Genotype-Phenotype Differential Analysis,Diagnosis And Treatment Of Urinary Bladder Paraganglioma

Background: Urinary Bladder Paraganglioma(UBPGL)originates from extra-adrenal chromatin cells in the sympathetic chain.UBPGL accounts for less than 1% of bladder tumors and is an extremely rare disease,with few studies at home and abroad.The existing studies are basically case analysis or literature review,and lack of systematic research on clinical characteristics,imaging characteristics and genetic characteristics of UBPGL,and there is no clear diagnosis and treatment standard for UBPGL.Patients with normal blood pressure or asymptomatic may be ignored,which is easy to cause preoperative misdiagnosis.If the preoperative diagnosis is not correct,it may affect the perioperative management and clinical prognosis of patients.In addition,our previous study found that the proportion of UBPGL patients in the Chinese cohort was significantly higher than that reported in the Occident,and there were certain differences in diagnosis and treatment.Objectives:(1)Systematically elucidate the clinical,imaging and genetic characteristics of UBPGL,and analyze the causes of misdiagnosis of UBPGL;(2)Clarify the association between genotype and phenotype in patients with UBPGL;(3)Compare the differences in diagnosis and treatment process of UBPGL and genetic background between Chinese and foreign patients.Methods: Patients with UBPGL who were surgically treated and pathologically confirmed from 2010 to 2020 were retrospectively included.We collected the clinical data,imaging characteristics and follow-up data.In order to clarify the gene mutation information of patients,DNA from paraffin-embedded tumor tissue,fresh frozen tumor tissue or peripheral blood(if any)was extracted for next-generation sequencing,Sanger sequencing and immunohistochemical verification.Multivariate analysis,prognostic analysis and association study were used in the study.In addition,patients were divided into Chinese population and Occidental population according to regional differences,and the differences in diagnosis and treatment of UBPGL and genetic background between the two groups were compared.Results: A total of 124 patients with UBPGL were included,including 73 patients from 11 research centers in China and 51 patients from 7 research centers in Europe and America.(1)Basic characteristics and influencing factors of preoperative diagnosisAmong all patients,50.8% were male,aged 51(30-60)years,87.9%had single tumor,40.5% had hypertension symptoms,27.3% had micturition attacks,47.6% had definite preoperative diagnosis.During a median follow-up of 2.6(1.0-6.0)years,14.7% had recurrence,23.6% had metastasis,and 90% were alive.Multivariate logistic regression analysis showed that age was a protective factor for preoperative biochemical testing(preoperative diagnosis)(OR=0.947,95%CI= 1.674-10.832,P=0.002),while micturition attacks(OR=8.159,95%CI= 1.896-35.607,P=0.005),hypertension(OR=5.463,95%CI=1.884-15.842,P=0.002)and sweating(OR=33.090,95%CI=1.772-685.345,P=0.020)were risk factors for preoperative biochemical testing(preoperative diagnosis).(2)Genetic characteristics and genotype-phenotype associationA total of 11 pathogenic mutations were detected in 59.4%(57/96)patients,of which SDHB mutations accounted for 36.5%.Compared with patients without gene mutations,patients with gene mutations were younger(38 vs.52 years old,P=0.029),more likely to undergo preoperative examination(64.9% vs.38.5%,P=0.011),and more likely to be diagnosed before surgery(63.2% vs.38.5%,P=0.017).Compared with patients without SDHB mutations,patients with SDHB mutations were younger(29 vs.52 years,P<0.001),had larger tumors(3.72 vs.1.90 cm,P=0.001),and had fewer single tumors(68.6% vs.95.1%,P=0.001).Hypertension(51.5% vs.28.3%,P=0.026)and catecholamine-related symptoms(45.5% vs.18.3%,P=0.005)were more common and more likely to be diagnosed preoperatively(85.7% vs.34.4%,P<0.001),and transfer(45.5% vs.11.9%,P< 0.001)and recurrence(30.3% vs.3.4%,P =0.001)higher percentage.Multivariate logistic regression analysis showed that tumor >5cm(OR=14.532,95%CI=2.272-92.955,P=0.005)and SDHB mutation(OR=3.966,95%CI=1.119-14.055,P=0.005).P=0.033)were risk factors for UBPGL recurrence/metastasis.COX regression analysis showed that bladder resection: partial and total resection(HR=0.000,95%CI=0.000-0.047,P=0.003)was a protective factor for the prognosis of UBPGL,while mean tumor diameter(HR=4.673,95%CI=1.248-17.494,P=0.022)and metastasis(HR=55.993,95%CI=2.288-1370.379,P=0.014)were risk factors for prognosis of UBPGL.(3)Differences in diagnosis/treatment and genetic background between Chinese and OccidentMost of the patients in the European and American cohorts(70.6%)were diagnosed before surgery,while more than 2/3 of the patients in the Chinese cohorts(68.5%)were diagnosed after surgery.About half of the patients(50.9%)in the European and American cohorts were first diagnosed by biochemical diagnosis,while about 3/4 of the patients(75.3%)in the Chinese cohorts were first diagnosed by pathology.Compared with patients in the Chinese cohort,patients in the European and American cohorts had a higher frequency of SDHB-related mutations(55.6% vs.19.6%,P<0.001),and postoperative metastasis rate was higher(54.2% vs.3.4%,P < 0.001),lower survival rate(80.4% vs.97.1%,P = 0.002).Conclusions: The majority of UBPGL patients are middle-aged and elderly patients,and most of them are single small tumors.Hypertension is the most common clinical manifestation and urination attack is the typical clinical symptom.SDHB gene is the most common mutated gene of UBPGL.Such patients have more obvious clinical symptoms,and the probability of recurrence/metastasis is significantly increased.The differences in clinical characteristics,diagnostic process and prognosis between the Chinese cohort and the Occident cohort are closely related to the genetic background or ethnic(regional)differences between the two groups.