VAF) of 48%, resulting in amino acid substitution of proline to glutamine at position 5 (p.Pro5Gln).

Combined with the tumor location, cellular morphology, and ICC staining findings, the final diagnosis was PCAS. The patient underwent four cycles of chemotherapy, with ifosfamide and epirubicin, as well as one section of radiotherapy. Following treatment, marked clinical improvement was achieved, with a marked reduction in tumor burden, decreased cellular effusion, and resolution of pleural effusion. As of February 2026, the patient remains alive with stable disease.

3. Discussion

PCAS, a highly invasive vascular endothelial tumor arising from mesenchymal tissue, is an exceptionally rare malignant subtype with an unclear etiology and dismal prognosis [6]. In our case, imaging showed a cardiac mass with invasive growth and hemorrhagic effusions. Tumor cells displayed marked atypia, and ICC was diffusely and strongly positive for CD31, CD34, and ERG, with a Ki‐67 proliferation index of approximately 50%—providing compelling evidence for angiosarcoma. A panel of negative markers (including EA, calretinin, D2‐40, MyoD1, Myogenin, HHV8, FOSB, S100, and MelanA) effectively ruled out metastatic carcinoma, mesothelioma, rhabdomyosarcoma, Kaposi sarcoma, pseudomyogenic hemangioendothelioma (PHE), and melanoma. Although epithelioid hemangioendothelioma (EHE) shares overlapping vascular immunophenotypes, the aggressive morphology (marked cytologic atypia and high Ki‐67) of PCAS clearly distinguishes it from the indolent behavior of EHE.

The PCAS is poorly understood, and most pathogenic driver gene mutations remain largely unclear. Odintsov et al. [7] presented the largest cohort of genomically PCAS, demonstrating that they are genomically distinct from their noncardiac counterparts and highlighting the importance of KDR, POT1, TERT, and MED12 alterations. Tian et al. [8] reported the first case of primary cardiac angiosarcoma with a DNMT3A gene mutation. Additionally, mutations in KRAS, TP53, KIT and KDR genes are also present in some cases [9]. In the present case, however, none of these known driver mutations were identified. Instead, NGS of the CB specimen revealed a missense mutation in MSH2 (c.14C>A, p.Pro5Gln), which has not been previously reported in PCAS. The detected mutation exhibited a VAF of 48%, indicating high tumor cell purity in the CB specimen and suggesting a clonal somatic heterozygous alteration. To date, no large‐scale analysis has specifically investigated MSH2 mutations in PCAS, its significance remains to be elucidated in future studies. While comprehensive molecular profiling tests (e.g., Caris MII Tumor Seek) have been applied to various sarcomas, their diagnostic utility in PACS remains to be systematically evaluated.

Taken together, the NGS testing expands the known molecular spectrum of PCAS and confirms the feasibility of utilizing CB specimens for molecular genetic profiling in cases where tissue samples are unavailable. Although the clinical significance and frequency of MSH2 mutations in primary cardiac angiosarcoma remain to be further clarified by large‐scale studies, this case provides valuable clinical, pathological, and molecular data for the diagnosis and understanding of this rare malignant tumor. Early recognition of the cytological, immunophenotypic, and molecular characteristics of primary cardiac angiosarcoma is essential for prompt diagnosis, formulation of appropriate treatment strategies, and optimization of patient prognosis.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.