The management of Castleman disease

Abstract

This ‘Good Practice Paper’ was compiled according to the British Society for Haematology (BSH) process at (http://www.b-s-h.org.uk/guidelines). The BSH produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. The PubMed database was searched for English language articles up to June 2021 using the keywords: Castleman, POEMS, HHV8, HIV, lymphoma, lymphadenopathy, investigation, imaging, histology. The references from relevant publications were searched as well. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the Haemato-oncology of sounding board of BSH. It was also on the members section of the BSH website for comment. Castleman disease (CD) describes a rare group of lymphoproliferative disorders with characteristic histopathological appearances.1 Unicentric CD (UCD) presents with isolated lymphadenopathy, usually accompanied by mild or localised symptoms. In contrast, multicentric CD (MCD), presents with lymphadenopathy across multiple sites, usually accompanied by mild to life-threatening constitutional symptoms. MCD represents a constellation of different clinicopathological subtypes that vary in their aetiology, presentation and management. The incidence of all forms of CD is estimated at 21–25 per million person-years, based on insurance registries in the USA.2 Application of this rate to the UK adult population provides an estimated incidence of CD in the UK of 1100–1300 patients per year.3 There is an approximately even distribution of CD between men and women. UCD is most commonly diagnosed in the fourth decade of life, whereas MCD usually presents later in the fifth and sixth decades.4, 5 The introduction of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code D47.Z2 in 2016 should facilitate the understanding of the epidemiology of the disease.6 Lymphadenopathy is found most in the chest and neck and less commonly in abdominal nodes or as a retroperitoneal mass.5, 7, 8 The clinical presentation of UCD often relates to the localised mass effect on organ function. Systemic symptoms are uncommon with fever in <10% of cases and inflammatory markers including C-reactive protein (CRP), erythrocyte sedimentation rate and tests of organ function usually being normal.7 Severe paraneoplastic phenomena such as pemphigus and bronchiolitis with organising pneumonia have been described very rarely.7, 9 The 5-year overall survival (OS) of UCD has been estimated at 91%.4 The presentation of MCD is usually with relapsing and remitting systemic symptoms, e.g. fatigue, sweats, weight loss, anaemia, dyspnoea, oedema, pulmonary fibrosis, hepato-splenomegaly and skin-lesions (such as cherry-coloured eruptions).7, 10 Such systemic symptoms may present rapidly with signs of organ dysfunction that require urgent admission to the intensive care unit and the input from a number of clinical specialities including respiratory and renal physicians. Many of the symptoms associated with MCD, have been attributed to the excessive secretion of the cytokine interleukin-6 (IL-6).11 IL-6 is a key modulator of lymphocyte maturation as well as the acute phase reactants CRP, vascular endothelial growth factor (VEGF), C-X-C motif chemokine ligand 13 (CXCL-13) and the iron regulatory hormone, hepcidin.12-14 Together with a fall in plasma albumin concentration, these inflammatory mediators contribute to the clinical features of fever, oedema and anaemia that may be observed in MCD. Survival rates for MCD are not clear given changes in in diagnostic criteria, reporting and therapy.7 Nevertheless, the 5-year OS rate for MCD have been estimated at ˜65%.4 A proportion of cases of MCD have been attributed to infection with HHV8. HHV8 infection predominantly occurs in the context of immunodeficiency, in particular following infection with human immunodeficiency virus (HIV). HIV negativity should prompt investigations designed to identify other causes of immune suppression.15, 16 Immunodeficient states facilitate the replication of HHV8 in blastic cluster of differentiation 20 (CD20)+ lymphocytes, which in turn leads to the secretion of a virally derived analogue of IL-6 (vIL-6) that drives the pathogenesis of MCD.17 Current assays for IL-6 do not detect vIL-6. Clinically, patients frequently present with fever, splenomegaly and effusions. Blood results may reveal hyperferritinaemia, direct anti-globulin test positive haemolysis and monoclonal gammopathy.5 HHV8 serology does not necessarily reflect viral activity. HHV8 polymerase chain reaction (PCR) in blood detects circulating viral DNA and detectable expression of the virally encoded protein latency associated nuclear antigen-1 (LANA-1) in the diagnostic lymph node biopsy better reflect active HHV8-driven pathology. Indeed, HHV8 viral load has been found to be positively correlated with relapse.18 The syndrome of POEMS is a rare disorder with other clinical features frequently encountered including osteosclerotic bone lesions and papilloedema. Occasionally, features of POEMS syndrome may co-exist with MCD. Diagnosis may be challenging in that idiopathic MCD (iMCD), may present with features such as rash, organomegaly and neuropathy similar to those found in POEMS but without evidence of a clonal plasma cell (PC) disorder.4, 7 The malignant PCs of POEMS are thought to drive the CD-like lymphadenopathy and the resulting immunoglobulin (Ig)G or IgA paraprotein is almost always λ light-chain restricted.19, 20 Thrombocytosis and elevated concentrations of VEGF are important features.4 There appears to be significant overlap in the pathophysiology and presentation of the related disorders of MCD and POEMS. Indeed, a diagnostic criterion of POEMS is the identification of CD histopathology.21 The complex presentation of these rare conditions emphasises the need for careful discussion with an experienced haemato-pathological multidisciplinary team (MDT). Autologous stem cell transplantation (ASCT) is established as a therapeutic modality in POEMS syndrome. But due to limited data, if ASCT is considered in this overlap POEMS-MCD, they should be conducted in experienced centres and as part of a trial, if available. In 2017, the Castleman Disease Clinical Network (CDCN) proposed diagnostic criteria for iMCD, which require the exclusion of HHV8 and POEMS-associated MCD as well as potential mimics of CD histopathology from autoimmune conditions, infections and other haematological disease (Figure 1).6 IgG4-related disease (IgG4-RD) is a systemic inflammatory disorder that is characterised histologically by a PC-rich sclerosing infiltrate of organs such as the pancreas, bile ducts, lungs and lymph nodes. It may, therefore, bear some resemblance clinically and histologically to CD. Biochemically, the IgG4/IgG ratio is significantly higher in IgG4-RD compared to CD; histologically sheets of PCs favour CD and clinically splenomegaly is found exclusively in CD, whereas IgG4-RD is typified by pancreatitis and sialo-dacryoadenitis.22 Key steps in the diagnosis and classification of Castleman disease (CD). CT, computed tomography; HHV8, human herpesvirus 8; IgG4, immunoglobulin G subclass 4; MCD, multicentric CD where ‘i’ prefix denotes idiopathic; NOS, not otherwise specified; PET, positron emission tomography; POEMS, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Proteins and Skin Changes; TAFRO, Thrombocytopenia, Anasarca, myelofibrosis, Renal dysfunction and Organomegaly; UCD, unicentric CD. †Exclusion of cytomegalovirus infection may be complicated by persistence of passively transferred antibody after blood transfusion. Patients with iMCD may present with a spectrum of systemic inflammatory symptoms with constitutional symptoms in approximately half of cases.4 Some patients experience only mild symptoms, whereas others experience severe inflammatory symptoms with multi-organ failure necessitating intensive care support. A particularly aggressive form of iMCD has emerged that appears to be clinicopathologically distinct from iMCD-not otherwise specified (NOS). It is characterised by Thrombocytopenia, Anasarca, Myelofibrosis, Renal dysfunction and Organomegaly (TAFRO). Anasarca is a state of extreme generalised oedema and is more commonly used in North America than in the UK. It occurs predominantly in patients of Japanese and East Asian descent, but this may be due to a reporting bias and data are awaited from the ACCELERATE registry (NCT02817997 http://www.cdcn.org/accelerate). In contrast to iMCD-NOS, renal impairment, peripheral oedema and thrombocytopenia are common.23 However, the diagnosis of the TAFRO-iMCD syndrome remains clinical, without any specific diagnostic laboratory test.24 Diagnostic criteria for TAFRO have been proposed (Iwaki et al.25 2015). Major criteria comprise at least three out of the five canonical features identified by the acronym with the absence of hypergammaglobulinaemia and small volume lymphadenopathy. Minor criteria include hyperplasia or normoplasia of megakaryocytes in the bone marrow and elevated serum alkaline phosphatase (ALP) in the absence of marked elevation of serum transaminase. In TAFRO, the platelet count tends to reflect iMCD activity, with greater thrombocytopenia correlating with greater disease activity.25 Figure 1 shows a summary of the clinical differential diagnosis of CD and its subtypes according to the classification proposed in 2017 by the CDCN.6 A lymph node excisional biopsy is required to ensure adequate histological assessment of suspected cases of CD. Core biopsy may be the means by which a first suspicion of CD is reached but should be followed-up with excision biopsy if at all feasible. The rare but important situation whereby highly atypical follicular dendritic cells that mimic poorly differentiated malignancy, such as a sarcoma, may be misinterpreted were it not for the context provided by an excision biopsy of a lymph node that reveals more typical features of CD. All cases should be reviewed by an experienced haemato-pathologist and reviewed in a MDT meeting.26 The CDCN curates online resources to aid in the diagnosis including case examples presented by a panel of expert pathologists (http://cdcn.org/pathology-toolkit/). As the classical histological findings of CD were first described in 1956 by Dr Benjamin Castleman,27 a spectrum of histological variants has been identified: hyaline vascular, plasma and mixed type. While follicular centres are classically atretic and traversed by penetrating vessels with perivascular hyalinisation in the hyaline vascular variant of UCD, follicular structures in the rarer PC variant of UCD are typically hyperplastic or normal sized. In the mixed variant of UCD, hyaline vascular features and prominent PC proliferations can be seen together. Various combinations of all these features can be identified in MCD. However, the presence of HHV8-infected plasmablasts is largely restricted to MCD and is almost always seen in the context of HIV infection.4, 20 These plasmablasts are immuno-positive for organic cation transporter 2 (OCT2) and interferon regulatory factor 4/melanoma-associated antigen (1IRF4/MUM1), but lack paired box 5 (PAX5), B-cell lymphoma 6 (BCL6) and CD138. They express IgM with monotypic λ light-chain expression, but typically demonstrate a polyclonal pattern of immunoglobulin gene rearrangement. HHV8 serology is not specific for MCD pathology. Rather, a diagnosis of MCD requires either histological staining with LANA-1 or quantitative PCR for HHV8 in peripheral blood.22 The histological appearances of CD are not in themselves pathognomonic of the condition and need to be distinguished from other infectious, inflammatory, autoimmune and malignant conditions that may mimic or co-exist with CD. The key histological differential diagnoses for CD include: non-specific lymphadenitis with polytypic PCs; autoimmune lymphadenitis; reactive follicular and paracortical hyperplasia; lymphoproliferative disorders including lymphoplasmacytoid lymphoma, plasmacytoma, follicular lymphoma and angioimmunoblastic T-cell lymphoma; follicular dendritic cell sarcoma and Kaposi sarcoma. Cross-sectional, whole body imaging is used to distinguish between UCD and MCD by establishing the extent of lymph node involvement; the presence of extra-nodal disease in the lungs, effusions and lytic or sclerotic bone lesions (POEMS), as well as accurately determine the extent of effusions and ascites. UCD appears on computed tomography (CT) imaging as a solitary node or a lymph node mass with most cases with nodes in the thoracic cavity and a small percentage are reported in the abdomen, retroperitoneal space and extra-nodal sites, particularly in the lung parenchyma. MCD does not have a predilection in distribution.8, 28 Positron emission tomography (PET) allows whole-body imaging and identifies the usually highly metabolically active lymphadenopathy of CD and may help to differentiate it from lymphoma by virtue of a lower, but still elevated, relative metabolic activity in CD.5, 29 In the absence of symptoms, patients with UCD, may be managed expectantly.28 There are no reported cases of UCD progressing to MCD, but paraneoplastic phenomena such as bronchiolitis obliterans and may rarely.7, 9 The of patients with UCD to detect disease should be on a in discussion with to care. represents a the node or group is not to with vascular or a of may be These may be at and may as to the mass small for of after is as only of patients with UCD due to the disease a is required as is rare but has been reported up to after is not even with or may adequate of was associated with a OS than but still at 10 can be as but is usually for the of presentation of UCD being in the fourth particular should be given to the of to normal In a proportion of the between UCD and MCD may be challenging due to an or distribution of pathology. 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and have been in a whereby of a a of 6 The rates to have been for those patients diagnosed and patients similar levels of to patients a and the or has regulatory in the UK for in iMCD, but as of requires an which may In the absence of a direct with of the of in MCD and overall rate of compared to However, is very well and therefore, may be considered as in mild disease or in the presence of the of there remains a significant clinical need not only for patients are of but also for a is a monoclonal antibody that the IL-6 to is in but not in the for the of is a described which is even rarer than other forms of CD. of to and have been has not been to a patients have been reported to significant in lymphadenopathy and of constitutional symptoms and In a antibody was at or and was associated with a in symptoms and in lymphadenopathy 1 A cases of TAFRO to that more were associated with and compared to Nevertheless, is in the UK for in highly inflammatory cytokine in the of a patient intensive care the that may be used on an given that is more than which usually requires an lymphoma such as and with or without have been described in multiple cases but no data to their A of MCD that a was in half of patients but the to was 6 significant and may of severe cases to has been to its of IL-6 The of has been reported to be associated with disease in and in have been observed in a mixed of MCD to of lymph nodes and symptoms in of which was after of with a survival of The for 2 for 1 1 for 1 has a phase in a of patients with diagnosed The was and for at least and was in of patients but in of The There were three in of which were after disease OS at 1 was but a was not for at least and up to 2 based on data in with for and as required at is is Castleman disease remains a diagnostic and therapeutic It is clear that UCD and the subtypes of MCD have different and different clinical which should the of to the the of for UCD, for and in iMCD, there remains a significant clinical 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