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Lymph nodes-inflammatory / reactive disorders

Castleman disease


Editorial Board Members: Elizabeth Courville, M.D., Roberto N. Miranda, M.D.
Jayalakshmi Balakrishna, M.D.

Last author update: 27 July 2022
Last staff update: 27 July 2022

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PubMed Search: Castleman disease lymph nodes

Jayalakshmi Balakrishna, M.D.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Venkateswaran J, Balakrishna J. Castleman disease. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphnodescastleman.html. Accessed February 8th, 2023.
Definition / general
  • Unusual heterogeneous group of lymphoproliferative disorders with some common morphological features involving lymph nodes or extranodal sites
  • 3 histological types: hyaline vascular variant (HVCD), plasma cell variant (PCCD) and mixed hyaline vascular and plasma cell variant
  • 3 distinct clinical entities:
    1. Unicentric Castleman disease (UCD): localized, stable and exhibiting hyaline vascular morphology (Cancer 1972;29:670)
    2. Multicentric Castleman disease (MCD): a systemic progressive disease with lymphadenopathy of multiple sites (Cancer 1985;56:2446)
      • MCD is divided into idiopathic (iMCD) and human herpesvirus 8 associated (HHV8 MCD) (Blood 1995;86:1276)
      • Histologically, most cases show features of plasma cell variant
    3. Oligocentric or regional Castleman disease: with involvement of 2 or 3 adjacent lymph node regions and clinical course like UCD (Blood Adv 2020;4:6039)
Essential features
  • Unusual heterogeneous group of lymphoproliferative disorders with some common morphological features involving lymph nodes or extranodal sites
  • 3 distinct clinical entities: unicentric Castleman disease (UCD), multicentric Castleman disease (MCD) and oligocentric or regional Castleman disease
    • MCD is divided into idiopathic (iMCD) and human herpesvirus 8 associated (HHV8 MCD)
  • 3 histological types: hyaline vascular variant (HVCD), plasma cell variant (PCCD) and mixed hyaline vascular and plasma cell variant
  • Clinical syndromes associated with MCD POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein spike, skin changes) and MCD TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly)
  • Castleman disease can show predisposition to certain neoplasms
Terminology
  • Angiofollicular hyperplasia
  • Giant lymph node hyperplasia
  • Unicentric Castleman disease (UCD)
  • Multicentric Castleman disease (MCD)
    • Idiopathic (iMCD)
    • Human herpesvirus 8 associated (HHV8 MCD)
      • Alternative / older terminology: Kaposi sarcoma herpesvirus associated (KSHV MCD)
  • Hyaline vascular type (HVCD)
  • Plasma cell type (PCCD)
  • MCD POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein spike, skin changes)
  • MCD TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly)
ICD coding
  • ICD-10: D47. Z2 - Castleman disease
Epidemiology
  • UCD can affect all age groups and shows no gender difference with the median age of onset in the fourth decade (Hematol Oncol Clin North Am 2018;32:1)
  • MCD affects patients of all ages with a median age of onset in the fifth to seventh decades
  • HHV8 MCD affects mainly HIV positive individuals; however, individuals who are immunocompromised from other causes can also be affected (Leuk Lymphoma 2015;56:1252)
  • HHV8 MCD in individuals who are HIV negative accounts for 2 - 50% of cases and this variation depends on the prevalence of HHV8 in the region (Blood 2020;135:1353)
  • With the introduction of antiretroviral therapy (ART), the incidence of HHV8 MCD has increased
    • Complex interplay between HIV and HHV8 and immune dysregulation of patients with HIV controlled by ART is thought to cause this increased incidence (Ann Oncol 2009;20:775)
  • UCD is more common in childhood (75%) than iMCD and only rare cases of HHV8 MCD are reported in children (Pediatrics 2012;129:e199, Pediatr Blood Cancer 2019;66:e27613)
Sites
  • UCD most commonly affects mediastinum; extrathoracic sites are also involved
    • Presents as a solitary lymph node mass
  • MCD affects multiple lymph node sites, predominantly in the cervical region
  • Reference: Surg Pathol Clin 2019;12:849
Pathophysiology
  • Etiopathogenesis remains not well known
  • UCD
    • Recent evidence suggests that UCD may be a neoplastic process involving follicular dendritic cells (Mod Pathol 2014;27:823)
    • Among UCD patients, 17% have shown to harbor mutations in the gene PDGFRB encoding platelet receptor growth factor β (Leukemia 2019;33:1035)
  • iMCD
    • iMCD is proposed to involve autoinflammatory or autoimmune diseases, paraneoplastic syndromes or an unidentified viral infection leading to polyclonal lymphoproliferation and hypercytokinemia (Blood 2014;123:2924)
    • Current concept is that a cytokine storm due to increased production of IL6 is associated with Castleman disease since patients have elevated levels of IL6 and symptoms improve with IL6 suppression (N Engl J Med 2020;383:2255)
    • VEGF, IL1, IL2, CXCL13 and TNF have also been shown to play a role in the pathogenesis of iMCD (Blood 1994;83:2587, Br J Haematol 1999;104:482, Am J Hematol 2018;93:902)
    • T cell activation, and activation of mTOR, JAK / STAT3 and type I interferon signaling pathways also thought to be pathogenetic mechanisms (J Clin Invest 2019;129:4451, Blood 2020;135:1673)
  • HHV8 MCD
    • HHV8 MCD occurs in HIV positive or negative individuals infected with HHV8 (Blood 2001;97:2130)
    • HHV8 infected B cells in the mantle zones show expression of IgM lambda immunogobulins
      • This is by the loss of Ig kappa due to the upregulation of V(D)J recombination mediated by RAG protein and Ig lambda expression by B lymphocytes with HHV8 infection (PLoS Pathog 2018;14:e1006967)
    • HHV8 encodes several viral genes; the resulting viral proteins and microRNAs stimulate cell growth, proliferation and cell survival among the infected cells, as well as among the neighboring cells by a paracrine mechanism (J Clin Invest 2016;126:3165)
    • HHV8 viral lytic protein expression is proposed to be the contributing pathobiological factor of HHV8 MCD (Am J Pathol 2000;156:743)
    • High viral load in patients with HHV8 MCD suggests active viral replication (Blood 2000;96:2069)
    • HHV8 viral protein vIL6 is expressed in high levels in plasmablasts surrounding lymphoid follicles (J Virol 1999;73:4181)
    • Additionally, human cytokines are elevated in patients with HHV8 MCD, which is thought to be driven by the virus (Blood 2013;122:4189)
    • Inflammatory cytokines like hIL6 and vIL6 cause anemia, fever and hypoalbuminemia (Blood 2013;122:4189)
Etiology
  • UCD: etiology is unclear
  • iMCD: etiology is unclear
  • HHV8 MCD: HHV8 infected endothelial cell proliferation and vascularization
Clinical features
  • UCD: asymptomatic or an enlarging lymph node or mass; secondary symptoms related to the mass (compression or pain) (Blood 2020;135:1353)
  • MCD: all subtypes of MCD show systemic inflammatory manifestations including fever, weight loss, anasarca, generalized lymphadenopathy and hepatomegaly
    • Anemia, hypoalbuminemia, cytopenias and elevated inflammatory markers are common (Blood Adv 2021;5:1660)
  • MCD POEMS: a syndrome characterized by peripheral neuropathy, organomegaly, skin changes and monoclonal paraproteins occurs in some patients with MCD (Blood 1994;83:2587)
  • MCD TAFRO: another syndrome characterized by thrombocytopenia, ascites, fever, reticulin fibrosis and organomegaly usually in patients with normal immunoglobulin levels and mixed or hyaline vascular histology (Sci Rep 2017;7:42316)
  • iMCD, NOS: shows elevated platelet counts and immunoglobulin levels and plasmacytic histology (Blood 2020;135:1353)
Diagnosis
  • Excisional biopsy of an affected lymph node with histopathological examination is the diagnostic modality of choice
  • 18F fluorodeoxyglucose positron emission tomography (FDG PET) is used to exclude alternative diagnoses; also used to select the lymph node for biopsy (J Infect Dis 2015;212:1250)
  • HHV8 MCD requires the pathologic features and HHV8 positivity
  • iMCD is confirmed by integration of pathological findings and clinical syndrome; a diagnosis of iMCD requires exclusion of infectious, malignant and autoimmune disorders that can mimic iMCD (Blood 2017;129:1646)
Laboratory
Radiology description
  • MCD: 18F FDG PET / CT shows increased uptake in the affected lymph nodes
    • Lymph nodes are nonconfluent with a symmetric pattern and SUV ranging from 2 - 19
    • Extramedullary involvement is demonstrated as pulmonary cysts, nodules and interstitial lung disease, hypermetabolic activity in spleen and bone marrow (Nucl Med Commun 2021;42:833)
Radiology images

Images hosted on other servers:

18F FDG PET / CT, HHV8 MCD

Prognostic factors
Case reports
Treatment
  • UCD
    • Asymptomatic patients: expectant management and follow up for disease progression; resection
    • Symptomatic patients: complete surgical resection (Br J Haematol 2021;195:328)
    • Unresectable symptomatic UCD: volume reduction by debulking resection, embolization or cryoablation of feeding vessels, rituximab, steroids and radiation therapy and follow up evaluation is recommended to determine the possibility of complete resection (Br J Haematol 2021;195:328, Eur J Haematol 2021;107:484)
  • MCD
    • Asymptomatic patients: no therapeutic intervention but follow up is needed to detect disease progression
    • Symptomatic patients: depending on the presentation and disease driver (Br J Haematol 2021;195:328)
      • HHV8 MCD
        • Antiretroviral therapy with HHV8 MCD specific therapy
        • Cytotoxic chemotherapies are used: etoposide, vincristine, vinblastine, cyclophosphamide and liposomal doxorubicin
        • Chemotherapy is used in combination with rituximab
        • Antiherpesvirus therapy: gancyclovir, zidovudine, valganciclovir, pomalidomide
        • Anti-hIL6 therapy: siltuximab and tocilizumab are under trial (Br J Haematol 2021;195:328)
      • MCD POEMS
        • Therapy for the plasma cell dyscrasia: consolidation with autologous stem cell transplant
        • Patients without clonal plasmacytosis in bone marrow: radiation therapy
        • Patients with disseminated bone marrow involvement: systemic chemotherapy followed by adjuvant radiation; melphalan and dexamethasone, cyclophosphamide dexamethasone, lenalidomide, thalidomide and bortezomib
        • Daratumumab, BCMA CAR-T, bevacizumab (anti-VEGF), interferon alpha, tamoxifen, transretinoic acid, ticlopidine, argatroban and strontium 89 are also used in rare cases
      • iMCD
        • Surgery, steroids, rituximab, combination chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), prednisolone] or CVAD [cyclophosphamide, vincristine, adriamycin, etoposide]-like regimens and VDTPACE [Velcade (bortezomib), dexamethasone, thalidomide, cisplatinum, adriamycin, cyclophosphamide, etoposide]), autologous stem cell transplantation, anti-IL6 monoclonal antibodies (siltuximab and tocilizumab), bortezomib, thalidomide, anakinra (IL1 antagonist), interferon alpha and all transretinoic acid are used (Hematol Oncol Clin North Am 2018;32:89, Blood 2018;132:2115)
      • MCD TAFRO
        • Corticosteroids, rituximab, tocilizumab, cyclosporin A
        • Thrombocytopenia: romiplostim and eltrombopag
        • Other options: plasma exchange, high dose cyclophosphamide, thalidomide, lenalidomide, bortezomib rapamycin and combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) (Ann Hematol 2022;101:485, Int J Hematol 2016;103:686)
Gross description
  • UCD: enlarged lymph node, firm and white cut surface with or without calcification
Gross images

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Tan-pink tissue with calcifications

Microscopic (histologic) description
  • HVCD is characterized by prominent vascular proliferation and hyalinization of the vessel walls
    • There are follicular changes and interfollicular / stromal changes described; based on the predominance of changes in each of these sites divided into follicular HVCD and stroma rich Castleman disease (Virchows Arch A Pathol Anat Histopathol 1993;423:369)
    • Atretic germinal centers traversed by sclerotic penetrating vessels and hyalinization - lollipop follicles
    • Mantle zones are thickened with lymphocytes arranged in layers - onion skin appearance
    • Mantle zones may fuse and contain more than 1 germinal center - twinning
    • Follicular dendritic cells may show proliferation and dysplastic features
    • In the interfollicular areas, there is usually extensive vascular proliferation of high endothelial venules with perivascular hyalinization
    • Clusters of plasmacytoid dendritic cells may be seen (Hum Pathol 2013;44:1003)
    • Plasma cells, immunoblasts and eosinophils are seen in the interfollicular areas but no sheets of plasma cells
    • Unapparent sinuses and obliteration of the subcapsular sinuses commonly seen
    • Capsular thickening
  • UCD - plasma cell type: rare (< 10% of UCDs) and MCD needs to be excluded (Surg Pathol Clin 2019;12:849)
    • Interfollicular areas and medulla containing sheets of small, mature plasma cells
    • Hyperplastic follicles and a subset of the follicles with hyaline vascular features
  • MCD can be hyaline vascular (rare < 10%) or plasmacytic but usually shows a mix of histological features of both plasma cell and hyaline vascular Castleman disease (Blood 2017;129:1658, Blood 2017;129:1646)
    • Hypervascular without dysplastic follicular dendritic cells or sclerotic vessels
    • Diffuse plasma cell proliferation, germinal center hyperplasia, some follicles may show hyaline vascular changes and patent sinuses
  • HHV8 MCD (Am J Surg Pathol 2003;27:91)
    • Plasmacytic
    • HHV8 infected cells in the mantle zones show plasmablastic or immunoblastic morphology with large nuclei, vesicular chromatin and prominent nucleoli and lambda light chain restriction
    • Polyclonal plasmacytosis
  • TAFRO (Hematol Oncol Clin North Am 2018;32:37)
    • Mixed hyaline vascular and plasmacytic
    • Lymph nodes: hypervascular
    • Bone marrow: reticulin fibrosis, megakaryocytic hyperplasia and emperipolesis
Microscopic (histologic) images

Contributed by Jayalakshmi Balakrishna, M.D., Amy Duffield, M.D., Ph.D., Tapan Bhavsar, M.D., Ph.D.,
Carlos Murga-Zamalloa, M.D. and Jackie D. Sublett II, M.D.

Hyaline vascular Castleman disease (HVCD)
Atretic follicles, interfollicular vascular proliferation   Atretic follicles, interfollicular vascular proliferation   Atretic follicles, interfollicular vascular proliferation

Atretic follicles, interfollicular vascular proliferation

Atretic germinal center   Atretic germinal center

Atretic germinal center

Twinning of germinal center

Twinning of germinal center


Twinning of germinal center

Twinning of germinal center

Twinning of germinal center, thickened mantle zones

Twinning of germinal center, thickened mantle zones

Lollipop follicle, thickened mantle zones

Lollipop follicle, thickened mantle zones

Twinning of germinal centers, sclerosed vessels

Twinning of
germinal centers,
sclerosed
vessels

Thickened mantle zones

Thickened mantle zones

Sclerosed vessels

Sclerosed vessels


Vascular proliferation   Vascular proliferation

Vascular proliferation

Lollipop follicle   Lollipop follicle

Lollipop follicle

Atretic follicle   Atretic follicle

Atretic follicle


Proliferation of T lymphoblasts

Proliferation of T lymphoblasts

 

Onion skin pattern

Twinning of germinal center, CD23

Twinning of germinal center, CD23

Interfollicular areas rich in T cells, CD3

Follicles and atretic germinal centers, CD20


Proliferation of TdT+ cells   Proliferation of TdT+ cells

Proliferation of TdT+ cells

Vascular proliferation, CD34

Vascular proliferation, CD34

Interfollicular areas rich in T cells, CD5   Interfollicular areas rich in T cells, CD5

Interfollicular areas rich in T cells, CD5


Follicular dendritic cell meshworks, CD21   Follicular dendritic cell meshworks

Follicular dendritic cell meshworks, CD21

Low proliferation rate in interfollicular areas

Low proliferation rate in interfollicular areas

Germinal centers, BCL6+

Germinal centers, BCL6+

Plasma cells, CD138

Plasma cells, CD138



Plasma cell Castleman disease (PCCD)
Aggregates of plasma cells   Aggregates of plasma cells   Aggregates of plasma cells

Aggregates of plasma cells


T cells in interfollicular areas, CD3

T cells in interfollicular areas, CD3

Atretic follicles, CD20

Atretic follicles, CD20

Aggregates of plasma cells, CD138

Aggregates of plasma cells, CD138

Vascular proliferation

Vascular proliferation, ERG



Human herpesvirus 8 associated multicentric Castleman disease (HHV8 MCD)
Aggregates of plasma cells

Aggregates of plasma cells

Atretic follicle, interfollicular plasma cell proliferation

Atretic follicle, interfollicular plasma cell proliferation

Kaposi sarcoma in a case of HHV8 MCD

Kaposi sarcoma in a case of HHV8 MCD

Kaposi sarcoma in a case of HHV8 MCD, HHV8   Kaposi sarcoma in a case of HHV8 MCD, HHV8

Kaposi sarcoma in a case of HHV8 MCD, HHV8

Kaposi sarcoma in a case of HHV8 MCD, MUM

Kaposi sarcoma in a case of HHV8 MCD, MUM1


HHV8+ cells

HHV8+ cells

Lambda light chain predominance in plasma cells   Lambda light chain predominance in plasma cells   Lambda light chain predominance in plasma cells

Lambda light chain predominance in plasma cells

Increased proliferation in interfollicular areas

Increased proliferation in interfollicular areas, Ki67

Virtual slides

Images hosted on other servers:

HVCD

Positive stains
Negative stains
Flow cytometry description
  • Serum concentrations of IL2, IL4, IL6, IL10, TNFα and IFNγ cytokines can be evaluated by flow cytometry (J Med Virol 2021;93:4033)
Molecular / cytogenetics description
  • HVCD
    • Subset of cases shows clonal cytogenetic abnormalities: t(1;16)(p11;p11), t(1;22)(p22;q13) and t(7;8)(qter;q12) (Am J Surg Pathol 2000;24:882)
    • In about 75% of cases studied HUMARA gene assays show monoclonal pattern (loss of heterozygosity) (Mod Pathol 2014;27:823)
  • MCD
Sample pathology report
  • Lymph node, left axillary, excisional biopsy:
    • Kaposi sarcoma and HHV8 positive multicentric Castleman disease (see comment and report)
    • Comment: The patient has a history of HIV / AIDS and presents with generalized lymphadenopathy and fever. The lymph node shows morphologic features consistent with plasma cell type Castleman disease and focal involvement by Kaposi sarcoma. Flow cytometry shows no evidence of an immunophenotypically abnormal lymphocyte or plasma cell population and molecular analysis to evaluate presence of clonal B cell population is negative ruling out B cell lymphoma and plasma cell neoplasm.
Differential diagnosis
  • Systemic lupus erythematosus:
    • Follicular hyperplasia, interfollicular expansion of lymphocytes and immunoblasts, and numerous plasma cells within germinal centers and medullary cords
    • Coagulative necrosis with abundant karyorrhectic debris and histiocytes
    • Hematoxylin bodies
    • Serological diagnosis of systemic lupus erythematosus
  • Rheumatoid arthritis:
    • Can resemble HVCD or PCCD
    • Follicular hyperplasia, interfollicular and intrafollicular plasmacytosis and neutrophils within sinuses
    • Lacks thickened mantle zones, twinning of germinal centers and piercing vessels
    • Clinical and serological diagnosis of autoimmune disease
  • Hemophagocytic lymphohistiocytosis:
    • Proliferation of benign histiocytes in the sinuses
    • Lymphocyte depletion may be seen
    • Phagocytosed red cells or white cells
  • Adult onset Still disease (Medicine (Baltimore) 2015;94:e787):
    • Paracortical hyperplasia or mixed follicular and paracortical hyperplasia
    • Vascular proliferation and immunoblasts
    • Pericapsular endarteritis
    • Clinical and serologic diagnosis of adult onset Still disease
  • IgG4 disease (Semin Diagn Pathol 2012;29:226):
    • Fibroinflammatory disorder with dense lymphoplasmacytic infiltrates containing numerous IgG4+ plasma cells
    • 5 different histological patterns - type resemble MCD
    • Hyperplastic and regressed follicles, some with penetrating vessels
    • Interfollicular areas with numerous plasma cells
    • Serological diagnosis
  • Follicular dendritic cell sarcoma:
    • Storiform or whorled bundles of spindle cells with interspersed small lymphocytes
    • Positive for follicular dendritic cell markers: CD21, CD23 and CD35
  • Plasma cell neoplasm:
    • Monoclonal plasma cells
  • HIV associated lymphadenitis:
    • Clinical and serological diagnosis of HIV infection
  • Angioimmunoblastic T cell lymphoma, early stages:
    • May resemble HVCD
    • Loss of architecture and expanded follicular dendritic cell meshworks
    • Atypical T cells: CD10, BCL6 and PD-1 positive
    • Monoclonal T cell gene rearrangements
  • Follicular lymphoma:
    • Atypical follicles of low grade follicular lymphoma can mimic HVCD
    • Atypical lymphocytes CD10, BCL6 and BCL2 positive
    • Clonal B cell population
    • BCL2::IGH translocation
  • Mantle cell lymphoma:
    • Mantle zone pattern may mimic HVCD
    • Atypical lymphocytes, CD5 and cyclin D1 or SOX11 positive
    • Clonal B cell population
    • CCND1::IGH translocation
  • Reactive lymph node enlargement:
    • Lack characteristic histological features of CD
    • Can show different histological patterns: follicular hyperplasia, sinus histiocytosis, interfollicular / mixed and diffuse patterns
Board review style question #1
BRQ image


What is the histopathological feature seen in this lymph node?

  1. Dysplastic dendritic cells
  2. Immunoblasts
  3. Plasma cell infiltrates
  4. Twinning of germinal centers
Board review style answer #1
D. Twinning of germinal centers. The features of hyaline vascular Castleman disease are atrophic follicles, penetrating vessels, onion skinning of mantle zones, twinning of germinal centers and hyalinized vessels.

Comment Here

Reference: Castleman disease
Board review style question #2
Which of these lymphomas occurs in the background of human herpesvirus 8 associated multicentric Castleman disease (HHV8 MCD)?

  1. Burkitt lymphoma
  2. EBV positive diffuse large B cell lymphoma, NOS
  3. Follicular lymphoma
  4. HHV8 positive large B cell lymphoma
Board review style answer #2
D. HHV8 positive large B cell lymphoma is known to occur in a background of HHV8 MCD. Other neoplasms occur in this setting are Kaposi sarcoma and primary effusion lymphoma.

Comment Here

Reference: Castleman disease
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