Surgical Treatment And Single-cell Sequencing Study Of Functional Cardiac Paraganglioma And Primary Cardiac Sarcom

Background:Functional cardiac paragangliomas are rare neuroendocrine tumors with the ability of secreting catecholamine.Early surgical treatment improves clinical symptoms and prolongs survival.However,the non-specific symptom and endocrine function makes it challenging in diagnosis and surgical treatment for this rare disease.Therefore,experience from high-volume referral center is necessary.Due to the rarity of this disease,the clinical spectrum of functional cardiac paraganglioma was not clearly described by studies in the literature.Based on a multidisciplinary diagnosis and treatment mode,this study aimed to summarize a process for early diagnosis,curative surgery and standard perioperative treatment,and to evaluate the prognosis.Methods:Seventeen patients underwent surgery for functional cardiac paraganglioma in our institution from January 2004 to June 2017 were included.Clinical data and short and long-term outcomes were extracted and analyzed.A multidisciplinary experience for functional cardiac paraganglioma was raised.Results:Eleven of the 17 patients(64.7%)were male.Twenty-four-hour-urinal catecholamine assay documented elevation of norepinephrine,epinephrine,and dopamine.Tumors were determined by Octreotide(OCT)scintiscan and metaiodoben-zylguanidine(MIBG)scintigraphy.Tumor sites included right atrioventricular groove,between the main arteries,interatrial groove.All patients underwent complete resection,and structural reconstruction.There was 1 in-hospital mortality(5.8%).There was no death during follow-up(median 6.5 years,IQR 3.5～11.4 years),16 patients are alive,13 patients(81.2%)remained symptom-free.Conclusion:The multidisciplinary treatment for cardiac paraganglioma includes early diagnosis by urine catecholamine assay and OCT or MIBG scintigraphy,multimodal imaging for surgical evaluation,individualized preoperative medical preparation,principles of radical resection and reconstruction surgery,and post-operational critical care with the core of PiCCO monitoring.With this protocol,early diagnosis,and curative surgery for functional cardiac paraganglioma are achievable for most patients and the long-term survival is promising.Backgrounds:Primary cardiac sarcomas are rare malignant neoplasms with invasive growth type.Prognosis of cardiac sarcoma is poor either underwent surgery or adjuvant treatment.Median postoperative survival was less than a year,according to the literature.Previous studies were impaired by the small sample size,long time span and not standardized treatment,and failed to depict the clinical spectrum of cardiac sarcomas based on pathological subtypes.As for the mechanisms of tumor development,replicated mutations was identified by chromosomic or exon sequencing and verified in classical tumor developing pathways by the previous literatures.Single cell sequencing has not been used in the studies of cardiac sarcoma.This study aims to compare the clinical characteristics of the various cardiac sarcomas and the surgical techniques used to treat them,to identify factors that influence the prognosis,and to find specific high expression genes of different cardiac sarcomas.Methods:Between February 2017 and April 2022,40 patients underwent surgery for cardiac sarcomas were included.Sixty percent of them had angiosarcoma.Clinical characteristics,tumor location,surgical techniques used,and the prognosis were compared between patients with angiosarcoma and those with other subtypes.KaplanMeier curves and multivariable Cox regression were used to identify predictors of postoperative survival.Seven samples of different subtypes of cardiac sarcoma from patients enrolled between September 2021 and April 2022 were collected,single cell sequencing was performed,and cell cluster analysis was used to demonstrate cell heterogenicity of these two cardiac neoplasms.Specific high expression genes were detected for further mechanism study.Results:Angiosarcomas were more likely than the other subtypes to present as pericardial effusion(85%vs 50%,P=0.014).Early surgery was done(median 24.0 days,IQR 12.8～60.8 days)regardless of histological subtype.The surgical technique varied according to histological subtype.Median postoperative survival was 10 months(IQR 5～23 months).A positive margin(P=0.13),Ki-67 index>50(P=0.19),Age<40(P=0.86),and angiosarcoma(P=0.87)were identified to be potentially poor prognostic factors in univariate analyses.Cox regression identified R0 resection to be the protective factor of the prognosis after surgery(hazard ratio 0.423,P=0.039).Clustering analysis based on single cell sequencing data showed different cell constitution between angiosarcoma and other cardiac sarcomas.A subset expressing lymphatic-specific marker PDPN,FLT-4,and Prox-1,and a subset with highly expressed APLNR protein were identified in the endothelial cluster of cardiac angiosarcoma.Conclusion:Angiosarcoma differs from other subtypes of cardiac sarcoma in terms of cell constitution,clinical symptoms,tumor location,surgical techniques used,and prognosis.Early surgery is needed regardless of subtype.R0 resection is the protective factor of postoperative survival,and complete resection is usually achievable.The prognosis may be poorer in patients with a positive margin,Ki-67 index>50,age<40,and angiosarcoma.A lymphatic subtype of angiosarcoma may exist in cardiac angiosarcomas.Apelin/APLNR pathway may play a role in the development of cardiac angiosarcoma.