（2026.V1）NCCN临床实践指南：Castleman病

指南综合与多学科· 未分类与其他 · 2026

NCCN Guidelines Version 1.2026

## Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

*Andrew D. Zelenetz, MD, PhD/Chair † Memorial Sloan Kettering Cancer Center

*Leo I. Gordon, MD/Vice Chair ‡ § Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Jeremy S. Abramson, MD, MMSc ‡‡ Mass General Cancer Center

Ranjana H. Advani, MD ‡ Stanford Cancer Institute

Alaa Altahan, MD ‡† B St. Jude Children's Research Hospital/The University of Tennessee Health Science Center

Babis Andreadis, MD, MSCE ‡ ‡ UCSF Helen Diller Family Comprehensive Cancer Center

Nancy L. Bartlett, MD † Sisteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

L. Elizabeth Budde, MD, PhD ‡ ξ City of Hope National Medical Center

Paolo F. Caimi, MD ‡† ξ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Sven DeVos, MD, PhD ‡†b UCLA Jonsson Comprehensive Cancer Center

Bhagirathbhai Dholaria, MD ‡† θ Vanderbilt-Ingram Cancer Center

Luis E. Fayad, MD ‡‡ $\blacktriangleright$ The University of Texas MD Anderson Cancer Center

Sameh Gaballa, MD ‡ Moffitt Cancer Center

Thomas M. Habermann, MD $ξ Mayo Clinic Comprehensive Cancer Center

Francisco Hernandez-lilizaliturri, MD † Roswell Park Comprehensive Cancer Center

Boyu Hu, MD ‡ ‡†

Huntsman Cancer Institute at the University of Utah

Yasmin Karimi, MD ‡ University of Michigan Rogel Cancer Center

Christopher R. Kelsey, MD § Duke Cancer Institute

Rebecca King, MD ≠ Mayo Clinic Comprehensive Cancer Center

Justin Kline, MD † The UChicago Medicine Comprehensive Cancer Center

Susan Krivacic, MPAff ¥ Patient advocate

Ann S. LaCasce, MD, MMSc †‡ Dana-Farber/Brigham and Women's Cancer Center

Daniel Landsburg, MD † Abramson Cancer Center at the University of Pennsylvania

Megan Lim, MD, PhD ≠ Memorial Sloan Kettering Cancer Center

Marcus Messmer, MD ‡‡ Fox Chase Cancer Center

Priyanka Pophali, MD ‡ University of Wisconsin Carbone Cancer Center

Rachel Rabinovitch, MD § University of Colorado Cancer Center Praveen Ramakrishnan, MD, MS ‡ UT Southwestern Simmons Comprehensive Cancer Center

Erin Reid, MD †‡ UC San Diego Moores Cancer Center

Kenneth B. Roberts, MD § Yale Cancer Center/Smilow Cancer Hospital

Aditi Saha, MD ‡ O'Neal Comprehensive Cancer Center at UAB

Naoyuki G. Saito, MD, PhD § Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Yazeed Sawalha, MD ‡ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Stephen D. Smith, MD ‡ Fred Hutchinson Cancer Center

Lode J. Swinnen, MBChB, MD †‡§ Johns Hopkins Kimmel Cancer Center

Joseph Tuscano, MD ‡ UC Davis Comprehensive Cancer Center

Julie M. Vose, MD, MBA ‡ § Fred & Pamela Buffett Cancer Center

NCCN Mary Dwyer, MS Megan Lyons, MS Hema Sundar, PhD

NCCN Guidelines Version 1.2026 Castleman Disease

Version 1.2026, 11/24/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

NCCN Castleman Disease Panel Members

Summary of the Guidelines Updates

• Diagnosis (CD-1)

• Workup (CD-2)

• Unicentric Castleman Disease (UCD) (CD-3)

• Multicentric Castleman Disease (MCD) (CD-4A)

• Relapsed/Refractory or Progressive Disease (MCD) (CD-6)

• Subtypes of Idiopathic MCD (CD-A)

• Consensus Diagnostic Criteria for Idiopathic MCD (CD-B)

• Suggested Treatment Regimens (CD-C)

Classification and Staging (ST-1)

Abbreviations (ABBR-1)

Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions.

NCCN Categories of Evidence and

Consensus: All recommendations are category 2A unless otherwise indicated. See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.

NCCN Guidelines Version 1.2026 Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Castleman Disease include: Global changes

• References for suggested treatment regimens were updated throughout the guidelines.

CD-1

• Footnote c revised: There are 3 variants: hypervascular (hyaline vascular), plasmacytic, and mixed variants. There are three histopathologic subtypes across a

spectrum, from hyaline vascular to plasmacytic, with mixed subtypes in between. All histopathologic subtypes can be observed across all subtypes of CD. Fajgenbaum DC, Blood 2017;129:1646-1657. Hypervascular variant is virtually always unicentric and human herpesvirus 8 (HHV8) (-). Plasmacytic and mixed variants are more

often multicentric and may be HHV8+.

CD-2

• Workup

Essential, 8th bullet revised: Serum protein electrophoresis (SPEP) and urine electrophoresis with immunofixation, serum light chains, quantitative Ig with serum

immunofixation electrophoresis (SIFE) and/or quantitative Ig levels, serum free light chain (FLC) assay

Essential, 12th bullet revised: Skull-base to mid thigh FDG-PET/CT scan

Essential, 13th bullet revised: Pregnancy testing in patients of childbearing age (if chemotherapy or radiation therapy [RT] planned)

Useful, 3rd bullet revised: Reticulin fibrosis of bone marrow Bone marrow biopsy with trichrome and reticulin stain

• Footnote f revised: Criteria for Active Disease (CD-A). Diagnostic Criteria for Idiopathic MCD (CD-B). Active disease is the presence of ≥2 minor criteria (with at least 1 of them being a lab abnormality). (also for CD-4A, CD-4B)

• Footnote j revised: Fertility preservation options include: sperm banking, semen cryopreservation,...

CD-4A

• MCD

First-line therapy, after response, 2nd bullet revised: If rituximab-based time-limited therapy, observe and retreat at progression

CD-5

• Fulminant/Severe HHV8(+) MCD ± organ failure or Fulminant/Severe HHV8(-)-iMCD

Footnote u added: Siltuximab is the preferred treatment option. Monitor organ function. Early intervention with chemoimmunotherapy is recommended for patients

with progressive organ dysfunction,

CD-A

• Removed table with Criteria for Active Disease

• Subtypes of Idiopathic MCD

Added: Idiopathic plasmacytic lymphadenopathy (IPL)

◊ Thrombocytosis

◊ Polyclonal hyperglobulinemia

◊ Less severe fluid accumulation

Continued

NCCN Guidelines Version 1.2026 Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Castleman Disease include:

CD-C 1 of 3

• Suggested Treatment Regimens, First-Line Therapy

UCD (surgically unresectable/incomplete resection)

◊ Revised: Rituximab ± Prednisone (for compressive symptoms)

◊ Added: Siltuximab (for primarily inflammatory symptoms) (if HIV-1- negative/HHV8-negative) (category 2A)

◊ Added: Tocilizumab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative) (category 2A)

◊ Removed: Rituximab + cyclophosphamide

◊ Removed: Rituximab + prednisone + cyclophosphamide

MCD - Criteria for active disease present but with no organ failure

◊ HHV8-negative/HIV-1-negative (iMCD - Nonsevere)

– Added: Tocilizumab (category 2A)

– Removed: Thalidomide/cyclophosphamide/prednisone

◊ HHV8-positive (HIV-1-positive or HIV-1-negative)

– Removed "preferred" from rituximab monotherapy

MCD - Fulminant/severe ± organ failure

◊ Fulminant/severe HHV8-negative (iMCD)

– Preference stratification applied to regimens

– Siltuximab moved to Preferred

– Added: Tocilizumab to Other recommended (category 2A)

• Footnote b added: Monitor organ function. If stable, continue siltuximab. Early intervention with chemoimmunotherapy is recommended for patients with progressive organ dysfunction.

• Footnote c added: Occult KS is prevalent in HIV/HHV8+ MCD and is likely to flare after rituximab or prednisone. Consider baseline imaging and direct visualization

to screen for pulmonary ± gastrointestinal (GI) involvement. Monitor closely for KS progression and continue KS-directed therapy for ~3 months post last rituximab to minimize risk of KS flare (given long action of rituximab). See NCCN Guidelines for Kaposi Sarcoma.

CD-C 2 of 3

• Suggested Treatment Regimens, Second-Line and Subsequent Therapy for Relapsed/Refractory or Progressive Disease

UCD

◊ Footnote moved to column as statement: Treat with alternative first-line therapy regimens (CD-C 1 of 3) before moving onto second-line and subsequent therapy for relapsed/refractory or progressive disease

◊ Removed: Tocilizumab (if HIV-1-negative/HHV8-negative)

◊ Removed: Rituximab + cyclophosphamide

◊ Removed: Rituximab + prednisone + cyclophosphamide

MCD

◊ HHV8(+) - Criteria for active disease present with no organ failure...

– Footnote moved to column as statement and revised: For active disease present with no organ failure, treat with alternative first-line therapy regimens (CD-C 1 of 3) before moving onto second-line and subsequent therapy for relapsed/refractory or progressive disease

◊ Fulminant/Severe disease [HHV8(+) or HHV8(-)] with organ failure

– Footnote moved to column as statement and revised: Treat with alternate second-line combination therapy regimens ± rituximab (not previously given) before moving onto subsequent therapy with alternative regimens for relapsed/refractory or progressive disease

◊ Alternative regimens, revised: High-Dose Zidovudine/Ganciclovir or Valganciclovir (if HHV8-positive)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

DIAGNOSIS

* Excisional or incisional biopsy is preferred for the definitive diagnosis.

* A fine-needle aspiration (FNA) biopsy is insufficient for the initial diagnosis or histologic assessment of Castleman disease (CD). A core needle biopsy is not optimal because features of CD are very nonspecific and seeing the whole node with architecture is essential to be confident of the diagnosis. Therefore, core needle biopsy is unlikely to be adequate for definitive pathologic diagnosis of CD.

* Hematopathology review of all slides with at least one paraffin block representative of the lesion. Rebiopsy if consult material is nondiagnostic, preferably the most fluorodeoxyglucose (FDG)-avid, accessible lymph node.

ADDITIONAL DIAGNOSTIC TESTING<sup>a,b,c</sup>

ESSENTIAL:

* Adequate immunophenotyping to establish diagnosis

$\blacktriangleright$ IHC panel: kappa/lambda, CD20, CD3, HHV8 latency-associated nuclear antigen (LANA)

USEFUL UNDER CERTAIN CIRCUMSTANCES:

$\bullet$ Molecular analysis to detect immunoglobulin (lg) gene rearrangements

$\bullet$ IHC panel: Ki-67 index; Ig heavy chains,$^{d}$ CD5, CD10, BCL2, BCL6, cyclin D1, CD21, or CD23, CD38, IRF4/MUM1, PAX5, CD138

* Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD19, CD20, CD5, CD23, CD10

$\bullet$ Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH)

Workup (CD-2)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[ESSENTIAL: ● Physical exam: attention to node-bearing areas, including Waldeyer’s ring, and to size of liver and spleen ● Performance status ● Assessment for active disease f ● Complete blood count(CBC) with differential ● Comprehensive metabolic panel ● LDH, C-reactive protein(CRP), erythrocyte sedimentation rate(ESR) ● Serum protein electrophoresis(SPEP) with serum immunofixation electrophoresis(SIFE) and/or quantitative Ig levels, serum free light chain(FLC) assay HIV, HCV8, Epstein-Barr virus(EBV) polymerase chain reaction(PCR) ● Hepatitis B testing¹ ● Hepatitis C testing² ● Skull-base to mid thigh FDG-PET/CT scan(preferred) or chest/abdomen/pelvis(C/A/P) CT with contrast of diagnostic quality ● Pregnancy testing in patients of childbearing age(if therapy planned) ● If HIV or HCV positive, screening for concurrent Kaposi sarcoma(KS) is strongly recommended ● Bone marrow biopsy+ aspirate ● Bone marrow biopsy with trichrome and reticulin stain(particularly in patients with TAFO syndrome) ● Neck CT with contrast ● Echocardiogram or multigated acquisition(MUGA) scan if anthracycline-based regimen is indicated ● IgG4, sIgL6, sIgL10, vasculature endothelial growth factor receptor(VEGF), uric acid, ferritin³ Discuss fertility preservation(MCD(CD-A). Rule out other diseases that can see Subtypes of ICPD(MCD)(see Exclusion Criteria on CD-B 1 of 2).If concurrent polyneuropathy and monoclonal plasma cell disorder, a workup for polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes(POEMS) syndrome is recommended. Patients with POEMS syndrome with MCD should have treatment directed at POEMS syndrome with regimens recommended for the treatment of multiple myeloma²(f see NCCN Guidelines for Multiple Myeloma). ⁴ Diagnostic Criteria for idiopathic MCD(CD-B). Active disease is the presence of 2 minor criteria(with at least 1 of them being a lab abnormality).] --> A2[Unicentric Castleman disease(UCD)]\n A2 --> A3[CD-3]\n A4[9 Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy+ chemotherapy. See Monoclonal Antibody Therapy and Viral Reactivation(NHODG-B) in the NCCN Guidelines B-Cell Lymphomas. Tests include hepatitis B surface antigen and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and consider consult with gastroenterologist. Hepatitis C antibody and if positive, viral load and consult with hepatologist. i Measurement of acute phase reactants may be helpful in monitoring therapy. j Fertility preservation options include sperm banking, in vitro fertilization(IVF), or ovarian tissue or oocyte cryopreservation.] --> A5[CD-4A]\n](1/parseimages/figure01b417ecae7e47b9ae81070819910c3a_0_4.png) Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[UCD] --> A2[Surically resectable]\n A2 --> A3[Complete resection]\n A2 --> A8[Incomplete resection]\n A3 --> A4[Observation]\n A4 --> A5[Recurrence]\n A5 --> A6[Relapsed/ refractory disease]\n A6 --> A7[Consider surgery or ISRT, or embolization if amenable or Suggested Treatment Regimens: Second-line and Subsequent Therapy （CD-C 2 of 3）]\n A8 --> A9[Asymptomatic]\n A8 --> A10[Symptomatic]\n A9 --> A4\n A10 --> A11[See Surgically unresctable below]\n A12[Involved-site RT （ISRT）, or Suggested Treatment Regimens: First-line Therapy（CD-C 1 of 3） or Consider embolization or Observation in asymptomatic patients] --> A13[Suricially resectable]\n A12 --> A14[Suricially unresctable]\n A13 --> A3\n A13 --> A8\n A14 --> A15[Alternate first-line therapy not previously given （CD-C 1 of 3）]\n A15 --> A6\n](1/parseimages/figurea46dd2ac947b4ab59196e5f2a7df83a4_0_4.png) $^{k}$ See Supportive Care for B-Cell Lymphomas for the management of complications associated with anti-CD20 monoclonal antibody (mAb) therapy in the NCCN Guidelines for B-Cell Lymphomas.

$^{1}$ The optimal dose of ISRT in unresectable UCD is not established. Doses as high as 40 Gy in 1.5–2 Gy fractions have been used (Chronowski GM, et al. Cancer 2001;92:670-676). Lower doses may be considered depending upon clinical circumstances (eg, proximity to critical structures, treatment intent). Advanced radiation techniques (eg, intensity-modulated RT [IMRT], image-guided RT [IGRT], protons) are recommended to limit dose to surrounding normal tissues (Matthiesen C, et al. Radiol Oncol 2012;46:265-270). RT Dose Constraint Guidelines for Lymphoma - Recommendations for normal tissue dose constraints can be found in the Principles of Radiation Therapy section of the NCCN Guidelines for Hodgkin Lymphoma.

$^{m}$ Patients with non-bulky disease may be observed after ISRT.

$^{n}$ Encourage biopsy to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[HIV-1(-)/HHV8(-) (idiopathic MCD [iMCD; Nonsereverel)] --> A2[Suggested Treatment Regimens: First-line Therapy (CD-C 1 of 3)]\n A2 --> A3[Responsea]\n A3 --> A4[If siltuximab, continue until progression • If rituximab-based time-limited therapy, observe]\n A3 --> A5[No responsea,q]\n A4 --> A6[Relapsed diseasef]\n A5 --> A12[progressivedisease]\n A6 --> A7[Alternate first-line therapy (CD-C 1 of 3) before moving onto treatment for relapsed/ refractory or progressive disease]\n A7 --> A8[Relapsed/ Refractory or Progressive Disease (CD-6)]\n A9[Criteria for active diseasepresent but no organ failure] --> A10[HHV8(+)]\n A9 --> A11[MCD]\n A10 --> A1\n A10 --> A11\n A10 --> A12\n A11 --> A13[Fulminant/Severe]\n A11 --> A14[CD-4B]\n A13 --> A15[CD-5]\n](1/parseimages/figurec666da6908b14f8d8407d523c694019d_0_4.png) f Diagnostic Criteria for Idiopathic MCD (CD-B). Active disease is the presence of ≥2 minor criteria (with at least 1 of them being a lab abnormality).

k See Supportive Care for B-Cell Lymphomas for the management of complications associated with anti-CD20 mAb therapy in the NCCN Guidelines for B-Cell Lymphomas.

$^{n}$ Encourage biopsy to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

$^{0}$ Severe disease defined as: Eastern Cooperative Oncology Group (ECOG) performance status ≥2; stage IV kidney dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m$^{2}$, creatinine >3 mg/dL); anasarca and/or ascites, pleural effusion, or pericardial effusion; hemoglobin ≤8 g/dL; pulmonary involvement/interstitial pneumonitis with dyspnea (van Rhee F, et al. Blood 2018;132:2115-2124).

P All patients with HIV infection should be on combination antiretroviral therapy (cART). For principles of concurrent HIV management and supportive care, see the NCCN Guidelines for Cancer in People with HIV.

$^{9}$ Response assessment using the imaging modalities performed during workup (C/A/P CT with contrast or PET/CT).

* [Rituximab ± prednisone may be repeated without limit if progression is ≥6 months after completion of rituximab](#).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

FIRST-LINE THERAPY$^{k}$

RELAPSED DISEASE$^{k}$

![graph TD\n A1[MCDCriteria for active diseasepresent but no organ failure] --> A2[HIV-1(+)/HHV8(+)or HIV-1(-)/HHV8(+)]\n A2 --> A3[SuggestedTreatmentRegimens:First-LineTherapy(CD-C 1 of 3)q]\n A3 -->|Responseq| A4[Observation]\n A3 -->|No response,n,q| A5[Alternate first-line therapy(CD-C 1 of 3)before moving onto treatmentfor relapsed/refractory or progressive disease'r]\n A4 --> A6[Relapsed disease'n]\n A5 --> A7[Relapsed/Refactory or Progressive Disease (CD-6)]\n A6 --> A5\n A7 --> A5\n](1/parseimages/figure6a8169deec74483d81188da25e6678e8_0_6.png) f Diagnostic Criteria for Idiopathic MCD (CD-B). Active disease is the presence of ≥2 minor criteria (with at least 1 of them being a lab abnormality).

k See Supportive Care for B-Cell Lymphomas for the management of complications associated with anti-CD20 mAb therapy in the NCCN Guidelines for B-Cell Lymphomas.

$^{n}$ Encourage biopsy to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

P All patients with HIV infection should be on cART. For principles of concurrent HIV management and supportive care, see the NCCN Guidelines for Cancer in People with HIV.

$^{9}$ Response assessment using the imaging modalities performed during workup (C/A/P CT with contrast or PET/CT).

* [Rituximab ± prednisone may be repeated without limit if progression is ≥6 months after completion of rituximab.](#).

$^{s}$ Occult KS is prevalent in HIV/HHV8+ MCD and is likely to flare after rituximab or prednisone. Consider baseline imaging and direct visualization to screen for pulmonary ± gastrointestinal (GI) involvement. Monitor closely for KS progression and continue KS-directed therapy for ~3 months post last rituximab to minimize risk of KS flare (given long action of rituximab). See NCCN Guidelines for Kaposi Sarcoma.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

FIRST-LINE THERAPY$^{k}$

RELAPSED DISEASE$^{k}$

![graph TD\n A1[Fulminant/Severe° HHV8(+) MCD ± organ failure or Fulminant/ Severe° HHV8(-) iMCDᵀᴥ] --> A2[Suggested Treatment Regimens: First-Line Therapy(CD-C 1 of 3ᵀᴥ]\n A2 -->|Responseᵐ| A3[Observation]\n A2 -->|No responseᵇ,ᴄ| A4[Relapsed/ Refractory or Progressive Disease(CD-6)]\n A3 --> A5[Relapsed diseaseᵐ]\n A5 --> A4\n](1/parseimages/figure568cff0b137842cb9be2bcfdc32f098d_0_6.png) $^{k}$ See Supportive Care for B-Cell Lymphomas for the management of complications associated with anti-CD20 mAb therapy in the NCCN Guidelines for B-Cell Lymphomas.

$^{n}$ Encourage biopsy to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

$^{0}$ Severe disease defined as: ECOG performance status ≥2; stage IV kidney dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m$^{2}$, creatinine >3 mg/dL); anasarca and/or ascites, pleural effusion, or pericardial effusion; hemoglobin ≤8 g/dL; pulmonary involvement/interstitial pneumonitis with dyspnea (van Rhee F, et al. Blood 2018;132:2115-2124).

$^{9}$ Response assessment using the imaging modalities performed during workup (C/A/P CT with contrast or PET/CT).

$^{s}$ Occult KS is prevalent in HIV/HHV8+ MCD and is likely to flare after rituximab or prednisone. Consider baseline imaging and direct visualization to screen for pulmonary ± GI involvement. Monitor closely for KS progression and continue KS-directed therapy for ~3 months post last rituximab to minimize risk of KS flare (given long action of rituximab). See NCCN Guidelines for Kaposi Sarcoma.

† Siltuximab is the preferred treatment option. Monitor organ function. Early intervention with chemoimmunotherapy is recommended for patients with progressive organ dysfunction.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE (MCD)$^{k}$

![graph TD\n A1[Relapsed/Refractory or progressive disease(MCD)n,s] --> A2[HHV8(+) - Criteria for active disease present with no organ failure or Fulminant/severe[HHV8(+) or HHV8(-)]]\n A2 --> A3[Suggested Treatment Regimens: Second-Line Therapy(CD-C 2 of 3)u]\n A3 --> A4[Responsea]\n A4 --> A5[Observation or Maintenance valganciclovir if HHV8(+)]\n A4 --> A7[No responsea,n,q]\n A5 --> A6[Relapsed/refractory diseasea]\n A6 --> A3\n A7 --> A8[Alternate second-line combination therapy± rituximab(CD-C 2 of 3) not previously given before moving onto subsequent therapy]\n A8 --> A6\n](1/parseimages/figured60f6a6b3b2d4e90a77796f6073bde8c_0_5.png) $^{k}$ See Supportive Care for B-Cell Lymphomas for the management of complications associated with anti-CD20 mAb therapy in the NCCN Guidelines for B-Cell Lymphomas.

$^{n}$ Encourage biopsy to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

$^{9}$ Response assessment using the imaging modalities performed during workup (C/A/P CT with contrast or PET/CT).

$^{s}$ Occult KS is prevalent in HIV/HHV8+ MCD and is likely to flare after rituximab and direct visualization to screen for pulmonary ± GI involvement. Monitor closely for KS progression and continue KS-directed therapy for ~3 months post last rituximab to minimize risk of KS flare (given long action of rituximab). See NCCN Guidelines for Kaposi Sarcoma.

$^{u}$ Single-agent therapy is preferred for asymptomatic patients with no organ failure; combination therapy is preferred for patients with fulminant disease and organ failure.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

CD-A

a Iwaki N, Fajgenbaum DC, Nabel CS, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol 2016;91:220-226.

b Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129:1646-1657.

SUBTYPES OF IDIOPATHIC MCD

• Idiopathic MCD (iMCD-TAFRO)a

Marked inflammatory syndrome

Thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), renal

dysfunction/reticulin myelofibrosis, organomegaly

Megakaryocytic hyperplasia, hypervascular or mixed histopathology Normal immunoglobulin levels

• Idiopathic MCD - not otherwise specified (iMCD-NOS)a

Less intense inflammatory syndrome

Normal/elevated platelet counts

Plasmacytic or mixed histopathology

Polyclonal hypergammaglobulinemia

• Idiopathic plasmacytic lymphadenopathy (IPL)b

Thrombocytosis

Polyclonal hyperglobulinemia

Less severe fluid accumulation

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Castleman Disease

NCCN Guidelines Index Table of Contents Discussion

|Consensus Diagnostic Criteria for Idiopathic $MCD^{a}$||| |---|---|---| |I. Major Criteria (need both):|1. Histopathologic lymph node features consistent with the iMCD spectrum. Features along the iMCD spectrum include (need grade 2-3 for either regressive GCs or plasmacytosis at minimum): - Regressed/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric rings of lymphocytes in an "onion skinning" appearance - FDC prominence - Vascularity, often with prominent endothelium in the interfolricular space and vessels penetrating into the GCs with a "lollipop" appearance - Sheetlike, polytypic plasmacytosis in the interfolricular space - Hyperplastic GCs 2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations|| |II. Minor Criteria (need at least 2 of 11 criteria with at least 1 laboratory criterion)|Laboratory* 1. Elevated CRP (>10 mg/L) or ESR (>15 mm/h)+ 2. Anemia (hemoglobin <12.5 g/dL for males, hemoglobin <11.5 g/dL for females) 3. Thrombocytopenia (platelet count <150 µm/L) or thrombocytosis (platelet count >400 µm/L) 4. Hypoalbuminemia (albumin <3.5 g/dL) 5. Renal dysfunction (eGFR <60 mL/min/1.73m²) or proteinuria (total protein 150 mg/24 h or 10 mg/100 mL) 6. Polyclonal hypergammaglobulinemia (total γ globulin or immunoglobulin G >1700 mg/dL)|Clinical 1. Constitutional symptoms: night sweats, fever (>38°C), weight loss, or fatigue (≥2 CTCAE lymphoma score for B-symptoms) 2. Large spleen and/or liver 3. Fluid accumulation: edema, anasarca, ascites, or pleural effusion 4. Eruptive cherry hemangiomatosis or violaceous papules 5. Lymphocytic interstitial pneumonitis| |III. Exclusion Criteria (must rule out each of these diseases that can mimic iMCD)|Infection-related disorders 1. HHV-8 (infection can be documented by blood PCR; diagnosis of HHV-8-associated MCD requires positive LANA-1 staining by IHC, which excludes iMCD) 2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV (detectable EBV viral load not necessarily exclusionary) 3. Inflammation and adenopathy caused by other uncontrolled infections (eg, acute or uncontrolled CMV, toxoplasmosis, HIV, active tuberculosis)|Autoimmune/autoinflammatory diseases (requires full clinical criteria; detection of autoimmune antibodies alone is not exclusionary) 1. Systemic lupus erythematosus 2. Rrieumatoid arthritis 3. Adult-onset Still disease 4. Juvenile idiopathic arthritis 5. Autoimmune lymphoproliferative syndrome Malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same time as iMCD to be exclusionary): 1. Lymphoma (Hodgkin and non-Hodgkin) 2. Multiple myeloma 3. Primary lymph node plasmacytoma 4. FDC sarcoma 5. POEMS syndrome‡|

a Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood 2017;129:1646-1657.

Note: All recommendations are category 2A unless otherwise indicated.

Continued

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Note: All recommendations are category 2A unless otherwise indicated.

CD-B 2 OF 2

a Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric

Castleman disease. Blood 2017;129:1646-1657.

Footnotes for CD-B 1 of 2

* Laboratory cutoff thresholds are provided as guidance. Since some laboratories have slightly different ranges, the upper and lower ranges from a particular laboratory should be used to determine if a patient meets a particular laboratory Minor Criterion.

† Evaluation of CRP is mandatory and tracking CRP levels is highly recommended, but ESR will be accepted if CRP is not available.

‡ POEMS is considered to be a disease “associated” with CD. Because the monoclonal plasma cells are believed to drive the cytokine storm, we do not consider it

iMCD, but rather “POEMS-associated MCD.”

Consensus Diagnostic Criteria for Idiopathic MCD (continued)a

• Select additional features supportive of, but not required for diagnosis

Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or B2M

Reticulin fibrosis of bone marrow (particularly in patients with TAFRO syndrome)

Diagnosis of disorders that have been associated with iMCD: paraneoplastic pemphigus, bronchiolitis obliterans organizing pneumonia,

autoimmune cytopenias, polyneuropathy (without diagnosing POEMS‡), glomerular nephropathy, inflammatory myofibroblastic tumor

National Comprehensive Cancer Network®

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SUGGESTED TREATMENT REGIMENSª

|FIRST-LINE THERAPY|FIRST-LINE THERAPY|FIRST-LINE THERAPY| |---|---|---| |UCD (surgically unresectable/incomplete resection)|MCD - Criteria for active disease present with no organ failure|MCD - Fulminant/severe ± organ failure| |• Rituximab ± Prednisone (for compressive symptoms) • Siltuximab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative) • Tocilizumab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative)|HHV8-negative/HIV-1-negative (iMCD-Nonsevere) • Siltuximab • Tocilizumab • Rituximab ± Prednisone • CVP (Cyclophosphamide/Vincristine/Prednisone) + Rituximab|Fulminant/severe HHV8-negative (iMCD) Preferred • Siltuximab Other Recommended • Tocilizumab • CHOP (Cyclophosphamide/Doxorubicin/Vincristine/ Prednisone) ± Rituximab • CVAD (Cyclophosphamide/Vincristine/ Doxorubicin/ Dexamethasone) ± Rituximab • CVP ± Rituximab • If not a candidate for combination therapy: ▷ Rituximab| |• Rituximab ± Prednisone (for compressive symptoms) • Siltuximab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative) • Tocilizumab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative)|HHV8-positive (HIV-1-positive or HIV-1-negative)$^{c}$ • Rituximab • Rituximab + Liposomal Doxorubicin • Rituximab + Prednisone • Rituximab + Prednisone + Liposomal Doxorubicin • High-dose Zidovudine/Ganciclovir or Valganciclovir|Fulminant/severe HHV8-positive MCD$^{c}$ • Rituximab + Liposomal Doxorubicin • Rituximab + Prednisone + Liposomal Doxorubicin • CVAD + Rituximab • CVP + Rituximab • If not a candidate for combination therapy: ▷ Liposomal Doxorubicin • Rituximab|

ª An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion. ᵇ Monitor organ function. If stable, continue siltuximab. Early intervention with chemoimmunotherapy is recommended for patients with progressive organ dysfunction. ᶜ Occult KS is prevalent in HIV/HHV8+ MCD and is likely to flare after rituximab or prednisone. Consider baseline imaging and direct visualization to screen for pulmonary ± gastrointestinal (GI) involvement. Monitor closely for KS progression and continue KS-directed therapy for ~3 months post last rituximab to minimize risk of KS flare (given long action of rituximab). See NCCN Guidelines for Kaposi Sarcoma.

Note: All recommendations are category 2A unless otherwise indicated.

References on CD-C 3 of 3

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SUGGESTED TREATMENT REGIMENSª

|SECOND-LINE AND SUBSEQUENT THERAPY FOR RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE (in alphabetical order)||| |---|---|---| |UCD (surgically unresectable/incomplete resection)|MCD|MCD| |UCD (surgically unresectable/incomplete resection)|HHV8(+) - Criteria for active disease present with no organ failure or Fulminant/Severe disease [HHV8(+) or HHV8(-)] with no organ failure|Fulminant/Severe disease [HHV8(+) or HHV8(-)] with organ failure| |Treat with alternative first-line therapy regimens (CD-C 1 of 3) before moving onto second-line and subsequent therapy for relapsed/refractory or progressive disease • Rituximab ± Prednisone • Siltuximab$^{e}$ (if HIV-1-negative/HHV8-negative)|For active disease present with no organ failure, treat with alternative first-line therapy regimens (CD-C 1 of 3) before moving onto second-line and subsequent therapy for relapsed/refractory or progressive disease Preferred (Add ganciclovir or valganciclovir, if HHV8-positive) • Etoposide (oral or IV) • Liposomal Doxorubicin (if HHV8-positive) • Siltuximab$^{e}$ (if HHV8-negative) • Vinblastine • Other Recommended • Sirolimus (if HHV8-negative) • If not previously given • CHOP ± Rituximab • CVAD ± Rituximab • CVP ± Rituximab|Treat with alternate second-line combination therapy regimens ± rituximab (not previously given) before moving onto subsequent therapy with alternative regimens for relapsed/refractory or progressive disease Preferred • If not previously given • CHOP ± Rituximab • CVAD ± Rituximab • CVP ± Rituximab • Liposomal Doxorubicin ± Rituximab (if HHV8-positive) • Siltuximab$^{e}$ (if HHV8-negative)| ||Alternative regimens for subsequent therapy: • Anakinra • Bortezomib ± Rituximab • Lenalidomide ± Rituximab • Thalidomide ± Rituximab • Tocilizumab • High-Dose Zidovudine/Ganciclovir or Valganciclovir (if HHV8-positive)||

d Maintenance therapy (optional) for patients with HHV8-positive disease responding to second-line and subsequent therapy.

e Tocilizumab is an appropriate option, if there is a shortage of siltuximab or if it is not available.

Note: All recommendations are category 2A unless otherwise indicated.

References on CD-C 3 of 3

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Note: All recommendations are category 2A unless otherwise indicated.

CD-C 3 OF 3

SUGGESTED TREATMENT REGIMENS REFERENCES

Unicentric Castleman Disease

Bandera B, Ainsworth C, Shikle J, et al. Treatment of unicentric Castleman disease with neoadjuvant rituximab. Chest 2010;138:1239-1241.

van Rhee F, Oksenhendler E, Srkalovic G, et al. International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease. Blood Adv 2020;4:6039-6050.

Multicentric Castleman Disease

Gerard L, Berezne A, Galicier L, et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's

disease: ANRS 117 Castleman B Trial. J Clin Oncol 2007;25:3350-3356.

Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood 2011;117:6977-6986.

Ramasamy K, Gandhi S, Tenant-Flowers M, et al. Rituximab and thalidomide combination therapy for Castleman disease. Br J Haematol 2012;158:421-423.

Uldrick TS, Polizzotto MN, Aleman K, et al. Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood 2014;124:3544-3552.

van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman's disease: a randomized, double-blind, placebo-controlled trial. Lancet Oncol 2014;15:966-974.

van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood

2018;132:2115-2124.

van Rhee F, Casper C, Voorhees PM, et al. Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label,

extension analysis of two trials. Lancet Haematol 2020;7:e209-e217.

Rehman MEU, Chattaraj A, Neupane K, et al. Efficacy and safety of regimens used for the treatment of multicentric Castleman disease: A systematic review. Eur J

Haematol 2022;109:309-320.

van Rhee F, Rosenthal A, Kanhai K, et al. Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease. Blood Adv

2022;6:4773-4781.

Pierson SK, Lim MS, Srkalovic G, et al. Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes. Blood Adv 2023;7:6652-6664.

Liu YT, Gao YH, Zhao H, et al. Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study. Ann Hematol 2024;103:4223-4230.

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NCCN Guidelines Index Table of Contents Discussion

Classification

Table 1

ST-1

Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood 2022;140:1229-1253.

WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed.; vol. 11). Lyon (France): International Agency for Research on Cancer; 2024.

The International Consensus Classification (ICC) of

Mature Lymphoid Neoplasms (2022)

Mature B-cell lymphomas

HHV-8–associated lymphoproliferative disorders

Multicentric Castleman disease

Primary effusion lymphoma

HHV8-positive diffuse large B-cell lymphoma, NOS

HHV8-positive germinotropic lymphoproliferative disorder

WHO Classification of Hematolymphoid Tumors:

Lymphoid Neoplasms (2022; 5th edition)

Tumour-like lesions with B-cell predominance

Reactive B-cell-rich lymphoid proliferations that can mimic lymphoma IgG4-related disease

Unicentric Castleman disease

Idiopathic multicentric Castleman disease

KSHV/HHV8-associated multicentric Castleman disease

Table 2

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ABBREVIATIONS

|C/A/P|chest/abdomen/pelvis|HHV8|human herpesvirus 8|mAb|monoclonal antibody| |---|---|---|---|---|---| |cART|combination antiretroviral therapy|HIV|human immunodeficiency virus|MCD|multicentric Castleman disease| |CBC|complete blood count|||MUGA|multigated acquisition| |CD|Castleman disease|lg|immunoglobulin||| |CMV|cytomegalovirus|IGRT|image-guided radiation therapy|NGS|next-generation sequencing| |CRP|C-reactive protein|IHC|immunohistochemistry|NOS|not otherwise specified| |CTCAE|Common Terminology Criteria for Adverse Events|iMCD|idiopathic multicentric Castleman disease||| |DLBCL|diffuse large B-cell lymphoma|IMRT|intensity-modulated radiation therapy|PCR|polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes| |EBER-ISH|Epstein-Barr virus-encoded RNA in situ hybridization|ISRT|idiopathic plasmacytic lymphadenopathy|POEMS|| |EBV|Epstein-Barr virus|IVF|involved-site radiation therapy||| |ECOG|Epstein-Barr virus|KS|in vitro fertilization|SIFE|serum immunofixation electrophoresis| |eGFR|Eastern Cooperative Oncology Group|KSHV|Kaposi sarcoma-associated herpesvirus|SPEP|serum protein electrophoresis| |ESR|erythrocyte sedimentation rate|LANA|latency-associated nuclear antigen|TAFRO|thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly| |FDC|follicular dendritic cell|LDH|lactate dehydrogenase||| |FDG|fluorodeoxyglucose|||UCD|unicentric Castleman disease| |FLC|free light chain|||VEGF|vascular endothelial growth factor| |FNA|fine-needle aspiration||||| |GC|germinal center||||| |GI|gastrointestinal|||||

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NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

NCCN

National Comprehensive NCCN Guidelines Version 1.2026 Cancer Castleman Disease Network®

This discussion corresponds to the NCCN Guidelines for Castleman Disease. Last updated: January 28, 2025.

Overview ..................................................................................................................MS-2

Guidelines Update Methodology ..................................................MS-2

Sensitive/Inclusive Language Usage ....................................................MS-2

Literature Search Criteria....................................................................................MS-2

Clinical Presentation ....................................................MS-3

Diagnosis ....................................................................................................................MS-3

Workup ..................................................MS-4

Treatment Recommendations..................................................MS-5

Unicentric Castleman Disease ....................................................MS-5

Multicentric Castleman Disease ....................................................MS-5

References ....................................................MS-9

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Overview

Castleman Disease

[Image] The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Castleman Disease provide recommendations for the diagnostic workup and treatment for UCD and MCD.

Overview

Castleman disease (CD) is a relatively uncommon heterogeneous group of lymphoproliferative disorders with an annual incidence of approximately 3336 to 5282 cases in the United States.$^{1}$ These disorders share common histopathologic features, and certain subtypes are associated with an increased risk of developing diffuse large B-cell lymphoma (DLBCL), Kaposi sarcoma (KS), and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes) syndrome.$^{2-4}$

Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD) are the two main clinical subtypes. In the 2022 newly revised WHO classification of hematolymphoid tumors (WHO5), UCD and MCD are classified as tumour-like lesions with B-cell predominance.$^{5}$ In the 2022 International Consensus Classification, UCD is not included and MCD is classified as human herpesvirus 8 (HHV8)-associated lymphoproliferative disorder.$^{6}$

MCD is further divided into HHV8-positive (also known as KS herpesvirus [KSHV]-positive), HHV8-negative (also known as idiopathic MCD [iMCD]), and POEMS-MCD.$^{5}$ KSHV/HHV8-positive MCD is most commonly diagnosed in people with HIV (PWH) or otherwise immunocompromised individuals and it has been reported as a precursor to aggressive B-cell lymphomas among PWH.$^{7,8}$

iMCD is subclassified into two clinicopathologic subgroups: 1) iMCD-TAFRO (defined by thrombocytopenia [T], anasarca [A], fever [F], reticulin fibrosis of the bone marrow [R], and organomegaly [O] but generally has normal γ-globulin levels); and 2) iMCD-not otherwise specified (NOS), which is typically characterized by hypergammaglobulinemia and thrombocytosis.$^{9,10}$

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Castleman Disease provide recommendations for the diagnostic workup and treatment for UCD and MCD.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Sensitive/Inclusive Language Usage

The NCCN Guidelines® strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Literature Search Criteria

Prior to the initial development of the NCCN Guidelines for Castleman Disease, an electronic search of the PubMed database was performed to obtain key literature in Castleman disease. The PubMed database was

![NCCN\n](1/parseimages/figuree77f6e8258f042c2be11f77f4070adcd_0_1.png)

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Cancer Castleman Disease

chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.$^{11}$

The search results were narrowed by selecting relevant studies in humans published in English. The data from key PubMed articles and articles from additional sources deemed as relevant to these guidelines and discussed by the Panel have been included in this version of the Discussion section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Clinical Presentation

The clinical presentation of CD is often relatively nonspecific with enlarged lymph nodes, lymphadenopathy, and systemic symptoms.

UCD is characterized by involvement of a single lymph node or lymph node station and usually the absence of systemic symptoms. This subtype generally has an indolent disease course with an excellent prognosis. UCD is most commonly (but not always) the histopathologic hypervascular (hyaline vascular) variant and is nearly always HIV negative and HHV8 negative.$^{7}$ While often asymptomatic, some patients may experience compression symptoms due to compression of vital organs or other structures.$^{12-15}$ In a series of 404 patients with UCD, the most common sites of involvement were the mediastinum (29%), neck (23%), abdomen (21%), and retroperitoneum (17%).$^{12}$ In another analysis of 74 patients (43 patients with UCD and 31 patients with iMCD), systemic inflammatory symptoms, elevated inflammatory factors, and abnormal bone marrow features were more common in patients with iMCD than UCD.$^{13}$

MCD is a remitting-relapsing disease with a variable natural history ranging from indolent disease with a very slow progression to acute and fulminant disease.$^{3}$,$^{16}$ HHV8-positive MCD follows a more aggressive course. Immunocompromising conditions is a primary risk factor for HHV8-

positive MCD, with HIV being the most common condition.$^{17}$ HHV8-positive MCD is more commonly associated with systemic symptoms such as fluid accumulation, cytopenias, liver and kidney dysfunction, and constitutional symptoms driven by cytokines such as interleukin 6 (IL-6).$^{13,16,18}$

iMCD affects multiple lymph node regions and exhibits lymphadenopathy in more than 1 lymph node or lymph node region. Clinical presentation can range from mild constitutional symptoms to life-threatening organ failure. iMCD-TAFRO generally presents with a more aggressive disease course and is associated with poorer outcomes than iMCD-NOS. The evaluation and determination of treatment should be similar to iMCD-NOS.$^{9,10}$

Diagnosis

Due to the nonspecific and heterogeneous nature of the disease, CD can often mimic other benign and malignant conditions.$^{2-4}$ Therefore, a high index of suspicion and histopathologic analysis is required for diagnosis of CD. Excisional or incisional biopsy of the lymph node (preferably the most fluorodeoxyglucose [FDG]-avid, accessible lymph node) is preferred for the definitive diagnosis of CD.$^{19-22}$

A combination of clinical, imaging, and pathologic features should be used to establish the diagnosis of UCD, HHV8-positive MCD, and iMCD.$^{19,21}$ In an asymptomatic patient, histopathology consistent with CD along with the involvement of a single lymph node or region of lymph nodes can establish a diagnosis of UCD.$^{21,22}$

Histopathologically, CD has been divided into hypervascular (also called hyaline vascular), plasmacytic, and mixed histologic subtypes.$^{23}$ The hypervascular variant is most commonly associated with UCD, whereas the plasmacytic and mixed variants are more common in HHV8-associated MCD. iMCD-NOS may exhibit any of the three histologic patterns, whereas iMCD-TAFRO is most commonly either hypervascular or mixed.

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The 2017 international diagnostic consensus criteria for the diagnosis of iMCD include two major criteria: histopathologic lymph node features consistent with the iMCD spectrum and enlarged lymph nodes in ≥2 lymph node stations; and 11 minor criteria:$^{19}$ anemia, thrombocytopenia, hypoalbuminemia, polyclonal hypergammaglobulinemia, renal dysfunction (elevated glomerular filtration rate [GFR] or proteinuria), elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), constitutional symptoms, enlarged spleen and/or liver, fluid accumulation, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis.

The diagnosis of iMCD requires the presence of both major criteria, at least 2 of 11 minor criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD.$^{19}$ See Consensus Diagnostic Criteria for Idiopathic MCD in the algorithm.

Adequate immunophenotyping of a surgically excised lymph node is required to confirm the diagnosis and exclude malignancy and other diseases.$^{19}$ The recommended immunohistochemistry (IHC) panel essential for diagnosis includes: CD20, CD3, CD5, CD138, HHV8 latency-associated nuclear antigen (LANA), kappa, and lambda. Additional IHC markers may be useful under certain circumstances: Ki-67 index, immunoglobulin (Ig) heavy chains, CD10, BCL2, BCL6, cyclin D1, CD21, CD23, CD38, IRF4/MUM1, and PAX5. Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) and flow cytometry with peripheral blood and/or biopsy specimen of kappa/lambda, CD19, CD20, CD5, CD23, and CD10 may also be useful in certain circumstances. Other diagnostic testing that may be useful under certain circumstances includes molecular analysis to detect Ig gene rearrangements.

Workup

Initial workup should include a physical examination (with attention given to node-bearing areas, liver, and spleen) and evaluation of performance status. Laboratory assessments should include standard blood work including complete blood count (CBC) with differential, and a comprehensive metabolic panel. Serum lactate dehydrogenase (LDH), CRP, and ESR should be measured. Serum protein electrophoresis should be evaluated if there is concern for POEMS syndrome. Pregnancy testing should be done in patients of childbearing potential if chemotherapy or radiation therapy (RT) is planned. PET/CT scan (preferred) or a chest/abdomen/pelvis CT with contrast of diagnostic quality are recommended as part of an initial diagnostic workup to confirm extent of disease and total nodal involvement.$^{20,22}$

Testing to detect the presence of HIV, HHV8, and Epstein-Barr virus (EBV) polymerase chain reaction (PCR) should also be done as part of routine workup. HHV8-positive MCD is distinguished by positive testing for HHV8 in lymph node tissue as well as PCR positivity for HHV8 in plasma in addition to multiple affected lymph nodes and histopathology consistent with CD.$^{16}$ Screening for concurrent KS is recommended in the setting of HHV8 or HIV positivity since HHV8-positive MCD may occur with concomitant KS in ≤72% of patients.$^{24}$ Hepatitis B testing (if rituximab-containing regimens are being considered due to the risk of viral reactivation anti-CD20 monoclonal antibody [mAb]-based regimens) and hepatitis C testing are also essential components of workup.

Bone marrow biopsy and aspirate as well as reticulin fibrosis of bone marrow (particularly in patients with TAFRO syndrome) may be useful under certain circumstances.$^{25}$ An echocardiogram or multigated acquisition (MUGA) scan can be considered if anthracycline-based regimens are being considered for treatment. Other components of workup that may be useful in certain circumstances include neck CT with

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contrast, IgG4, serum IL-6, serum IL-10, vascular endothelial growth factor (VEGF), uric acid, and ferritin.

Treatment Recommendations

Unicentric Castleman Disease

UCD has an indolent disease course with an excellent prognosis. Careful consideration should be given to the risks and benefits of any therapy for patients with UCD, and observation can be considered in asymptomatic patients.$^{21}$

contrast, IgG4, serum IL-6, serum IL-10, vascular endothelial growth factor (VEGF), uric acid, and ferritin.

Treatment Recommendations

Unicentric Castleman Disease

First-Line Therapy

Surgical resection is the optimal treatment, wherever possible, as it has been associated with very low rates of recurrence and high relapse-free survival (RFS) in multiple case series and retrospective studies.$^{2}$,$^{12}$,$^{15}$,$^{21}$,$^{26}$⁻$^{28}$ One case series of 53 patients reported a 5-year overall survival (OS) rate of 91%,$^{2}$ and another retrospective analysis of 278 patients showed an OS rate of >90% with up to 10-year follow up.$^{12}$ Therefore, all patients with a diagnosis of UCD should be evaluated for resectability of disease.$^{21}$

Observation until recurrence is recommended following complete resection. Patients who are asymptomatic following an incomplete resection may be observed until recurrence. Patients who remain symptomatic following incomplete resection should be treated as described below for unresectable disease.

Observation is also appropriate for asymptomatic patients with unresectable UCD. Available evidence (mostly from case reports) supports the use of RT or rituximab with or without steroids in patients with symptomatic unresectable UCD.$^{21}$,$^{29}$,$^{30}$ RT should be reserved for severe symptomatic and unresectable disease due to potential long-term complications.$^{21}$ The optimal dose of RT in unresectable UCD is not established. Doses as high as 40 Gy in 1.5 to 2 Gy fractions have been used.$^{29}$ Lower doses may be considered depending upon clinical

circumstances and advanced radiation techniques are recommended to limit the radiation dose to surrounding normal tissues.$^{31}$

Involved-site RT (ISRT) or systemic therapy (rituximab ± prednisone ± cyclophosphamide) with the intent of eventual surgical resection are included as options for patients with unresectable disease.$^{21,29,30}$ Patients with non-bulky disease may be observed after ISRT. Embolization may also be considered in certain situations to render surgical resection more feasible and reduce the risk of severe perioperative bleeding.$^{21}$

Relapsed/Refractory Disease

Biopsy is encouraged in patients with relapsed/refractory disease to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

Treatment options for relapsed/refractory disease are the same as described above for unresectable disease: ISRT, embolization (if amenable), or systemic therapy with the intent of eventual surgical resection (rituximab ± prednisone ± cyclophosphamide).$^{21}$

Patients with inflammatory symptoms (eg, night sweats, fevers, weight loss) or laboratory disturbances (increased ESR or CRP) may have excessive cytokine production and may benefit from anti-IL-6 monoclonal antibodies (anit-IL-6 mAbs) such as siltuximab and tocilizumab, although evidence in this setting is sparse.$^{21}$ Siltuximab or tocilizumab is included as an option for relapsed/refractory disease that is HIV-negative and HHV8-negative.

Multicentric Castleman Disease

Treatment recommendations for MCD are based on the presence of criteria for active disease, fulminant/severe disease, or organ failure and HHV8 status. Patients may experience symptoms related to an excess of IL-6 production; establishing the severity of symptoms is a vital component of management, as severity can vary widely between patients.

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Corticosteroid monotherapy is not very effective for disease control but may be combined with other therapies for symptom control. Due to the rarity of the condition, available evidence for most of the treatment options is based on case reports making comparison between treatment options difficult.$^{20,32,33}$

Patients with POEMS-associated MCD should have treatment directed at POEMS syndrome with regimens recommended for the treatment of multiple myeloma. High-dose therapy followed by autologous stem cell rescue (HDT/ASCR) may also result in favorable outcomes, particularly for patients with MCD associated with POEMS.$^{34,35}$

First-Line Therapy

Criteria for Active Disease Present With No Organ Failure

In patients with criteria for active MCD (fever, increased serum CRP level >20 mg/L in the absence of any other etiology, and at least three other MCD-related symptoms) with no organ failure, first-line therapy options are based on HHV8 status as described below.

Idiopathic MCD (non-severe; HIV-1 and HHV8 negative)

Rituximab- and cyclophosphamide-containing regimens have demonstrated activity in patients with iMCD.$^{36}$⁻$^{38}$ A systematic review of 47 patients treated with cytotoxic chemotherapy, with or without rituximab, reported a complete response (CR) rate of 44% with 93% of patients alive at 2 years.$^{36}$ In a retrospective study of 27 patients with iMCD, rituximab-and cyclophosphamide-containing regimens resulted in an overall response rate (ORR) of 56% with a CR rate of 33%.$^{37}$ In a single-arm, phase 2 study of 25 patients with newly diagnosed iMCD treated with the TCP regimen, primary endpoint (durable tumor and symptomatic response for at least 24 weeks) was achieved in 48% of patients; 12% of patients had stable disease and the estimated 1-year PFS and OS rates were 60% and 88%, respectively.$^{38}$

Siltuximab is FDA approved for the treatment of patients with iMCD that is HIV-1 and HHV8 negative based on the results of a double-blind, placebo-controlled, international trial.$^{39-41}$ In this trial 79 patients with iMCD were randomized to siltuximab (n = 53) or placebo (n = 26). Siltuximab resulted in significantly improved durable tumor and symptomatic response rate compared to placebo (34% vs. 0%; P = .0012).$^{39}$ Long-term follow-up data, after a median follow-up of 6 years, also established the efficacy and safety of siltuximab.$^{40}$ Siltuximab was also associated with significantly improved progression-free survival (PFS) compared to placebo (median PFS was not reached for siltuximab compared to 15 months for placebo; P = .0001).$^{41}$ Adverse events of grade 23 were reported in 60% of patients, with hypertension (13%), fatigue (8%), nausea (7%), neutropenia (7%), and vomiting (5%) being the most common adverse events.

It is worth noting that in this pivotal trial responses were predominant in patients with the plasmacytic or mixed histologic variants and were not seen in the hyaline vascular variant where siltuximab may have less clinical activity.$^{39}$ However, secondary analyses of clinical trial and real-world data demonstrated that siltuximab resulted in similar clinical benefit across histopathologic subtypes, confirming the efficacy of siltuximab in the hyaline vascular variant also.$^{42}$ Importantly, in the aforementioned clinical trial, placebo was used as the control arm instead of an active treatment regimen, so it is unknown whether siltuximab is superior to chemoimmunotherapy. Therefore, chemoimmunotherapy can be considered as an appropriate treatment option in selected patients, particularly for patients with fulminant/severe disease.$^{36}$

Rituximab (with or without prednisone), RCVP (rituximab, cyclophosphamide, vincristine, and prednisone), siltuximab, or TCP (thalidomide, cyclophosphamide, and prednisone) are included as options for first-line therapy. Patients with disease responding to rituximab-based regimens should be observed until disease progression requiring retreatment. Unlike chemoimmunotherapy, which is a fixed-duration

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treatment option, siltuximab is given continuously every 3 weeks by intravenous infusion in the absence of disease progression or intolerance. In patients with disease responding to siltuximab, treatment should be continued until disease progression, as disease may relapse on discontinuation of therapy.$^{20}$

HHV8-Positive MCD (HIV-1-negative or HIV-1-positive)

Rituximab monotherapy is included as the preferred first-line treatment option, and the strongest evidence for rituximab monotherapy comes from two phase II studies.$^{43,44}$ Rituximab has also been shown to decrease the risk of lymphoma in patients with HIV-associated disease.$^{45}$ Combination antiretroviral therapy (cART) should be given to all patients with HIV-1-positive disease.

In one prospective study of rituximab in HIV-associated MCD, 24 patients with relapsed/refractory, chemotherapy-dependent disease were given 4 weekly doses of rituximab at 375 mg/m$^{2}$. Twenty-two of the 24 patients were able to become independent of chemotherapy, and more than three quarters remained free from symptoms and progression 2 years after treatment.$^{43}$ In another phase II study of 21 patients with plasmablastic MCD, 20 patients achieved remission of symptoms, and 14 (67%) achieved a radiologic response. The median follow-up was 12 months. The OS and disease-free survival (DFS) rates at 2 years were 95% and 79%, respectively. The main adverse effect was reactivation of KS.$^{44}$ In another retrospective analysis of 113 patients (48 had previously received rituximab and 60 were previously diagnosed with KS), treatment with rituximab was associated with a higher 5-year OS rate compared to treatment with chemotherapy alone (90% vs. 47%).$^{45}$

Occult KS is prevalent in HIV-1/HHV8-positive MCD and may flare after treatment with rituximab or prednisone.$^{45}$ The use of rituximab in combination with liposomal doxorubicin may reduce the incidence of KS

exacerbation and may be particularly useful for patients with HHV8-positive MCD with concurrent KS.$^{46,47}$

Zidovudine with valganciclovir has also been shown to be active in HHV8-positive MCD.$^{47,48}$ In a study that included 20 patients with HHV8-MCD alone and 34 patients with HHV8-MCD and KS, the 5-year PFS rate was 26% for treatment with the combination of zidovudine and valganciclovir.$^{47}$ The median PFS was 6 months. In a pilot study of 14 patients with HHV8-positive MCD, high-dose zidovudine in combination with valganciclovir resulted in major clinical and biochemical responses being attained in 86% and 50% of patients, respectively.$^{48}$

Rituximab + prednisone, rituximab + liposomal doxorubicin (with or without prednisone), and zidovudine with either ganciclovir or valganciclovir are also included as options for first-line therapy.

Fulminant or Severe MCD With or Without Organ Failure Combination chemotherapy regimens (CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone], and CVP [cyclophosphamide, vincristine, prednisone]) with rituximab or liposomal doxorubicin with rituximab (with or without prednisone) are included as options for first-line therapy for HHV8-positive MCD. Combination chemotherapy may result in durable remissions.$^{20,29,32,33,49}$ Liposomal doxorubicin or rituximab monotherapy are appropriate treatment options for patients who are not candidates for combination chemotherapy.$^{43,44,46}$

Siltuximab or combination chemotherapy (CHOP, CVAD, and CVP) with or without rituximab are included as options for first-line therapy for HHV8-negative iMCD.$^{20,29,32,33,49}$ Tocilizumab is an appropriate option, if there is a shortage of siltuximab or if it is not available. Rituximab monotherapy is an appropriate treatment option for patients who are not candidates for combination chemotherapy.

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Refractory or Progressive Disease (criteria for active disease present or fulminant/severe disease)

Biopsy is encouraged in patients with relapsed/refractory disease to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

Single-agent therapy (with ganciclovir or valganciclovir for HHV8-positive disease) is preferred for those with no organ failure, and combination chemotherapy (with or without rituximab) is preferred for patients with organ failure. Etoposide (PO or IV), vinblastine, liposomal doxorubicin (for HHV8-positive disease), siltuximab (for HHV8-negative disease), or sirolimus are included as options for single-agent therapy. CHOP, CVAD, and CVP are the chemotherapy options recommended for second-line therapy.$^{20,32,33}$ Liposomal doxorubicin +/- rituximab is included as an option for HHV8-positive disease with organ failure. Observation or maintenance with valganciclovir may be considered for HHV8-positive disease responding to treatment.

Refractory or Progressive Disease (criteria for active disease present or fulminant/severe disease)

Biopsy is encouraged in patients with relapsed/refractory disease to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.

A prespecified analysis of the patients enrolled in the pivotal trial also showed that siltuximab is equally effective in patients with newly diagnosed as well as those with previously treated MCD (29 patients with previously treated iMCD in the siltuximab group and 17 patients in the placebo group). Siltuximab is included as an option for second-line therapy in patients with HHV8-negative disease.$^{50}$ Patients who received chemoimmunotherapy as initial treatment may receive siltuximab if needed subsequently for relapsed/refractory disease. Tocilizumab is an appropriate option, if there is a shortage of siltuximab or if it is not available.

The results of the retrospective study (n = 26 patients) showed that the mTOR inhibitor sirolimus was a well-tolerated and effective treatment for patients with relapsed/refractory iMCD.$^{51}$ After a median follow-up of 12 months, sirolimus resulted in a response rate of 69% (biologic and

symptomatic response) and the median time to next treatment was 46 months. Sirolimus is included as a single-agent therapy option for second-line therapy in patients with HHV8-negative disease.

Alternative single-agent or combination therapy should be considered for disease progression following the aforementioned second-line treatment options for relapsed/refractory disease. Tocilizumab is an effective treatment option for patients with MCD that is refractory to rituximab and chemoimmunotherapy.$^{34,52-54}$ Other options include bortezomib +/- rituximab, thalidomide +/- rituximab, lenalidomide +/- rituximab, high-dose zidovudine + valganciclovir, and anakinra (IL-1 receptor antagonist), based on case reports and case series.$^{20,47,48,55-60}$

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表 1
Consensus Diagnostic Criteria for Idiopathic $MCD^{a}$
I. Major Criteria (need both):	1. Histopathologic lymph node features consistent with the iMCD spectrum. Features along the iMCD spectrum include (need grade 2-3 for either regressive GCs or plasmacytosis at minimum): - Regressed/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric rings of lymphocytes in an "onion skinning" appearance - FDC prominence - Vascularity, often with prominent endothelium in the interfolricular space and vessels penetrating into the GCs with a "lollipop" appearance - Sheetlike, polytypic plasmacytosis in the interfolricular space - Hyperplastic GCs 2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations
II. Minor Criteria (need at least 2 of 11 criteria with at least 1 laboratory criterion)	Laboratory* 1. Elevated CRP (>10 mg/L) or ESR (>15 mm/h)+ 2. Anemia (hemoglobin <12.5 g/dL for males, hemoglobin <11.5 g/dL for females) 3. Thrombocytopenia (platelet count <150 µm/L) or thrombocytosis (platelet count >400 µm/L) 4. Hypoalbuminemia (albumin <3.5 g/dL) 5. Renal dysfunction (eGFR <60 mL/min/1.73m²) or proteinuria (total protein 150 mg/24 h or 10 mg/100 mL) 6. Polyclonal hypergammaglobulinemia (total γ globulin or immunoglobulin G >1700 mg/dL)	Clinical 1. Constitutional symptoms: night sweats, fever (>38°C), weight loss, or fatigue (≥2 CTCAE lymphoma score for B-symptoms) 2. Large spleen and/or liver 3. Fluid accumulation: edema, anasarca, ascites, or pleural effusion 4. Eruptive cherry hemangiomatosis or violaceous papules 5. Lymphocytic interstitial pneumonitis
III. Exclusion Criteria (must rule out each of these diseases that can mimic iMCD)	Infection-related disorders 1. HHV-8 (infection can be documented by blood PCR; diagnosis of HHV-8-associated MCD requires positive LANA-1 staining by IHC, which excludes iMCD) 2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV (detectable EBV viral load not necessarily exclusionary) 3. Inflammation and adenopathy caused by other uncontrolled infections (eg, acute or uncontrolled CMV, toxoplasmosis, HIV, active tuberculosis)	Autoimmune/autoinflammatory diseases (requires full clinical criteria; detection of autoimmune antibodies alone is not exclusionary) 1. Systemic lupus erythematosus 2. Rrieumatoid arthritis 3. Adult-onset Still disease 4. Juvenile idiopathic arthritis 5. Autoimmune lymphoproliferative syndrome Malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same time as iMCD to be exclusionary): 1. Lymphoma (Hodgkin and non-Hodgkin) 2. Multiple myeloma 3. Primary lymph node plasmacytoma 4. FDC sarcoma 5. POEMS syndrome‡

表 2
FIRST-LINE THERAPY	FIRST-LINE THERAPY	FIRST-LINE THERAPY
UCD (surgically unresectable/incomplete resection)	MCD - Criteria for active disease present with no organ failure	MCD - Fulminant/severe ± organ failure
• Rituximab ± Prednisone (for compressive symptoms) • Siltuximab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative) • Tocilizumab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative)	HHV8-negative/HIV-1-negative (iMCD-Nonsevere) • Siltuximab • Tocilizumab • Rituximab ± Prednisone • CVP (Cyclophosphamide/Vincristine/Prednisone) + Rituximab	Fulminant/severe HHV8-negative (iMCD) Preferred • Siltuximab Other Recommended • Tocilizumab • CHOP (Cyclophosphamide/Doxorubicin/Vincristine/ Prednisone) ± Rituximab • CVAD (Cyclophosphamide/Vincristine/ Doxorubicin/ Dexamethasone) ± Rituximab • CVP ± Rituximab • If not a candidate for combination therapy: ▷ Rituximab
• Rituximab ± Prednisone (for compressive symptoms) • Siltuximab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative) • Tocilizumab (for primarily inflammatory symptoms) (if HIV-1-negative/HHV8-negative)	HHV8-positive (HIV-1-positive or HIV-1-negative)$^{c}$ • Rituximab • Rituximab + Liposomal Doxorubicin • Rituximab + Prednisone • Rituximab + Prednisone + Liposomal Doxorubicin • High-dose Zidovudine/Ganciclovir or Valganciclovir	Fulminant/severe HHV8-positive MCD$^{c}$ • Rituximab + Liposomal Doxorubicin • Rituximab + Prednisone + Liposomal Doxorubicin • CVAD + Rituximab • CVP + Rituximab • If not a candidate for combination therapy: ▷ Liposomal Doxorubicin • Rituximab

表 3
SECOND-LINE AND SUBSEQUENT THERAPY FOR RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE (in alphabetical order)
UCD (surgically unresectable/incomplete resection)	MCD	MCD
UCD (surgically unresectable/incomplete resection)	HHV8(+) - Criteria for active disease present with no organ failure or Fulminant/Severe disease [HHV8(+) or HHV8(-)] with no organ failure	Fulminant/Severe disease [HHV8(+) or HHV8(-)] with organ failure
Treat with alternative first-line therapy regimens (CD-C 1 of 3) before moving onto second-line and subsequent therapy for relapsed/refractory or progressive disease • Rituximab ± Prednisone • Siltuximab$^{e}$ (if HIV-1-negative/HHV8-negative)	For active disease present with no organ failure, treat with alternative first-line therapy regimens (CD-C 1 of 3) before moving onto second-line and subsequent therapy for relapsed/refractory or progressive disease Preferred (Add ganciclovir or valganciclovir, if HHV8-positive) • Etoposide (oral or IV) • Liposomal Doxorubicin (if HHV8-positive) • Siltuximab$^{e}$ (if HHV8-negative) • Vinblastine • Other Recommended • Sirolimus (if HHV8-negative) • If not previously given • CHOP ± Rituximab • CVAD ± Rituximab • CVP ± Rituximab	Treat with alternate second-line combination therapy regimens ± rituximab (not previously given) before moving onto subsequent therapy with alternative regimens for relapsed/refractory or progressive disease Preferred • If not previously given • CHOP ± Rituximab • CVAD ± Rituximab • CVP ± Rituximab • Liposomal Doxorubicin ± Rituximab (if HHV8-positive) • Siltuximab$^{e}$ (if HHV8-negative)
	Alternative regimens for subsequent therapy: • Anakinra • Bortezomib ± Rituximab • Lenalidomide ± Rituximab • Thalidomide ± Rituximab • Tocilizumab • High-Dose Zidovudine/Ganciclovir or Valganciclovir (if HHV8-positive)

表 4
C/A/P	chest/abdomen/pelvis	HHV8	human herpesvirus 8	mAb	monoclonal antibody
cART	combination antiretroviral therapy	HIV	human immunodeficiency virus	MCD	multicentric Castleman disease
CBC	complete blood count			MUGA	multigated acquisition
CD	Castleman disease	lg	immunoglobulin
CMV	cytomegalovirus	IGRT	image-guided radiation therapy	NGS	next-generation sequencing
CRP	C-reactive protein	IHC	immunohistochemistry	NOS	not otherwise specified
CTCAE	Common Terminology Criteria for Adverse Events	iMCD	idiopathic multicentric Castleman disease
DLBCL	diffuse large B-cell lymphoma	IMRT	intensity-modulated radiation therapy	PCR	polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes
EBER-ISH	Epstein-Barr virus-encoded RNA in situ hybridization	ISRT	idiopathic plasmacytic lymphadenopathy	POEMS
EBV	Epstein-Barr virus	IVF	involved-site radiation therapy
ECOG	Epstein-Barr virus	KS	in vitro fertilization	SIFE	serum immunofixation electrophoresis
eGFR	Eastern Cooperative Oncology Group	KSHV	Kaposi sarcoma-associated herpesvirus	SPEP	serum protein electrophoresis
ESR	erythrocyte sedimentation rate	LANA	latency-associated nuclear antigen	TAFRO	thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly
FDC	follicular dendritic cell	LDH	lactate dehydrogenase
FDG	fluorodeoxyglucose			UCD	unicentric Castleman disease
FLC	free light chain			VEGF	vascular endothelial growth factor
FNA	fine-needle aspiration
GC	germinal center
GI	gastrointestinal

表 5
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 6
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

图示：NCCN

引用 / 出处

（2026.V1）NCCN临床实践指南：Castleman病. 2026.