In principle, all malignant tumors can metastasize to the heart. In fact, cardiac metastatic disease is more common than primary heart tumors [6
], and its incidence has increased during recent decades due to the prolonged survival of patients with cancer and the increased prevalence of the disease in the general population [7
]. Neoplasms that most commonly metastasize to the heart include malignant melanoma, lymphoma, and leukemia; however, overall numbers are greater for breast and lung cancer, reflecting their higher incidence. In pNET, the liver is the most commonly invaded organ by direct extension or metastasis, followed by regional lymph nodes, and bone [4
], whereas cardiac metastasis from pNET has not been previously reported.
The heart is rarely the first site for metastases, and they are usually only found later when diffuse involvement of other organs has already occurred. Tumor cells can metastasize to the heart and pericardium by one of four different pathways: lymphatic, hematogenous, direct extension, or transvenous extension via the superior or inferior vena cava [8
]. Lymphatic spread often gives rise to pericardial metastases, whereas hematogenous spread has a propensity to migrate to myocardium. Tumors that are in close proximity to the heart, such as bronchial, breast, and esophageal tumors, usually spread by direct extension and give rise to pericardial disease. The most common site of cardiac involvement is the pericardium, with frequencies ranging from 62% to 81%, whereas myocardial or endocardial involvement is rare. In the case described here, metastatic cardiac involvement of pNET occurred in a disseminated setting with regional lymph node and bone metastases, and, via lymphatic spread, multiple pericardial metastases with myocardial involvement.
In such cases, cardiac metastases are usually asymptomatic because the masses are small and do not affect cardiac function [8
]. When present, clinical signs and symptoms of cardiac metastases are extremely variable, depending on the site and intensity of involvement. Symptoms include dyspnea or tachypnea, and clinical signs include systolic heart murmur, peripheral edema, and pleural or pericardial effusion. Hypotension, peripheral cyanosis, pulsus paradoxus, and venous congestion are also hallmarks of clinical diagnosis. Cardiac metastases can cause disturbances of atrial and ventricular heart rhythm, as well as conduction defects. Pericardial involvement can lead to development of pericarditis with pericardial effusion, which may compromise hemodynamics. Angina pectoris, myocardial infarction, syncope, and sudden death have been reported. Although cardiac metastases cause mild symptoms, more extensive spread of tumors to the pericardium or to other cardiac sites may lead to production of dramatic clinical patterns, resulting in occurrence of medical emergencies and sudden death, unlike other metastatic sites. In the case described here, the diagnosis of cardiac metastases resulted from an incidental finding during a metastatic work-up; there were no early cardiac symptoms. Approximately three years from the initial diagnosis, the patient's cardiac symptoms were chest discomfort and dyspnea on exertion.
No standard treatment modality has been established for cardiac metastases, and, because most patients have disseminated disease, the treatment is generally primary tumor systemic therapy. Therefore, treatment of cardiac metastases is mainly confined to palliation of cardiac symptoms, which may improve the quality of life of affected patients. Surgical resection is only indicated in exceptional cases of solitary intracavitary heart metastases that obliterate cardiac chambers or cause valvular obstruction. Malignant pericardial effusion, especially cardiac tamponade, requires percutaneous pericardiocentesis within a short period of time. Radiotherapy for treatment of cardiac metastases should be used with caution as it may lead to fibrosis of the lung or myocardium, and may be associated with disturbance of the conduction system and pericarditis. The chemotherapeutic agents doxorubicin, daunorubicin, and high-dose cyclophosphamide have cardiotoxic side effects, which may induce recalcitrant myocardial failure.
Systemic chemotherapy for advanced pNETs has been studied in many clinical trials over the past three decades; however, despite a multitude of publications, debate over its efficacy continues. Streptozocin alone or in combination with doxorubicin remains the only chemotherapeutic agent approved for treatment of advanced pNETs; however, it is associated with considerable adverse events [10
]. Recent large prospective trials have shown that the molecular targeting agent, sunitinib, a multi-target receptor tyrosine kinase inhibitor, and the mammalian target of rapamycin inhibitor, everolimus, has promising antitumor activity [12
]. Due to his economic circumstances, our patient was not treated with streptozocin or a molecular targeting agent, and instead received etoposide and cisplatin but failed to respond. Nevertheless, he has been relatively well for the last 33 months; patients with pNETs can live with metastatic disease for several years.
This report describes a case of nonfunctioning pNET with multiple metastases to previously undescribed cardiac sites. Although rare, pNET has the potential to metastasize to the heart or pericardium, and, for patients with pNETs who present with new cardiac symptoms or signs, whether based on history or physical examination, the clinician should be alert to the possibility of cardiac metastases.