Page 53 - Haematologica Atlas of Hematologic Cytology

CHAPTER 6 - Hemophagocytic syndrome
Chapter 6. HEMOPHAGOCYTIC SYNDROME
A spectrum of proliferative histiocytic disorders ranging from true malignant histiocytosis to potentially self-li- miting syndromes, such as hemophagocytic syndrome (HS), has been recognized. Hemophagocytic syndromes include primary (familial) and secondary conditions characterized by uncontrolled T-cell and macrophage activa- tion and phagocytosis of red cells, platelets, granulocytes or precursors in the histiocytes of bone marrow, spleen or lymph nodes. Familial hemophagocytic lymphohistiocytosis (FHL) is a heterogeneous, generally autosomal recessive genetic disorder that affects very young children often within the first three months of life. Most cases are due to mutations in the perforin gene (PRF1) or in genes involved in the pathways leading to perforin delivery; other cases are linked to chromosome 9q21.3-q22 (Table 1). Male patients with mutations in SH2DIA, the gene responsible for X-linked lymphoproliferative disease, have also been reported. However, in some familial cases, the genetic defect has not yet been defined (Sieni et al., 2014).
Table 1. Genetic classification of familial hemophagocytic lymphohistiocytosis (FHL) (Sieni et al., 2014).
Secondary forms can be reactive to an underlying infection, particularly in immunocompromised hosts. They have also been reported in association with malignancies such as cancer and lymphomas (Table 2).
Table 2. Conditions associated with hemophagocytosis.
Infection
Viral (e.g. herpesviruses, adenoviruses, cytomegalovirus) Bacterial, especially tuberculosis
Fungal
Parasitic
Tumors
Hematologic (lymphoma)
Other
Drugs Phenytoin
According to the International Histiocyte Society (Henter et al., 2007), at least five of the following eight crite- ria must be fulfilled for establishing the diagnosis, unless a patient has a molecular anomaly consistent with fami- lial hemophagocytic lymphohistiocytosis: fever, cytopenia (2 or 3 lineages), splenomegaly, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis (phagocytosis of red cells, platelets, granulocytes or precursors in the histiocytes of bone marrow, spleen or lymph nodes), low or absent natural killer (NK) lymphocyte activity, hyperferritinemia and high levels of soluble IL-2 receptor.
Both familial and Epstein-Barr virus (EBV)-associated HS are often lethal disorders; they can only be cured by hematopoietic stem cell transplantation.
The HS immune dysfunction consists in an absent or reduced cytotoxic T- and NK-cell activity and in hype- ractivation of T lymphocytes and macrophages. Whatever the pathogenic mechanism, unrestricted release of inflammatory cytokines, such as interferon, tumor necrosis factor, soluble IL-2 receptor, IL-10 and IL-12, accounts for many of their clinical features.
Subtype
Mutated gene
Locus
ected protein
FHL1
Unknown
9q21.3-22
Unknown
FHL2
PRF1
10q21-22
Perforin
FHL3
UNC13D
17q25.1
Munc13-4
FHL4
STX11
6q24
Syntaxin 11
FHL5
STXBP2
19p13
Munc18-2
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