Histiocytosis encompasses a group of diverse proliferative disorders characterized by the accumulation and infiltration of variable numbers of monocytes, macrophages, and dendritic cells in the affected tissues of children and adults. Their clinical behavior ranges from mild to disseminated and, sometimes, life-threatening forms [1-3]. The first classification of histiocytosis, published in 1987 by the Working Group of the Histiocyte Society (HS), consisted of 3 categories: Langerhans cell (LC) or non-LC-related, and malignant histiocytosis (MH) . In 2010, a major breakthrough came with the discovery of recurrent
For several decades, LCH has been considered to be a reactive clonal proliferation of LCs. However, an ongoing debate over the grouping of LCH was finally settled in favor of neoplasm after the discovery of the
A diagnosis of LCH is made by typical positive staining with CD1a or CD207 . With the development of new technology for accurate detection of cell-free DNA,
The clinical manifestations of LCH depend on the organ involved and the extent of involvement. Bone is the most commonly involved organ; bony involvement is present in 80% of cases, and a painful bony lesion is the most common presentation. Skin is the second most frequently involved organ; the presentation may be a rash (generalized, papular, ulcerative, or vesicular) and/or seborrheic involvement of the scalp. Features of weight loss, diarrhea, edema, dyspnea, jaundice (conjugated hyperbilirubinemia), cytopenias, hepatosplenomegaly, lymphadenopathy, polydipsia, and polyuria indicate specific organ involvement. LCH of the central nervous system (CNS) can present as a neurodegenerative disease (ND-LCH) and/or intracranial tumorous lesions. Patients with ND-LCH may develop clinical symptoms of dysarthria, ataxia, dysmetria, and behavior changes. Due to its heterogenous presentation, from self-limited to disseminated disease, LCH has been clinically classified according to the number of lesions and sites of involvement coupled with the number of risk organs affected . At present, patients of LCH are risk-stratified according to the extent of disease [single system versus (vs.) multisystem] and risk organ (RO) involvement (presence or absence of involvement of the liver, spleen, or bone marrow), in which “risk” refers to higher risk of mortality .
(2) Multisystem LCH
(3) High-risk LCH
The current standard therapy for high-risk LCH consists of treatment with vinblastine, prednisone, and mercaptopurine for 1 year based on the LCH-III trial . Prolongation of the treatment duration from 6 months in LCH-II to 12 months in LCH-III was beneficial. But, adding etoposide (LCH-II) and methotrexate (LCH-III) did not improve the response or relapse-free survival of high-risk patients [22,23].(4) CNS lesion
Diabetes insipidus (DI) is the most frequent initial sign of LCH in the CNS . Due to risks of pituitary biopsy, it is reasonable to initiate LCH therapy empirically in such patients and monitor for early response by brain magnetic resonance imaging (MRI). Mass lesions of the brain may respond to vinblastine/prednisone, cladribine, cytarabine, and clofarabine [25,26].
A brain MRI demonstrates hyperintensity of the dentate nucleus and white matter of the cerebellum on FLAIR and T2-weighted images, or hyperintense lesions of the basal ganglia on T1-weighted images . Intravenous g-globulin (IVIG) and retinoic acid have been reported to stabilize progression of ND-LCH [28,29]. Some studies reported that vincristine/cytarabine was associated with improvement in clinical symptoms and MRI images . In LCH-IV study, additionally the effectiveness of 2-CdA in tumorous CNS-LCH and of IVIG and intravenous cytarabine (Ara-C) in ND-LCH will be prospectively studied.
With the identification of
The ongoing LCH-IV trial has broad goals that aim to determine optimal therapy for all patients, as stratified: high-risk multisystem, low-risk multisystem, low-risk single system, and LCH with special site involvement, particularly focusing on the difficult problem of diffuse CNS disease. The randomized studies in the LCH-IV protocol strive to optimize the outcomes of first line treatments by testing prolonging (12 vs. 24 months) and intensifying (6-mercaptopurine) treatment of high risk patients, and by comparing treatment duration (6 vs. 12-months) for single system disease. The protocol is also testing a randomized study of new combinations as second-line treatment for those individuals with low-risk disease either reactivating or not initially responding. Targeted therapy must be considered not as a replacement but as additional tool that should be used judiciously. The choice of the optimal timing of targeted therapy (as salvage, up-front, or maintenance) and whether it should be treated alone or combination with chemotherapy needs to be studied.
HLH is a syndrome describing patients with severe systemic hyperinflammation that it is characterized by unremitting fever, cytopenias, hepatosplenomegaly, coagulopathy, and elevations in typical biomarkers including ferritin and soluble interleukin-2 receptor (sIL-2R). The high mortality rate makes prompt recognition and treatment of this hyperinflammatory syndrome essential . HLH is classified into primary and secondary forms. Primary HLH is a hereditary immune disorder, whereas secondary HLH develops as a complication in various conditions such as infection, malignancy, autoimmune disease, and post-HSCT [45,46].
Patients with active HLH have markedly elevated serum inflammatory cytokines, namely, interferon (IFN)‐g, tumor necrosis factor (TNF)‐α, IL‐1β, IL‐2, IL‐6, IL‐12, IL‐16, and IL‐18 . This cytokine storm arises from the excessive secretion of cytokines by uncontrolled activated cytotoxic T lymphocyte (CTL) and natural killer (NK) cells that in turn hyperactivate macrophages. Of the various cytokines that are elevated in HLH, IFN‐g plays a particularly key role in the development of HLH [47,48].
The HS established a set of clinical and laboratory criteria to help the diagnosis of the syndrome of HLH for its HLH-94 and 2004 clinical trials and this has been modified partly in 2009 [40-42]. However, the diversity of the clinical presentation of HLH has led to confusion. Patients presenting in early disease may not yet show 5 of 8 criteria, and some patients may never meet this criteria, including those with atypical presentations such as isolated CNS disease or acute liver failure [49-52]. Fever above 38.3°C is nearly universal in untreated HLH. While splenomegaly and hepatomegaly are very common in HLH, adenopathy is not . Cytopenias are ubiquitous in HLH. Lack of cytopenias should make one doubt a diagnosis of HLH, except in the special case of isolated, CNS-only disease . Some laboratory tests are used to help in the diagnosis of HLH and are also useful biomarkers for disease activity monitoring. Most patients have much higher levels of ferritin than the threshold suggests (>500 μg/L); however, serum ferritin is also driven by iron overload states and can be elevated in many inflammatory contexts. A serum ferritin level greater than 500 μg/L is over 90% sensitive, but its specificity is only robust at levels greater than 2,000-10,000 μg/L, and in adults, levels greater than 10,000 μg/L are still most commonly associated with malignancy [54,55]. Recently, higher levels of ferritin (e.g.,>3,000 μg/L) have been suggested . One study compared 123 patients with HLH to 320 patients with other hyperferritinemic conditions. At 2,000 μg/L, a trade-off was reached with sensitivity at 70% and specificity at 68% for HLH in that study . Elevated sIL-2R should always be observed in untreated HLH since T-cell activation in central to HLH pathogenesis [58,59]. However, an extremely elevated sIL-2R (>10 to 20-fold above normal) in noninfantile patients suggests undiagnosed lymphoma, especially when ferritin is not similarly elevated [60,61]. Very low or absent NK cell function can indicate a genetic HLH disease, but, other acute illness and various treatments can also temporarily impair NK numbers and function, and a low result has been found to have poor specificity (43%) [62, 63]. A recent study reported that perforin and CD107a tests are more sensitive and no less specific compared with NK cytotoxicity testing for screening for genetic HLH and suggested they be considered for addition to current HLH criteria . New laboratory options such as IL-18 levels, which reflect inflammasome activation, or CXCL9, which indicates pathway activity, and IFN‐g are being more frequently used. A total IL-18 level greater than 24,000 pg/mL distinguished MAS from primary HLH with 83% sensitivity and 94% specificity, and the ratio of IL-18 to CXCL9 has been used to differentiate patients with rheumatologic disease and MAS from patients with HLH. IL-18 binding protein (IL-18BP) was found to be more elevated in FHL and malignancy-associated HLH . Work-up of some other cytokines such as IL-10 and IFN‐g can be helpful in the differential diagnosis of HLH from sepsis [65,66]. The sensitivity and specificity of these biomarkers in the diagnostic criteria should be elucidated and updated through evidence-based international consensus and further study. Fig. 1 displays an updated diagnostic algorithm for consideration of HLH in suspected patients.
Immediate treatment of HLH is generally warranted once a diagnosis is made, while it is important to rule out HLH disease mimics or malignancies before starting therapy in order to avoid inappropriate treatment and/or obscuring the underlying diagnosis . The mainstays of HLH treatment consist of immunosuppressive, chemotherapeutic agents and biologics that aim to control the cytokine storm and eliminate activated T-cells and macrophages .(1) Chemoimmunotherapy
Currently, standard therapy for HLH consists of dexamethasone and etoposide based on the experience of the HS HLH-94 and HLH-2004 studies [67,68]. The 5-year overall survival (OS) rate in children with (n=168) and without (n=201) family history/genetically verified primary HLH was 59% and 64%, respectively . The HS recently published formal recommendations for the use of etoposide-based treatment, and CSA upfront therapy in HLH-2004 is no longer recommended due to toxicity, and the HLH-94 is the standard of care . Though aggressive treatment is needed for most patients, initial therapy with dexamethasone alone with close monitoring may be appropriate before starting etoposide in patients who are not infants and not severely ill . Patients with CNS involvement receive additional intrathecal treatment with methotrexate and steroid, and need treatment of seizures or therapies for specific neurologic deficits . Treatment of HLH should be accompanied by appropriate therapy of the identified underlying trigger. Rituximab containing chemoimmunotherapy can be helpful in the treatment of EBV-HLH [70-72]. IVIG, therapeutic plasma exchange, and/or corticosteroids may be used to temper cytokine storm while the work-up continues. Anakinra (recombinant IL-1 receptor antagonist) can be used for secondary HLH, especially when given early in the disease course . Anakinra is currently being studied in a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT02780583) to test its safety and efficacy in the treatment of secondary HLH/MAS in children and adults. Patients with multi-organ failure may require organ-specific therapy.(2) Treatment of CNS-HLH
The clinical presentation of CNS disease in HLH is highly variable. Furthermore, occurrence of neurological symptoms is not included as a diagnostic criteria of HLH. However, it is important to suspect HLH in a child with unexplained neurologic manifestations, especially patients with fever, cytopenia, and hepatosplenomegaly. To make a diagnosis of CNS-HLH, a lumbar puncture with cerebrospinal fluid (CSF) analysis and MRI should always be done in all cases regardless of the presence or absence of neurological signs or symptom . Treatment options for CNS-HLH include, those commonly used in systemic HLH, including corticosteroids, etoposide, cyclosporine A, anti-thymocyte globulin (ATG), and alemtuzumab. In addition, intrathecal treatment with methotrexate and corticosteroids has become a standard care and is likely to be beneficial . Therapy must be started without delay to prevent late effects in HLH. An ongoing trial (NCT01818492) is an anti-IFN-g antibody (NI-0501), which is currently being tested. Another very promising agent is the Janus kinase (JAK)1/2 inhibitor ruxolitinib shown in a recent study of two murine models of HLH to be effective. In the Rab27a-/-mice, CNS involvement was significantly reduced with ruxolitinib therapy . HSCT also represents an important CNS-HLH treatment .(3) HSCT
HSCT is mandatory in patients with primary HLH, recurrent or progressive HLH despite recommended chemoimmunotherapy, and CNS involvement [56,67,78-80]. The pediatric HLH-94 trial reported a 5-year OS of 66% of those who underwent HCT . Other studies reported similar outcomes with 5-year OS ranging from 49% to 64% with myeloablative conditioning (MAC) approaches, with the vast majority of mortality occurring in the first 6 months after HCT [82,83]. Several studies also note feasibility of umbilical cord transplant for HLH, with retrospective series reporting 65% to 71% long-term OS [84, 85]. The Cincinnati Children’s group showed potential superiority of reduced intensity conditioning (RIC) for HLH in a retrospective review which identified 43% estimated 3-year survival for patients transplanted with MAC (n=14) compared with 92% for patients transplanted with RIC (n=26) in 2010 . RIC regimens are generally recommended as they are associated with better survival, though they can be complicated by high rates of mixed chimerism and graft failure since then [87,88]. Future study with the RIC approach is expected to improve the level and stability of donor engraftment. To avoid delays in proceeding to HSCT, human leukocyte antigen (HLA) typing and initiation of the stem cell donor search should be done as soon as it is suspected that a patient has a genetic form of HLH.(4) Salvage therapy
It is clear that approximately 25-50% of patients will fail to achieve a complete response to standard therapy and may require additional treatment with the same drugs or alternative “salvage” agents. Relapses may respond to intensification of standard therapy, or may require additional or alternative therapies .
HLH in children remains a challenge, but significant advances have been made in the last 20 years. Advances in rapid screening diagnostics makes it possible to quickly evaluate patients for many inherited diseases, and newer biomarkers are helping to elucidate the physiologic processes in patients with HLH. Novel targeted treatment agents are being developed. Well-designed clinical trials through international cooperation between investigators will bring further improved outcomes for patients with HLH.
The author has no conflict of interest to declare.