Clinical Manifestation,Pathological Feature,Therapies And Prognostic Factors Of HHV-8/HIV Negative Castleman Disease

Objective:The lack of longitudinal clinical and immunophenotypic data for Castleman disease(CD)has made the diagnosis,treatment,and management of the disease challenging.A deeper understanding of the clinical and immunophenotypic features and response to therapy should lead to more accurate diagnoses and more successful treatments.Thus,we performed this study to characterize the clinical,immunophenotypic and pathological features,treatments,and prognoses for UCD and iMCD in Aemrica,investigated 5 CD cases of the clinic and pathologic character in The Second Affiliated Hospital Of Nanchang University,and reviewed the public published paper of CD with clinic,pathologic and treatment information in China,which helps to elucidate the clinical and biological behavior of CD and provide more option evidences for the treatment.Methods:After obtaining approval from The University of Texas MD Anderson Cancer Center's(MDACC)internal review board,we identified 228 patients with CD who had been diagnosed and treated at the institution between 1 January 1994 and 31 December 2014.Seventy-four patients(43 UCD and 31 iMCD)with clinical and laboratory data in America were available at diagnosis and throughout treatment,and plus an additional 22 HIV-/HHV-8-negative and 51 HIV-/HHV-8-positive CD patients with treatment data were provided by the Castleman Disease Collaborative Network(CDCN)Research Database and the National Institutes of Health.In this study,we analyzed the clinical and pathologic findings of clinical manifestations,laboratory and radiological finding,pathological character,including histopathological and immunophenotypic findings of lymph nodes,manifestations and immunophenotyping of bone marrow,as well as treatment outcome of different targeted agents comparing with traditional drugs and independent risk factor.Aditionally,there were 5 cases analysed in The Second Affiliated Hospital of Nanchang University.A systematic search was conducted of the published leterature on Castleman's disease in the form of case reports,controlled or compatative studies,or small case series in China,then clinic and pathologic character were analysised.Results:HIV/HHV-8 negative CD patients in America as follow:(1)The heterogeneity lied between HIV-/HHV-8 UCD and iMCD patients as well as within iMCD subtype,including clinical manifestations,histopathological pathology,laboratory and radiological finding.(2)About 39%of iMCD patients had a history of autoimmune diseases,which were typically stable at the time of diagnosis.(3)The bone marrow was involved both in UCD and iMCD,and abnormal bone marrow changes occurred in a significantly higher proportion of patients with iMCD(177.28%)compared with UCD(45.45%).The most frequent finding was reactive plasmacytosis,from 3.0%to 30.34%.(4)Histopathological and immunophenotypic findings of lymph nodes:The number of T cells(CD3+)was higher in iMCD patients than in those with UCD(P ?0.048),but CD19+/CD5+ lymphocytes were higher in UCD patients than in iMCD patients(P = 0.032).(5)In UCD,surgical complete resection is found to be the best first-line treatment,with 90%complete remission.Though patients' refractory to surgical resection or inoperable,rituximab or radiotherapy can be effective.(6)Treatments differed considerably among the iMCD cases:no systemic inflammatory symptoms or complaints at diagnosis were initially biopsied and observed only.iMCD patients treated with glucocorticoids or chemotherapy are less likely to achieve CR(both 10%to 20%),and those patients who do achieve CR often experience recurrence of disease within 1 to 2 years.Rituximab is better overall response as monotherapy in HHV-8-associated MCD than that in iMCD which only 20%achieved a CR.Siltuximab effectively controlled and improved the clinical man-ifestations and PFS in iMCD patients,even among those for whom rituximab or chemotherapy failed.(7)Patients with the TAFRO subtype tended to have a poorer overall survival rate than those with the non-TAFRO subtype(P = 0.017).(8)We conducted a univariate analysis of PFS with a mean follow-up duration of 64.66 months and identified 3 significant risk factors;multicentricity,PC pathological subtype,and anemia;using a multivariate analysis,multicentric disease was independently associated with PFS.Cases investigated and systematic analysis of CD patients from the literature as follow:(1)The heterogeous of clinical symptoms and inflammative factor are similar with the patients between America and China.(2)The itiologic research of CD is few;No HHV-8 positive CD cases was reported,and 18 cases with EB virus infected were found,though most cases did not test EB virus of CD patients.(3)The complete remission of CD with CHOP therapy in China(72.23%)is higher than that in America.Conclusions:CD share some common histopathological pathologic features but have heterogeniety and different treatment outcomes.Systemic inflammatory symptoms and elevated inflammatory factors were more common in patients with iMCD than those in UCD.Complete surgical resection remains the best option for patients with UCD.For iMCD,siltuximab appears to be an effective first treatment option,rituximab and rituximab-based therapy have relatively inferior efficacy,corticosteroids may be helpful as an initial adjunct for the improvement of acute symptoms in some patients.CD patients treated by CHOP chemotherapy have high complete remission in China,which can be a routine option.Our study includes the largest review series in which the results would lead to deeped understanding of CD.