Castleman Disease

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Castleman Disease

• Leslie Andritsos, M.D.
• Hematology Grand Rounds
• January 15, 2004

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Case Presentation

• 25 y/o woman with follicular lymphoma diagnosed
  at OSH
• Consult prelim path report Castleman Disease
• Final follicular lymphoma

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Castleman Disease

• Atypical lymphoproliferative disorder
• 1st described 1956 by Benjamin Castleman
• Series of patients with mediastinal LAN
• Hyalinized follicles with interfollicular
  vascular proliferation
• Hyperplastic germinal centers with sheets of
  plasma cells in interfollicular spaces
• Early cases were all unicentric CD
• Multicentric form not recognized until 1978

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Other Names

• Angiofollicular lymph node hyperplasia
• Giant lymph node hyperplasia
• Angiomatous lymph node hamartoma
• Lymph nodal hamartoma
• Lymph node hyperplasia of Castleman

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Atypical Lymphoid Hyperplasia
Hematology 2000
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Subtypes

• Histologic
• Hyaline vascular variant
• Plasma cell variant
• Mixed
• Radiographic
• Unifocal
• Multicentric

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Hyaline Vascular Variant

• Atrophic germinal centers
• Broad mantle zones of small lymphocytes
• Expansion of follicular dendritic cells (onion
  skin)
• Hypervascular interfollicular lymphoid tissue

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Plasma Cell Variant

• Hyperplastic germinal centers, may have
  hyalinized follicles
• Interfollicular region sheets of plasma cells
• Must r/o reactive LN with increased PC

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Unicentric CD

• Isolated lymphadenopathy
• Most are asymptomatic
• 70 mediastinum, hilum, or lung
• Peripheral LAN unusual
• Males females equally affected
• Median age at dx 35
• Good prognosis

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Unicentric CD Cont

• 70-80 hyaline vascular subtype
• Treatment Surgery
• If incomplete resection RT or chemo
• Even with complete resection, can still rarely
  eventually develop malignancy
• NHL
• HD
• Amyloidosis

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Multicentric CD

• Multiple lymph node regions
• Majority plasma cell variant or mixed
• Median age at dx 60
• Male predominance
• Constitutional sx
• Peripheral LAN
• Elevated ESR, anemia, hypergammaglobulinemia

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Multicentric CD cont

• Forms
• Rapidly Progressive
• Chronic persistent
• Episodic relapsing
• Median survival 26-30 mo
• Most common causes of death
• Infection
• Progressive disease
• Progression to lymphoma

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Multicentric CD, KS, and HIV

• 1983-84 reports of patients with both CD and
  Kaposis sarcoma
• Majority of pts later found to be coinfected with
  HIV, HHV-8 (KSHV)
• HHV-8 now implicated in KS, MCD, primary effusion
  lymphoma, and has been found in MM

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HHV-8

• Discovered 1994
• Gammaherpes virus
• Found in 100 of HIV/KS/MCD, up to 40 of HIV-
  cases
• Viral homologue of IL-6 (vIL-6)
• Viral homologue of cyclin D1

Blood, 977, 2001 J Virol, 735, 1999 Blood,
9110, 1998
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HHV-8 Cont

• Type of diseased caused is related to cellular
  tropism and gene expression
• PEL and KS latent and lytic cycle gene
  expression, predominantly infects B cells
• MCD lytic cycle gene expression, infects B and
  T cells

Blood, 977 2001
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HHV-8 Cont

• HHV-8 infects IgM positive naïve B-cells
• Cells do not have somatic mutations of Ig gene
• Polyclonal
• Localize to mantle zone of B-cell follicles
• Surrounded by HHV-8 negative polyclonal plasma
  cells
• Infected cells may coalesce to form regions of
  monoclonality (microlymphomas)

Blood, 977 2001
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Role of IL-6

• Induces proliferation and differentiation of
  B-cells into antibody-producing cells
• Induces proliferation/differentiation of T-cells
• Induces synthesis of hepatic acute phase proteins
• Induces proliferation of vascular smooth muscle
  cells
• vIL-6 can induce production of VEGF in mice

Blood 977, 2001
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IL-6 in MCD

• Elevated serum IL-6 in some pts with MCD
• Increased expression of gene coding for IL-6
  found in LN tissue in some cases
• IL-6 gene transfected into mouse model and
  overexpressed causes similar disorder
• Anti-IL-6 MoAb reduces symptoms
• Surgical resection of UCD leads to fall in serum
  IL-6, resolution of symptoms

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Cyclin D1

• Cell cycle activator
• Forms complex with Cdk4
• Activation of cyclin D1/cdk4 complex
  phosphorylates Rb
• Rb then dissociates from E2F, cell is able to
  enter S phase

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Etiology of Castlemans

• Remains Unknown
• Theories
• Infection (HHV-8, other?)
• Autoimmunity
• Cytokine dysregulation (IL-6)

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Treatment

• Unicentric Disease
• Surgery
• RT if incomplete resection
• Chemotherapy

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Treatment

• Multicentric CD
• No standard therapy
• Options
• Steroids (60-70 ORR, 15 CR, usually not
  durable)
• Chemotherapy
• Rituximab
• Auto BMT
• Antivirals
• Anti-IL-6

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AIM Clinical Behavior of Localized and
Multicentric CD, 1998
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Multicentric CD
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Unicentric CD
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Blood 2002, High incidence of NHL in HIV/HHV-8
MCD

• Prospective cohort of 60 patients
• Median follow-up 20 mo
• 14 NHL
• 3 PEL
• 5 visceral large cell with PEL-like phenotype
• 6 plasmablastic leukemia/lymphoma
• CD4 count, HIV RNA, HAART, KS not predictive of
  transformation

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14 HIV Pts with MCD and NHL
Blood 2002, 997
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Anti-IL-6 MoAb

• Blood 2000 7 patients with MCD (plasma cell or
  mixed) treated weekly or biweekly x 3 months.
  Resolution of symptoms, normalization of lab
  values, improvement in LAN.
• NEJM 1994 1 patient with PCV MCD treated.
  Resolution of sx and improvement in lab values.
  Followed by high dose steroids and resection.

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Case Report Remission of HHV-8 and MCD with
Ganciclovir, Blood 2003

• 3 HIV/HHV-8 patients treated with ganciclovir
• All had clinical improvement after rx
• Symptomatic flares assd with HHV-8 viremia,
  responded to rx

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Rituxumab

• Patient with HIV, MCD, failed multiple regimens,
  received Rituxan, achieved 14 mo remission (Blood
  2001)
• Patient with MCD resistant to RT, received
  Rituxan x 4 weekly doses, maintenance steroids,
  NED x 10 months
• 5 pts with HIV, MCD. 2 died quickly after
  starting therapy, 3 are in CR and asymptomatic at
  14 months (Blood 2003)

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Complications of CD

• Infections
• NHL
• HD
• POEMS (MCD PCV)