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Case Report  |  Open Access  |  6 Jul 2023

Current diagnosis and management of cardiac melanoma: a case series and review

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J Cancer Metastasis Treat 2023;9:27.
10.20517/2394-4722.2022.113 |  © The Author(s) 2023.
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Abstract

Malignant melanoma is believed to have the highest rate of cardiac metastasis of any cancer based on autopsy studies, but descriptions of clinical findings, diagnosis, and treatment remain lacking. In particular, the use of immunotherapy has been only sparingly described. We present eight cases of malignant melanoma treated at our institution. Four patients displayed symptoms, three were diagnosed on routine surveillance imaging, and one was diagnosed postmortem. Locations of cardiac tumors varied with all four chambers and septum involved between the cases. Six patients underwent genetic profiling: two patients had a CDKN2A variant detected in their cardiac tumor, one patient had a BRAF mutation, and one patient had an NRAS mutation. Six patients underwent immunotherapy with either anti-PD-1 and/or anti-CTLA-4 therapy. This report highlights the importance of considering cardiac melanoma in surveillance imaging and the use of immunotherapy for management.

Keywords

Melanoma, metastasis, cardiac tumor

INTRODUCTION

Metastases of malignant melanoma occur in up to 30% of cases, but reports of cardiac involvement are rare[1]. While melanoma comprises only 1%-3% of cutaneous tumors in the United States due to its propensity to metastasize, it accounts for 60% of skin cancer-related deaths[2,3]. Melanoma metastases have been associated with a wide variety of neuroendocrine signaling pathways that disrupt homeostasis[4]. Hematogenous spread commonly results in metastases to the lungs, liver, and brain. Malignant melanoma is believed to have the highest rate of cardiac metastases of any cancer, although cardiac metastases from lung and breast carcinoma remain more common in absolute numbers due to the relatively higher frequency of these cancers in the population[5]. An autopsy study of 70 patients with known metastatic melanoma found cardiac metastases in 64% of cases[6]. However, cardiopulmonary symptoms were present in only 16% of cases, suggesting that clinically silent cardiac involvement is not uncommon. Cardiac melanoma has a poor prognosis with a median survival of 12 to 24 months reported in past case series[7,8].

Clinical findings described in cardiac melanoma have been mixed. Metastases appear to be most common on the right side of the heart but have been described in many locations with various resulting symptom profiles[8,9]. Features of several imaging modalities have been described, including magnetic resonance imaging, echocardiography, and positron emission tomography (PET)[10,11]. For representative images of commonly used imaging modalities in our patient cohort, see Figure 1. While echocardiography is often used to provide preliminary diagnostic information for cardiac tumors and PET scans may aid in identifying metastases in general, CT and MRI scans are most useful for further characterization and tumor demarcation[12]. Cardiac MRI, in particular, provides information on tissue properties such as vascularity that can inform diagnosis[13]. Surgical management is often avoided due to advanced disease and is aimed at amelioration of cardiac symptoms[14,15].

Current diagnosis and management of cardiac melanoma: a case series and review

Figure 1. Multiple imaging modalities have been used to detect suspected cardiac melanoma. (A) Echocardiogram showing a 3.1 cm × 2.4 cm mobile echodensity at the apex of the left ventricle concerning for thrombus or tumor. (B) Chest CT showing a 4.3 cm mass in the right ventricle consistent with malignancy. (C) Cardiac T2-weighted MRI displaying a mixed tumor and thrombus at the apex of the left ventricle. (D) PET scan of a hypermetabolic mass at the apex of the left ventricle.

While cases of cardiac melanoma have been described, optimal medical and surgical management has not been fully elucidated. With the advent of newer targeted therapies and checkpoint inhibitors combined with minimally invasive surgical treatment, there may be an opportunity to improve the management of cardiac metastasis. We present eight cases of metastatic melanoma to the heart and describe diagnosis, oncologic and surgical management, and patient course.

CASE REPORT

Electronic medical records of previously identified patients with known diagnoses of melanoma with metastases to the heart between 2012 and 2022 at the Yale-New Haven Hospital were reviewed. Data on patient demographics, clinical notes, treatment plans, pathology reports, genetics reports, imaging reports including MRI, PET/CT, CT, echocardiography, and operative notes were collected.

The records of eight patients were reviewed, including three women (38%) and five men (62%). The median age at first melanoma diagnosis was 67.5 years (Range: 23-81 years). The median time to identification of cardiac involvement was 4 years (Range: 0-15 years). Melanoma first presented with cardiac findings in one case, and cardiac involvement was identified postmortem in one case [Table 1].

Table 1

Characteristics of patients with cardiac melanoma

Age at diagnosis of melanomaAge at diagnosis of cardiac metastasisGenderRacePrimary lesion locationCardiac metastasis locationTreatmentCardiac presentationOther metastatic sites
8083MaleWhiteUnknownIntra-atrial septumCombination ipilimumab and nivolumab followed by nivolumab maintenance therapy and radiation therapy to left hilum/ heartNew atrial fibrillationLeft hilum
7979FemaleWhiteUnknownLeft atriumNivolumab monotherapyDyspneaLung
7981MaleWhiteLeft great toeRight ventricle and right ventricular outflow tractPembrolizumabNonePsoas muscles, left thigh muscle, and lung
70Postmortem*MaleWhiteRight calfUnspecifiedN/AUnclear - history of congestive heart failure and pulmonary embolism pre-date melanomaLungs, peritoneum, lymph nodes, heart, small intestine, adrenals, and peripelvic fat
6367MaleWhiteRight neckRight ventricleIpilimumab and nivolumabNoneLung, liver, right ventricle, right groin, and clivus
6570MaleWhiteRight shoulderRight atrium (abutting interatrial septum)Combination ipilimumab and nivolumab followed by nivolumab monotherapy. Received gamma knife radiation therapy for brain metastasesNoneLiver, brain, lungs, and ribs
2338FemaleWhiteLeft armLeft atrioventricular septum invading into myocardium; malignant pericardialAdjuvant low-dose interleukin-2 and GM-CSF followed by VemurafenibDyspneaScapula
6066FemaleWhiteLeft medial heelMalignant pericardial effusionTopical imiquimod and intralesional IL-2 followed by combined nivolumab and ipilimumab.DyspneaLeft inguinal metastases and intra-abdominal lymphadenopathy

Four patients displayed symptoms associated with cardiac metastasis: two with new-onset dyspnea, one with worsened existing dyspnea, and one with new-onset atrial fibrillation. An additional patient had a history of congestive heart failure and pulmonary embolism pre-dating their melanoma diagnosis, and cardiac metastasis was discovered postmortem. The remaining three patients did not display cardiopulmonary symptoms. Three patients had a cardiac mass discovered on surveillance imaging as an incidental finding. Seven of eight patients had at least one other site of metastasis identified including six patients with pulmonary involvement, two with lymph node involvement, two with liver involvement, one with small intestine and adrenal involvement, and one with brain involvement [Table 1]. Biopsy specimens of intracardiac lesions were not uniformly obtained and comparative genetic/histological data is unavailable.

The location of cardiac melanoma varied in all the patients [Table 1]. Locations included the left ventricular apex, left atrium, tricuspid valve, right ventricle, right atrium, inter-atrial septum, left atrioventricular septum, as well as malignant pericardial effusion. Six patients underwent additional study for genetic profiling and immunohistochemistry staining for PD-1 and PD-L1 on the resected tumor. Tumor mutational panels were used to detect common driver mutations associated with melanoma. Specifically, two patients had CDKN2A mutations, one patient had a BRAFV600E mutation, and one patient had an NRAS mutation. Five patients underwent surgery for primary and/or metastatic melanoma; none had resection of their cardiac lesions, although two patients required pericardial effusion drainage. All patients were also receiving immunotherapy or targeted therapy in conjunction with surgical management. Six patients were treated with immunotherapy with nivolumab (anti-PD-1 therapy) or ipilimumab (anti-CTLA-4 therapy); one patient was deceased before these therapies were approved for use in metastatic melanoma and the other had a discovery of metastasis postmortem. Two patients out of six patients treated with both nivolumab and ipilimumab had complete regression of their cardiac melanoma based on surveillance imaging, while three had progression of their cardiac metastasis. One patient with complete regression of melanoma later developed gastric adenocarcinoma with hepatic metastasis.

DISCUSSION

Cardiac tumors are uncommon, and clinical reports of malignant melanoma with metastasis to the heart are particularly rare[16][Table 2]. Our study examines the management and clinical course of eight patients diagnosed with cardiac melanoma. In general, management was in line with current treatment options available for patients with stage IV melanoma, including combinations of targeted therapy and immunotherapy. Direct surgical management of cardiac tumors was not pursued in these cases.

Table 2

Literature review of clinical case and retrospective studies of cardiac metastatic melanoma. patients were considered to have received immunotherapy, regardless of whether they began therapy before or after diagnosis

StudyYearnAge at diagnosis (years)SexPresentationLocation of cardiac metastasesSurgical resectionImmunotherapy
Balinski et al.[17]20222358 (34-105)13 M, 10 FFatigue (35%)
dyspnea (30%)
Right ventricle (65%),
left ventricle (35%),
right atrium (35%)
3 (15%)13 (57%)
Bortolotti
et al.[18]
1990149MFatigue, dyspneaRight atriumYN
Burn et al.[19]2014133FExertional dyspneaRight atriumNot reportedNot reported
Canver et al.[14]1990132MFatigue, dyspneaLeft atriumYN
Grazziotin
et al.[20]
2002164FArterial embolizationLeft ventricleNN
Kaulen et al.[21]2018180sMUnexplained sudden deathAll 4 chambersNN
Lee et al.[22]2012159FCoughRight atriumNN
Liebana et al.[23]2009167Not reportedAsymptomaticRight atriumNot reportedNot reported
Malouf et al.[24]1996173MAsymptomaticRight atriumNY
Messner et al.[15]20032 46 (41-50)1 M, 1 FDyspnea, lower extremity swellingRight ventricleYNot reported
Morosin et al.[25]2019166Not reportedNot reportedRight atriumYNot reported
Mousseaux
et al.[11]
1999457 (46-67)3 M, 1 F1 cardiac tamponade,
1 superior vena cava syndrome,
2 asymptomatic
Left atrium,
left ventricle
1 (25%)1 (24%)
Onan et al.[26]2010131MHeartburn, dyspepsiaRight atriumYN
Ozyunca
et al.[27]
2006158MComplete atrioventricular blockInterventricular and interatrial septumNN
Poggi et al.[28]2005141FAsymptomaticLeft ventricleNN
Poulsen et al.[29]2019165MFatigue, dyspneaLeft ventricleNY
Ramchand
et al.[30]
2016155FMild coughLeft ventricleYY
Safa and Olivia[31]2019161FAsymptomaticLeft ventricleNY
Savoia et al.[32]2000153FPostmortemRight atrium and ventricleNY
Spiliopoulus
et al.[33]
2021171MDyspnea on exertionRight atrium and ventricleYY
Tas et al.[34]2010144FAsymptomaticInteratrial septumNN
Tesolin et al.[35]2005117FTachycardiaApical left ventricleNN
Thant et al.[13]2021179FAtrial flutter, presyncopeRight atrium, interatrial septumNY
Tse et al.[7]20171163 (54-72)7 M, 3 FDyspnea (64%)5 right atrium (46%),
2 right ventricle (18%),
2 left atrium (18%),
1 left ventricle (9%),
1 pericardium (9%)
10 (91%)4 (36%)
de Vasconcelos
et al.[36]
2013139MChest pain, numbness from the waist downAnterolateral wall of left ventricleYN
Villa et al.[37]2014161MDyspnea, syncopeInterventricular septum, right cardiac apex, right atrial polypoid massNN
Vukicevic
et al.[38]
2020142FHypotension, dyspnea, tachycardiaRight ventricle and atriumYN
Wood et al.[8]2008760 (31-79)4 F, 3 MDyspnea or substernal pressure4 right atrium,
2 right ventricle,
1 left ventricle
Either biopsy or ResectionNot reported
Zitzelsberger et al.[9]20172558 (26-89)12 M, 13 FAsymptomatic17 right atrium (67%),
8 right ventricle (33%)
1 (4%)Not reported

However, the presence of cardiac metastases postmortem in patients with metastatic melanoma suggests that there is a gap in detection with current surveillance imaging modalities[9]. As techniques and resolution in imaging improve, cardiac metastasis to the endocardium and myocardium should theoretically be better detected. In previously published case series in cardiac melanoma, pericardial or myocardial metastasis was most frequently described, which may indicate a biased detection due to imaging modalities and their sensitivities to detect small metastasis that protrudes into the cardiac cavity[39]. In our cohort of patients, cardiac MRI was used for confirmation of cardiac lesions first seen on other imaging modalities; indeed, cardiac MRI has the capability to differentiate tissues, incorporate multiple imaging planes, and evaluate valve disturbance, which neither echocardiogram nor CT is capable of performing[40]. Though abnormal lesions can be identified with contrast-enhanced CT, a multimodal approach was necessary for accurate localization of the metastasis; the patients studied for this case series had undergone a cardiac MRI to differentiate the lesion along with PET/CT. PET scans have a higher sensitivity and specificity relative to CT scans for detection of all melanoma metastases, but cardiac metastases may be more challenging to detect on this modality due to the typical uptake observed regularly in the heart[41]. In a study of 103 patients, Holder et al. found a sensitivity and specificity of 94.2% and 83.3%, respectively, for detection of all melanoma metastases with PET, compared to 55.3% and 84.4% for CT imaging[41]. A recent study by El-Shourbagy et al. examining 18 patients similarly found a sensitivity and specificity of 100% and 66.66% for detection of metastases of any location with FDG-PET/CT[42]. A 2019 review of imaging for staging and re-staging of cutaneous melanoma in adults noted that existing literature primarily focuses on PET/CT imaging, while comparative data with MRI and CT imaging are lacking[43].

It has been previously described that the right atrium is the most common site of metastasis[9]. In our series, we had a wide array of cardiac metastatic locations. In a study describing CT imaging of cardiac melanoma in 25 patients, left ventricle and left atrium involvement were described in 17% and 8% of cases, respectively, while in the present series, one case involved the left atrium and one involved the left atrioventricular septum[9]. Other reports of left heart involvement have been rare[8,14].

Surgical management of cardiac tumors in melanoma has been described to palliate symptoms of heart failure and outflow tract obstruction. In the present series, no patients underwent surgery to resect cardiac metastases, given that the majority of the cardiac tumors were asymptomatic. The role of surgical management for cardiac metastases is quite limited and, if pursued, particularly for symptomatic or oligometastatic disease, should be discussed by a multi-disciplinary team.

Treatment of metastatic melanoma to the heart treated with immunotherapy has only been described recently[17,29]. Immunotherapy with either blockade of PD-1 or CTLA-4 therapy is based on activation of cytotoxic T cells to induce an antitumor immune response[44]. The pharmaceuticals, both approved for the treatment of unresectable and metastatic melanoma, function by selectively inhibiting negative regulators of cytotoxic T-cell function to produce a more robust antitumor response. CTLA-4 is believed to regulate the proliferation of T-cells early in the tumor response and decrease regulatory T cells. PD-1 suppresses the later-stage T-cell response in the peripheral tissues[45]. In instances with cardiac metastatic lesions, our institution favors the use of a combination of anti-PD-1 and anti-CTLA-4 therapy because of the improved responses with this regimen. These patients are monitored closely for immune-related adverse events. The heart is mainly thought of as an area of immune privilege, but our series demonstrates that responses can be seen[45]. Interestingly, in these patients, none experienced immune-related myocarditis, highlighting a continued need to understand the specific immune environment of the heart and honing of circulating T cells to this microenvironment. There are currently no available predictors of response to immunotherapy. We observed that 33% of the study patients had a temporary clinical response in their cardiac metastases, but most later developed progression while on immunotherapy. This is consistent with previous papers demonstrating that patients even with PD-L1 positive tumors show resistance or relapse with PD-1 blockade[46,47]. This may demonstrate the need for improved biomarkers in stratifying patients for immunotherapy treatments and assessing the efficacy of combination immunotherapy after initial nonresponse to single-immune checkpoint inhibitor therapy with either anti-CTLA-4 or anti-LAG-3[48]. Targeting different combinations of immune checkpoints may be important for improving response rates and decreasing rates of acquired resistance[49].

This report builds upon others to highlight the importance of considering cardiac involvement in surveillance. This series highlights the need for further research into the utility of surveillance imaging for cardiac melanoma and the potential role of immunotherapy in limiting its progression. While cardiac melanoma should be considered in patients with a history of melanoma who present with new or worsened cardiopulmonary symptoms, half of the patients in this series were asymptomatic. Consideration of cardiac involvement in surveillance imaging may be valuable for improving identification of cardiac metastasis and determining treatment strategies.

DECLARATIONS

Authors’ contributions

Conceptualized and designed the study, collected data, drafted the initial manuscript, and revised the manuscript: Long AS, Chang J

Revised the manuscript and generated figures: Glahn JZ

Critically reviewed the manuscript for intellectual content: Tran TT

Conceptualized and designed the study, provided administrative, technical, and material support, and critically reviewed the manuscript for intellectual content: Clune J, Olino K

Availability of data and materials

Not applicable.

Financial support and sponsorship

None.

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

This study was deemed exempt from review by the Yale University Institutional Review Board (HIC#2000032566). Individual patient consent was not required.

Consent for publication

This study was reviewed by the Yale Institutional Review Board (HIC#2000032566), which determined that consent was not necessary for publication.

Copyright

© The Author(s) 2023.

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OAE Style

Long AS, Chang J, Glahn JZ, Olino K, Tran TT, Clune J. Current diagnosis and management of cardiac melanoma: a case series and review. J Cancer Metastasis Treat 2023;9:27. http://dx.doi.org/10.20517/2394-4722.2022.113

AMA Style

Long AS, Chang J, Glahn JZ, Olino K, Tran TT, Clune J. Current diagnosis and management of cardiac melanoma: a case series and review. Journal of Cancer Metastasis and Treatment. 2023; 9: 27. http://dx.doi.org/10.20517/2394-4722.2022.113

Chicago/Turabian Style

Aaron S. Long, Jungsoo Chang, Joshua Z. Glahn, Kelly Olino, Thuy T. Tran, James Clune. 2023. "Current diagnosis and management of cardiac melanoma: a case series and review" Journal of Cancer Metastasis and Treatment. 9: 27. http://dx.doi.org/10.20517/2394-4722.2022.113

ACS Style

Long, AS.; Chang J.; Glahn JZ.; Olino K.; Tran TT.; Clune J. Current diagnosis and management of cardiac melanoma: a case series and review. J. Cancer. Metastasis. Treat. 2023, 9, 27. http://dx.doi.org/10.20517/2394-4722.2022.113

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