Risk stratification of cardiac metastases using late gadolinium enhancement cardiovascular magnetic resonance: prognostic impact of hypo-enhancement evidenced tumor avascularity

Abstract

Background

Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is widely used to identify cardiac neoplasms, for which diagnosis is predicated on enhancement stemming from lesion vascularity: Impact of contrast-enhancement pattern on clinical outcomes is unknown. The objective of this study was to determine whether cardiac metastasis (C_MET) enhancement pattern on LGE-CMR impacts prognosis, with focus on heterogeneous lesion enhancement as a marker of tumor avascularity.

Methods

Advanced (stage IV) systemic cancer patients with and without C_MET matched (1:1) by cancer etiology underwent a standardized CMR protocol. C_MET was identified via established LGE-CMR criteria based on lesion enhancement; enhancement pattern was further classified as heterogeneous (enhancing and non-enhancing components) or diffuse and assessed via quantitative (contrast-to-noise ratio (CNR); signal-to-noise ratio (SNR)) analyses. Embolic events and mortality were tested in relation to lesion location and contrast-enhancement pattern.

Results

224 patients were studied, including 112 patients with C_MET and unaffected (C_MET -) controls matched for systemic cancer etiology/stage. C_MET enhancement pattern varied (53% heterogeneous, 47% diffuse). Quantitative analyses were consistent with lesion classification; CNR was higher and SNR lower in heterogeneously enhancing C_MET (p < 0.001)—paralleled by larger size based on linear dimensions (p < 0.05). Contrast-enhancement pattern did not vary based on lesion location (p = NS). Embolic events were similar between patients with diffuse and heterogeneous lesions (p = NS) but varied by location: Patients with right-sided lesions had threefold more pulmonary emboli (20% vs. 6%, p = 0.02); those with left-sided lesions had lower rates equivalent to controls (4% vs. 5%, p = 1.00). Mortality was higher among patients with C_MET (hazard ratio [HR] = 1.64 [CI 1.17–2.29], p = 0.004) compared to controls, but varied by contrast-enhancement pattern: Diffusely enhancing C_MET had equivalent mortality to controls (p = 0.21) whereas prognosis was worse with heterogeneous C_MET (p = 0.005) and more strongly predicted by heterogeneous enhancement (HR = 1.97 [CI 1.23–3.15], p = 0.005) than lesion size (HR = 1.11 per 10 cm [CI 0.53–2.33], p = 0.79).

Conclusions

Contrast-enhancement pattern and location of C_MET on CMR impacts prognosis. Embolic events vary by C_MET location, with likelihood of PE greatest with right-sided lesions. Heterogeneous enhancement—a marker of tumor avascularity on LGE-CMR—is a novel marker of increased mortality risk.

Background

Nearly 17 million Americans are living with cancer [1], among whom cardiac metastases (C_MET)bear a major impact on therapeutic decision-making and prognosis. Survival has markedly improved for patients with advanced (stage IV) cancer, resulting in a growing population at risk for C_MET and its serious consequences. Data from our group and others have shown C_MET to be common with advanced cancer, occurring in up to 20% of patients. [2,3,4,5,6] Embolic events—which can occur when lesions dislodge from the heart—are a leading source of morbidity and mortality among patients with C_MET. Given that a growing array of new therapies and anticoagulants are available to potentially reduce risk, improved strategies to guide therapy and refine prognostic risk stratification for patients at risk for C_MET are of substantial importance.

Cardiovascular magnetic resonance (CMR) has been well-validated for tissue characterization of cardiac masses. [2, 4, 7,8,9,10,11,12] Whereas neoplasms can vary in morphology, vascular supply is an intrinsic requirement for tumor growth and this property can be leveraged for diagnostic purposes. Using the technique of late gadolinium enhancement (LGE), CMR can identify neoplasms based on vascularity as manifested by presence of contrast-enhancement. [13] It is also known that neoplasms can vary in pattern of contrast enhancement on LGE-CMR, and that some lesions can include enhancing and non-enhancing components. [2,3,4] Consistent with this, pathology studies have shown that some neoplasms can have avascular foci (“tumor necrosis”)—a finding linked to aggressive tumor growth and adverse outcomes. [14] Impact of tumor avascularity—as manifested by contrast hypo-enhancement on LGE-CMR—has yet to be tested as a prognostic marker among patients with C_MET.

This study encompassed a broad cohort of systemic cancer patients with C_MET as well as controls (without C_MET) matched for cancer etiology and stage. CMR was performed using a tailored protocol to assess presence and pattern of C_MET enhancement—including standardized grading and quantitative analyses—as well as standardized assessment of lesion size and mobility. The goal was to test impact of C_MET anatomic distribution and contrast enhancement pattern on embolic events and mortality.

Methods

Study population

The population was comprised of adults (≥ 18 years) with advanced (stage IV) systemic cancer and C_MET, and controls without C_MET, matched (1:1) for cancer diagnosis: Presence or absence of C_MET was established using the reference of LGE-CMR, on which it was defined via established criteria as a discrete tissue prominence with vascularity as evidenced by contrast-enhancement. [2,3,4] Subjects with CMR-evidenced intracardiac thrombi were excluded.

Figure 1 provides a schematic of the research protocol. As shown, study participants were accrued at two tertiary care centers with dedicated cancer care programs (Memorial Sloan Kettering Cancer Center [MSKCC], Weill Cornell Medicine—New York Presbyterian Hospital, New York, New York, USA) that share an integrated CMR program. Clinical data were collected in a standardized manner, including cancer diagnosis and stage, anti-cancer and anticoagulant therapies, as well as clinically documented embolic events (pulmonary embolism (PE), cerebrovascular events (CVA), systemic [splenic, peripheral] emboli) within 6 months of CMR. Mortality was assessed to test prognosis in relation to anatomic and tissue characteristics of C_MET.

Fig. 1

Study design. Overall schematic of multicenter enrollment as well as standardized cardiovascular magnetic resonance (CMR) acquisition and analysis. Note that both enrolling sites employed a tailored CMR protocol for assessment of C_MET, inclusive dedicated long inversion time (TI) late gadolinium enhancement (LGE)-CMR for evaluation of contrast-enhancement pattern within lesions. Ancillary clinical data were collected in a uniform manner, including baseline cancer-related indices, embolic events, and mortality following CMR

This study entailed analysis of data acquired for clinical purposes between 2012 and 2020; no dedicated interventions were performed for research purposes. Ethics approval for this protocol was provided by the MSKCC and Weill Cornell Medicine institutional review boards, each of which approved a waiver of informed consent for analysis of pre-existing clinical data.

Imaging protocol

CMR was performed on commercial (1.5 T [87%], 3 T [13%]) scanners (General Electric Healthcare, Waukesha, Wisconsin, USA). Exams included electrocardiogram (ECG)-gated cine- and LGE components; both were obtained in contiguous left ventricular (LV) short (mitral annulus—apex) and long axis (2, 3, and 4 chamber) orientations. Cine-CMR utilized a balanced steady-state free precession (bSSFP) pulse sequence. LGE-CMR utilized an inversion recovery pulse sequence; images were acquired after gadolinium (0.2 mmol/kg) infusion (“long-TI” [600 ms] = 5–10 min, conventional [~ 300 ms] 10–30 min post contrast). Contrast administration entailed gadoterate meglumine (Dotarem, Guerbet, Villepinte, France) or gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma, Berlin, Germany), which were respectively utilized in 53% and 47% of exams. Conventional and long inversion time (TI) LGE-CMR were used to discern presence and pattern of enhancement in C_MET, concordant with prior methods validated by our group and others. [2,3,4, 9,10,11] Conventional LGE-CMR was acquired in all patients; additional breath holds for long TI imaging were tolerated in 92% (103/112) of patients with C_MET.

Image analysis

C_MET was identified on LGE-CMR based on lesion-associated vascularity in accordance with established qualitative (visual) criteria. [2,3,4] To test modifying impact of C_MET tissue properties on cancer associated outcomes, lesions were further classified into two distinct categories—diffuse enhancement (homogenous contrast enhancement throughout lesion) or heterogeneous enhancement (enhancing and non-enhancing components within a lesion).

C_MET were scored in a binary manner (present/absent), localized based on chamber (right atrium [RA], right ventricle [RV], left atrium [LA], left ventricle [LV]) or pericardial involvement, and classified as intra-cavitary (predominantly localized to cardiac chamber) or intramural (invading into myocardium). Intra-cavitary lesions were further graded for lesion mobility, with highly mobile lesions classified as demonstrating dys-synchronous mobility in relation to adjacent myocardium. Figure 2 provides representative examples of C_MET types, including heterogeneous and diffusely enhancing lesions with intra-cavitary or intramyocardial involvement.

Fig. 2

Representative examples. Representative examples of C_MET classifications, including heterogeneously (left) and diffusely (right) enhancing lesions with intracavitary or intramural location [top: cine-CMR ∣ bottom: LGE-CMR). Lesions denoted by green circles. Note focal hypo-enhancement (yellow arrows) within heterogeneously enhancing lesions, corresponding to C_MET avascular components

Quantitative analyses were used to assess magnitude of contrast enhancement within C_MET. Concordant with established methods used by our group, [2, 4] aggregate signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) ratios were measured on the long TI LGE-CMR image on which the lesion was most prominent. Intra-cardiac lesion size (area, linear dimensions) was measured on cine-CMR datasets, which were co-localized with LGE-CMR for purpose of analyses. For patients with multiple C_MET, the largest lesion was used for quantitative analysis and patient categorization (i.e. heterogeneous or diffusely enhancing). Ancillary analyses included quantification of cardiac chamber size and function, which were measured on cine-CMR using standard planimetry methods. [3]

Prognostic assessment

Electronic medical records were reviewed to assess embolic events (PE, CVA, systemic [i.e. splenic, peripheral] emboli) within 6 months of imaging, as well as all-cause mortality after CMR so as to test clinical events in relation to presence and type of C_MET. All-cause mortality and embolic events were ascertained blinded to CMR analyses.

Statistical methods

Comparisons between groups with or without C_MET, and between C_MET subtypes (heterogeneous, diffusely enhancing) were made using Student’s t-tests (expressed as mean ± standard deviation) for continuous variables, and Chi-square or Fisher’s exact tests for categorical variables: Paired testing (t-tests or McNemar’s tests) was employed for matched case–control comparisons. Univariate logistic regression was used to test variables associated with mortality and embolic events; variables significantly associated with outcomes in univariate analysis were then then tested together in adjusted models. The Kaplan–Meier method was used to calculate survival; follow-up duration was reported as median with interquartile range (IQR). Cox proportional hazards models compared mortality risk between groups, including prognostic utility of C_MET features. Calculations were performed using SPSS (Statistical Package for the Social Sciences, International Business Machines, Inc., Armonk, New York, USA). Two-sided p < 0.05 was deemed indicative of statistical significance.

Results

Population characteristics

The population comprised 224 adults with advanced (stage IV) systemic cancer undergoing CMR, including 112 patients with C_MET as defined by LGE-CMR, and unaffected (C_MET -) controls matched for primary cancer diagnosis and stage.

Table 1 details population characteristics, together with comparisons between cancer patients with C_MET and their respective controls. As shown, cancer diagnosis varied among patients with C_MET: Sarcoma, lung, genitourinary, gastrointestinal cancers, and skin/melanoma comprised the leading primary cancer diagnoses, although the population also included patients with primary cancers not typically associated with C_MET (e.g. endocrine, head/neck). Regarding anti-cancer regimen, patients with C_MET were more likely to be treated with mediastinal radiation therapy and low molecular weight heparin (both p = 0.01) but were otherwise similar with respect to matched controls. Of note, nearly half (49%) of patients with CMR-evidenced C_MET had a subsequent change in anti-cancer medication regimen following CMR; 16% received new mediastinal/chest radiation within 3 months after imaging.

Table 1 Population characteristics

Regarding cardiac indices, cancer-matched controls referred for CMR were more likely to have adverse left sided chamber remodeling—as evidenced by lower LV ejection fraction and larger chamber size (both p < 0.01), but groups had similar right sided structural and functional indices (p = NS).

Cardiac metastasis location in relation to contrast enhancement

Anatomic location of C_MET varied (LV 32% │LA 22% │, RV 37%│ RA 30%│multi-chamber involvement 30%): Left and right sided chamber involvement were near equal in prevalence (50%, 58% respectively). Regarding C_MET tissue properties, 53% of patients had heterogeneously enhancing lesions (enhancing and non-enhancing components on LGE-CMR), whereas 47% had diffusely enhancing lesions without non-enhancing components.

Table 2 compares heterogeneously enhancing and diffusely enhancing C_MET. As shown, lesions were similar with respect to anatomic distribution, as evidenced by equivalent patterns of chamber involvement and rates of intra-cavitary location (all p = NS). Regarding lesion size, heterogeneously enhancing lesions were larger, based on linear dimensions (p < 0.05). Quantitative analyses were consistent with lesion classification, as evidenced by higher CNR (reflecting greater differences between enhancing and non-enhancing regions) and lower normalized SNR (reflecting impact of non-enhancing lesions on aggregate lesion signal intensity) in heterogeneously enhancing C_MET (both p < 0.001 vs. diffusely enhancing C_MET).

Table 2 Anatomic and tissue properties of cardiac metastases

Embolic events

Embolic events (within 6 months of CMR) were assessed to test if presence of C_MET impacted likelihood of clinical events, and whether this was modified by lesion location or tissue characteristics. A total of 33 embolic events occurred in the study population; events occurred at a median interval of 2 weeks from CMR [IQR 0.5, 9.5 weeks]. As shown in Table 3A, embolic events were over twofold more common among patients with C_MET as compared to cancer matched controls (21% vs. 8%, p = 0.006), including increased incidence of PE (13% vs. 5%, p = 0.08): Embolic events occurred at a median interval of 2 weeks from CMR [IQR 0.5, 9.4 weeks].

Table 3 Embolic events

Data shown in Table 3A also demonstrates that C_MET location modified likelihood of clinical events: Whereas patients with right sided lesions had a more than threefold increase in PE (20% vs. 6%, p = 0.02), those with left sided lesions had near identical rates of PE compared to cancer-matched controls (4% vs. 5%). Among patients with left sided lesions, CVA was more common compared to matched controls, although statistical differences between groups was not achieved in context of low clinical event rates (7% vs. 2%, p = 0.38). Sub-group analyses limited to intracavitary C_MET demonstrated a stronger association between lesion location and embolic event rates: Among patients with right sided intracavitary C_MET, PE occurred in over one fourth of cases–a rate more than fourfold higher than in matched controls (27% vs. 7%, p = 0.01). Two-thirds (8/12; 67%) of patients with right sided intracavitary C_MET who developed PE had lesions graded as highly mobile on cine-CMR.

Notably, increased PE rates among patients with right sided C_MET occurred despite frequent anticoagulation: Anticoagulant therapies (warfarin or direct oral anticoagulants) were more commonly utilized in patients with right sided C_MET as compared to matched controls (33% vs. 15%, p = 0.02), but were equivalent when among C_MET patients with left sided involvement and controls (16% vs. 21%, p = 0.63). Of note, 60% of patients with PE were on anticoagulation at the time of their clinical event (64% in C_MET vs 50% in controls, p = 0.64).

Regarding impact of C_MET tissue characteristics on embolic events, Table 3B demonstrates that rates of PE were similar between patients with heterogeneous and diffusely enhancing lesions (p = NS), as were rates of left sided embolic events. Figure 3 reports PE rates among patients stratified by both lesion location and tissue characteristics: As shown, PE rates were highest among patients with intracavitary right ventricular lesions (p < 0.001 vs. other groups), whereas partitioning based on lesion tissue characteristics did not stratify event risk (p = NS). Table 4 demonstrates that increased PE risk among patients with right ventricular C_MET was accompanied by impaired RV function, as evidenced by lower absolute RV ejection fraction (RVEF) and higher prevalence of RV dysfunction (both p < 0.05). Of note, among patients with RV C_MET, RVEF was similar between those who had PE prior to, compared to those who had PE after CMR (51.0 ± 12.7% vs 53.5 ± 3.8%, p = 0.72)–consistent with the notion that event driven changes in RV systolic function were not responsible for observed associations between impaired RV function and PE. Data shown in Additional file 1: Table S1 tests both clinical and CMR parameters in relation to PE. As shown, both gastrointestinal cancer etiology and right sided C_MET were each associated with increased likelihood of PE in univariate regression analysis, and each parameter remained associated with PE (p < 0.01) when the two parameters (gastrointestinal cancer etiology, right sided intracavitary C_MET) were tested together in an adjusted model.

Fig. 3

Pulmonary Embolism (PE) in Relation to C_MET Location and Tissue Properties. Top: Clinically documented PE (within 6 months of CMR) among patients grouped based on presence and location of C_MET. Note higher rate of PE among patients with C_MET involving the right ventricle, with differences most marked in analysis limited to intra-cavitary lesions (p < 0.001). Bottom: Location-based comparisons of PE rates among patients with heterogeneous and diffusely enhancing C_MET. Note equivalent rates of PE between patients grouped based on C_MET contrast enhancement pattern

Table 4 Cardiac remodeling in patients with and without right ventricular cardiac metastases

Mortality

Follow-up was performed for a median duration of 0.8 years [IQR 0.3–1.67], during which a total of 145 deaths occured. Figure 4 provides Kaplan Meier survival curves for the overall cohort of C_MET patients and cancer-matched controls, as well as for subgroups based on C_MET tissue characteristics. As shown (a), mortality risk was higher among C_MET patients compared to controls (HR = 1.64 [CI 1.17–2.29], p = 0.004): Median survival after CMR was shorter among patients with C_MET (9.7 months [IQR 4.0–21.7] vs. 15.1 months [5.4–60.3], p = 0.004), paralleled by increased 6-month (39% vs. 28%, p = 0.12) and 1 year (57% vs. 46%, p = 0.2) mortality.

Fig. 4

Mortality status. a Kaplan Meier survival curves for patients with C_MET (solid line) and cancer-matched controls (dotted line), demonstrating increased mortality among patients with C_MET compared to (C_MET -) controls matched for primary cancer type and stage (p = 0.004). b Kaplan–Meier curves among sub-groups with heterogeneously (left) and diffusely enhancing (right) C_MET as compared to respective cancer-matched controls. Note that prognosis varied based on C_MET tissue properties, as evidenced by equivalent mortality risk between diffusely enhancing C_MET and controls (p = 0.21) but increased mortality for patients with heterogeneously enhancing lesions (p = 0.004)

Figure 4b demonstrates that mortality differed in relation to tissue characteristics of C_MET: Whereas patients with diffusely enhancing C_MET had near equivalent mortality to matched controls (p = 0.21), prognosis was worse among patients with heterogeneously enhancing C_MET (p = 0.005)—including increased 6-month (44% vs. 26%) and 1 year (65% vs. 41%) mortality in respective case–control comparisons (both p < 0.05). As shown in Table 5, heterogeneously enhancing C_MET conferred higher risk for mortality (HR 1.97 [CI 1.23–3.15], p = 0.005) than did number of lesions (HR 1.67 [CI 1.31–2.12], p < 0.001) or lesion size (1.11 per 10 cm [CI 0.53–2.33], p = 0.79). Additionally, whereas lymphoma was the sole cancer diagnosis associated with differential (improved) prognosis, an adjusted model analysis inclusive of this variable together with LGE-CMR tissue characterization data demonstrated heterogeneously enhancing C_MET to remain associated with increased mortality (1.97 [CI 1.23–3.16], p = 0.005).

Table 5 Mortality predictors

Discussion

To our knowledge, this is the first study to test LGE-CMR pattern of C_MET as a prognostic marker in patients with systemic cancer, with focus on localized hypo-enhancement (a marker of tumor avascularity) as a novel marker of adverse prognosis. Results add to a growing body of literature by our group and others validating LGE-CMR in relation to histopathology and demonstrating clinical utility of this approach to guide diagnostic, prognostic, and therapeutic decision-making for patients with known or suspected cardiac masses. Key findings are as follows: First, among a broad cohort of advanced cancer patients, C_MET contrast-enhancement pattern varied—prevalence of diffusely (47%) and heterogeneously enhancing (53%) lesions was near equivalent. Quantitative analyses demonstrated heterogeneously enhancing C_MET to have more aggressive features, as evidenced by larger lesion size and lower SNR (as would be expected in context of tumor avascularity). Second, presence and distribution of C_MET impacted likelihood of embolic events. Aggregate embolic events were higher among patients with C_MET compared to cancer matched controls (21% vs. 8%, p = 0.006), C_MET location modified likelihood of events: Whereas patients with right sided lesions had a threefold increase in PE (20% vs. 6%, p = 0.02), those with left sided lesions had near identical event rates to those of (C_MET -) controls (4% vs. 5% p = 1.00). Embolic event rates did not vary in relation to C_MET by tissue properties, as evidenced by equivalent rates of PE among patients with diffuse and heterogeneously enhancing right ventricular lesions. Third, mortality risk conferred by C_MET varied in relation to contrast-enhancement pattern. During a median follow-up of 0.7 years [IQR 0.3–1.7], patients with and without diffusely enhancing C_MET had equivalent mortality to controls (p = 0.21), whereas prognosis was worse among patients with heterogeneously enhancing C_MET compared to controls matched for cancer etiology and stage (p = 0.005).

Our finding that heterogeneous lesion enhancement constitutes an adverse prognostic marker among patients with C_MET is consistent with established concepts in tumor biology: Tumor necrosis—as would be expected to result in avascularity and thus impaired contrast uptake—is a known marker of aggressive phenotype: Uncontrolled oncogene driven proliferation of neoplastic cells exhausts oxygen supply from normal vasculature, resulting in localized hypoxia which upregulates production of angiogenic factors and triggers neovascularization. [15, 16] However, vessels formed in response to hypoxia lack normal physiological angiogenesis—providing a nidus for chaotic tumor architecture and vascular leakiness. Hypoxia alters cancer metabolism to foster survival during stress and drive malignant progression, resulting in resistance to anti-cancer therapy and accelerated tumor growth. Consistent with this, magnetic resonance imaging (MRI) studies focused on extra-cardiac areas—including neurologic and renal cancers—have associated contrast hypo-enhancement (tumor necrosis) with chemotherapeutic resistance and increased mortality. [14, 17, 18].

Regarding embolic events, our data demonstrated C_MET location to be strongly associated with outcomes—as evidenced by increased rates of PE among patients with RV intracavitary C_MET. Our finding that embolic events were equivalent between patients with diffuse and heterogeneous C_MET is not unexpected, given that avascular components were typically centrally located within lesions and would thus be unexpected to provide a nidus for embolization. Regarding mechanism, our data demonstrated patients with RV C_MET to have lower RV systolic function than those with C_MET in other locations (p < 0.05)—possibly due to mechanical tumor effects or treatment related (i.e. radiation-induced) cardiac injury. Based on this, it is possible that localized stasis could contribute to development of super-imposed thrombosis on neoplastic lesions—providing a nidus for embolic events. Whereas heterogeneous enhancement (as would be expected in context of tumor with superimposed thrombus) was not identified as a risk factor for embolic events, it is possible that micro-thrombi developed prior to or following the time of CMR, or that spatial resolution of LGE-CMR was insufficient for diagnostic detection. It is also possible that emboli stemmed from tumor dislodgement rather than primary thrombotic processes or from insufficient anticoagulation—concepts supported by the fact that nearly two-thirds (63%) of C_MET patients were on anticoagulation at the time of clinical events, as well as recent data showing high embolic event rates in non-cancer [10, 19] and cancer populations [20] with cardiac thrombus treated with anticoagulants. Future research, including imaging using high resolution 3D LGE-CMR [21] and prospective trials testing relative efficacy of anticoagulant regimens or targeted resection in cancer patients with C_MET, are necessary to further test these concepts.

Limitations

Several limitations should be noted. First, whereas our study encompassed a broad cohort of cancer patients undergoing CMR and clinical follow-up at two institutions, it should be recognized that embolic events were ascertained based on clinical documentation and/or diagnostic testing. In this context, it is likely that subtle clinical events were under-reported, or that clinical considerations may have influenced testing such that embolic events such as stroke were under-diagnosed. It should be noted that our study was unable to reliably ascertain all potential cancer related clinical indices or derive aggregate classifications of disease chronicity and performance status. Thus, while our results demonstrate that location and contrast-enhancement pattern of LGE-CMR evidenced C_MET impacts clinical outcomes, further research is warranted to test whether associations observed in the current study are modified by cancer etiology, treatment type, and/or overall health status. Second, whereas our study utilized LGE-CMR for tissue characterization of C_MET, alternative approaches to assess vascularity such as quantitative LGE thresholds, perfusion, parametric mapping, or susceptibility weighted CMR were not tested. Whereas current findings demonstrate heterogeneous contrast uptake pattern within C_MET to be a marker of increased mortality risk, knowledge gaps persist as to the relative utility of different imaging approaches to assess tumor necrosis or additional tissue properties such as hemorrhage and calcification. It is also important to recognize that whereas prior studies have validated LGE-CMR tissue characterization of masses in relation to pathology and other standards including metabolic imaging and outcomes, [3, 4, 10] lack of systematic biopsy sampling in the current cohort (for whom invasive cardiac tissue sampling was uncommon in context of advanced cancer) prohibited direct comparison of LGE-CMR enhancement pattern to pathology findings. An additional limitation relates to the relatively small number of embolic events (n = 33) in this study, which may explain the wide confidence intervals with respect to observed associations of C_MET and GI cancer etiology with PE: In this context, current results should be considered more exploratory than definitive, thus highlighting the need to test them further in larger scale studies. Future research is also warranted to test whether alternative protocols using low dose contrast administration or non-contrast approaches (e.g. T1 mapping) provide equivalent diagnostic and prognostic utility in cancer patients with known or suspected C_MET.

Conclusions

Location and contrast-enhancement pattern of C_MET impact clinical outcomes, with RV lesion location associated with PE and heterogeneous enhancement conferring increased mortality. Given current findings, future research is warranted to test anticoagulant strategies in cancer populations, whether adverse prognosis conferred by heterogeneous lesion enhancement stems from accelerated tumor growth, and whether tailored therapies—paired to lesion tissue characteristics—improves clinical outcomes for cancer patients with C_MET.