Bridging the gap in cardiac mass diagnosis: Advanced imaging, genetic associations, and biomarkers

Abstract

In this editorial we comment on the article by Huffaker et al published in a recent issue of the World Journal of Clinical Cases. We focus on cardiac tumors linked to genetic syndromes and the differential diagnosis of cardiac masses. As cardiomyocytes lack the ability to actively divide, primary cardiac tumors are extremely rare across all ethnicities and age groups. Once they occur, these tumors are often associated with genetic mutations and, occasionally, genetic syndromes. This underscores the importance of considering genetic mutations and syndromes when encountering these cases. The more common growths in the heart are thrombi and vegetations, which can mimic tumors, further making the differential diagnosis challenging. Among the imaging techniques, contrast-enhanced cardiac magnetic resonance imaging has the highest sensitivity for differential diagnosis. To aid in the differential diagnosis of cardiac masses, especially thrombi, appropriate utilization of biomarkers (i.e. D-dimer level) may provide pivotal clinical implications. Employing a multidisciplinary approach that integrates personal history, epidemiological insights, imaging findings, genetic markers, and biomarkers is therefore critical in the diagnostic process of cardiac masses.

Key Words: Cardiac masses, Genetic syndromes, Thrombi, Imaging, D-dimer

Core Tip: The diagnosis of cardiac masses can be challenging because of their frequent atypical manifestations. Accurate differentiation between a thrombus, vegetation, and tumor requires a comprehensive approach that integrates imaging techniques, biomarkers, genetic testing, and a detailed medical history. The management strategies for these masses can vary significantly depending on the diagnosis, which has a direct impact on therapeutic outcomes.

INTRODUCTION

Cardiac masses are composed mainly of thrombi and vegetations, and tumors are rarely found. The differential diagnosis of these masses depends on the regional location, morphological features, clinical manifestations, and the interactions with valve motion. Notably, the complex interplay between these masses and genetic syndromes such as Li-Fraumeni and Lynch syndromes, which are known for their increased tumor predisposition, remains underexplored. Although case reports, such as that by Huffaker et al[1], provide significant insights, a comprehensive understanding is limited by the scarcity of these conditions. Furthermore, the inherent link between malignancies, hypercoagulability, and compromised immunity raises pivotal questions regarding their roles in the formation of thrombi and vegetations. Among the imaging techniques used, cardiac magnetic resonance imaging (MRI) stands out for its superior sensitivity in tumor diagnosis, especially when echocardiography or computed tomography scans fall short in differentiating tumors. However, the educational case reported by Huffaker et al[1] reminds us that cardiac magnetic resonance (MR) may misinterpret an atypical lesion, re-emphasizing the importance of understanding cardiac MR manifestations in different cardiac masses. The adjuvant use of D-dimer can aid in the diagnosis of thrombus, but the low specificity of this alternative should not be disregarded. This editorial aims to highlight some commonly missed details within a comprehensive approach for accurate diagnosis, management, and patient care in cardiovascular oncology.

DIAGNOSIS OF CARDIAC MASSES BASED ON PERSONAL HISTORY AND EPIDEMIOLOGY

Cardiac tumors, although uncommon in clinical practice, may be correlated with genetic mutations or syndromes. Maleszewski et al[2] have provided a comprehensive overview of the genetic underpinnings of these tumors. For primary cardiac tumors, cases involving TP53 mutation, regardless of whether they meet the diagnostic criteria of Li-Fraumeni syndrome (LFS), have been reported to be associated with several types of tumors, including leiomyosarcoma, osteosarcoma, myxofibrosarcoma[2], and possibly angiosarcoma and undifferentiated pleomorphic sarcoma[3,4]. However, none of these tumors are prevalent in heart valves unless infiltration occurs[4]. Hence, in patients with LFS, focusing on metastasis from extracardiac tumors associated with TP53 mutations or LFS when diagnosing a tricuspid mass is justified. This approach is also supported by the finding that secondary metastatic tumors, which account for about one-fifth of cancer-related deaths, are more prevalent in the heart[5,6]. Remarkably, endocardial metastases, though rare, typically localize to the right heart and are always secondary to endovascular growths, such as renal, liver, and uterine cancer[7].

GENETIC SYNDROMES ASSOCIATED WITH PRIMARY CARDIAC TUMORS

Many genetic drivers of primary cardiac tumors are well-established. However, other than LFS, which genetic syndromes are directly linked to these tumors? This section discusses other genetic syndromes with well-established links to primary cardiac tumors. Table 1 summarizes information from reviews by Szczałuba et al[8] and Maleszewski et al[2]. While these genetic diseases are rare, it is important to clearly demonstrate their association with intracardiac tumors for diagnostic purposes.

Table 1 Genetic syndromes associated with primary cardiac tumors.

Genetic syndrome	Cardiac tumor, primary	Gene mutation	Life stage	Location	Ref.
Tuberous sclerosis	Rhabdomyoma; Lipoma	TSC1 or TSC2	Pediatric	Ventricle; Atria/Pericardium	Winterkorn et al[24], Hinton et al[25]
Carney complex	Myxoma	PRKAR1A	Adult	Atrium/Ventricle	Maleszewski et al[26], Pitsava et al[27], Kuyama et al[28]
Familial myxoma	Myxoma	PRKAR1A	Pediatric	Atrium	Puntila et al[29]
Cowden syndrome	Lipomas; Hemangioma	PTEN	Adult	Atrium/Pericardium; Atrium	Ceresa et al[30], Lamanna et al[31]
Hereditary paraganglioma-pheochromocytoma syndromes	Paraganglioma	MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127	Adult	Atrium/Ventricle	Miraldi et al[32], Martucci et al[33], Carafone et al[34]
Beckwith-Wiedemann syndrome	Rhabdomyoma or angiofibroma or hamartoma	CDKN1C, H19, IGF2, KCNQ1OT1	Pediatric	Atrium/Ventricle	Reddy et al[35], Satgé et al[36], Longardt et al[37]
Birt-Hogg-Dube	Rhabdomyomas	FLCN	Pediatric	Ventricle	Toro et al[38], Bondavalli et al[39]
Neurofibromatosis type 1	Neurofibromas	NF1	Adult	Ventricle	Iino et al[40], Li et al[41]
Gorlin syndrome	Fibromas & rhabdomyomas	PTCH1	Pediatric	Ventricle	Szczałuba et al[8], Herceg et al[42]
Lynch syndrome	Pericardial carcinoma	MLH1, MSH2, MSH6, PMS2, EPCAM	Adult	Pericardium	Paolisso et al[43]

CARDIAC MRI MANIFESTATIONS IN PRELIMINARY DIFFERENTIATION OF THROMBUS, VEGETATIONS AND TUMOR

Gadolinium, an MR contrast agent, effectively shortens the longitudinal relaxation time (T1) of water protons, rendering the accumulating organs hyperintense on T1-weighted images[9]. It preferentially binds to tumors with disrupted, “leaky” vasculatures[10]. Late gadolinium enhancement (LGE), which is measured about 10 to 20 minutes after contrast infusion, indicates interstitial enhancement in pathological or fibrosed tissues owing to longer retention[10,11]. In contrast to tumors, thrombi typically do not show enhancement on LGE because they are avascular[12]. Nonetheless, LGE can theoretically have atypical appearances due to the alteration of tissue composition, despite the absence of reports regarding thrombi enhancement in LGE-MRI. Neovascularization, a possible explanation for LGE in thrombi, is rare but possible in chronic cardiac thrombi[13]. One pattern of LGE was, however, found to be relatively specific in thrombi: (1) Hyperintensity at the short inversion time (TI, the waiting period for longitudinal magnetization to recover toward its initial value); (2) an “edged” appearance with a hypointense border and brighter central zone at the intermediate TI; and (3) hypointensity at the long TI[14]. This pattern has the highest accuracy (95%) in differentiating thrombi from tumors, as the latter always have a prolonged hyperintensity at the long TI[13].

On the other hand, distinguishing a thrombus from vegetation, a clinical sign of endocarditis, is challenging for clinicians. Cardiac MRI is generally not recommended for evaluating valvular vegetations because of its low spatial resolution[15]. While cardiac MRI findings of vegetations are expected to resemble thrombi, distinct features that may specify infective endocarditis have been reported: (1) A characteristic marginal rim enhancement in vegetation observed on LGE; and (2) LGE of adjacent myocardial tissues or endothelial lining secondary to damage or fibrosis[16-18].

USE OF D-DIMER AS AN ADJUVANT DIAGNOSTIC TOOL TO DISTINGUISH INTRACARDIAC THROMBUS

Intracardiac thrombi most commonly form in the left ventricle, followed by the left atrium, right atrium, and least frequently, the right ventricle. Among the etiologies of tricuspid thrombi, which rarely occur, published studies report cardiac structural anomalies, deep venous thrombosis (DVT), and antiphospholipid syndrome as notable causes[19-21]. Notably, a malignancy-associated hypercoagulable state may also lead to thrombus formation.

While it was not measured in the discussed case report, a test of D-dimer level could provide important diagnostic information. A thrombus in the tricuspid mass or right heart could originate from: (1) Venous thromboembolism (VTE; including DVT), or (2) primary intracardiac processes (including atrial fibrillation, tricuspid regurgitation, low cardiac output, pulmonary hypertension, etc). Published reports indicate that D-dimer has a good negative predictive value for intracardiac thrombi as their association is consistent across ethnicity, age, cardiac function, and renal function[22]. Furthermore, the D-dimer test has a high sensitivity for detecting VTE, despite its low specificity[23]. In patients with dilated cardiomyopathy, it was reported that the elevation of D-dimer at a cutoff value of 484 ng/mL had a sensitivity of 0.769, a specificity of 0.646, and a high negative predictive value of 0.953 for diagnosing intracardiac thrombi[22]. Consequently, we recommend D-dimer testing as a valuable tool for excluding intracardiac thrombi, although the optimal cutoff value for patients with malignancies warrants further investigation.

However, it should be emphasized that D-dimer levels can be easily affected by external factors. In the authors’ experience, a comprehensive interpretation of D-dimer together with fibrin degradation products (FDP) is of utmost importance. When the elevation of FDP does not align with D-dimer levels, i.e. an abnormally high or low FDP/D-dimer ratio, the likelihood of a thrombus is reduced. This approach is theoretically applicable in cases of intracardiac thrombus as well. In short, utilizing D-dimer as a preliminary tool to exclude intracardiac thrombi offers a convenient yet highly feasible alternative.

CONCLUSION

The link between rare genetic syndromes and cardiac tumors, despite their low individual incidence, demands careful consideration. Examining cardiac masses in such patients requires a comprehensive diagnostic approach. A multimodal approach integrating imaging techniques, laboratory tests (e.g., D-dimer), genetic profiling, and a detailed personal history is needed to achieve an accurate differential diagnosis. Further research to identify novel diagnostic markers and therapeutic targets should include the genetic properties of cardiac masses. The case report by Huffaker et al[1] provides significant educational insight, and highlighting the complexity of diagnosing and treating cardiac masses in patients with rare genetic syndromes like LFS.