When you hear the word ‘Castleman’, the thoughts that might come to mind first would be of ancient kingdoms and lands of fairytales. 

However, Castleman disease is a rare disorder of our immune system. This article will run through:

• What is Castleman disease (CD)
• Classification of CD
• Clinical features
• How does a virus cause CD
• Genetic factors responsible for CD
• Diagnosis, treatment, and prognosis of CD

Introduction

Castleman disease is grouped under the category of lymphoproliferative disorders, presenting with a wide spectrum of clinical manifestations. Dr. Benjamin Castleman was a pioneer in describing Castleman disease (CD) in 1956.¹           

Males and females are equally affected. It can occur at any age; however, the condition is more common in adults.¹ Every year, 5000 new cases are diagnosed.⁵ This disease not only affects lymph nodes but can occur in the pancreas, lacrimal glands, and muscles.¹

Castleman disease is further sub-divided into unicentric and multicentric types on the basis of the clinical features, number of affected lymph node regions and course of the disease.¹

Unicentric CD (UCD)

UCD is a localized disease in which there is unifocal or single region lymph node enlargement, such as in the mediastinum, axillary, inguinal regions or the abdominal region. The patient might be asymptomatic or exhibit mild symptoms, and the disease has a benign clinical course.¹

Multicentric CD (MCD)

There is involvement of multiple lymph node regions in MCD. It usually presents with systemic symptoms and has a poorer clinical outcome than UCD. The person can experience loss of weight, fever with night sweats, generalised edema, enlargement of the liver/spleen, kidney dysfunction and respiratory issues.

Based on the cause, MCD can be further sub-classified into:

• Human herpes virus-8 associated MCD (HHV8-MCD), also called Kaposi sarcoma herpes virus associated MCD (KSHV-MCD)
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS)-associated MCD (POEMS-MCD)
• Idiopathic MCD (iMCD), which is not related to HHV8 or POEMS

Further, it is again sub-divided into:

• iMCD-TAFRO (thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly) 
• iMCD-NOS (not otherwise specified)¹ 

HHV8/KSHV-associated MCD predominantly occurs among HIV-affected persons.²

Risk factors

There is no association of ethnicity, family history or risk factors related to UCD or iMCD.⁶

Pathogenesis

What causes CD exactly is not fully explored. However, it is believed that our immune system gets dysregulated and starts producing chemical mediators abnormally called cytokines, particularly interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), IL-1, IL-2 and tumour necrosis factor (TNF).¹

In particular, IL-6 is produced by inflammatory cells, fibroblasts, cells lining the blood vessels (endothelial cells) and cancer cells.⁶ Interleukin-6 (IL-6) is responsible for the proliferation of lymphoid cells and for inducing inflammation.³

Vascular endothelial growth factor has also been implicated in the pathogenesis of iMCD.⁶

Role of HHV8/KSHV in the pathogenesis of CD:

KSHV undergoes two phases of the life cycle i.e. latent phase and the lytic phase.

• Latent phase: During this phase, the virus is dormant and expresses very few viral genes
• Lytic phase: The virus is highly active during this phase and expresses numerous lytic proteins that help in viral replication and the production of infectious virions

The various viral proteins responsible for its pathogenicity are: KSHV latency-associated nuclear antigen (LANA), viral IL-6 (vIL-6), the viral processivity factor ORF59 (also known as PF-8), and viral interferon regulatory factor 1 (vIRF1). 

Out of these, KSHV vIL-6 is the most important as it mimics human IL-6 (hIL-6). hIL-6 promotes cell proliferation, immune regulation, and inflammation and is responsible for the survival of plasmablasts. 

The immune status of the person plays a significant role in the release of cytokines in viral infection, particularly HIV. Those with low immunity as a result of the KSHV replication in plasmablasts within the lymph node express vIL-6, thereby eliciting the expression of multiple cytokines. Both vIL-6 and hIL-6 are involved in the proliferation of B cells and antibody-producing cells (plasma cells). 

In CD, there is a cytokine storm, i.e. overproduction of IL-6 and this causes overstimulation of B-lymphocytes and plasma cells, leading to follicular hyperplasia and lymph node enlargement. IL-6 also increases the secretion of Vascular Endothelial Growth Factor (VEGF), a factor responsible for the proliferation of blood vessels.^1,6

Viral causes

UCD is not linked to be associated with the infectious cause.² 

HHV8 MCD: HHV8 MCD occurs in HIV-positive or HIV-negative individuals with HHV8. The viral genes encode proteins such as viral lytic protein, viral protein vIL6 and microRNAs, which stimulate cell growth, proliferation and cell survival. HHV8 viral protein (vIL6) is expressed at high levels in cells producing antibodies (plasmablasts) surrounding lymphoid follicles. The virus is also responsible for raised levels of the cytokine IL6.

The person who encounters HHV8 MCD is at risk of developing malignancies such as Kaposi sarcoma, HHV8+ large B cell lymphoma, and Primary effusion lymphoma. Similarly, iMCD patients can develop Classic Hodgkin lymphoma, Diffuse large B-cell lymphoma, Peripheral T-cell lymphoma, and Mantle cell lymphoma.⁴

Classic Hodgkin lymphoma is associated with Epstein-Barr virus (EBV). Thus, the interplay between these viruses and HIV may increase the risk of concomitant KSHV-associated and EBV-associated disorders with KSHV-MCD.

Genetic Factors

Genetic testing helps in special cases, especially when atypical symptoms are present or when coexisting autoinflammatory disease is suspected.¹

• Various chromosomal abnormalities including translocations, deletions, and inversions, are seen in CD. The most common abnormality noted is the deletion of chromosome 7
• Point mutations in the PDGFRB gene, genetic mutations within interleukin signaling pathways, MAPK pathway, and IgH gene arrangements are reported in UCD
• Point mutations in the NCOA4 gene, IgH gene arrangements, mutations in genes related to chromatin organization, methylation abnormalities, and genetic mutations within the MAPK pathway are present in iMCD.⁵ These genetic anomalies ultimately contribute to cellular proliferation and survival

Diagnosis of Castleman Disease

Radiological findings are not commonly used in the diagnosis of CD. Contrast-enhanced CT (CECT) scans instead can detect the involvement of lymph nodes based on size, shape, and contrast enhancement pattern. However, CT imaging cannot distinguish between a reactive lymph node and pathological enlargement.² 

18F-fluorodeoxyglucose positron emission tomography (FDG PET) can help select the lymph node for biopsy and is used to exclude alternative diagnoses.⁴

The histopathological examination of a lymph node biopsy is the gold standard technique for confirmation of diagnosis. The lymph nodes show three main patterns: 

• Hyaline vascular type (HV-CD)
• Plasma cell infiltration pattern (PC-CD)
• Mixed pattern¹

Another method for the diagnosis of MCD is by confirmation of viroblasts in blood or effusions, respectively.²

Treatment and prognosis

• For the management of UCD, the involved lymph nodes are removed surgically
• The prognosis of MCD is poor and has a fatal outcome. The treatment of MCD requires immunosuppressive therapies. The death rates in cases of iMCD are high because of progressive multi-organ failure, complications from immunosuppressive therapy, thrombotic events and the occurrence of secondary malignancies, such as lymphomas

However, the use of targeted therapies such as siltuximab and tocilizumab has helped improve the patient outcomes.  

The management of CD depends on the severity of the disease. These therapies target IL-6 and neutralise it.¹

Summary

Castleman disease is a rare lymphoproliferative disorder that has a wide spectrum of clinical manifestations. The patients present with enlargement of lymph nodes predominantly, non-specific symptoms such as fever, weight loss, night sweats, and enlargement of the liver/spleen. The exact cause of this disorder has not been elucidated, but HHV8/Kaposi Sarcoma Herpes Virus and genetic mutations have been linked to its pathogenesis. Based on the number of lymph node systems involved, it can be unicentric or multicentric. 

Unicentric CD has a benign course and is not associated with a viral cause. On the contrary,  HHV8 viral infection-associated MCD has a poor prognosis, and these patients are at increased risk of developing malignancies such as lymphoma. HHV8 virus produces certain viral lytic proteins that cause cytokine storm (IL-6), which promotes cell proliferation, cell survival, and induces inflammation. Histopathological examination is mandatory for diagnosis. Surgical excision of the lymph nodes and immunosuppressive therapies that target IL-6 are the therapeutic measures adopted in these patients.