Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of cytokine-driven immune activation. Cardinal features include fever, hemophagocytosis, hepatosplenomegaly, lymphocytic infiltration, and hypercytokinemia that result in multisystem organ dysfunction and failure. Familial HLH is genetically driven, whereas secondary HLH (SHL) is caused by drugs, autoimmune disease, infection, or cancer. SHL is associated with worse outcomes, with a median overall survival typically of less than 1 year. This reflects difficulty in both diagnostic accuracy and in establishing reliable treatments, especially in cases of malignancyinduced SHL, which have significantly worse outcomes. Malignancy-induced HLH is seen almost exclusively with hematologic malignancies, constituting 97% of cases in the literature over the past 2 years. In these situations, the native immune response driven by CD8 T cells produces an overabundance of T helper 1 cytokines, notably interferon-g, tumor necrosis factor-a, and interleukin-6, which establish a positive feedback loop of inflammation, enhancing replication of hematologic malignancies while leaving the host immune system in disarray. In this paper, we present 2 case studies of secondary HLH driven by HM, followed by a review of the literature discussing the cytokines driving HLH, diagnostic criteria, and current treatments used or undergoing investigation. Case 1A previously healthy 34-year-old male presented with progressive malaise, fevers, and abdominal discomfort. He was found to have massive splenomegaly along with pancytopenia and coagulopathy. Initial laboratory studies showed lactate dehydrogenase (LDH) 470 U/L, ferritin 4450 ng/dL, white blood cell count 1.3 3 10 9 /L, platelets 31 3 10 9 /L, hematocrit 22%, and fibrinogen level 130 mg/dL. A bone marrow (BM) biopsy was performed and showed lymphohistiocytic aggregation without hemophagocytosis. The patient underwent splenectomy; pathology showed splenic red pulp congestion and proliferation of sheets of normal histiocytes with marked erythrophagocytosis. No conclusive evidence of B-or T-cell lymphoma was found at that time, although features suggestive of but not diagnostic for T-cell rich diffuse large B-cell lymphoma (DLBCL) were seen in the spleen. The patient subsequently had a positron emission tomography/computed tomography scan and was found to have small hyperactive para-aortic lymph nodes that were not accessible for biopsy. The patient began therapy for HLH with dexamethasone and etoposide for 6 cycles and tolerated it well, with resolution of his laboratory abnormalities and symptoms.A year and a half after initial diagnosis, he presented to the hospital again with back pain and fevers. A computed tomography scan showed multiple retroperitoneal and periaortic lymph nodes along with liver lesions. He was started on dexamethasone and admitted to the hospital. Multiple lymph node biopsies were performed and were inconclusive, possibly from steroid pretreatment. Further evaluation with bilateral BM biopsies reported T-cell rich ...

A case of hemophagocytic syndrome progressing into large granular lymphoma in a dog

“…Few reports of HPS in dogs have been published, and canine HPS is challenging to diagnose either clinically or cytologically . In human medicine, HPS is divided into two subcategories: primary hemophagocytic lymphohistiocytosis and macrophage activation syndrome . The development of primary hemophagocytic lymphohistiocytosis is caused by gene abnormalities of cytotoxic T cells and natural killer cells .…”

“…In human medicine, HPS is divided into two subcategories: primary hemophagocytic lymphohistiocytosis and macrophage activation syndrome . The development of primary hemophagocytic lymphohistiocytosis is caused by gene abnormalities of cytotoxic T cells and natural killer cells . Macrophage activation syndrome is HPS secondary to neoplastic diseases, such as T‐cell lymphoma, autoimmune disease, or infectious disease .…”

“…Macrophage activation syndrome is HPS secondary to neoplastic diseases, such as T‐cell lymphoma, autoimmune disease, or infectious disease . Both subcategories are known to cause a cytokine storm that is defined as abnormal production of inflammatory cytokines including interferon‐ɤ, interleukin (IL)‐6, ‐12, and ‐18, and tumor necrosis factor‐α . In addition, activated macrophages are known to produce serum ferritin .…”

“…In addition, activated macrophages are known to produce serum ferritin . Therefore, in humans, elevated serum ferritin and soluble IL‐2 receptor levels are helpful in diagnosing HPS . Unfortunately, soluble IL‐2 receptor and ferritin serum levels cannot be measured in veterinary medicine in Japan.…”

Hemophagocytic Lymphohistiocytosis and Inflammatory Bowel Disease: Case Report and Systematic Review

“…Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe systemic syndrome characterized by a rapidly progressive generalized inflammatory response associated with the release of pro-inflammatory cytokines and the Balbinot/Balbinot/Soldera Inflamm Intest Dis 2020;5:49-58 50 DOI: 10.1159/000506514 activation of the immune system. It can be mistaken for sepsis due to similar clinical characteristics [1]. Thus, HLH is a differential diagnosis to be considered in cases of multiple system organ failure in the presence of hepatosplenomegaly and pancytopenia.…”