Nationwide Survey of Hemophagocytic Lymphohistiocytosis in Japan

Abstract

Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

“…Secondary HLH is associated with a variety of infections, autoimmune diseases and malignancies. Epstein-Barr virus (EBV)-associated HLH (EBV-HLH) is the most frequent subtype of HLH in Japan [4]. Establishing a diagnosis of HLH may be difficult when based solely on clinical and laboratory findings, because those findings are often present in severely ill patients.…”

Hemophagocyte Lymphohistiocytosis Secondary to Bilateral Epididymal Diffuse Large B-Cell Lymphoma

“…Although HLH is extremely rare in Western areas of the world, it is common in Asia. In Japan, the annual incidence of HLH was estimated as 1 in 800,000 per year (primarily the acquired form) [3]. HLH was the most common in NK/ T cell lymphoma (i.e., up to 24.7 %) [10].…”

“…Importantly, survival has been shown to be dependent on the type of lymphoma. Indeed, B cell lymphoma has been reported to be much more favorable than T-NK cell lymphoma [3]. Machaczka [15] examined eight patients and found that only one patient with HLH-04 who was treated with an allogeneic stem cell transplant survived.…”

“…The acquired forms of HLH have been associated with infections, inflammatory diseases and malignancies. Lymphoma is the primary malignancy-related cause of HLH [2,3]; however, HLH secondary to lymphoma in a sanctuary site, such as the central nervous system, testis or epididymides, has not been reported. The present study reports a rare case of HLH secondary to bilateral epididymal lymphoma.…”

Between a rock and a hard place

“…The mutations identified to date lead to abnormalities in the perforin cytotoxic pathway causing decreased function of NK-and/or cTC, indicating a pivotal role of this event in the pathogenesis of HLH [2]. Recently, there have been increasing reports of adult onset HLH in the context of conditions associated with immune dysregulation: hematologic malignancies, infections, autoimmune diseases, organ/ stem cell transplants and chemo-or immunosuppressive therapies [3][4][5][6][7]. Some of the cases affecting young adults represent attenuated familial forms of the disease due to partial loss of function of the HLH-causing genes [8], while in older adults (>60 yr.) malignancy associated HLH is most common.…”