David C. Fajgenbaum

HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy

Multicentric Castlemans disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6. Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human herpes virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV-negative and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new subclassification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative MCD or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.

Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV‐8‐negative multicentric Castleman disease

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi‐organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus‐8 (HHV‐8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV‐8‐negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese‐born and two US‐born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23–72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed. Am. J. Hematol. 91:220–226, 2016.

Eruptive Cherry Hemangiomatosis Associated With Multicentric Castleman Disease A Case Report and Diagnostic Clue

BACKGROUND Eruptive cherry hemangiomatosis, which involves the sudden onset of multiple small vascular proliferations, has been rarely reported as a heralding sign of multicentric Castleman disease (MCD) and other lymphoproliferative diseases. We report a case wherein the rapid appearance of cherry hemangiomata is the presenting sign of MCD. OBSERVATIONS A 25-year-old man with a 10-year history of benign vascular growths developed 23 cutaneous vascular proliferations and systemic symptoms 5 days prior to presentation. Biopsy of the cutaneous lesions revealed a polypoidal proliferation of vessels consistent with cherry hemangiomata. Laboratory studies disclosed systemic abnormalities, and the findings of a subsequent lymph node biopsy confirmed MCD. Combination chemotherapy was initiated, and the cutaneous proliferations improved in association with the systemic disease. CONCLUSIONS There is a scarcity of literature describing the association between eruptive cherry hemangiomatosis and MCD. The likely underlying mechanism is hypersecretion of vascular endothelial growth factor secondary to an elevated interleukin 6 level. Failure to recognize this association may have led to diagnostic delays. The authors suggest careful evaluation and follow-up of all patients presenting with the sudden onset of cherry hemangiomata, particularly with systemic symptoms, lymphadenopathy, or other benign vascular endothelial growths, for the potential development of MCD and other lymphoproliferative diseases.

Clinical and pathological characteristics of HIV-and HHV-8-negative Castleman disease

Castleman disease (CD) comprises 3 poorly understood lymphoproliferative variants sharing several common histopathological features. Unicentric CD (UCD) is localized to a single region of lymph nodes. Multicentric CD (MCD) manifests with systemic inflammatory symptoms and organ dysfunction due to cytokine dysregulation and involves multiple lymph node regions. Human herpesvirus 8 (HHV-8) causes MCD (HHV-8-associated MCD) in immunocompromised individuals, such as HIV-infected patients. However, >50% of MCD cases are HIV and HHV-8 negative (defined as idiopathic [iMCD]). The clinical and biological behavior of CD remains poorly elucidated. Here, we analyzed the clinicopathologic features of 74 patients (43 with UCD and 31 with iMCD) and therapeutic response of 96 patients (43 with UCD and 53 with iMCD) with HIV-/HHV-8-negative CD compared with 51 HIV-/HHV-8-positive patients. Systemic inflammatory symptoms and elevated inflammatory factors were more common in iMCD patients than UCD patients. Abnormal bone marrow features were more frequent in iMCD (77.0%) than UCD (45%); the most frequent was plasmacytosis, which was seen in 3% to 30.4% of marrow cells. In the lymph nodes, higher numbers of CD3+ lymphocytes (median, 58.88 ± 20.57) and lower frequency of CD19+/CD5+ (median, 5.88 ± 6.52) were observed in iMCD patients compared with UCD patients (median CD3+ cells, 43.19 ± 17.37; median CD19+/CD5+ cells, 17.37 ± 15.80). Complete surgical resection is a better option for patients with UCD. Siltuximab had a greater proportion of complete responses and longer progression-free survival (PFS) for iMCD than rituximab. Centricity, histopathological type, and anemia significantly impacted PFS. This study reveals that CD represents a heterogeneous group of diseases with differential immunophenotypic profiling and treatment response.

The collaborative network approach: a new framework to accelerate Castleman's disease and other rare disease research

Despite technological advances and substantial investments of time and funding, many challenges exist for rare disease research and drug development. Basic disease mechanisms are often poorly understood, selection of suitable research participants can be diffi cult, and endpoints for clinical trial registration might not be established. Progress is further impeded by limited collaboration and data coordination, misaligned incentives, funding decisions made in isolation from community consensus, and inter-institutional barriers to tissue sharing. Although frequently used, off -label treatments are infrequently tracked, and thus valuable opportunities to build on observations are lost. One coauthor (DCF) comments, “Despite being a physician, I didn’t fully understand the barriers that slowed down life-saving progress until I was dying from a rare illness. I received my last rites in 2010 while battling idiopathic multicentric Castleman’s disease and found that [the disease] had no Food and Drug Administration [FDA]-approved therapies, a poorly understood model of pathogenesis, and a 65% 5-year survival rate”. After surviving three life-threatening episodes, DCF began to assess how non-profi t research funding was allocated for rare diseases, for which 95% of conditions do not have an FDA-approved therapy. Disease research organisations (DROs) make important contributions by funding research. However, the framework through which many (but not all) DROs traditionally distribute funding can present challenges (fi gure). DROs typically fundraise fi rst and then invite researchers to apply through a request for proposals (RFP) to use the funding for their specifi c purposes. In parallel, these organisations often provide patients with supportive resources and facilitate referrals to experts, who collect and store clinical data and biomaterials at their respective institutions. This model can in some cases result in organisations funding studies targeted at questions proposed by a small selection of researchers with requisite tissue samples rather than the studies that may have the highest impact on the fi eld, which might require collaboration and sample sharing. A more effi cient, collaborative, and consensus-driven framework than exists at present is needed to fully harness the opportunities aff orded by technological advances for the approximately 7000 rare diseases and 350 million individuals affl icted globally. One such neglected rare condition is Castleman’s disease, which describes a heterogeneous group of lymphoproliferative disorders straddling the fi elds of immunology, oncology, and virology. Castleman’s disease ranges from a single region of enlarged lymph nodes (unicentric Castleman’s disease) to multicentric lymphadenopathy with systemic infl ammation and multiple organ system dysfunction (multicentric Castleman’s disease) caused by immune activation and proinfl ammatory hypercytokinaemia, often including interleukin 6. Multicentric Castleman’s disease is either caused by human herpesvirus 8 (HHV8) infection, which is called HHV8-associated multicentric Castleman’s disease, or is idiopathic in HHV8-negative patients and called idiopathic multicentric Castleman’s disease. The absence of a unique international classifi cation of disease (ICD) code for Castleman’s disease has made epidemiological studies diffi cult. The estimated incidence of all forms of Castleman’s disease is 6500–7700 individuals of all ages every year in the USA or about 2·2 per 100 000.

Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease

Human herpes virus-8 (HHV-8)-negative or idiopathic multicentric Castleman disease (iMCD) is a rare and deadly disorder that sits at the nexus of hematology/oncology, virology and immunology. Management of iMCD has been challenging due to limited understanding of etiology and pathogenesis and few treatment options. The recent approvals in North America, Europe and Brazil of siltuximab, a monoclonal antibody against IL-6, for iMCD now provide a safe and effective therapy that targets a key aspect of pathogenesis. In the first ever randomized, placebo-controlled trial in iMCD, siltuximab significantly reduced disease burden and symptoms in a large portion (34%) of patients. The optimal dose is 11 mg/kg intravenously every 3 weeks. At this time, duration of treatment is often life-long or until treatment failure. Additional research is needed to identify biomarkers that may assist with predicting treatment effectiveness in iMCD and to investigate the role of siltuximab in HHV-8-positive MCD and pediatric iMCD patients.

TAFRO Syndrome in Caucasians: A Case Report and Review of the Literature

Background TAFRO syndrome has been reported in Japan among human herpesvirus 8 (HHV-8)-negative/idiopathic multicentric Castleman’s disease (iMCD) patients. To date, the majority of iMCD patients with TAFRO syndrome originate from Japan. Case presentation Herein, we report a 67-year-old HIV/HHV-8-negative Caucasian iMCD patient diagnosed with TAFRO. He presented with marked systemic inflammation, bicytopenia, terminal renal insufficiency, diffuse lymphadenopathies, and anasarca. Lymph node and bone marrow biopsies revealed atrophic germinal centers variably hyalinized and megakaryocytic hyperplasia with mild myelofibrosis. Several other biopsies performed in kidneys, liver, gastrointestinal tract, prostate, and lungs revealed unspecific chronic inflammation. The patient had a complete response to corticosteroids, tocilizumab, and rituximab. He relapsed twice following discontinuation of rituximab. When reviewing the literature, we found seven other Caucasian cases with TAFRO syndrome. There were no significant differences with those described by the Japanese cohort except for the higher frequency of kidney failure and auto-antibodies in Western patients. Conclusion This case illustrates that patients with TAFRO syndrome can develop non-specific inflammation in several tissue sites. Furthermore, this case and our review of the literature demonstrate that TAFRO syndrome can affect Caucasian and Japanese patients highlighting the importance of evaluating for this syndrome independently of ethnic background.

The full spectrum of Castleman disease: 273 patients studied over 20 years

The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria. Twenty of these patients with Castleman‐like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy). Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV‐8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV‐8 negative/idiopathic multicentric CD (iMCD). 2‐(18F)fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline‐vascular histopathological features, and most patients were asymptomatic. Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV‐8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV‐8+ MCD, particularly in HIV‐infected patients.

TAFRO syndrome: New subtype of idiopathic multicentric Castleman disease

Castleman disease (CD) describes a group of three rare and poorly understood lymphoproliferative disorders that have heterogeneous clinical symptoms and common lymph node histopathological features. Unicentric CD (UCD) involves a single region of enlarged nodes. Multicentric CD (MCD) involves multiple regions of enlarged lymph nodes, constitutional symptoms, and organ dysfunction due to a cytokine storm often including interleukin 6. MCD is further divided into Human Herpes Virus-8 (HHV-8)-associated MCD, which occurs in immunocompromised individuals, and HHV-8-negative/idiopathic MCD (iMCD). Recently, iMCD has been further sub-divided into patients with TAFRO syndrome, which involves thrombocytopenia (T), anasarca (A), fevers (F), reticulin myelofibrosis (R), organomegaly (O), and normal or only slightly elevated immunoglobulin levels, and those who do not have TAFRO syndrome. Non-TAFRO iMCD patients typically have thrombocytosis, less severe fluid accumulation, and hypergammaglobulinemia. iMCD patients with TAFRO syndrome may have a worse prognosis, but more research is needed.

Potential value of FDG PET-CT in diagnosis and follow-up of TAFRO syndrome

Dear Editor, Beginning in 2010, Takai and other Japanese physicians described a group of patients with a common set of clinical features, including thrombocytopenia (T), ascites (A), myelofibrosis (F), renal dysfunction (R), and organomegaly (O), hence TAFRO [1]. The majority of initial case reports were reported from Japan [2–4]. More recently, TAFRO syndrome has been reported in non-Asian patients around the world. TAFRO syndrome is considered to describe a sub-type of idiopathic multicentric Castleman disease (iMCD) that shares common symptoms and laboratory abnormalities due to a cytokine storm [5]. Whereas human herpes virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is not known, hence idiopathic MCD (iMCD) [6]. Patients present with heterogeneous clinical features and often deadly multiple organ dysfunction. Lack of familiarity with the disease is a major challenge for clinicians often resulting in delay or lack of proper treatment leading to death [7]. Imaging modalities, such as 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), CT, and ultrasound, are commonly used as part of the work-up in these patients to reach a diagnosis; however, no specific imaging diagnostic criteria have been suggested. Herein, we present the first-reported Hispanic case and a Caucasian case of TAFRO syndrome with iMCD. Both cases received PET-CTas a part of their work-up and evaluation.We discuss findings and potential benefits of PET-CT over CT.