Intimal sarcoma of the left atrium presenting with transient ischaemic attack — A case report and review of the literature

Abstract

A 31-year-old female with a history of polycystic ovary syndrome and two recent miscarriages presented with symptoms of a transient ischemic attack. Echocardiography to assess for possible embolic source identified a 4.8 cm left atrial mass, presumed to be an atrial myxoma.

At surgery the tumor was suspicious of malignancy. Histopathology revealed a heterogeneous hyper- and hypo-cellular spindle cell tumor showing mild atypia. Atrial myxoma markers were negative. The Ki67 proliferation factor was 30% and fluorescence in situ hybridization (FISH) analysis showed MDM2 amplification. Expert review confirmed the morphological, immunohistochemical, and FISH features to be of a cardiac intimal sarcoma.

Recent improvements in imaging, surgery, and molecular testing have increased diagnoses of primary cardiac intimal sarcomas. Here we discuss the pathological and clinical implications of these rare atrial myxoma mimics.

<Learning objective: Intimal sarcomas are rare, aggressive tumors typically associated with great vessels, however, molecular diagnoses of cardiac intimal sarcomas are increasing. Presentation is varied. Cardiac symptoms and emboli in young patients should prompt investigation with high levels of suspicion. Intimal sarcomas show MDM2 amplification with genetic aberration. Careful pre-operative planning to achieve clear surgical margins almost doubles life expectancy. Chemoradiotherapy may be beneficial. MDM2 and PDGFRa inhibitors are in development.>

Introduction

Primary cardiac tumors are rare with a post-mortem incidence of <0.03%; ˜25% cardiac tumors are malignant, of these 95% will be sarcomas [1], [2], [3], [4]. Angiosarcomas and undifferentiated pleomorphic sarcomas were previously thought to be most frequent, however, a study using fluorescence in situ hybridization (FISH) for MDM2 amplification as a classification parameter proposed intimal sarcomas as the commonest primary cardiac sarcomas (42/100 cases) [2], [5]; although this has been contested [6]. Of benign cardiac tumors, approximately 50% are atrial myxomas [1], [5].

Many cardiac tumors are asymptomatic [1], [6]. However, they can present in numerous ways, characteristically with a triad of cardiac symptoms and signs (due to luminal obstruction and myocardial invasion); systemic emboli and constitutional symptoms [1]. Metastatic disease may be a presenting feature [2]. The most important symptomatic and prognostic feature is anatomical location as complete surgical removal remains optimal treatment [1], [2].

Here we discuss a left atrial intimal sarcoma that presented in a young woman as a transient ischemic attack, with the clinical impression being of an atrial myxoma on echocardiography.

Case report

A 31-year-old Caucasian female, with a past medical history of polycystic ovaries and two recent miscarriages, presented with left-sided weakness compatible with a transient ischemic attack. Brain computed tomography showed no significant lesions. Echocardiography to assess for possible embolic sources revealed a 4.8 cm mass in the left atrium (Fig. 1a). There was mild mitral stenosis and regurgitation, but good ventricular function. The impression was of an atrial myxoma, however lymphoma and sarcoma were differentials.

Fig. 1.

Macroscopic appearance of tumor. (a) Echocardiography image showing a large echogenic mass measuring 2.8 × 4.8 cm attached to the posterior mitral valve leaflet/left atrial free wall. Appearance is highly suggestive of myxoma, possible differentials include sarcoma and lymphoma. (b,c) Macroscopic image of specimen which shows atrial muscle base, which was inked black to indicate surgical resection margin and tumor cut surface. Scale bar = 10 mm.

She was referred for urgent resection. She underwent cardiopulmonary bypass with hypothermic circulatory arrest, median sternotomy, and subsequent transeptal approach. A large tumor attached to the posterior left atrial wall occupied most of the left atrium. The posterior wall of the left atrium was resected and the myocardial defect was closed using interrupted mattress sutures and a pericardial patch.

Macroscopically, a pale-white, smooth lobulated firm mass weighing 22 g was retrieved. It showed a uniform white and focally myxoid cut surface, with broad base including attached atrial muscle (Fig. 1b,c).

Microscopically, it comprised a vaguely nodular hyaline, densely collagenized, spindle-cell lesion. It was heterogeneous, consisting of bland hypercellular areas and hypocellular fascicular areas of spindle cells showing mild cytological atypia. There were focal myxoid changes and scattered, dilated, thin-walled blood vessels that showed variable lymphocyte and plasma cell extravasation. Whilst no necrosis or mitoses were identified, vasopermeation by spindle cell nodules was noted (Fig. 2a,b). The morphology was atypical and the typical atrial myxoma immunohistochemical markers (calretinin, CD31, and CD34) were entirely negative. The Ki67 proliferation factor was high at 30% (Fig. 2c).

Fig. 2.

Microscopic appearance of tumor. (a) Low power microscopy image (×2.5 magnification) showing cellular spindle cell tumor including vasopermeation (arrow indicates tumor nodule breaching vascular space). (b) High power microscopy image (×40 magnification) showing pleomorphic spindled tumor cells showing mild nuclear atypia. (c) Ki 67 staining showing 30% positivity.

Due to the unusual appearance it was sent for specialist review at Birmingham Royal Orthopaedic Hospital, where it was confirmed with FISH analysis for MDM2 amplification (Fig. 3) that this represented an intimal sarcoma. Due to the extensive vasopermeation and bland nature of the tumor spindle cells, completeness of excision was unclear. The patient was referred for chemo-radiotherapy.

Fig. 3.

Fluorescent in-situ hybridization appearance of tumor (FISH). Interphase FISH using Zytolight MDM2/CEN12 Dual color probe (ZytoVision GmbH, Bremerhaven, Germany). MDM2 gene labelled green and alpha satellite centromeric region of chromosome 12 labelled orange. Nuclei counterstained using DAPI (Vector Laboratories, Burlingame, CA, USA). Image shows tumor cells with clustering of MDM2 gene in a ratio of MDM2:centromere of >2.0 typical of intimal sarcomas.

Discussion

Intimal sarcomas are highly aggressive mesenchymal tumors classified as undifferentiated sarcomas [1], [2], [5], [7]. They typically involve large vessels arising from intimal subendothelial cells [1], [4], [5]. Whilst exceptionally rare, recent improvements in imaging, surgery, and molecular testing (including characterization by MDM2 assessment) has led to an increase in their diagnosis in the heart [5], [6]. Less than 20 primary cardiac intimal sarcomas are reported on PubMed [8]. The median presenting age of primary cardiac sarcomas is 42 years; incidence in children is exceptionally rare [3]. Intimal sarcomas have no definite age or gender predilection but occur with slightly greater incidence in women over 40 years [5].

Presentation is variable; approximately half are asymptomatic. Symptomatic cases typically present with heart failure, valvular disorders, and/or chest pain [1], [2], [3], [4], [7], [8]. The majority of cases without metastasis were initially diagnosed as atrial myxoma on imaging with malignancy only considered at surgery [1], [2], [3], [4], [7], [8]. Most tumors were primarily imaged with echocardiography which is sensitive at predicting the etiology of intra-cavitary lesions, however, it is less reliable at defining intra-mural or extra-myocardial lesions. Three-dimensional echocardiography demonstrates better sensitivity and can be used to visualize anatomical relationships pre-operatively and intra-operatively (using a transesophageal approach) [4]. On imaging, intimal and undifferentiated sarcomas typically occur in the left side of the heart, angiosarcomas almost exclusively on the right. Synovial sarcomas have no side predilection [5]. Benign lesions (such as atrial myxoma) tend to arise from the intra-atrial septum, have a stalk-like base with well-demarcated margins, and usually do not encroach the pulmonary vessels. Malignant tumors are often non-septal with broad bases and poorly defined margins [3]. Careful preoperative assessment can enable complete resection in up to 65% of patients [1].

Macroscopically, intimal sarcomas are usually lobulated, polypoid, tumors with broad bases and smooth, white-grey whorled cut surfaces. Consistency is variable occasionally with hard and bony areas. Necrosis and ulceration may be present [7]. Microscopically, they show poorly specific heterogeneous features, tending to comprise nodules, of tightly packed, fascicular, atypical spindled and/or pleomorphic cells with areas of myxoid or epithelioid morphology [1], [2], [5]. Intimal sarcomas show variable mesenchymal, and (myo)fibroblastic differentiation [7]. Three quarters of tumors are undifferentiated (comprised of spindle and pleomorphic cells), whereas one quarter show areas of differentiation mimicking other sarcomas. The extent of necrosis, hemorrhage, cellular atypia, pleomorphism, and mitotic activity is variable [1], [2], [4], [5], [7].

In comparison, atrial myxomas macroscopically are motile; pedunculated or sessile polypoid gelatinous smooth or frondular tumors with shiny grey-pink cut surfaces. Microscopically, they comprise myxoid stroma containing blood vessels and complex cords, nests or poorly formed glands of stellate or globular, eosinophilic “myxoma cells” with variable fibrosis, hemorrhage and Gamna–Gandy bodies. They may be morphologically and cytologically pleomorphic, but cellular atypia is rare. Immunohistochemically, atrial myxomas show CD31/34 highlighted vascular channels and calretinin- and vimentin-positive myxoma cells [9].

Immunohistochemically, almost all intimal sarcomas will express MDM2, >66% will express CDK4 and HMGA2, and 33% express SMA and desmin [5]. Osteopontin and vimentin are typically positive [1], [2]. Cytokeratin, EMA, S100, CD31, CD34, CD117, CD68, factor VIII, P53, BCL-2, and other markers are usually only focal or weak and vary depending on tumor differentiation [1], [2], [5]. All reported cardiac intimal sarcomas have been H-caldesmon negative [5], [7].

When differentiating intimal sarcoma mimics: strong CD31, CD34 positivity is expected in angiosarcoma; strong SMA, desmin, and H-caldesmon positivity is expected in epithelioid leiomyosarcoma, and focal cytokeratin should be seen in biphasic synovial sarcoma [usually with the characteristic t(x:18)(p11;q11) translocation] [2], [5]. Dedifferentiated liposarcoma can be morphologically indistinguishable (and demonstrate MDM2 expression); however, sufficient sampling usually reveals a well-differentiated lipomatous component [5]. As intimal sarcoma mimics may be immunohistochemically MDM2-positive, FISH analysis to confirm MDM2 amplification is paramount [5]. Whilst FISH amplification of MDM2 is deemed specific for intimal sarcoma, other sarcomas can also show MDM2 amplification (notably 95% dedifferentiated liposarcomas, 36% angiosarcomas, and 18% of other sarcomas) [5]. However, FISH in intimal sarcomas may show a characteristic pattern of small clustering of signals not seen in dedifferentiated liposarcomas [5]. In cases that are unclear, further cytogenetic array analysis can be helpful as intimal sarcomas tend to show amplification of the 12q12-15 region (including MDM2, CDK4, and HMGA2). Also KIT and PDGFRa amplification with gain in function of EGFR and loss of CDKN2A is seen in most cases [4], [5], [10]. Molecular profiling is still ongoing however “MDM2 amplification with molecular aberration” is deemed typical of intimal sarcoma [5].

Anatomical location is the most important prognostic factor for intimal sarcoma as surgery remains the mainstay of treatment with clear margins doubling life expectancy [1], [2]. The role of chemo-radiotherapy remains uncertain [1]. Genetically-targeted novel therapeutics (including multiple tyrosine kinase and MDM2 inhibitors) are being considered, with PDGFR inhibitor dasatinib demonstrating potential therapeutic effects on intimal sarcoma cells ex-vivo [1], [10]. Despite left-sided sarcomas demonstrating better outcomes than right-sided tumors [1], prognosis for intimal sarcomas remains poor with a mean survival of 3–12 months although survival (following multiple surgeries) of up to 11 years has been reported [2], [3]. Unfortunately, intimal sarcomas have a relentless course with recurrence and metastasis typically occurring within 1 year [2], [3]. Metastatic site predilection of cardiac intimal sarcomas is not documented. However, lung metastases occur in 40% of pulmonary artery intimal sarcomas whilst extra-thoracic metastases occur in 20% (typically involving kidneys, lymph nodes, brain, and skin). Aortic intimal sarcomas have a high rate of tumor embolization and usually cause distant metastasis to bone, peritoneum, liver, and lymph nodes [2]. Due to the critical nature of the anatomical structures involved by these tumors morbidity and mortality remains high with death occurring due to iatrogenic, cardiorespiratory, metastatic, and infective causes [1], [2].

Conclusion

Due to their relative obscurity, varied presentation, and morphology, diagnosing intimal sarcomas can be challenging. A high level of suspicion is needed, particularly in young patients with unusual symptoms (e.g. cardiac, constitutional, and emboli). Timely diagnosis to ensure optimum resection of these aggressive atrial myxoma mimics is critical. MDM2 amplification with genetic aberration is typical and further understanding of these cytogenetics may hold the key to novel therapeutics.

Funding

N/A.