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

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: 1241-1252Crossref PubMed Scopus (33) Google Scholar Pulmonary involvement was confirmed by combining radiologic and clinical findings. Patients with iMCD-NOS with abnormal findings on chest CT scan at baseline were selected. Then, medical records of these patients were reviewed to identify lung disease of other etiologies (eg, heart failure, lung infection, malignancy, diseases mimicking iMCD), which were excluded. The following data at baseline were extracted from patient medical records for analysis: age, sex, duration of symptoms, histology subtype, constitutional symptoms, respiratory symptoms, Eastern Cooperative Oncology Group performance status, physical examination, laboratory findings, and treatment. The duration of symptoms was obtained by calculating the time interval between the onset of symptoms and baseline chest CT scan examination. Before evaluating all images, an experienced thoracic radiologist (W. Z.) formulated an evaluation protocol with three steps. In the first step, the baseline chest CT scan was used to analyze all patients with iMCD-NOS with pulmonary involvement. The following abnormal manifestations were evaluated: nodules, cysts, consolidation, thickening of the interlobular septa, thickening of the pleura, thickening of the bronchoarterial bundles, thickening of the pulmonary venous branches, and ground-glass opacities (GGOs). The definitions of the aforementioned pulmonary abnormalities are available in e-Appendix 1. Representative CT scan images and schematics of pulmonary abnormalities are shown in e-Figure 1. In the second step, all patients were further divided into different subgroups, which were defined according to the abnormal lung manifestations (nodules, cysts, and consolidation) evaluated in the first step. Considering that therapies had an impact on imaging characteristics, a comparison of clinical features between different subgroups was carried out among patients who were not receiving systemic treatment for iMCD before the initial chest CT scan examination. In the third step, when follow-up chest CT scans were available, they were reviewed to evaluate interval changes. For patients who had not received systemic treatment for iMCD before the latest follow-up chest CT scan, we reviewed serial chest CT scan images to highlight the evolution of lung lesions. For patients who received systemic treatment for iMCD before the latest follow-up chest CT scan, we recorded lung abnormalities that improved, remained stable, or progressed by comparing the latest and initial chest CT scan. In these steps, high-resolution chest CT scans (≤ 2 mm) were independently reviewed by two thoracic radiologists (J. Z. and X. L.). Discrepancies were resolved with the assistance of the experienced thoracic radiologist. All statistical analyses were performed using SPSS 26 (SPSS Inc). Comparisons between groups were conducted by using analysis of variance (for parameters with a normal distribution) or the Kruskal-Wallis H test (for parameters that were not normally distributed) for continuous variables and Fisher exact or χ2 test for categorical variables when appropriate. Two-tailed P < .05 was considered to denote statistical significance. From January 1, 2000, to April 1, 2022, 233 patients were diagnosed with iMCD-NOS, of whom 162 patients underwent chest CT scans. Fifty-eight of 162 patients (35.8%) were identified to have pulmonary involvement. The baseline demographic and clinical characteristics of the 58 patients are summarized in Table 1. The median age at the baseline chest CT scan was 41 years (range, 17-70 years), with a male-to-female ratio of 1:1.1. The median duration of symptoms before initial chest CT scan examination was 26 months (range, 1-384 months). Three patients (5.2%) demonstrated the hyaline-vascular histopathologic subtype, 50 patients (86.2%) were classified as having the plasmacytic subtype, and five patients (8.6%) were considered to have a mixed subtype. A total of 79.3% of patients had constitutional symptoms. Among 31 patients (53.4%) with respiratory symptoms, 26 patients presented with shortness of breath, 15 patients presented with cough, and one patient presented with hemoptysis. Twenty-nine patients (50%) had hepatomegaly and/or splenomegaly, and 21 patients (36.2%) had skin involvement. Anemia was seen in 38 patients. Twenty-seven patients had abnormal platelet counts; thrombocytopenia was seen in two patients, whereas thrombocytosis was recorded in 25 patients. The median levels of albumin and serum creatinine were 31.5 g/L (range, 17.0-49.0 g/L) and 61.5 μmol/L (range, 43.0-546.0 μmol/L), respectively. Elevated IgG, IgA, and IgM were noted in 46, 35, and 22 patients, respectively. Forty-seven patients had elevated C-reactive protein levels, and 51 patients had an increased erythrocyte sedimentation rate. Serum IL-6 levels were elevated in 48 patients.Table 1Demographic and Clinical Characteristics of Patients Exhibiting Idiopathic Castleman Disease-Not Otherwise Specified With Pulmonary Manifestations (n = 58)CharacteristicsNormal RangeValueAge, y…41 (17-70)Male sex…28 (48.3)Duration of symptoms, mo…26 (1-384)Histology Hyaline vascular…3 (5.2) Plasmacytic…50 (86.2) Mixed…5 (8.6)Constitutional symptomsaFever (> 37.3 °C), night sweats, fatigue, anorexia, or weight loss (grade ≥ 1 Common Terminology Criteria for Adverse Events score).…46 (79.3)Respiratory symptoms…31 (53.4) Shortness of breath…26 (44.8) Cough…15 (25.9) Hemoptysis…1 (1.7)ECOG-PS 0…9 (15.5) 1…35 (60.3) ≥ 2…14 (24.1)Hepatosplenomegaly…29 (50)Skin involvement…21 (36.2)Hemoglobin, g/LMen: 120-160Women: 110-150105.5 (44.0-154.0)Platelet count, 109/L100-350332 (71-740)Albumin, g/L35-5231.5 (17.0-49.0)Serum creatinine, μmol/LMen: 59-104Women: 45-8461.5 (43.0-546.0)IgG, g/L7.00-17.0032.97 (4.96-87.29)IgA, g/L0.70-4.004.84 (0.91-10.03)IgM, g/L0.40-2.301.91 (0.59-8.44)CRP, mg/L0-864.86 (0.33-282.06)ESR, mm/hMen: 0-15Women: 0-2099.00 (1-140)IL-6, pg/mL< 5.919.20 (2.0-403.0)Values are No. (%) or median (range). CRP = C-reactive protein; ECOG-PS = Eastern Cooperative Oncology Group performance status; ESR = erythrocyte sedimentation rate.a Fever (> 37.3 °C), night sweats, fatigue, anorexia, or weight loss (grade ≥ 1 Common Terminology Criteria for Adverse Events score). Open table in a new tab Values are No. (%) or median (range). CRP = C-reactive protein; ECOG-PS = Eastern Cooperative Oncology Group performance status; ESR = erythrocyte sedimentation rate. The CT scan findings of all patients with iMCD-NOS with pulmonary manifestations are listed in Table 2. Nodules (56 of 58, 96.6%) were the most frequent findings, with centrilobular nodules (55 of 58, 94.8%) dominating, followed by interlobular septal nodules (38 of 58, 65.5%), peribronchovascular nodules (32 of 58, 55.2%), and subpleural nodules (18 of 58, 31.6%). Cysts were present in 38 patients (65.5%), with intralobular cysts found in 35 patients (60.3%), peribronchovascular cysts found in 30 patients (51.7%), and subpleural cysts found in 24 patients (41.4%). Thirteen patients (22.4%) showed consolidation. Interstitial thickening of different locations had frequencies as follows: interlobular septa in 47 patients (81.0%), pleura in 51 patients (87.9%), bronchoarterial bundles in 42 patients (72.4%), and pulmonary venous branches in 29 patients (50.0%). The thickening of the bronchoarterial bundles was segmental in 32 patients (55.2%) and diffuse in 10 patients (17.2%). GGOs were seen in 32 patients (55.2%).Table 2Chest CT Scan Findings of Patients Exhibiting Idiopathic Castleman Disease-Not Otherwise Specified With Pulmonary Manifestations (n = 58)CT Scan FindingsValueNodules56 (96.6) Centrilobular55 (94.8) Interlobular septal38 (65.5) Peribronchovascular32 (55.2) Subpleural18 (31.6)Cysts38 (65.5) Intralobular35 (60.3) Peribronchovascular30 (51.7) Subpleural24 (41.4)Consolidation13 (22.4)Thickening of Interlobular septa47 (81.0) Pleura51 (87.9) Bronchoarterial bundles42 (72.4)Segmental32 (55.2)Diffuse10 (17.2) Pulmonary venous branches29 (50.0)Ground-glass opacities32 (55.2)Values are No. (%). Open table in a new tab Values are No. (%). All patients were further divided into three subgroups according to the presence of nodules, cysts, and consolidation on initial chest CT scan. The nodule subgroup only manifested nodules without the findings of cysts and consolidation (Figs 1A, 1B). The cyst subgroup was defined as the presence of a cyst and the absence of consolidation (Figs 1C, 1D). The consolidation subgroup was recorded as long as consolidation was present, with or without nodules or cysts (Figs 1E, 1F). There were 15 patients in the nodule subgroup (25.9%), 33 patients in the cyst subgroup (56.9%), and 10 patients in the consolidation subgroup (17.2%). Before the initial chest CT examination, 11 patients received systemic treatment for iMCD, and the remaining 47 patients did not receive systemic treatment for iMCD. Among the 47 treatment-naïve patients, the comparison of clinical characteristics between the three CT scan subgroups is listed in Table 3. There were 13 patients in the nodule subgroup, 25 patients in the cyst subgroup, and nine patients in the consolidation subgroup. The duration of symptoms significantly differed between the three subgroups (P = .016). Compared with the nodule subgroup (median, 12 months; range, 2-99 months), the cyst subgroup (median, 23 months; range, 1-384 months) and consolidation subgroup (median, 67 months; range, 19-230 months) were more likely to have longer durations of symptoms before the first CT scan examination. Based on the difference in the duration of symptoms, pulmonary abnormalities could be classified into three stages (Fig 2): nodule stage, cyst stage, and consolidation stage. The nodule subgroup corresponded to the early stage of the disease, whereas the cyst subgroup and consolidation subgroup had late stages. There were no significant differences in age or sex distribution among the three subgroups. A significant difference was observed in the distribution of histologic subtypes among the three subgroups (P = .023). All three patients with the hyaline vascular subtype were classified into the nodule subgroup and did not show any cysts or consolidation. All four patients of the mixed subtype were in the cyst subgroup. All patients in the consolidation subgroup were of the plasmacytic subtype. The consolidation subgroup and cyst subgroup were more likely to have respiratory symptoms than the nodule subgroup (P = .024). Except for the level of IgG (P = .038), there were no significant differences in clinical characteristics among the three subgroups. The cyst subgroup and consolidation subgroup had higher levels of IgG than the nodule subgroup.Table 3Comparison of Clinical Characteristics Between Three Subgroups Among Patients With Idiopathic Castleman Disease-Not Otherwise Specified Without Treatment Before Baseline (n = 47)CharacteristicsNodulesSubgroup (n = 13)CystsSubgroup (n = 25)Consolidation Subgroup (n = 9)P ValueAge, y48 (33-63)40 (26-70)49 (17-59).158Male8 (61.5)9 (36.0)5 (55.6).308Duration of symptoms, mo12 (2-99)23 (1-384)67 (19-230).016Histology.033 Hyaline vascular3 (23.1)0 (0.0)0 (0.0) Plasmacytic10 (76.9)21 (84.0)9 (100) Mixed0 (0.0)4 (16.0)0 (0.0)Constitutional symptomsaFever (> 37.3 °C), night sweats, fatigue, anorexia, or weight loss (grade ≥ 1 Common Terminology Criteria for Adverse Events score).10 (76.9)21 (84.0)7 (77.8).790Respiratory symptoms4 (30.8)14 (56.0)8 (88.9).024ECOG-PS.175 03 (23.1)2 (8.0)1 (11.1) 18 (61.5)17 (68.0)3 (33.3) ≥ 22 (15.4)6 (24.0)5 (55.6)Hepatosplenomegaly5 (38.5)15 (60.0)4 (44.4).393Skin involvement6 (46.2)8 (40.0)3 (33.3).717Hemoglobin, g/L106 (67-143)105 (44-147)89 (57-154).661Platelet count, 109/L331 (71-740)333 (186-561)354 (124-550).974Albumin, g/L33 (25-48)33 (17-46)27 (20-45).245Serum creatinine, μmol/L71 (46-88)55 (43-110)62 (45-89).286IgG, g/L20.59 (4.96-74.10)36.93 (12.18-87.29)35.05 (10.83-86.95).038IgA, g/L4.75 (0.91-8.96)5.18 (1.87-10.03)5.03 (2.28-7.27).409IgM, g/L1.42 (0.61-3.67)2.19 (0.59-8.44)1.79 (0.78-7.99).070CRP, mg/L54.82 (0.33-169.96)53.69 (0.65-282.06)94.65 (0.98-146.99).738ESR, mm/h95 (2-130)100 (6-140)88 (1-140).501IL-6, pg/mL14.2 (3.6-112.0)21.3 (2.0-339.0)15.9 (3.9-403.0).262Continuous data are expressed as median (range), and categorical data are expressed as No. (%). Significant P values are in boldface font. CRP = C-reactive protein; ECOG-PS = Eastern Cooperative Oncology Group performance status; ESR = erythrocyte sedimentation rate.a Fever (> 37.3 °C), night sweats, fatigue, anorexia, or weight loss (grade ≥ 1 Common Terminology Criteria for Adverse Events score). Open table in a new tab Continuous data are expressed as median (range), and categorical data are expressed as No. (%). Significant P values are in boldface font. CRP = C-reactive protein; ECOG-PS = Eastern Cooperative Oncology Group performance status; ESR = erythrocyte sedimentation rate. Of the 47 patients who were treatment-naive at baseline, eight patients did not receive any systemic treatment for iMCD before the latest follow-up chest CT scan. The lung abnormalities progressed in two cases during follow-up. One was categorized into the cyst subgroup and had a 20-month duration of symptoms at baseline. After 87 months of follow-up, the latest chest CT scan showed more severe thickening of the interlobular septa and pleura and an increase in the size and number of nodules and cysts. Some cysts were newly formed on the nodular lesions. Another patient, with a 10-month duration of symptoms at baseline, showed scattered nodules in both lungs on initial CT scan, some of which evolved into cysts on CT scan 29 months later (Fig 3). The follow-up CT scan changes in these two patients also confirmed the evolution of pulmonary lesions (ie, from nodules to cysts) over time. During the 15-month median (range, 1-91 months) follow-up period from baseline, 35 patients received systemic treatment for iMCD and underwent follow-up chest CT scan. The therapies included a thalidomide-based regimen (n = 24); a bortezomib-based regimen (n = 24); a cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone-like regimen (n = 8); a rituximab-containing regimen (n = 6); IL-6 targeting therapy (n = 1); zanubrutinib treatment (n = 8); and lenalidomide treatment (n = 2). Follow-up changes in pulmonary manifestations after systemic treatment are listed in Table 4. The pulmonary lesions improved in most patients within an average 10 months after systemic treatment. Except for the cysts, all abnormalities, including the nodules, consolidation, interstitial thickening, and GGOs, improved. However, pulmonary radiologic abnormalities still progressed in seven patients, six of whom were associated with systemic progression; the remaining one was considered stable. Three patients demonstrated an increase in the number or size of nodules on the latest CT scan. The cystic areas increased in five patients. Interestingly, in four of these five patients, other lung abnormalities improved, but some cysts became larger, and some cysts were newly formed in the areas where previous nodules and consolidation had improved or resolved (Fig 4). Four patients showed progressive consolidation on the latest CT scan. Two of these four patients showed newly appeared consolidation in the areas of previous nodules or cysts (Fig 5), which also confirmed the evolution of pulmonary lesions (ie, from nodules or cysts to consolidation) over time. Interstitial thickening was more severe in five patients, and GGOs were newly developed in one patient.Table 4Pulmonary Abnormalities at Baseline and the Latest Chest CT Scan in Patients After Systemic Treatment (n = 35)Pulmonary AbnormalitiesNo. on Baseline CT ScanLatest CT ScanNo.ImprovedStableProgressedNodules3534aOne patient showed that the area of nodules completely resolved.17153Cysts23230185Consolidation810bTwo patients had newly appeared consolidation lesions.334Interstitial thickening31311975Ground-glass opacities2017cOne patient had newly appeared ground-glass opacities, and ground-glass opacities completely resolved in four patients.1191a One patient showed that the area of nodules completely resolved.b Two patients had newly appeared consolidation lesions.c One patient had newly appeared ground-glass opacities, and ground-glass opacities completely resolved in four patients. Open table in a new tab Figure 5A-D, Formation of consolidation of two patients with idiopathic multicentric Castleman disease-not otherwise specified after systemic treatment. A-B, A 38-year-old woman with a 41-month history of cough and fever at initial chest CT scan examination. Her initial chest CT scan (A) revealed multiple cysts and scattered nodules in the right lung. On the latest follow-up CT scan (B), which was performed 6 years later, new consolidation (arrowhead in B) was formed in the areas of previous cysts (arrow in A). During the 6 years, she was administered multiple chemotherapy regimens, but the lung abnormalities continued to progress. She was defined as having a relapsed/refractory type of idiopathic multicentric Castleman disease. C-D, A 37-year-old man with a 20-month history of cough and hemoptysis at his first visit. The initial chest CT scan (C) showed multiple nodules of different sizes and locations, and some of the nodules were clustered (arrows in C). After 3 years of systemic treatment, the latest chest CT scan (D) showed that the nodules had gradually increased in size and number, and some had fused to form consolidation (arrowheads in D).View Large Image Figure ViewerDownload Hi-res image Download (PPT) We retrospectively described chest radiologic characteristics of pulmonary manifestations and analyzed their evolution over time among 58 patients with iMCD-NOS. To our knowledge, this is the first study to focus on pulmonary manifestations in iMCD-NOS, which is a distinct clinical phenotype according to CDCN classification criteria. Our results 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 results revealed that patients with iMCD-NOS with pulmonary manifestations were not rare, with a frequency of 35.8%. It has been previously reported that there is a slightly higher prevalence of pulmonary involvement, with 43.8% (14 of 32) in HIV-negative MCD and 48.0% (13 of 27) in iMCD.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,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 The distinction in the prevalence of pulmonary involvement may stem from the different patient enrollment standards. Our results were more convincing because we focused on a specific clinical phenotype defined in the CDCN classification criteria. Approximately one-half of the patients had no respiratory symptoms. Therefore, chest CT scan examination can help to identify potential pulmonary abnormalities. We herein described various lung abnormalities in iMCD-NOS. In summary, pulmonary abnormalities manifested as nodules, interstitial thickening at different locations, cysts, GGOs, and consolidation. Nodules were the most frequent findings. Moreover, we detailed the anatomic location of the main lesions and obtained two meaningful findings. The first one was that these lesions involved anatomic regions (including the centrilobular area, interlobar septa, pleura, and peribronchovascular area) corresponding to the distribution of lymphatic vessels. Several previous studies have also indicated that lung abnormalities in MCD are distributed along lymphatic tracts.18Nishimura M.F. Igawa T. Gion Y. et al.Pulmonary manifestations of plasma cell type idiopathic multicentric castleman disease: a clinicopathological study in comparison with IgG4-related disease.J Pers Med. 2020; 10: 269Crossref PubMed Scopus (10) Google Scholar,19Tashiro H. Egashira R. Takahashi K. et al.Thin-section computed tomographic findings of multicentric castleman disease changing over 10 years.J Thorac Imaging. 2017; 32: W81-W83Crossref PubMed Scopus (1) Google Scholar Second, we found that abnormalities in the centrilobular regions, interlobular septa, and pleura were more common than those in the peribronchovascular areas, which implied that the distal lymphatic vessels were more susceptible than the proximal vessels in iMCD. A hypothesis is that obstruction of the distal lymphatic vessels is more liable to occur because of their smaller diameters than those of the proximal vessels anatomically. Therefore, abnormalities of the distal lymphatic vessels were more easily detected on CT scan in the early phase of disease. Tashiro et al19Tashiro H. Egashira R. Takahashi K. et al.Thin-section computed tomographic findings of multicentric castleman disease changing over 10 years.J Thorac Imaging. 2017; 32: W81-W83Crossref PubMed Scopus (1) Google Scholar and Peng et al20Peng M. Shi J. Feng R. Multicentric Castleman disease as a rare cause of diffuse lung cysts.Am J Respir Crit Care Med. 2020; 201: 1292-1293Crossref PubMed Google Scholar reported one case of the evolution of pulmonary lesions in iMCD over 10 years of follow-up without treatment. Their results simultaneously revealed a slow evolution of pulmonary lesions in iMCD, with nodules being the initial manifestation. Sun and Han21Sun X. Han B. Multicentric Castleman's disease presenting with multiple nodes in lungs: a case report and literature review.Int J Hematol. 2008; 88: 278-282Crossref PubMed Scopus (5) Google Scholar reported an iMCD case in which the nodules increased in extent and evolved into masses and consolidation after 1 year of follow-up. In our study, the comparison of the duration of symptoms between three subgroups showed that the nodule subgroups had a shorter duration of symptoms than the cyst and consolidation subgroups. Moreover, the transformation from nodules to cysts was also observed on follow-up CT scan of two patients who had not received systemic treatment. Despite systemic treatment, pulmonary abnormalities still worsened in a small number of patients. We noticed the evolution from nodules or cysts to consolidation in two patients. Therefore, we concluded that nodules were early manifestations of pulmonary involvement, preceding the formation of cysts and consolidation. Our study is the first to clarify the existence of three stages during the progression of iMCD-NOS pulmonary lesions in a cohort. Identifying the stage of pulmonary manifestations will be helpful for physicians to assess the severity of lung disease in patients at their first visit. Notably, all three patients with the hyaline vascular subtype only presented nodules, two of whom had follow-up CT scan and remained radiologically stable. All patients with progressive radiologic abnormalities were nonhyaline vascular subtype. Sheet-like plasmacytosis has been observed in the lung involved.18Nishimura M.F. Igawa T. Gion Y. et al.Pulmonary manifestations of plasma cell type idiopathic multicentric castleman disease: a clinicopathological study in comparison with IgG4-related disease.J Pers Med. 2020; 10: 269Crossref PubMed Scopus (10) Google Scholar,22Otani K. Inoue D. Fujikura K. et al.Idiopathic multicentric Castleman's disease: a clinicopathologic study in comparison with IgG4-related disease.Oncotarget. 2018; 9: 6691-6706Crossref PubMed Scopus (30) Google Scholar Our study indicated that the severity and progression of lung abnormalities may associate with plasma cells. Improvements in pulmonary abnormalities were not taken into account in the CDCN evaluative criteria of the treatment response in iMCD, which included laboratory markers, lymph node size, and symptoms.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 were no available studies evaluating changes in pulmonary abnormalities after treatment, except for several case reports.20Peng M. Shi J. Feng R. Multicentric Castleman disease as a rare cause of diffuse lung cysts.Am J Respir Crit Care Med. 2020; 201: 1292-1293Crossref PubMed Google Scholar,21Sun X. Han B. Multicentric Castleman's disease presenting with multiple nodes in lungs: a case report and literature review.Int J Hematol. 2008; 88: 278-282Crossref PubMed Scopus (5) Google Scholar,23Iyonaga K. Ichikado K. Muranaka H. Fujii K. Yamaguchi T. Suga M. Multicentric Castleman's disease manifesting in the lung: clinical, radiographic, and pathologic findings and successful treatment with corticosteroid and cyclophosphamide.Intern Med. 2003; 42: 182-186Crossref PubMed Scopus (25) Google Scholar, 24Chen M.T. Lee S.C. Lu C.C. Tsai C.L. Unusual presentation of Castleman's disease mimicking lung cancer.Respirol Case Rep. 2019; 7e00416Crossref Scopus (6) Google Scholar, 25Han P.Y. Chi H.H. Su Y.T. Idiopathic multicentric Castleman disease with pulmonary and cutaneous lesions treated with tocilizumab: a case report.World J Clin Cases. 2020; 8: 4922-4929Crossref PubMed Scopus (1) Google Scholar, 26Ma W. Li J. Zhang L. A case of idiopathic multicentric Castleman disease presenting with diffuse lung cysts: how to evaluate treatment response?.Ann Hematol. 2020; 99: 1401-1402Crossref PubMed Scopus (1) Google Scholar Our follow-up results first demonstrated that all abnormalities except for cysts could improve after effective systemic treatment. Perhaps treatment should be started before cyst formation in patients with iMCD-NOS with pulmonary manifestations. Interestingly, cysts increased in extent or number in four patients, whereas the same patients showed improvements in pulmonary lesions other than cysts after treatment. Similar findings have been reported in lymphocytic interstitial pneumonia.27Johkoh T. Ichikado K. Akira M. et al.Lymphocytic interstitial pneumonia: follow-up CT findings in 14 patients.J Thorac Imaging. 2000; 15: 162-167Crossref PubMed Scopus (75) Google Scholar,28Dong X. Gao Y.L. Lu Y. Zheng Y. Characteristics of primary Sjogren's syndrome related lymphocytic interstitial pneumonia.Clin Rheumatol. 2021; 40: 601-612Crossref PubMed Scopus (10) Google Scholar Therefore, for patients who receive treatment, newly forming cysts are not hallmarks of pulmonary disease advancement. Evaluation of the treatment efficacy of pulmonary lesions in iMCD should combine cysts with other manifestations rather than analyzing cysts alone. Our study has several limitations. First, it was a single-center retrospective study with small samples. However, because of the rarity of iMCD, our research includes the largest cohort to date. Second, our subjects were enrolled from a cohort of patients with iMCD-NOS receiving chest CT scan examination. This may have led to an overstatement of the frequency of pulmonary involvement because patients without pulmonary symptoms are less likely to undergo chest CT scans. Third, pulmonary function testing was absent in our study. Fourth, the relationship between iMCD and lymphocytic interstitial pneumonia remains controversial. We could not elucidate the relationship between these disease entities without referring to the involved lung pathology. Additional histopathologic studies of the lung will be warranted to clarify their relationship. Finally, reported data were derived from an Asiatic population, and their applicability to worldwide population should be further investigated. 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 important because all abnormalities except for cysts could improve after effective systemic treatment. This work was supported by the CAMS Innovation Fund for Medical Sciences [Grant 2021-1-I2M-019 to J. L.], the National Natural Science Foundation of China [Grant 81900202 to L. Z.], the Dongcheng District Outstanding Talent Nuturing Program [Grant 2022-dchrcpyzz-69 to L. Z.], the National High Level Hospital Clinical Research Funding [Grant 2022-PUMCH-A-021 to L. Z.], and the Research and Translation Application of Beijing Clinical Diagnostic Technologies Funds from Beijing Municipal Commission of Science and Technology [Grant Z211100002921016 to L. Z.].