Update and new approaches in the treatment of Castleman disease

Figures & data

Figure 1 The hyaline vascular variant of CD.

Notes: Hematoxylin and eosin–stained sections (panel A, 200× magnification) demonstrate a vascular, atrophic germinal center with surrounding concentric “onion skin” layers of lymphocytes. Immunohistochemical staining for CD23 (panel B, 200× magnification) highlights several follicular dendritic cell clusters within an expanded mantle zone of CD23-positive cells. CD34 (panel C, 200× magnification) identifies a positively staining blood vessel within an atrophic follicle.
Abbreviation: CD, Castleman disease.

Figure 2 The plasma cell variant of CD.

Notes: Hematoxylin and eosin–stained sections (panel A, 200× magnification) demonstrate preservation of the lymph node germinal center, with associated paracortical plasmacytosis. Immunohistochemical staining for CD21 (panel B, 100× magnification) highlights the follicular dendritic cells within the germinal centers, while CD20 (panel C, 100× magnification) identifies the normal background B-cell population. Immunoperoxidase staining for HHV-8 (panel D, 100× magnification) reveals HHV-8-positive plasma cells within the expanded mantle zones, which play a key role in the pathogenesis of this CD variant.
Abbreviations: CD, Castleman disease; HHV-8, human herpesvirus-8.

Table 1 Summary of CD subtypes and important differential diagnoses

CD subtypes	Key features	Differential diagnoses
Hyaline vascular variant	• Multiple tight aggregates of follicular dendritic cells or atrophic follicles	• Reactive follicular hyperplasia
	• Concentric “onion-skin” layers of lymphocytes	• Follicular lymphoma
	• Radially penetrating vessels, perivascular hyalinization	• HIV-associated lymphadenopathy
Plasma cell variant	• Preserved lymph node architecture, variable follicular hyperplasia • Marked paracortical plasmacytosis • May also have some hyaline vascular changes (“mixed” pattern)	• Plasmacytomas • Follicular lymphoma, marginal zone lymphoma • Autoimmune-associated lymphadenopathy:  ○ Rheumatoid arthritis  ○ Systemic lupus erythematosus • Infections:  ○ HIV-associated lymphadenopathy  ○ Toxoplasma lymphadenitis • IgG4-related disease
Plasmablastic variant	• Similar histological features to the plasma cell variant, but also has distinctive polyclonal IgM-positive plasmablasts within the expanded mantle zone • Plasmablasts may be CD20-positive and CD138-negative, and are usually lambda light chain restricted • Strong association with HHV-8 (±HIV) infection	–
Important associated conditions
POEMS syndrome	• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes • Associated with the HHV-8-negative plasma cell variant	–
TAFRO syndrome	• Thrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly	–

Note: “–” there are no relevant differential diagnoses for these categories.

Abbreviations: CD, Castleman disease; HIV, human immunodeficiency virus; HHV-8, human herpesvirus-8.

Table 2 Summary of radiotherapy outcomes in unresectable UCD

Study	Age (years)/sex	Location	Size (cm)	Dose (Gy)	Response	Follow-up (months)	Alive?
Fitzpatrick and Brown^Citation47	54/M	Pelvis	Not stated	45	PR	24	Yes
Nordstrom et al^Citation48	50/F	Mesenteric	7×7	27	CR	8	Yes
Stokes et al^Citation49	45/M	Paraspinal	Not stated	39.39	SD	60	Yes
Weisenburger et al^Citation50	51/F	Mesenteric	7	27	PR	15	Yes
Massey et al^Citation51	15/F	Mediastinum	Not stated	30.4	PR	26	Yes
Veldhuis et al^Citation52	62/M	Right axilla, supraclavicular	Not stated	40	CR	24	Yes
Bowne et al^Citation53	30/M	Pelvis	20×15	45	MR	24	Yes
Chronowski et al^Citation54	38/F	Retroperitoneum	10	40	CR	17	No (unrelated)
	24/F	Mediastinum	9	39.6	PR	12	Yes
	37/M	Mediastinum	6	40	CR	20	No (unrelated)
	51/F	Right axilla	4.4	39.6	CR	35	Yes
Neuhof and Debus^Citation55	24/F	Mediastinal	13	45	SD	12	Yes
	71/M	Mediastinal	10	45	PD	5	No (related)
	38/F	Cervical	3.9	40	CR	175	Yes
Li et al^Citation56	55/F	Mediastinal	4.3	60	PR	8	Yes
Matthiesen et al^Citation57	47/F	Mediastinal	5.5×4.6	43.2	PR	10	Yes
Miranda et al^Citation58	33/M	Left lung	7.2×5.5	40	PR	36	Yes

Abbreviations: UCD, unicentric Castleman disease; cm, centimeters; Gy, Gray; M, male; F, female; SD, stable disease; MR, minor response; PR, partial response; CR, complete response; PD, progressive disease.

Table 3 Summary of combination chemotherapy in MCD

Study	Patients	Age range (years)	Treatment	Response	Follow-up (months)	Status at last follow-up
Herrada et al^Citation62	3	28–54	CHOP =1 CVAD =1 Chlorambucil + prednisolone =1	CR =3 (100%)	8–58 (median 39)	Alive, disease-free =3 (100%)
Chronowski et al^Citation54	9	31–83	CHOP =2 CVAD =5 Chlorambucil + prednisolone =2	CR =4 (44%) SD =1 (11%) − CR after salvage therapy Response not stated in 4 (44%)	12–119 (median 65)	Alive, disease-free =5 (56%) Alive, with disease =4 (44%)
Zhu et al^Citation63	10	31–75	CHOP =4 COP =6	CR =1 PR =6 SD =2 (post-COP − but achieved PR after CHOP)	5–77 (median 34) one patient lost to follow-up	Alive, disease-free =1 (11%) Alive, with disease =6 (67%) Dead, progressive disease =2 (22%)

Abbreviations: MCD, multicentric Castleman disease; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; COP, cyclophosphamide, vincristine, prednisolone; SD, stable disease; PR, partial response; CR, complete response.

Table 4 Summary of immunomodulatory drugs and autologous stem cell transplantation in MCD

Study	Age (years)/sex	HIV/HHV-8	Prior therapies	Dose	Response	Follow-up (months)	Alive?	Toxicities
Interferon alpha
Tamayo et al^Citation73	27/M	Negative/not stated	Steroids, splenectomy	3 million IU, three times per week	CR	33	Yes	Nil
Kumari et al^Citation74	51/M	Positive/positive	HAART	5 million IU, three times per week	PR	24	Yes	Nil
Andrès and Maloisel^Citation75	52/M	Negative/not stated	Nil	4.5 million IU, three times per week for 1 year	CR	46	Yes	Nil
Thalidomide
Lee and Merchant^Citation76	37/F	Negative/not stated	Steroids	200–300 mg daily	SD	12	Yes	Constipation
Jung et al^Citation77	33/M	Positive/not stated	HAART, steroids, chemotherapy	200 mg daily, with etoposide	CR	9	Yes	Nil
Stary et al^Citation78	46/M	Positive/positive	HAART	200 mg daily, with rituximab	CR	20	Yes	Nil
Ramasamy et al^Citation79 (eleven patients)	60/M 52/M 40/M 42/F 35/M 49/M 43/M 60/M 58/M 42/M 32/F	Not stated/positive Negative/negative Positive/positive Positive/positive Positive/positive Positive/positive Negative/positive Positive/positive Negative/positive Positive/positive Positive/positive	Chlorambucil Nil HAART HAART HAART HAART Nil HAART Nil HAART HAART	100 mg daily for 4 weeks, with rituximab and steroids Nine patients received maintenance thalidomide (100 mg daily) for 2–8 months Three patients relapsed, achieving CR again after retreatment	PD CR CR CR CR CR CR CR CR CR CR	18 36 24 16 18 18 28 7 14 43 4	No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes	Neuropathy in two patients
Lenalidomide
Szturz et al^Citation80	46/M	Not stated/not stated	Chemotherapy, thalidomide, tocilizumab	25 mg daily, Days 1–21 of a 28-day cycle	PR	11	Yes	Bronchitis
Bortezomib
Yuan et al^Citation81	70/M	Negative/negative	Nil	1.3 mg/m^2 on Days 1, 4, 8, and 11 every 3–4 weeks, for four cycles	VGPR	18	Yes	Nil
Sobas et al^Citation82	49/M	Negative/negative	Steroids, rituximab, chemotherapy	1.3 mg/m^2 on Days 1, 4, 8, and 11 every 3 weeks, for six cycles	CR	48	Yes	Neuropathy (due to POEMS) – no change with bortezomib
Sbenghe et al^Citation83	43/M	Negative/positive	Nil	1.3 mg/m^2 on Days 1, 4, 8, and 11 every 3–4 weeks, with valganciclovir and two doses of tocilizumab	PR	18	Yes	Neuropathy
Khan et al^Citation84	51/M	Not stated/not stated	Nil	2 mg weekly for 4 weeks, for eight cycles, with dexamethasone Maintenance thalidomide 50 mg daily	VGPR	24	Yes	Nil
Lin et al^Citation85	16/M	Negative/negative	Chemotherapy, interferon	1.3 mg/m^2 on Days 1, 4, 8, and 11 every 3–4 weeks, for eight cycles, with six cycles of hyper-CVAD Maintenance thalidomide 200 mg daily, for 6 months	CR	24	Yes	Nil
Autologous stem cell transplantation
Repetto et al^Citation86	42/M	Not stated/not stated	Chemotherapy, steroids	Melphalan 200 mg/m^2 conditioning	CR	15	Yes	Nil
Ganti et al^Citation87	39/M	Negative/negative	Rituximab, chemotherapy, steroids	Melphalan 200 mg/m^2 conditioning	CR, improved neuropathy (POEMS)	24	Yes	Nil
Tal et al^Citation88	52/M	Negative/negative	Rituximab, chemotherapy	Etoposide, thiotepa, cytarabine, cyclophosphamide, and melphalan conditioning	CR	50	Yes	Nil

Abbreviations: MCD, multicentric Castleman disease; HIV, human immunodeficiency virus; HHV-8, human herpesvirus-8; M, male; F, female; IU, international units; HAART, highly active antiretroviral therapy; SD, stable disease; PR, partial response; VGPR, very good partial response; CR, complete response; hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

Table 5 Summary of clinical trials and case series for siltuximab and tocilizumab in MCD

Study	Design	Patient numbers and characteristics	Dose given (patients)	Median overall follow-up	ORR	OS	Median TTP
Siltuximab
Kurzrock et al^Citation89	Phase I, open-label dose-finding study	37 patients: • 35 MCD, 2 UCD • All HIV-negative • 1 HHV-8-positive	• 3 mg/kg q2w (1) • 6 mg/kg q2w (2) • 12 mg/kg q3w (16) • 6 mg/kg qw (3) • 12 mg/kg q2w (3) • 9 mg/kg q3w (12)	29.4 months	86%	92% for follow-up period	Not reached
van Rhee et al^Citation90	Phase II, open-label randomized study	79 patients: • All MCD • All HIV- and HHV-8-negative	• 11 mg/kg q3w (53) • Placebo (26)	14 months	34% (vs 0% in placebo arm)	100% at 1 year (though two patients in siltuximab arm and four patients in placebo arm subsequently died)	Not reached
van Rhee et al^Citation91	Extension of earlier Phase II study, in ongoing responders	19 patients: • All MCD • All HIV- and HHV-8-negative	• 11 mg/kg q3w (19) – 8 changed to extended dosing frequency (q6w)	61 months	100% sustained disease control	100% for follow-up period	Not reached
Tocilizumab
Nishimoto et al^Citation92	Multicenter, open-label study	28 patients: • All MCD • All HIV-negative • 2 HHV-8-positive	• 8 mg/kg q2w (28)	15 months	52% (nodal) 71% (biochemical)	96% for follow-up period	Not reached
Matsuyama et al^Citation93	Case series	Three patients: • All MCD • HIV and HHV-8 status not reported	• 8 mg/kg q2w (3)	Not stated	100%	Not stated	Not stated
Galeotti et al^Citation94	Case series	Two patients: • All MCD • All HIV- and HHV-8-negative	• 8 mg/kg q2w (2)	3 years (Patient 1), 8 months (Patient 2)	100%	100%	Not reached
Nagao et al^Citation99	Case series	Two patients: • All MCD • All HIV-and HHV-8-positive	• 8 mg/kg q2w (2)	4 years (Patient 1) and 1 year (Patient 2)	100%	100% for follow-up period – ongoing remission after rituximab	15 weeks (Patient 1), 22 weeks (Patient 2)

Abbreviations: MCD, multicentric Castleman disease; ORR, overall response rate; OS, overall survival; TTP, time to progression; HIV, human immunodeficiency virus; HHV-8, human herpesvirus-8; UCD, unicentric Castleman disease; qw, weekly; q2w, every 2 weeks; q3w, every 3 weeks; q6w, every 6 weeks.

FitzpatrickPJBrownTCAngiofollicular lymph node hyperplasiaCan Med Assoc J19689925125912625700853

 PubMed Web of Science ®Google Scholar

NordstromDGTewfikHHLatouretteHBPlasma cell giant lymph node hyperplasia responding to radiation therapyAJR Am J Roentgenol19781301169171413407

 PubMed Web of Science ®Google Scholar

StokesSHGriffithRCThomasPRAngiofollicular lymph node hyperplasia (Castleman’s disease) associated with vertebral destructionCancer19855648768794016679

 PubMed Web of Science ®Google Scholar

WeisenburgerDDDeGowinRLGibsonPArmitageJORemission of giant lymph node hyperplasia with anemia after radiotherapyCancer1979442457462476562

 PubMed Web of Science ®Google Scholar

MasseyGVKornsteinMJWahlDHuangXLMcCradyCWCarchmanRAAngiofollicular lymph node hyperplasia (Castleman’s disease) in an adolescent female. Clinical and immunologic findingsCancer1991686136513721873789

 PubMed Web of Science ®Google Scholar

VeldhuisGJvan der LeestAHde WolfJTde VriesEGVellengaEA case of localized Castleman’s disease with systemic involvement: treatment and pathogenetic aspectsAnn Hematol199673147508695726

 PubMed Web of Science ®Google Scholar

BowneWBLewisJJFilippaDAThe management of unicentric and multicentric Castleman’s disease: a report of 16 cases and a review of the literatureCancer199985370671710091744

 PubMed Web of Science ®Google Scholar

ChronowskiGMHaCSWilderRBCabanillasFManningJCoxJDTreatment of unicentric and multicentric Castleman disease and the role of radiotherapyCancer200192367067611505414

 PubMed Web of Science ®Google Scholar

NeuhofDDebusJOutcome and late complications of radiotherapy in patients with unicentric Castleman diseaseActa Oncol20064581126113117118850

 PubMed Web of Science ®Google Scholar

LiYMLiuPHZhangYHRadiotherapy of unicentric mediastinal Castleman’s diseaseChin J Cancer201130535135621527068

 PubMedGoogle Scholar

MatthiesenCRamgopolRSeaveyJAhmadSHermanTIntensity modulated radiation therapy (IMRT) for the treatment of unicentric Castlemans disease: a case report and review of the use of radiotherapy in the literatureRadiol Oncol201246326527023077466

 PubMed Web of Science ®Google Scholar

MirandaFAFariaVHArrudaGVSilvaLGRadiation therapy in the treatment of unicentric Castleman’s diseaseJ Bras Pneumol201339111611823503497

 PubMed Web of Science ®Google Scholar

HerradaJCabanillasFRiceLManningJPughWThe clinical behavior of localized and multicentric Castleman diseaseAnn Intern Med199812886576629537940

 PubMed Web of Science ®Google Scholar

ZhuSHYuYHZhangYSunJJHanDLLiJClinical features and outcome of patients with HIV-negative multicentric Castleman’s disease treated with combination chemotherapy: a report on 10 patientsMed Oncol201330149223400962

 PubMed Web of Science ®Google Scholar

TamayoMGonzalezCMajadoMJCandelRRamosJLong-term complete remission after interferon treatment in a case of multicentric Castelman’s diseaseAm J Hematol19954943593607639289

 PubMed Web of Science ®Google Scholar

KumariPSchechterGPSainiNBenatorDASuccessful treatment of human immunodeficiency virus-related Castleman’s disease with interferon-alphaClin Infect Dis200031260260410987728

 PubMed Web of Science ®Google Scholar

AndrèsEMaloiselFInterferon-alpha as first-line therapy for treatment of multicentric Castleman’s diseaseAnn Oncol200011121613161411205472

 PubMed Web of Science ®Google Scholar

LeeFCMerchantSHAlleviation of systemic manifestations of multicentric Castleman’s disease by thalidomideAm J Hematol2003731485312701121

 PubMed Web of Science ®Google Scholar

JungCPEmmerichBGoebelFDBognerJRSuccessful treatment of a patient with HIV-associated multicentric Castleman disease (MCD) with thalidomideAm J Hematol200475317617714978701

 PubMed Web of Science ®Google Scholar

StaryGKohrgruberNHernethAMGaigerAStinglGRiegerAComplete regression of HIV-associated multicentric Castleman disease treated with rituximab and thalidomideAIDS200822101232123418525273

 PubMed Web of Science ®Google Scholar

RamasamyKGandhiSTenant-FlowersMRituximab and thalidomide combination therapy for Castleman diseaseBr J Haematol2012158342142322583139

 PubMed Web of Science ®Google Scholar

SzturzPAdamZChovancováJLenalidomide: a new treatment option for Castleman diseaseLeuk Lymphoma201253102089209121902577

 PubMed Web of Science ®Google Scholar

YuanZGDunXYLiYHHouJTreatment of multicentric Castleman’s disease accompanying multiple myeloma with bortezomib: a case reportJ Hematol Oncol200921919400935

 PubMed Web of Science ®Google Scholar

SobasMAAlonso VenceNDiaz AriasJBendaña LopezAFraga RodriguezMBello LopezJLEfficacy of bortezomib in refractory form of multicentric Castleman disease associated to poems syndrome (MCD-POEMS variant)Ann Hematol201089221721919636554

 PubMed Web of Science ®Google Scholar

SbengheMMBesaEMahipalADulau FloreaABrayPCaroJHHV-8-associated multicentric Castleman’s disease in HIV-negative patient: a novel therapy for an orphan diseaseOncologist2012171145146 author reply 147–14822286773

 PubMed Web of Science ®Google Scholar

KhanAASirajFBhargavaMAggarwalSSuccessful treatment of multicentric Castleman’s disease accompanying myeloma with bortezomibBMJ Case Rep20122012 pii:bcr2012007646

 Google Scholar

LinQFangBHuangHEfficacy of bortezomib and thalidomide in the recrudescent form of multicentric mixed-type Castleman’s diseaseBlood Cancer J20155e29825794134

 PubMed Web of Science ®Google Scholar

RepettoLJaiprakashMPSelbyPJGustersonBAWilliamsHJMcElwainTJAggressive angiofollicular lymph node hyperplasia (Castleman’s disease) treated with high dose melphalan and autologous bone marrow transplantationHematol Oncol1986432132173533746

 PubMed Web of Science ®Google Scholar

GantiAKPipinosICulceaEArmitageJOTarantoloSSuccessful hematopoietic stem-cell transplantation in multicentric Castleman disease complicated by POEMS syndromeAm J Hematol200579320621015981232

 PubMed Web of Science ®Google Scholar

TalYHaberGCohenMJAutologous stem cell transplantation in a rare multicentric Castleman disease of the plasma cell variantInt J Hematol201193567768021437636

 PubMed Web of Science ®Google Scholar

KurzrockRVoorheesPMCasperCA phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman diseaseClin Cancer Res201319133659367023659971

 PubMed Web of Science ®Google Scholar

van RheeFWongRSMunshiNSiltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trialLancet Oncol201415996697425042199

 PubMed Web of Science ®Google Scholar

van RheeFCasperCVoorheesPMA Phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman diseaseOncotarget2015630304083041926327301

 PubMed Web of Science ®Google Scholar

NishimotoNKanakuraYAozasaKHumanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman diseaseBlood200510682627263215998837

 PubMed Web of Science ®Google Scholar

MatsuyamaMSuzukiTTsuboiHAnti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman’s diseaseIntern Med2007461177177417541233

 PubMed Web of Science ®Google Scholar

GaleottiCBoucheronAGuillaumeSKoné-PautISustained remission of multicentric Castleman disease in children treated with tocilizumab, an anti-interleukin-6 receptor antibodyMol Cancer Ther20121181623162622638145

 PubMed Web of Science ®Google Scholar

NagaoANakazawaSHanabusaHShort-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two casesJ Hematol Oncol201471024438824

 PubMed Web of Science ®Google Scholar