Evolution of Pulmonary Involvement in Idiopathic Multicentric Castleman Disease-Not Otherwise Specified

Abstract

BackgroundPrevious studies about multicentric Castleman disease-associated pulmonary manifestations have been limited by small cohorts and not following the Castleman Disease Collaborative Network classification criteria of multicentric Castleman disease. The pulmonary manifestations in idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS), a distinct clinical phenotype in the classification criteria, have not been reported.Research QuestionWhich pulmonary abnormalities in iMCD-NOS are advanced manifestations and which are reversible after effective treatment?Study Design and MethodsPatients diagnosed with iMCD-NOS with pulmonary involvement were enrolled. The baseline CT scan was evaluated for the presence and anatomic locations of pulmonary abnormalities. Patients were further divided into different subgroups according to baseline CT scan manifestations. Follow-up CT scan was reviewed to assess the changes in pulmonary lesions among patients without and with treatment.ResultsOf 162 patients with iMCD-NOS, 58 individuals (35.8%) with pulmonary involvement were identified. Pulmonary manifestations included nodules (96.6%), cysts (65.5%), consolidation (22.4%), interstitial thickening (50.0%-87.9%), and ground-glass opacities (55.2%). Patients (n = 58) were further classified into nodule (n = 15), cyst (n = 33), and consolidation (n = 10) subgroups. Patients in the consolidation (median, 67 months) and cyst (median, 23 months) subgroups had a longer duration of symptoms before the baseline CT examination than those in the nodule subgroup (median, 12 months) (P = .016). During follow-up, the evolution of pulmonary lesions from nodules to cysts was observed in two patients without treatment. After treatment, pulmonary lesions, except for cysts, improved in most patients. Moreover, nodules or cysts progressed into consolidation in two patients.InterpretationPulmonary involvement is not rare in iMCD-NOS. Chest CT scan examination is very essential in finding potential pulmonary abnormalities. Pulmonary manifestations follow a unique pattern with evolution from nodules to cysts or consolidation, the latter of which can also form in cystic areas. Timely diagnosis of pulmonary involvement is crucial because of possible reversibility after treatment. Previous studies about multicentric Castleman disease-associated pulmonary manifestations have been limited by small cohorts and not following the Castleman Disease Collaborative Network classification criteria of multicentric Castleman disease. The pulmonary manifestations in idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS), a distinct clinical phenotype in the classification criteria, have not been reported. Which pulmonary abnormalities in iMCD-NOS are advanced manifestations and which are reversible after effective treatment? Patients diagnosed with iMCD-NOS with pulmonary involvement were enrolled. The baseline CT scan was evaluated for the presence and anatomic locations of pulmonary abnormalities. Patients were further divided into different subgroups according to baseline CT scan manifestations. Follow-up CT scan was reviewed to assess the changes in pulmonary lesions among patients without and with treatment. Of 162 patients with iMCD-NOS, 58 individuals (35.8%) with pulmonary involvement were identified. Pulmonary manifestations included nodules (96.6%), cysts (65.5%), consolidation (22.4%), interstitial thickening (50.0%-87.9%), and ground-glass opacities (55.2%). Patients (n = 58) were further classified into nodule (n = 15), cyst (n = 33), and consolidation (n = 10) subgroups. Patients in the consolidation (median, 67 months) and cyst (median, 23 months) subgroups had a longer duration of symptoms before the baseline CT examination than those in the nodule subgroup (median, 12 months) (P = .016). During follow-up, the evolution of pulmonary lesions from nodules to cysts was observed in two patients without treatment. After treatment, pulmonary lesions, except for cysts, improved in most patients. Moreover, nodules or cysts progressed into consolidation in two patients. Pulmonary involvement is not rare in iMCD-NOS. Chest CT scan examination is very essential in finding potential pulmonary abnormalities. Pulmonary manifestations follow a unique pattern with evolution from nodules to cysts or consolidation, the latter of which can also form in cystic areas. Timely diagnosis of pulmonary involvement is crucial because of possible reversibility after treatment. Take-home PointsStudy Question: Which pulmonary abnormalities in idiopathic multicentric Castleman disease-not otherwise specified are advanced manifestations and which are reversible after effective treatment?Results: Pulmonary lesions evolve over time, from nodules to cysts or consolidation, the latter of which can also form in cystic areas. All pulmonary lesions, except for cysts, improved in most patients after effective treatment.Interpretation: Pulmonary manifestations in idiopathic multicentric Castleman disease-not otherwise specified follow a unique evolution pattern. Effective treatment can reverse all pulmonary lesions except cysts. Study Question: Which pulmonary abnormalities in idiopathic multicentric Castleman disease-not otherwise specified are advanced manifestations and which are reversible after effective treatment? Results: Pulmonary lesions evolve over time, from nodules to cysts or consolidation, the latter of which can also form in cystic areas. All pulmonary lesions, except for cysts, improved in most patients after effective treatment. Interpretation: Pulmonary manifestations in idiopathic multicentric Castleman disease-not otherwise specified follow a unique evolution pattern. Effective treatment can reverse all pulmonary lesions except cysts. Castleman disease incorporates a group of rare lymphoproliferative disorders characterized by specific lymph node histopathologic abnormalities, including hyaline vascular, plasmacytic, and mixed variants.1Dispenzieri A. Fajgenbaum D.C. Overview of Castleman disease.Blood. 2020; 135: 1353-1364Crossref PubMed Google Scholar The disease is classified as unicentric Castleman disease (UCD), involving a single region of enlarged lymph nodes, and multicentric Castleman disease (MCD), involving multiple regions of enlarged lymph nodes. UCD usually shows no or mild symptoms and normal laboratory tests, and complete surgical excision is the first-line and curative treatment.2van Rhee F. Oksenhendler E. Srkalovic G. et al.International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.Blood Adv. 2020; 4: 6039-6050Crossref PubMed Scopus (57) Google Scholar Unlike UCD, MCD typically presents with constitutional symptoms, various laboratory abnormalities, and poor prognosis.1Dispenzieri A. Fajgenbaum D.C. Overview of Castleman disease.Blood. 2020; 135: 1353-1364Crossref PubMed Google Scholar,3Dispenzieri A. Armitage J.O. Loe M.J. et al.The clinical spectrum of Castleman's disease.Am J Hematol. 2012; 87: 997-1002Crossref PubMed Scopus (170) Google Scholar Systemic treatments are required for patients with MCD. According to the status of human herpes virus-8 (HHV-8), MCD can be further divided into HHV-8-associated MCD and HHV-8-negative MCD, the latter of which is also called idiopathic multicentric Castleman disease (iMCD) and contains two different clinical phenotypes, idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS) and thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow, and organomegaly (TAFRO).4van Rhee F. Voorhees P. Dispenzieri A. et al.International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.Blood. 2018; 132: 2115-2124Crossref PubMed Scopus (173) Google Scholar There are great challenges in both diagnosis and treatment of iMCD because of the nonspecific clinical features and unknown etiology. Within iMCD, the two phenotypes present notably different clinical manifestations. Compared with TAFRO, iMCD-NOS is more common and characterized by a less aggressive clinical course, normal or slightly elevated platelet counts, hypergammaglobulinemia, more responsiveness to corticosteroids, and better prognosis.5Oksenhendler E. Boutboul D. Fajgenbaum D. et al.The full spectrum of Castleman disease: 273 patients studied over 20 years.Br J Haematol. 2018; 180: 206-216Crossref PubMed Scopus (108) Google Scholar, 6Fujimoto S. Sakai T. Kawabata H. et al.Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease?.Am J Hematol. 2019; 94: 975-983Crossref PubMed Scopus (51) Google Scholar, 7Iwaki N. Fajgenbaum D.C. Nabel C.S. et al.Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease.Am J Hematol. 2016; 91: 220-226Crossref PubMed Scopus (176) Google Scholar Moreover, iMCD-NOS is more liable to involve the pulmonary system than TAFRO.8Kiguchi T. Sato C. Takai K. Nakai Y. Kaneko Y. Matsuki M. CT findings in 11 patients with TAFRO syndrome: a variant of multicentric Castleman's disease.Clin Radiol. 2017; 72: 905.e1-905.e5Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar In the new consensus diagnostic criteria and treatment guidelines for iMCD proposed by the Castleman Disease Collaborative Network (CDCN), pulmonary involvement was considered a minor clinical diagnostic criterion for iMCD and an indicator for severe iMCD.4van Rhee F. Voorhees P. Dispenzieri A. et al.International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.Blood. 2018; 132: 2115-2124Crossref PubMed Scopus (173) Google Scholar,9Fajgenbaum D.C. Uldrick T.S. Bagg A. et al.International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.Blood. 2017; 129: 1646-1657Crossref PubMed Scopus (304) Google Scholar Our previous reports also indicated that the treatment response to different regimens was associated with the presence or absence of pulmonary involvement.10Zhang L. Zhao A.L. Duan M.H. et al.Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease.Blood. 2019; 133: 1720-1728Crossref PubMed Scopus (34) Google Scholar,11Zhang L. Zhang M.Y. Cao X.X. et al.A prospective, multicenter study of bortezomib, cyclophosphamide, and dexamethasone in relapsed/refractory iMCD.Leuk Lymphoma. 2022; 63: 618-626Crossref PubMed Scopus (10) Google Scholar It is vital for physicians to understand the pulmonary manifestations in iMCD for timely and accurate diagnosis and treatment. However, because of the rarity of MCD, pertinent studies of pulmonary involvement are extremely limited and have several limitations.12Johkoh T. Muller N.L. Ichikado K. et al.Intrathoracic multicentric Castleman disease: CT findings in 12 patients.Radiology. 1998; 209: 477-481Crossref PubMed Scopus (118) Google Scholar, 13Johkoh T. Muller N.L. Pickford H.A. et al.Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients.Radiology. 1999; 212: 567-572Crossref PubMed Scopus (289) Google Scholar, 14Huang H. Feng R. Li J. et al.Castleman disease-associated diffuse parenchymal lung disease: a STROBE-compliant retrospective observational analysis of 22 cases in a tertiary Chinese hospital.Medicine (Baltimore). 2017; 96e8173Crossref Scopus (13) Google Scholar, 15Luo J.M. Li S. Huang H. et al.Clinical spectrum of intrathoracic Castleman disease: a retrospective analysis of 48 cases in a single Chinese hospital.BMC Pulm Med. 2015; 15: 34Crossref PubMed Scopus (37) Google Scholar, 16Guihot A. Couderc L.J. Agbalika F. et al.Pulmonary manifestations of multicentric Castleman's disease in HIV infection: a clinical, biological and radiological study.Eur Respir J. 2005; 26: 118-125Crossref PubMed Scopus (42) Google Scholar First, MCD is considered a highly heterogeneous entity in both its clinical features and underlying pathogenesis. Except for the Guihot et al study,16Guihot A. Couderc L.J. Agbalika F. et al.Pulmonary manifestations of multicentric Castleman's disease in HIV infection: a clinical, biological and radiological study.Eur Respir J. 2005; 26: 118-125Crossref PubMed Scopus (42) Google Scholar previous studies have described MCD-associated pulmonary manifestations in general terms without following the CDCN classification criteria of MCD, which is not conducive to a better understanding of lung disease in MCD. Second, no studies have referred to the evolution of pulmonary abnormalities. It is not clear which pulmonary abnormalities are severe patterns and which are reversible after effective treatment. Finally, the number of enrolled patients in the aforementioned studies was very small. Accordingly, we were interested to look at pulmonary disease evolution in iMCD-NOS in this investigation, which is a distinct clinical phenotype of MCD according to CDCN classification criteria. Patients with iMCD-NOS with pulmonary involvement were enrolled from a cohort of patients with iMCD-NOS undergoing chest CT scan examination. The study protocol was approved by the medical ethics committee of Peking Union Medical College Hospital (No. S-K2053). The need for informed consent was waived because anonymized clinical data were used for this study. Patients who were diagnosed with iMCD-NOS met the following criteria: (1) histopathology of lymph nodes in accordance with iMCD; (2) lymphadenopathy (≥ 1 cm in short-axis diameter) in at least two lymph node regions; (3) HHV-8 negativity confirmed by latency-associated nuclear antigen-1 staining of lymph node tissue by immunohistochemistry or blood polymerase chain reaction and HIV negativity confirmed by serology screening;10Zhang L. Zhao A.L. Duan M.H. et al.Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease.Blood. 2019; 133: 1720-1728Crossref PubMed Scopus (34) Google Scholar and (4) no fulfillment of the diagnostic criteria for TAFRO syndrome.17Nishimura Y. Fajgenbaum D.C. Pierson S.K. et al.Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease.Am J Hematol. 2021; 96: PubMed Scopus Google Scholar Pulmonary involvement was confirmed by and clinical Patients with iMCD-NOS with findings chest CT scan at baseline were medical of patients were reviewed to lung disease of lung which were The following data at baseline were from medical for duration of symptoms, constitutional symptoms, symptoms, laboratory and treatment. The duration of symptoms was by the the of symptoms and baseline chest CT scan examination. all an an protocol with In the the baseline chest CT scan was used to all patients with iMCD-NOS with pulmonary The following manifestations were cysts, consolidation, thickening of the thickening of the thickening of the thickening of the pulmonary and ground-glass opacities The of the aforementioned pulmonary abnormalities are in CT scan and of pulmonary abnormalities are in In the all patients were further divided into different which were according to the lung manifestations cysts, and evaluated in the that had an a of clinical features different subgroups was among patients who were not treatment for iMCD before the chest CT scan examination. In the chest CT were were reviewed to patients who had not treatment for iMCD before the chest CT we reviewed chest CT scan to the evolution of lung patients who treatment for iMCD before the chest CT we lung abnormalities that or progressed by the and chest CT In chest CT 2 were reviewed by two and were with the of the All were using were by using analysis of with a normal or the that were not for and or for was considered to to patients were diagnosed with iMCD-NOS, of 162 patients chest CT of 162 patients (35.8%) were to have pulmonary The baseline and clinical of the 58 patients are in The at the baseline chest CT scan was with a of The duration of symptoms before chest CT scan examination was patients the histopathologic patients were classified as the and patients were considered to have a mixed of of patients had constitutional patients with symptoms, patients with of patients with and with patients had and patients had was in patients. patients had platelet was in two was in patients. The of and were and and were in and 22 patients had elevated and patients had an were elevated in 48 and of Patients Castleman Pulmonary (n = of symptoms, or 1 for of are or = = = or 1 for in a new are or = = = The CT scan findings of all patients with iMCD-NOS with pulmonary manifestations are in of were the most with nodules of by nodules of nodules of and nodules of were present in patients (65.5%), with cysts in patients cysts in patients and cysts in patients patients thickening of different locations had as in patients in patients in patients and pulmonary in patients The thickening of the was in patients and diffuse in patients were in patients CT of Patients Castleman Pulmonary (n = of Pulmonary are in a new are All patients were further divided into subgroups according to the presence of cysts, and consolidation chest CT The nodule subgroup nodules without the findings of cysts and consolidation The cyst subgroup was as the presence of a cyst and the absence of consolidation The consolidation subgroup was as as consolidation was with or without nodules or cysts There were patients in the nodule subgroup patients in the cyst subgroup and patients in the consolidation subgroup the chest CT 11 patients treatment for iMCD, and the patients not treatment for the the of clinical the CT scan subgroups is in There were patients in the nodule patients in the cyst and patients in the consolidation The duration of symptoms the subgroups (P = .016). Compared with the nodule subgroup (median, 12 the cyst subgroup (median, 23 months) and consolidation subgroup (median, 67 months) were more to have longer of symptoms before the CT scan examination. the in the duration of symptoms, pulmonary abnormalities be classified into nodule cyst and consolidation The nodule subgroup to the of the the cyst subgroup and consolidation subgroup had There were no in or among the subgroups. was observed in the of among the subgroups (P = All patients with the hyaline subtype were classified into the nodule subgroup and not cysts or All patients of the mixed subtype were in the cyst All patients in the consolidation subgroup were of the The consolidation subgroup and cyst subgroup were more to have symptoms than the nodule subgroup (P = Except for the of (P = were no in clinical among the subgroups. The cyst subgroup and consolidation subgroup had of than the nodule of Patients Castleman (n = (n = (n = (n = of symptoms, or 1 for 22 data are as and data are as are in = = = or 1 for in a new data are as and data are as are in = = = Of the patients who were at patients not treatment for iMCD before the chest CT The lung abnormalities progressed in two cases was into the cyst subgroup and had a duration of symptoms at After of follow-up, the chest CT scan more severe thickening of the and and an in the and number of nodules and cysts. cysts were the with a duration of symptoms at nodules in both CT of which into cysts CT scan The CT scan changes in two patients also confirmed the evolution of pulmonary lesions from nodules to over During the months) from patients treatment for iMCD and chest CT The included a (n = a (n = a cyclophosphamide, and (n = a (n = (n = treatment (n = and treatment (n = Follow-up changes in pulmonary manifestations after treatment are in The pulmonary lesions improved in most patients an after treatment. Except for the cysts, all abnormalities, including the consolidation, interstitial and However, pulmonary abnormalities progressed in of were associated with the was considered patients an in the number or of nodules the CT The cystic in patients. in of lung abnormalities cysts and cysts were in the previous nodules and consolidation had improved or patients consolidation the CT of patients consolidation in the of previous nodules or cysts which also confirmed the evolution of pulmonary lesions from nodules or cysts to over thickening was more severe in and were in at and the Chest CT in Patients After Systemic (n = CT CT that the of nodules patients had consolidation had ground-glass and ground-glass opacities in that the of nodules patients had consolidation had ground-glass and ground-glass opacities in patients. in a new of consolidation of two patients with idiopathic multicentric Castleman disease-not otherwise specified after treatment. with a of and at chest CT scan examination. chest CT scan multiple cysts and nodules in the the CT scan which was new consolidation in was in the of previous cysts in During the was multiple the lung abnormalities to was as a relapsed/refractory of idiopathic multicentric Castleman disease. with a of and at The chest CT scan multiple nodules of different and and of the nodules were in After of treatment, the chest CT scan that the nodules had in and and had to form consolidation in described chest of pulmonary manifestations and evolution over among 58 patients with iMCD-NOS. this is the study to pulmonary manifestations in iMCD-NOS, which is a distinct clinical phenotype according to CDCN classification criteria. Our indicated that pulmonary manifestations of iMCD-NOS follow a unique pattern with evolution from nodules to cysts or consolidation, the latter of which can also form in cystic areas. Our that patients with iMCD-NOS with pulmonary manifestations were not with a of It been that is a slightly of pulmonary with of in MCD and of in E. Boutboul D. Fajgenbaum D. et al.The full spectrum of Castleman disease: 273 patients studied over 20 years.Br J Haematol. 2018; 180: 206-216Crossref PubMed Scopus (108) Google J.M. Li S. Huang H. et al.Clinical spectrum of intrathoracic Castleman disease: a retrospective analysis of 48 cases in a single Chinese hospital.BMC Pulm Med. 2015; 15: 34Crossref PubMed Scopus (37) Google Scholar The in the of pulmonary involvement from the different Our were more because we a specific clinical phenotype in the CDCN classification criteria. of the patients had no chest CT scan examination can to potential pulmonary abnormalities. described various lung abnormalities in iMCD-NOS. In pulmonary abnormalities as interstitial thickening at different cysts, and were the most Moreover, we the anatomic of the lesions and two The was that lesions anatomic regions the and to the of previous studies have also indicated that lung abnormalities in MCD are T. Y. et al.Pulmonary manifestations of idiopathic multicentric disease: a study in with Med. 2020; PubMed Scopus (10) Google H. R. K. et findings of multicentric disease over 2017; PubMed Scopus (1) Google Scholar Second, we that abnormalities in the and were more common than those in the which that the were more than the in is that of the is more liable to because of than those of the abnormalities of the were more CT scan in the of disease. et H. R. K. et findings of multicentric disease over 2017; PubMed Scopus (1) Google Scholar and et M. J. Feng R. Castleman disease as a rare of diffuse lung J Respir Med. 2020; PubMed Google Scholar of the evolution of pulmonary lesions in iMCD over of without treatment. a evolution of pulmonary lesions in iMCD, with nodules the and Castleman's disease with multiple nodes in a and J Hematol. PubMed Scopus Google Scholar an iMCD in which the nodules in and into and consolidation after 1 of In the of the duration of symptoms subgroups that the nodule subgroups had a duration of symptoms than the cyst and consolidation subgroups. Moreover, the from nodules to cysts was also observed CT scan of two patients who had not treatment. treatment, pulmonary abnormalities in a small number of patients. the evolution from nodules or cysts to consolidation in two patients. we that nodules were manifestations of pulmonary the of cysts and Our study is the to the of the of iMCD-NOS pulmonary lesions in a the of pulmonary manifestations be for physicians to assess the of lung disease in patients at all patients with the hyaline subtype two of had CT scan and All patients with abnormalities were been observed in the lung T. Y. et al.Pulmonary manifestations of idiopathic multicentric disease: a study in with Med. 2020; PubMed Scopus (10) Google K. D. K. et multicentric Castleman's disease: a study in with 2018; PubMed Scopus Google Scholar Our study indicated that the and of lung abnormalities with in pulmonary abnormalities were not into in the CDCN criteria of the treatment response in iMCD, which included laboratory lymph node and Rhee F. Voorhees P. Dispenzieri A. et al.International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.Blood. 2018; 132: 2115-2124Crossref PubMed Scopus (173) Google Scholar There were no studies changes in pulmonary abnormalities after treatment, except for several M. J. Feng R. Castleman disease as a rare of diffuse lung J Respir Med. 2020; PubMed Google Castleman's disease with multiple nodes in a and J Hematol. PubMed Scopus Google K. Ichikado K. H. K. T. M. Castleman's disease in the clinical, and findings and treatment with and Med. PubMed Scopus Google Scholar, of Castleman's disease lung 2019; Scopus Google Scholar, multicentric Castleman disease with pulmonary and lesions with a J 2020; PubMed Scopus (1) Google Scholar, Li J. Zhang L. of idiopathic multicentric Castleman disease with diffuse lung to treatment Hematol. 2020; PubMed Scopus (1) Google Scholar Our that all abnormalities except for cysts after effective treatment. treatment be before cyst in patients with iMCD-NOS with pulmonary manifestations. cysts in or number in the patients in pulmonary lesions than cysts after treatment. findings have been in interstitial T. Ichikado K. M. et al.Lymphocytic interstitial pneumonia: CT findings in 15: PubMed Scopus Google Y. Y. of syndrome interstitial 2021; PubMed Scopus (10) Google Scholar for patients who treatment, cysts are not of pulmonary disease of the treatment of pulmonary lesions in iMCD cysts with manifestations than cysts Our study several First, was a retrospective study with small However, because of the rarity of iMCD, the cohort to Second, were enrolled from a cohort of patients with iMCD-NOS chest CT scan examination. have to an of the of pulmonary involvement because patients without pulmonary symptoms are less to chest CT pulmonary was in study. the iMCD and interstitial not the disease without to the lung histopathologic studies of the lung be to Finally, data were from an and to be further Pulmonary involvement is not rare in iMCD-NOS. Chest CT scan examination is essential in finding potential pulmonary abnormalities. Pulmonary manifestations follow a unique pattern with evolution from nodules to cysts or consolidation, the latter of which can also form in cystic areas. Timely diagnosis of pulmonary involvement is because all abnormalities except for cysts after effective treatment. was by the for Medical to J. the of to L. the to L. the Hospital to L. and the and of from of and to L.

Topics & Concepts