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. 2025 Apr 22;9(8):1952-1965.
doi: 10.1182/bloodadvances.2024014391.

Characterizing the heterogeneity of Castleman disease and oligocentric subtype: findings from the ACCELERATE registry

Sheila K Pierson  1 , Joshua D Brandstadter  2 , Drew A Torigian  3 , Adam Bagg  4 , Mary Jo Lechowicz  5 , Daisy Alapat  6 , Corey Casper  7   8   9 , Amy Chadburn  10 , Shanmuganathan Chandrakasan  11 , Angela Dispenzieri  12 , Alexander Fosså  13   14 , Christian Hoffmann  15 , Makoto Ide  16 , Razelle Kurzrock  17 , Sudipto Mukherjee  18 , Sunita Nasta  19 , José-Tomás Navarro  20 , Ariela Noy  21 , Eric Oksenhendler  22 , Mateo Sarmiento Bustamante  1 , Saishravan Shyamsundar  1 , Matthew Streetly  23   24 , Raymond S M Wong  25 , Lu Zhang  26 , Megan S Lim  27 , Gordan Srkalovic  28 , Frits van Rhee  29 , David C Fajgenbaum  1
Affiliations

Characterizing the heterogeneity of Castleman disease and oligocentric subtype: findings from the ACCELERATE registry

Sheila K Pierson et al. Blood Adv. .

Abstract

Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8-negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm-driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have "oligocentric" lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.

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Conflict of interest statement

Conflict-of-interest disclosure: J.D.B. is supported by a Doris Duke Foundation Physician Scientist Fellowship and American Society of Transplantation and Cellular Therapy New Investigator Award; and has consulted for Recordati Rare Diseases and EUSA Pharma. D.A.T. is a cofounder of Quantitative Radiology Solutions LLC. M.J.L. reports consulting fees from Secura Bio, EUSA Pharma, and Kyowa Kirin, and travel support from Secura Bio. C.C. is a paid consultant and speaker for Recordati Rare Diseases, and receives research funding from Johnson & Johnson and Immunity Bio. A.D. has served on the advisory board and independent review committees for Janssen Pharmaceuticals; has received research funding from Alnylam, Pfizer, Takeda, and Bristol Myers Squibb; and serves on the scientific advisory board for AbbVie and HaemaLogiX. R.K. has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, MedImmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, TopAlliance, and the National Cancer Institute; has received consultant and/or speaker fees and/or advisory board/consultant fees from Actuate Therapeutics, AstraZeneca, Bicara Therapeutics Inc, Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, Eisai, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, and X-Biotech; has an equity interest in CureMatch Inc; serves on the board of CureMatch and CureMetrix; and is a cofounder of CureMatch. S.M. reports advisory board participation for Celgene/Acceleron, Bristol Myers Squibb, Novartis, Blueprint Medicines, Genentech, EUSA/Recordati, and AbbVie; reports honoraria from Aplastic Anemia and MDS International Foundation, Celgene (now Bristol Myers Squibb), Bristol Myers Squibb, McGraw Hill Hematology Oncology Board Review, Partnership for Health Analytic Research, LLC, and EUSA/Recordati; reports consultancy for BioPharm, Celgene, Novartis, Bristol Myers Squibb, EUSA/Recordati; and received research funding (institution funding) from Bristol Myers Squibb (formerly Celgene), Novartis, and Jazz Pharmaceuticals. S.N. reports research funding from Caribou biosciences, ONO therapeutics, Astex, Atara, LOXO/Lilly, Pharmacyclics, Genentech/Roche, and Seattle Genetics; reports advisory board membership from Genmab, ADC Therapeutics, Genentech, and Acrotech; and reports data safety monitoring board membership with Merck. J.-T.N. received research grants not related to this manuscript from Gilead and EUSA Pharma/Recordati Rare Diseases; and received honoraria not related to this manuscript from AstraZeneca, Blueprint Medicines, EUSA Pharma/Recordati Rare Diseases, Novartis, and Roche. A.N. received research funding from Pharmacyclics/AbbVie, Kite/Gilead, and Cornerstone; received consulting fees from Janssen, MorphoSys, Cornerstone, Epizyme, EUSA, TG therapeutics, ADC Therapeutics, and AstraZeneca; and received honoraria from Pharmacyclics/AbbVie. M.S. reports speakers bureau and consultancy fees from Regeneron. R.S.M.W. has received grants/research support from AbbVie, Acerta, Alexion, Amgen, Apellis, Astella, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Celgene, Daiichi-Sankyo, GSK, Janssen, Kartos, MorphoSys, MSD, Novartis, Pfizer, Regeneron, and Roche; and consultant and/or speaker fees and/or advisory board/consultant fees from Alexion, Amgen, Astella, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Pfizer, and Roche. M.S.L. reports research funding and advisory board and speakers bureau fees from Thermo Fisher Scientific. G.S. reports speakers bureau fees from Recordati Rare Diseases. F.v.R. has received consulting fees from EUSA Pharma, GlaxoSmithKline, Janssen, Karyopharm, and Takeda; and has received research funding from Janssen Pharmaceuticals and Bristol Myers Squibb. D.C.F. receives funding from the National Heart, Lung, and Blood Institute (R01HL141408; 2018 to present); has consulted for and received research funding from Recordati Rare Diseases and EUSA Pharma; was provided study drug for a clinical trial of a Pfizer product (sirolimus); and has provisional patent applications filed by the University of Pennsylvania (provisional patent applications: 63/113,045; 62/989,437). The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
A large and richly annotated cohort of patients with CD reveals a small subset of cases with a form of CD that does not meet UCD or iMCD criteria. A total of 304 cases with sufficient diagnostic radiologic data underwent preliminary review for categorization by probable subtype. Forty-one cases had insufficient documentation to undergo panel review. The remaining cases were categorized probable UCD (n = 63), probable iMCD (n = 168), and probable CD with an undefined subtype (n = 32). After expert panel review for diagnosis adjudication, 46 UCD, 119 iMCD, and 14 CD-undefined cases were panel confirmed. Cases whose CD diagnosis was panel confirmed were significantly more likely to be classified as UCD or iMCD than as CD-undefined (P = .007). IgG4RD, IgG4 related disease; MIS-C, multisystem inflammatory syndrome in children.
Figure 2.
Figure 2.
Investigation of involved LN stations reveals that patients with an undefined subtype demonstrate oligocentricity. (A) The relationship between the number of enlarged LN stations plotted against the number of minor diagnostic criteria. Patients with CD-undefined can be visualized separately from both UCD and iMCD. (B) Most of CD-undefined cases had ≤4 enlarged LNs in the same general region. These patients demonstrate oligocentric lymphadenopathy and henceforth will be referred to as OligoCD. (C) Cases that were panel-confirmed iMCD were typically diagnosed iMCD by their treating physician (n = 109; 91.6%), and cases that were panel-confirmed UCD were typically diagnosed UCD by their treating physician (n = 41; 89.1%). Patients with CD-undefined were diagnosed as UCD in 64.3% of cases (n = 9), and iMCD in the remaining 35.7% (n = 5).
Figure 3.
Figure 3.
Disease features of OligoCD more closely resemble UCD than iMCD. OligoCD demonstrates features that are more similar to UCD than to iMCD. (A) Clinical, (B) laboratory, and (C) histopathologic features of UCD, iMCD, and OligoCD cases demonstrate stronger similarities between UCD and OligoCD. Significance: ns, P > .05; ∗P ≤ .05; ∗∗P ≤ .01; ∗∗∗P ≤ .001; ∗∗P ≤ .0001. HV, hyaline vascular; hyperV, hypervascular; ns, not significant.
Figure 4.
Figure 4.
A summary of common clinical, laboratory, and histopathological features on the spectrum of patients with UCD to those with OligoCD and with iMCD. Patients demonstrate differences in lymphadenopathy, histopathology, laboratory and clinical abnormalities, and degree of inflammation. The patients with the least severe disease typically have UCD, and the most severe cases are typically iMCD-TAFRO. Severity of symptoms along this spectrum should be considered when making a diagnosis. HV, hyaline vascular; hyperV, hypervascular; PC, plasmacytic.
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