1. GENERAL INFORMATION
1.1 Epidemiological data
There are two major forms of hemophagocytic lymphohistiocytosis (HLH), a primary form (familial hemophagocytic lymphohistiocytosis, abbreviated to FHL or FHLH) and secondary hemophagocytic lymphohistiocytosis (sHLH). In an extensive Swedish study the incidence of primary (familial) hemophagocytic lymphohistiocytosis in children was estimated to be 0.12 per 100,000 children per year, corresponding to 1:50 000 live-born children (Henter 1991b). In the majority the onset occurs during the first 2 years of life, but the primary form has also been reported in adolescents. The male to female frequency ratio of FHL is around 1:1. “Secondary” HLH (sHLH) may occur at any age, commonly in association with infections and/or malignancy.
1.2 Etiologic and risk factors
Primary (familial) hemophagocytic lymphohistiocytosis is an autosomal recessive disease. By homozygosity mapping two loci for FHL have been identified, one each at 9q21.3-22 (FHL1) (Ohadi 1999) and 10q21-22 (FHL2) (Dufourcq-Lagelouse 1999). Subsequently, the chromosome 10q21-22 locus was shown to be the gene encoding perforin (PRF1) (Stepp 1999), an important mediator of cellular cytotoxicity, and a number of mutations in the perforin gene have now been identified. In an analysis of 34 families, it was estimated that 20-40% of children suffering from FHL could be explained by perforin mutations (Goransdotter 2001). Little is known about the gene located on 9q 21.3. Moreover, a third gene causing FHL has been reported, UNC13D encoding the protein Munc13-4. Lymphocyte cytotoxicity requires the rapid transfer of perforin containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane, and Munc 13-4 is essential for this function. Hence UNC13D mutations (the gene is mapped to 17q25) also cause FHL ( Feldmann 2003). More recently, mutations in the gene syntaxin11 (STX11) (at chromosome 6q24) encoding the protein syntaxin-11 has also been shown to cause FHL (zur Stadt 2005). NK cells from patients with STX11 mutations fail to degranulate the perforin-containing granulae when encountering susceptible target cells (Bryceson 2007). It is important to be aware that the onset of FHL is often associated with, and possibly precipitated by, an infection. Secondary HLH may be also associated with infections (usually viruses), sometimes in patients receiving immunosuppressive therapy (Risdall 1979). Another important association is with malignancies, malignancy-associated hemophagocytic syndrome (MAHS), most commonly with leukemias and non-Hodgkins lymphoma (NHL), often of T cell origin in young adults (20-40 years, and often of B cell origin in those more than 40 years old. An association with intravenous nutrition with lipid-containing solutions has also been reported (fat overload syndrome). HLH may also be secondary toLangerhans cell histiocytosis, with the two conditions occuring simultaneously. The knowledge of sHLH is now gradually increasing, and it appears to be related to more medical fields than previously thought (Janka 2007; Allen 2008; Henter 2008).
2. PATHOLOGY AND BIOLOGY
2.1 Biological data
In FHL (FHLH), there is an accumulation of macrophages and T-lymphocytes. A possible explanation for this pathologic finding is the deficiency in apoptotic triggering mechanisms that has been shown in a subset of affected children (Fadeel 1999 ). A perforin mutation results in a deficient perforin protein and, as a consequence, deficient apoptosis of lymphocytes, and deficient natural killer (NK) cell activity, both of which are typical of FHL. The hypercytokinemia, affecting cytokines such as IL-2, interferon-gamma and tumour necrosis factor alpha, is probably a secondary phenomenon, and contributes to the development of a number of the clinical features as well as to the hemophagocytosis (Henter 1991c). The perforin gene is a simple gene with in only three exons, of which only exon 2 and 3 are translated. Perforin is secreted from cytotoxic T lymphocytes and NK cells upon conjugation between effector and target cell (de Saint Basile 2003). In the presence of calcium, it is able to penetrate the membrane of the target cell, where it polymerizes to form a cell death-inducing pore (Darmon 1998). Pore formation leads to destruction of target cells by osmotic lysis and by allowing cellular entrance to granzymes, which trigger apoptosis ( Fadeel 1999). Mutations in the genes encoding Munc13-4 and syntaxin-11 result in deficient perforin secretion (Marcenaro 2006; Bryceson 2007; Ménager 2007; Rudd 2008). It is now known that several human inherited immune disorders are caused by molecular defects of the perforin-dependent cytotoxic process exerted by both T and NK lymphocytes, highlighting the important role of this lytic pathway in the control of lymphocyte expansion and homeostasis. These disorders include (a) X-linked lymphoproliferative syndrome (XLP), in which 60-70% of the patients have mutations in the gene SAP (SLAM-associated protein), also termed SH2-DIA (SH2-domain containing gene 1A) or DSHP (Nichols 1998; Dupre 2005), (b) Chédiak-Higashi syndrome, which is linked to the LYST-gene (lyzosomal trafficking regulator gene, 1q42) and (c) Griscelli syndrome type 2 which is linked to a gene on 15q21, RAB27a, a key effector of cytotoxic granule exocytosis that functions in association with Munc13-4 ( Ménasché 2000).
Affected organs, most commonly spleen, bone marrow, liver and lymph nodes, show a dense infiltrate of histiocytes with round nuclei and abundant cytoplasm and a variegate population of lymphocytes (Favara 1992; Ladisch 1997). Hemophagocytosis is often, although not always, detected. Histologic changes in the liver may be characteristic with infiltration by lymphocytes around portal spaces and some portal fibrosis. Hemophagocytosis by prominent Kupffer cells must be looked for carefully. However, hemophagocytosis, per se, is not diagnostic of HLH. Other criteria must also be fulfilled before the diagnosis is made.
2.3 Accuracy and reliability of pathological diagnosis
In hemophagocytic lymphohistiocytosis, a false negative pathological diagnosis is common, partly because the pathology itself is not specific. The organ most commonly sampled is bone marrow, but the initial examination may not be diagnostic in up to two thirds of cases. Serial marrow aspirates or biopsies days or weeks apart may be helpful. Alternatively, examination of an enlarged lymph node or the liver will often improve the reliability of the pathological investigation, but a liver biopsy may be assocaited with severe and potentially life-threatening bleedings. Importantly, it has by time become increasingly clear that evidence of hemophagocytosis is not a prerequisite for establishing the diagnosis hemophagocytic lymphohistiocytosis.
There is no generally accepted grading system for hemophagocytic lymphohistiocytosis.
3.1 Signs and symptoms
Hemophagocytic lymphohistiocytosis may affect a number of different organs, so signs and symptoms may be extremely variable (Janka 1983; Henter 1991a; Arico 1996). The symptoms occur during the first year of life in approximately 70% of children with primary hemophagocytic lymphohistiocytosis. Secondary hemophagocytic lymphohistiocytosis can affect all ages including adults. The most common symptoms are a fluctuant fever and progressive hepato-splenomegaly. Lymph node enlargement, jaundice and a maculopapular skin rash are less common. Central nervous system symptoms (irritability, convulsions, cranial nerve palsies, ataxia, neck stiffness and non-specific signs of increased intracranial pressure) are reported at diagnosis in 35-40% of the patients; abnormal CSF in half of the patients and either or both in about 60% ( Henter 1997b;Horne 2008). Common laboratory findings include cytopenias (particularly thrombocytopenia), hypertriglyceridemia, hypofibrinogenemia and decreased NK-cell functional activity (despite a normal number of NK-cells) (Henter 1991a; Schneider 2002; Bryceson 2007). Elevation of serum transaminases and ferritin is also frequent (Allen 2008; Henter 2008), as is hypercytokinemia, including elevated levels of tumour necrosis factor alpha (TNF-alpha), soluble CD25, and CD95 ligand.
3.2 Diagnostic strategy
To clinically establish the diagnosis hemophagocytic lymphohistiocytosis, guidelines with diagnostic criteria have been developed. The initial criteria were developed in 1991 and they were revised in the HLH-2004 treatment protocol ( Henter 1991a; Henter 2007). The 1991 criteria included five criteria, and in the 2004 modification of the diagnostic criteria it is suggested that the diagnosis can be established if five out of the altogether eight diagnostic criteria are fulfilled. These eight criteria are 1) fever, 2) splenomegaly, 3) bicytopenia (cytopenia in two or more of the three lineages: hemoglobin < 90g/L (in infants < 4 weeks: hemoglobin < 100 g/L), platelets 2400 U/ml) (Henter 2007). With a positive family history, the diagnosis of familial hemophagocytic lymphohistiocytosis is definitive (parental consanguinity is suggestive). The diagnosis of primary (familial) hemophagocytic lymphohistiocytosis can also be based on molecular findings, i.e. mutations in the genes PRF1, UNC13D and STX11 mentioned above. In addition, examination of serum transaminases (often elevated) (Schneider 2002) and of the spinal fluid (cell count and protein and also morphology/immunology of a cytospin preparation- with caution to exclude increased intracranial pressure before spinal tap) are also recommended. In some patients, that do not fulfil all the diagnostic criteria, it is emphasised that treatment may have to be commenced “in experienced hands” before overwhelming disease activity causes irreversible damage and/or makes a response to treatment less likely. As a screening technique one may consider, as a general diagnostic approach in HLH, to first study perforin expression by flow cytometry analysis, which will identify most patients with PRF1 mutations ( Kogawa 2002). Then, in patients with normal perforin expression, the degranulation capacity can be studied in order to identify patients with UNC13D, STX11 and RAB27A mutations (all associated with degranulation deficiencies) (Marcenaro 2006; Bryceson 2007; Ménager 2007; Rudd 2008). Because of difficulties in the differential diagnosis between primary and secondary forms, a thorough investigation for possible infections and occult malignancy, with a special emphasis on search for leukemias and non-Hodgkin’s lymphomas, is important. It must also be appreciated that it may sometimes be difficult to distinguish the EBV-driven X-linked lymphoproliferative syndrome (XLP) from hemophagocytic lymphohistiocytosis, both in children and in adults (Seemayer 1993; Nichols 1998). Among other differential diagnoses causing a hemophagocytic syndrome are Chédiak-Higashi syndrome and Griscelli syndrome typ 2; molecular diagnosis is now available for both these conditions.
3.3 Pathological diagnosis
In hemophagocytic lymphohistiocytosis, histopathological examination of affected tissue(s) is recommended to establish a diagnosis, but the findings may be difficult to interpret. Initial bone marrow examination is often not diagnostic and may only show erythroid hyperplasia, but serial aspirations days or weeks apart may be helpful. Typically, the specimen will show a mixed lymphohistiocytic infiltrate and accumulation. In later stages, lymphocyte depletion may develop. The cells involved have a morphologically normal appearance without cytological atypia. If initial bone marrow investigation is not diagnostic, examination of enlarged lymph nodes or the liver can be considered. Lymph nodes may be examined by fine needle aspiration biopsy. With regards to the liver, a larger biopsy may be considered in order to examine the portal zones, where a mixed lymphohistiocytic infiltration resembling chronic persistent hepatitis is highly indicative of hemophagocytic lymphohistiocytosis in children. In the case of liver biopsy (and particularly spleen biopsy), there is a considerable risk of severe bleeding. The procedure should only be carried out by an experienced team, meticulous control of coagulopathy and platelet numbers and function and after biopsy, close monitoring is essential. In the spinal fluid, mild to moderate pleocytosis may be seen (usually 50×106/L) and, in about half of the children, a hyperproteinemia ( Horne 2008). Most of the cells are lymphocytes and macrophages. Evidence of hemophagocytosis is sometimes seen.
4.1 Staging classifications
There is no staging system for hemophagocytic hymphohistiocytosis. It is valuable, but often difficult, to distinguish primary disease (FHL, FHLH) from secondary forms (sHLH) (Henter 1991a;Henter 1997a; Henter 2007). Presently, a primary form can only be ascertained in affected children with a molecular diagnosis or if there are at least two affected members in the family. If there is no molecular abnormality, it is often not possible to state whether a disease affecting the first member of a kindred is familial or not, and it may appear to be sporadic despite, in fact, being a primary disease (FHL, FHLH).
4.2 Staging procedures
In principle, the HLH-2004 diagnostic criteria are to be evaluated (Henter 2007). Full blood count with differential, liver function tests, ferritin, plasma triglycerides, coagulation profile and plasma fibrinogen level should be assayed. Markedly elevated ferritin values are particularly specific for hemophagocytic lymphohistiocytosis (Allen 2008; Henter 2008). Bone marrow examination (searching for hemophagocytosis as well as differential diagnoses) and cerebrospinal fluid cell analysis – watch out for the risk of elevated intracranial pressure – should be performed in every patient. In addition, analysis of NK-cell activity is also recommended, and soluble CD25 levels are of interest if available. The NK cell activity deficiency can be classified into 4 subgroups (Schneider 2002). For patients in subgroup 3 it is highly likely that BMT is necessary for cure whereas there is no guidance with regard to the need of BMT for the other subgroups ( Horne 2005a). Furthermore, perforin expression by flow cytometry (Kogawa 2002) and evaluation of degranulation are also most valuable (Marcenaro 2006; Bryceson 2007; Rudd 2008). Obviously, genetic analyses for PRF1, UNC13D and STX11 as well as for other genes causing hemophagocytic syndromes may be appropriate. Importantly, some patients with missense mutations may have NK-cell activity levels that are not defined as abnormal. Chest X-ray (or CT) and abdominal ultrasound (or CT) are suggested. Other diagnostic procedures should be planned according to clinical presentation and specific symptoms. Early CT or, preferably, MRI of the brain should also be considered, since CNS involvement or its sequelae may cause irreversible CNS destruction or intra-cranial bleeding (Henter 1997b; Horne 2008).
5.1 Natural history
Without treatment, primary (familial) hemophagocytic lymphohistiocytosis (FHL, FHLH) is usually rapidly fatal, with a median survival of around 2 months from onset (Janka 1983). The usual course is characterised by intermittent high fever, progressive hepato-splenomegaly and pancytopenia, in many patients accompanied by progressive symptoms from central nervous system involvement (Janka 1983; Henter 1991b; Arico 1996; Henter 1998). Secondary hemophagocytic lymphohistiocytosis may resolve, with or without specific treatment, in particular if prior immunosuppressive therapy is withdrawn or underlying infections or malignancy are controlled (Janka 2007). However, mortality in sHLH is also reported to be high ( Janka 1998).
5.2 Prognostic factors
In primary hemophagocytic lymphohistiocytosis, an important prognostic factor is making the diagnosis early. A common cause of death is still the failure to make a correct diagnosis, with subsequent lack of appropriate treatment. Moreover, late diagnosis and onset of therapy will increase the risk and severity of the most important late sequele, neurological sequele secondary to CNS disease activity (Henter 1992; Haddad 1997; Henter 1997b; Horne 2008). With regards to pre-BMT chemotherapy, it has been suggested but not yet proven, that the response to the first two months of therapy is associated with a better survival. Since successful BMT is a prerequisite for cure, the availability of a suitable bone marrow donor is a “positive” prognostic factor. In EBV-associated HLH, early initiation of VP-16 (etoposide) is associated with improved survival in children as well as young adults ( Imashuku 2001; Imashuku 2003).
6.1 Hemophagocytic lymphohistiocytosis, primary form (sporadic or familial)
6.1.1 All patients
Initial induction treatment with VP-16 (etoposide), steroids and cyclosporin A, with or without intrathecal therapy, is standard treatment on a type C basis (recommendation of the International Histiocyte Society). The first prospective international treatment study (HLH-94) was initiated 1994 (Henter 2002), and the 2nd study (HLH-2004) was launched 2004 (Henter 2007). In HLH-2004, induction therapy includes VP-16, dexamethasone and cyclosporin A, with the addition of intrathecal therapy with methotrexate and cortocosteriods in patients in whom there was progressive neurologic deterioration after 2 weeks of systemic treatment. It is important to start induction therapy prior to the development of irreversible tissue destruction, particularly in case of CNS involvement ( Horne 2008). With this therapy most patients achieve clinical remission but BMT is necessary for cure. An alternative approach to achieve remission is the use of antithymocytic globulins (ATG), steroids, cyclosporin A, and intrathecal methotrexate (Stephan 1993; Mahlaoui 2007).
6.1.2 Maintenance therapy
Continuation therapy” is normally essential to maintain remission, and combined chemoimmunotherapy based on VP-16 and dexamethasone pulses, together with cyclosporin A, is a standard treatment on a type C basis (HLH-94 and HLH-2004 protocols recommended by the International Histiocyte Society) (Henter 1997a; Henter 2007). With this approach, most patients stay alive and relatively well until a bone marrow donor is identified, and BMT is performed.
6.1.3 Bone marrow transplantation
Allogeneic BMT is essential and the only possibility for cure and standard treatment on a type C basis (Fischer 1986; Bolme 1995; Jabado 1997; Henter 2002; Ouachée-Chardin 2006). It is not necessary per se that the patient is in complete remission at the time of BMT, but the results are better in patients with “quiet” disease (i.e. in more or less normal health and activity) at the time of BMT (Horne 2005b). Since primary HLH cannot be cured without BMT, child patients who do not have matched related or registry donors are recommended transplants with mismatched unrelated donors or haploidentical donors, on a type C basis (Horne 2005b; Ouachée-Chardin 2006). Importantly, a sustained remission can be achieved in patients with a donor chimerism at least 20% of leukocytes (Ouachée-Chardin 2006 ). In line, reduced intensity condition treatment can be considered, and pilot studies are promising (Cooper 2006).
6.1.4 Treatment results
The first international study on HLH (HLH-94) focused on patients aged less than 15 years that all either had an affected sibling and/or fulfilled the Histiocyte Society diagnostic criteria. The study revealed, at a median follow-up of 3.1 years, an estimated 3-year probability of survival of 55% overall (95% confidence interval +/-9%) and in the familial cases 51% (+/-20%). Twenty enrolled children were alive and off-therapy for >12 months without BMT, and thus presumed to be patients with secondary hemophagocytic lymphohistiocytosis. For patients who died prior to BMT (n=25), were transplanted (n=65), or were still on therapy (n=3), 3-year survival was 45% (+/-10%). The 3-year probability of survival after BMT was 62% (+/-12%) (Henter 2002 ). In a subsequent analysis on the outcome of BMT, the overall estimated three-year-survival post-BMT was 64% (n=86); 71% with matched related donors (n=24), 70% with matched unrelated donors (n=33), 50% with family haploidentical donors (n=16), and 54% with mismatched unrelated donors (n=13). In children with active disease after two-months of therapy (n=43), the estimated odds ratio for mortality was 2.75 (1.26-5.99) compared with non-active disease (n=43) (Horne 2005b). Based on a single-center study, the overall survival with ATG-based therapy followed by BMT was 55% (21/38) (Mahlaoui 2007). Importantly, in HLH-94 studies in children with active disease at BMT (n=37), the estimated odds ratio was 1.80 (0.80-4.06) compared to non-active disease (n=49), indicating that although patients with non-active disease at the time of BMT fared best, some persisting HLH activity should not automatically preclude performing a BMT (Horne 2005b ).
6.2 Hemophagocytic lymphohistiocytosis, secondary form
In patients with secondary hemophagocytic lymphohistiocytosis, definitive treatment of the underlying disease process (infection, malignancy) is standard option on a type C basis. In patients with infection-associated hemophagocytic lymphohistiocytosis, treatment of the associated infection is recommended on a type C basis, but the possibility of a primary hemophagocytic lymphohistiocytosis, elicited by the infection, has to be considered, and if the disease is severe, prolonged or recurrent, HLH-specific therapy is recommended on a type R basis. In newly diagnosed malignancy-associated hemophagocytic lymphohistiocytosis, the syndrome may resolve if the malignancy is controlled. In patients with ongoing cancer chemotherapy the situation is more difficult and one has to consider whether the “Hemophagocytic Syndrome” is due to reactivation of the malignancy or is secondary to the immunosuppression caused by the chemotherapy itself. In immunocompromised hosts, withdrawal of immunosuppressive therapy is recommended on a type C basis. In patients with disease progression despite the steps outlined above, treatment with VP-16 and steroids with or without intrathecal therapy is suitable for individual non standard clinical use on a type R basis ( Fischer 1985; Henter 2002).
7. LATE SEQUELAE
7.1 Treatment of late effects and sequelae
In hemophagocytic lymphohistiocytosis, late sequelae of CNS involvement may be severe and damage irreversible (Henter 2002; Haddad 1997; Henter 1997; Horne 2008). In a report from the HLH-94 study, altogether 16/107 (15%) of the survivors had neurological sequelae at a follow-up after a median of 5.3 years (Horne 2008). Progressive CNS symptoms prior to BMT must be considered as a sign of ongoing disease activity and treated promptly with systemic therapy.
7.2 Related and secondary tumours
In effect, hemophagocytic lymphohistiocytosis has now been shown to be a genetic disorder, not a cancer. However, primary hemophagocytic lymphohistiocytosis has been associated with the development of malignancies. More specifically, perforin mutations have been associated with the development of lymphomas, both Hodgkin and non-Hodgkin lymphomas (Clementi 2005). In addition, a few patients have developed myelodysplastic syndrome/acute myeloblastic leukaemia, considered to be secondary to prolonged treatment with VP-16 (Henter 1993). After BMT, post-transplant lymphoproliferative disease (PTLD) may occur.
8.1 General principles and objectives
The crucial point is to determine the degree of disease activity, since the risk of reactivation in inherited HLH is very high, particularly in patients not treated with BMT ( Henter 2002). After BMT, in addition to regular post transplant follow-up examinations including sustained engraftment, specific attention should be focused on CNS functions, since HLH involvement in the CNS prior to BMT may cause late CNS sequelae.
8.2 Suggested protocols
It is recommended that hemoglobin, WBC and platelets be determined initially at least every second week, with cytopenias as a possible sign of reactivation, usually with a falling platelet count as an early “marker”. Rising levels of serum transaminases, and triglycerides are other indicators of increasing disease activity, as are fever and splenomegaly. Increasing ferritin levels is also an important disease activity marker (Esumi 1989; Allen 2008). It is also important to watch for signs of CNS involvement, which warrant prompt therapy (Horne 2008). If secondary HLH was the suspected diagnosis and treatment has been stopped and the patient is in remission, the interval between blood counts can be increased as time goes by and stopped after 2 years when the risk of recurrence is minimal.
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Prof. Jan-Inge Henter (Author)
Karolinska Hospital – Stockholm, Sweden
Prof. Jon Pritchard (Reviewer)
Passed away on January 20th, 2007
Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy