Castleman disease consists of several lymphoproliferative subtypes that share some histological features in the lymph nodes. On the other hand, numerous clinical findings and etiologies make the disease challenging to understand. The origin of the disease is the hyaline vascular-type unicentric Castleman disease (UCD), first reported by Benjamin Castleman et al. in 1954. Although UCD is characterized by localized lesions and lack of symptoms, multicentric Castleman disease (MCD) with multiple lesions and systemic symptoms was reported by Frizzera in 1983. MCD is further divided according to KSHV/HHV8 infection status. In KSHV/HHV8-related MCD, viral infection signals lead to excessive cytokine production, and cause clinical and pathologic abnormalities. Some cases of plasma cell-type KSHV/HHV8-negative MCD can be found in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes), which is a paraneoplastic syndrome. The others are idiopathic MCD, which are currently considered a heterogeneous group of diseases with overlapping pathological and clinical features. In this article, we summarize the historical evolution of Castleman disease to help understand the disease concept. We also review the latest ideas and definitions of the subtypes within the MCD spectrum and summarize the histopathological findings.
Since thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome was first proposed in 2010, there has been considerable progress in this area, particularly regarding its association with idiopathic multicentric Castleman disease (iMCD). TAFRO syndrome is a heterogeneous category with a constellation of symptoms that can develop in the setting of infection, rheumatologic disorder, malignancy, and iMCD. Now, iMCD with TAFRO symptoms is subtyped as iMCD-TAFRO. However, confusion between TAFRO syndrome and iMCD-TAFRO remains. In this article, we discuss the current understanding and future research agenda of TAFRO syndrome and iMCD-TAFRO from the perspective of its new validated international definition.
The current consensus on Castleman disease is that it is a group of several distinct lymphoproliferative disorders with different underlying pathogenesis and clinical outcomes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL), a disease of unknown etiology, characterized by severe polyclonal hypergammaglobulinemia and generalized superficial lymphadenopathy. After Frizzera et al.’s landmark report in 1983, the term multicentric Castleman disease (MCD) gradually became established, and for a time, IPL was regarded as identical to MCD. However, with the subsequent recognition of human herpesvirus 8 (HHV8)-related MCD in the 1990s and the contributions by Kojima et al. in the 2000s, in which non-HHV8-related MCD (now called idiopathic MCD) was at least subclassified into IPL and others (non-IPL), it is now clear that the original distinctiveness of IPL is still maintained in MCD, which is a diverse collection of diseases.
The clinical manifestations of idiopathic multicentric Castleman disease (iMCD) are thought to be caused by an excess of inflammatory cytokines; however, the mechanism is yet to be known. In addition to IL-6, inflammatory cytokines, such as IL-1β and TNF-α, are noted to be elevated in iMCD, which are common in autoinflammatory diseases. The first-line treatment for iMCD is an IL-6 inhibitor. Furthermore, increases in inflammatory cytokines such as serum IL-10 and IL-23, chemokines such as CXCL13 and CXCL-10 (especially in iMCD-TAFRO), and VEGF-A have been observed, and their relationship to pathogenesis has attracted the attention of researchers. The PI3K/Akt/mTOR pathway, JAK/STAT3 pathway, and type I IFN as drivers have recently been identified as important signals and are expected to be therapeutic targets in cases where IL-6 inhibitors are ineffective.
Bendamustine-rituximab (BR) therapy has been established as a highly effective regimen for indolent non-Hodgkin lymphoma (NHL). However, patients who receive BR therapy exhibit persistent hypogammaglobulinemia and lymphopenia, resulting in an increased incidence of infections. As a sustained immunosuppressive state is a risk factor for infections, early predictive biomarkers for infections related to BR therapy need to be identified. We retrospectively analyzed 61 patients with indolent NHL who were followed up for 2 years after the end of BR therapy. Progression-free survival was significantly influenced by the incidence of infections. Patients with infections related to BR therapy exhibited persistent hypogammaglobulinemia and lymphopenia. In addition, we determined the cutoff values of serum IgG values and lymphocyte counts for infections using receiver operating characteristic curve analysis. Minimum serum IgG and lymphocyte counts at the first BR treatment cycle were significantly associated with the incidence of infections during and after BR treatment. Furthermore, the development of skin reactions during BR therapy was significantly associated with the incidence of infections after BR therapy. Our study suggested that these values and symptom are predictive biomarkers for infections related to BR therapy. Based on these findings, better management of indolent NHL patients will be possible.
Idiopathic multicentric Castleman disease (iMCD) is a systemic disorder characterized by systemic inflammation and organ dysfunction associated with an increase in pro-inflammatory cytokines. Some patients with iMCD are positive for autoantibodies, although their significance and relationship with specific associated autoimmune diseases are unclear. This study retrospectively analyzed the clinicopathological features of iMCD patients focusing on autoantibodies. Among 63 iMCD patients in our database, 19 were positive for at least one autoantibody. Among the 19, we identified five with plasma cell type (PC)-iMCD lymph node histopathology and positive anti-phospholipid antibodies. These patients were likely to have thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, organomegaly (TAFRO) symptoms, and thrombotic events. The present study suggests that patients with undiagnosed or atypical autoimmune diseases, including anti-phospholipid syndrome (APS), were treated for iMCD. APS may present with thrombocytopenia or even multi-organ failure, which overlap with clinical presentations of iMCD. Due to differences in the treatment regimen and follow-up, recognition of the undiagnosed autoimmune disease process in those suspected of iMCD is essential. Our study highlights the importance of complete exclusion of differential diagnoses in patients with iMCD in their diagnostic workup.
Immune evasion mediated by PD-L1 plays an important role in the development of B-cell malignancies. However, PD-L1 expression is infrequently observed in tumor cells of extranodal diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Other than copy number alterations, PD-L1 is aberrantly upregulated by structural variations in the 3′-UTR of PD-L1. We report four cases with PD-L1 expression on tumor cells, including two with structural variations in the 3′-UTR of PD-L1 and two without. Our report demonstrates the presence of a small number of “immune evasion-type” extranodal DLBCL, NOS cases.
Lymphomatoid gastropathy (LyGa)/natural killer (NK)-cell enteropathy (NKCE) is recognized as a benign NK-cell lymphoproliferative disease. Due to its histological similarity to NK/T cell lymphoma, it is easy to misdiagnose, leading to unnecessary chemotherapy and poor quality of life. This disease is typically observed in the small and large intestines in North America, whereas almost all cases in Japan occur locally in the stomach. Only 11 LyGa/NKCE cases involving both gastric and intestinal lesions have been reported, and there are few reports providing endoscopic images throughout the gastrointestinal tract. We report a case of LyGa/NKCE involving both the stomach and small and large intestines with detailed upper gastrointestinal endoscopy, colonoscopy, capsule endoscopy and pathology images. Its pathogenesis currently remains elusive, but most patients with LyGa/NKCE in Japan have Helicobacter pylori (H. pylori) infection. Our patient was also positive for H. pylori infection at disease onset, but after receiving eradication therapy, ulcerative lesions in both stomach and intestine regressed and no recurrence was observed. This case suggests a link between the pathogenesis of LyGa/NKCE and H. pylori infection.