Patients with NF are at greatest risk for developing sarcomas, including MPNST. The incidence of MPNST arising in NF is 4.6%, which is much higher than the 0.001% in general population . The most common metastatic site of MPNST is the lung [1, 4]. Cardiac involvement from metastatic MPNST is extremely rare, whether with or without a background of NF [2–4]. Our patient is one of the extremely rare cases of cardiac metastasis of MPNST associated with NF1. Most of the cardiac metastases are preceded by other metastatic lesions, such as in the lung. Although the possibility of cardiac involvement becomes higher as the tumor progresses, details of the histopathological features specific to cardiac metastasis remain to be investigated. Recent studies have in part revealed the genomic imbalance in sporadic and NF1-associated MPNST [6, 7]. The biology of metastatic features of MPNST, however, is still unknown.
The prognosis of patients with MPNST is generally poor. Aggressive surgery significantly improved disease-free survival [5, 8]. Adjuvant chemotherapy and radiotherapy has not been proven to prolong patient survival, but it is effective as a palliative option [4, 8, 9]. If clinical symptoms of cardiac dysfunction occur during the progression of MPNST, it might be that the heart is involved. In such cases of MPNST, it is necessary to exclude cardiac involvement, even if it is rare, by occasional echocardiography. Early diagnosis can allow timely surgical intervention, if the patient is operable, which may improve results, as in the case described here.
Clinical features vary according to the site of cardiac involvement, such as pericardium, epicardium, myocardium or endocardium. The present case showed a large mass in the myocardial region, which was accompanied with increasing pericardial effusion and arrhythmia. Serial histological sections revealed that the metastatic tumor markedly affected the common bundle of His, in addition to the ordinary myocardium. Based on these findings, we surmised that complete atrioventricular block was attributable to cardiac metastasis of MPNST, which is causative of circulatory failure . Related features of cardiac involvement of MPNST are uncertain. More cases should be reported to elucidate the clinical entity associated with cardiac involvement of MPNST and to formulate an appropriate treatment strategy.
Most NF1 patients carry a constitutional mutation of the NF1 tumor suppressor gene . Biallelic inactivation of NF1 and mutations of numerous additional tumor suppressor genes within the p19
-MDM2-TP53 and p16
INK4A-Rb signaling cascades have been identified in MPNSTs [12, 13]. These abnormalities of suppressor genes, except for NF1, are not present in neurofibromas. It is therefore thought that the development of neurofibromas and their subsequent progression to become MPNSTs involves a sequential series of tumor suppressor mutations. Deletions and other mutations that result in loss of function of the TP53 tumor suppressor gene are some of the more common abnormalities found in MPNSTs. Biallelic inactivation of the TP53 locus is found rarely in MPNST, which has led to the suggestion that hemizygous TP53 mutations may suffice for neurofibromas to progress and become MPNSTs.
A recent study has demonstrated that two MPNST cell lines derived from sporadically occurring MPNSTs have functional and intact NF1 genes . Paradoxically, however, microarray studies that have compared the transcriptomes of sporadic and NF1-associated MPNSTs have not found a molecular signature that distinguishes these neoplasms [14, 15].
For understanding of these complex neoplasms and the development of the effective new therapy, further investigation will be needed into the clinical features and the basic science.