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Advances in the management of histiocytic disorders 2011
SYMPOSIUM: ONCOLOGY
Advances in the management of histiocytic disorders 2011
Langerhans in 1868, who because of their dendritic processes, thought they were part of the nervous system. Whilst this did not prove to be the case, these epidermal APC were called Langerhans cells (LC). Other histiocytic cells have a primary role as tissue phagocytic cells (PC), cleaning up damaged or inflamed areas by ingesting and recycling foreign material and cellular debris. As with many rare diseases, the nomenclature for histiocytic disorders and their classification is complex and continually evolving as a result of increasingly sophisticated phenotypic, genotypic and functional analyses. There are various sub-classifications relating to function and morphology. For the purposes of this article Table 1 is based on the current clinical terms in common usage. Whilst this article will focus on Langerhans cell histiocytosis, significant progress in the understanding and treatment of other histiocytoses will be discussed.
Kevin Windebank Johannes Visser Vasanta Nanduri
Abstract Childhood histiocytoses span a range of illnesses that can present with a small skin or single bony lesion that may spontaneously regress or a systemic disease resulting in multiorgan failure and death. For practical purposes they can be classified into four groups: Langerhans cell histiocytosis (LCH), Non-Langerhans cell histiocytoses (Non-LCH), Haemophagocytic lymphohistiocytoses (HLH) and Histiocyte lineage-related malignancies. The establishment of diagnostic, staging and response criteria for LCH has enabled a series of international randomized clinical trials to be conducted that are the basis of current evidence based treatment. However, as with non-LCH, individual cases are often difficult to manage and require expert advice. Although in most cases the disease responds to treatment many children are left with significant permanent consequences commonly affecting the skeleton and endocrine system. Familial HLH is an inherited disease in which initial remission can be gained by chemotherapeutic or immunological strategies, but then requires allogeneic stem cell transplant for cure. There are a variety of leukaemias and sarcomas that are phenotypically derived from the histiocytic lineage. Treatment and outcomes for these are generally similar to those of the wider malignant spectrum.
Langerhans cell histiocytosis Pathology and classification In 1953, having identified similar abnormal histiocytic cells in € llereChristian eosinophilic granuloma, LetterereSiwe and Schu disease, Lichtenstein grouped them together under the single name of Histiocytosis X. Subsequently it was found that these abnormal histiocytes closely resembled epidermal Langerhans cells (LC) and the name Langerhans cell histiocytosis (LCH) was adopted. Although pathological LCH cells do share many features in common with normal epidermal LC, recent experimental findings suggest that they may result from oncogenic mutations in APC precursors of similar but distinct lineage. In particular, Rollins’ group has reported finding mutations in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in nearly 60% of a series of LCH cases tested. Interestingly so far, the presence of mutations has not correlated with the severity of the disease.
Keywords classification; complications; diagnosis; epidemiology; Langerhans cell histiocytosis; physiopathology; therapy
non-Langerhans
cell
histiocytosis;
Introduction
Classification of histiocytic disorders
The term histiocyte was first used to describe a type of tissue macrophage, but in time has taken on a broader meaning which embraces a wide variety of cells of monocyte/macrophage lineage including dendritic and phagocytic cells. Dendritic cells are antigen presenting cells (APC) that ingest foreign material, process their antigens and present them to lymphocytes thereby initiating an immune response. Characteristic APC populations are found in many organs but were first described in skin by Paul
Langerhans cell histiocytosis Non-Langerhans cell histiocytoses C Juvenile xanthogranuloma Family Cutaneous Juvenile xanthogranuloma Cutaneous and systemic Xanthoma disseminatum Systemic Erdheim Chester disease C Non-juvenile xanthogranuloma family Cutaneous Solitary reticulohistiocytoma Cutaneous and systemic Multicentric reticulohistiocytosis Systemic RosaieDorfman disease Haemophagocytic lymphohistiocytoses C Familial C Secondary (reactive) Histiocyte lineage-related malignancies C Leukaemias Acute myelomonocytic and monocytic Chronic myelomonocytic/juvenile myelomonocytic leukaemia C Monocytic and histiocytic sarcomas
Kevin Windebank DM MA BMBCh FRCP FRCPCH is a Senior Lecturer in Child Health at Newcastle University & Honorary Consultant in Paediatric and Adolescent Oncology at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Conflict of interest: none. Johannes Visser MBChB MMed(Paed) FCPaed(SA) FRCPCH is a Consultant Paediatric Oncologist at the University Hospitals of Leicester, UK. Conflict of interest: none. Vasanta Nanduri MBBS MRCP FRCPCH MD is a Consultant Paediatrician at Watford General Hospital, UK. Conflict of interest: none.
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Table 1
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Thus LCH appears not to be due to “reactive” epidermal LC responding to an inflammatory stimulus and migrating to and causing problems in other organs, but in many cases may be due to “oncogenic” transformation in precursors of related APC lineages. Does this mean LCH is cancer? The answer as so often with this disease is ‘yes’ and ‘no’. There are such wide variations in the natural history of LCH, from unresponsive, rapidly progressive and fatal disease to cases of spontaneous remission that it is clearly not a malignancy in the same way as acute leukaemia. It is perhaps best regarded as a proliferative process that may have some malignant characteristics. LCH may involve skin, bone, lung, bone marrow, spleen, liver, bowel, lymph nodes and the central nervous system. Depending on organ involvement, staging distinguishes between single system (SS) and multisystem (MS) disease. MS disease involving bone marrow, spleen or liver is associated with a worse prognosis and is designated risk organ positive (ROþ). Multisystem patients without involvement of these systems are designated risk organ negative (RO). In cases of SS, bony or nodal disease, several sites may be involved, which is then described as multifocal (MF) disease.
Presentation and investigation of organ involvement in LCH Presentation
Investigation
Skin
Odd rash Unresponsive eczema Cradle cap Chronic otitis externa Anal excoriation Visible swelling Proptosis Floating teeth Bone/joint pain Fracture Breathlessness Pneumothorax
Biopsy
Bone
Lung
Epidemiology and aetiology LCH is a rare disease. The British Paediatric Surveillance Unit study in conjunction with Newcastle University during 2003/5 revealed an incidence of 4 per million children (age 0e15 years) in UK & Ireland. More than half the patients presented with SS, single site, bony disease e or as previously classified, “isolated eosinophilic granuloma”, whilst a quarter of the cases had MS disease (ROþ: RO, 1:2). During the period of the study three deaths were identified, all of which occurred in infants with MS ROþ disease. Twin studies and familial clustering suggest the possibility that a genetic predisposition may exist in some cases. There is no convincing evidence to implicate specific environmental factors or infectious agents. An association between malignancies and LCH has been described in many reports and a Malignancy Registry established by the Histiocyte Society in 1991 has identified over 150 cases world wide e an association greater than would be expected by chance alone. In some cases the malignancy develops after treatment for LCH suggesting the possibility of therapy induced “second” malignancy. In others it is possible that LCH develops as a paraneoplastic phenomenon. Adults can be affected by the same spectrum of disorders as children. Their predicament is that there is no adult multidisciplinary service equivalent of paediatric oncology that cares for adults with LCH. They therefore tend to be seen in multiple clinics by different subspeciality teams depending on which system is causing their predominant symptoms. Efforts are underway to remedy this situation, including provision of information (written and electronic), organizing clinical meetings and development of adult protocols.
Lymph node Liver
Swollen gland Acute hepatitis Chronic sclerosing cholangitis
Spleen Bone marrow
Splenomegaly Cytopenias
Posterior pituitary Gastrointestinal tract
Polydipsia Polyuria Weight loss Malabsorption
Skeletal survey Consider PET scan
Chest Xray High resolution CT scan Lung function tests Bronchoalveolar lavage Biopsy Biochemical screen Clotting screen Ultrasound Biopsy Ultrasound FBC and film Bone marrow aspirate & trephine MRI of brain Water deprivation test Biochemical screen Biopsy
Table 2
dermatitis. It is only when it becomes more florid or waxes and wanes for months despite “appropriate” treatment that referral to specialist services results in the correct diagnosis. The rash is very characteristic and if untreated excoriated and ulcerated lesions may develop in skin creases (Figure 1). Bone Single or multifocal osteolytic lesions can occur at any age, in any part of the skeleton and may present with pain or an obvious bony mass. Small lesions in long bones have a typical radiographic appearance as do multiple skull vault lesions that present as lumps on the head (Figure 2). Base of skull and membranous bone lesions may have very dramatic imaging appearances that often lead to referral and investigation for suspected bone tumour. Lesions in the jaw may present with “floating teeth”. Lung SS lung disease is rare in children, but is well recognized in adults with LCH who smoke. Lung involvement is often asymptomatic in children and found as part of screening for MS disease. Initially appearing as generalized reticulonodular shadowing, it may progress to so-called honeycomb lung with an inherent risk of pneumothorax. Although previously considered a “risk organ” in childhood LCH, it is now recognized that lung
Presentation Children present with a variety of symptoms and signs depending on which organ systems are involved as outlined in Table 2. Skin The rash often appears shortly after birth and if this is the only manifestation of LCH it is often diagnosed as eczema or allergic
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Figure 1 (a) Widespread distribution of active skin LCH. (b) Axilla, showing typical excoriated and exudative appearance seen in skin creases.
Liver Whilst the liver is considered a risk organ different patterns of hepatic dysfunction may be present. LCH cells may invade and damage larger bile drainage ducts causing cholestasis eventually resulting in sclerosing cholangitis. Children with this type of damage are generally older and have less widespread, less aggressive LCH. Although they are likely to be long-term survivors they are at a high risk of developing cirrhosis. Alternatively, as part of MS LCH, children may present with hepatomegaly and some impairment of liver synthetic function without evidence of obstruction to bile drainage. These children tend to be younger and have widespread multisystem involvement with a relatively poor survival rate. This inflammatory process is probably driven by the inappropriate release of cytokines and if the LCH is successfully treated this type of liver dysfunction often resolves without long-term consequences.
involvement does not confer a worse outcome and therefore is no longer classified as such. Bone marrow and spleen Cytopenia of one or more of the bone marrow produced cell lineages may occur. Fascinatingly, even in the presence of very low circulating levels of blood cells the marrow may appear relatively normal with little or no evidence of infiltration by LCH cells. This suggests that the effect may be mediated by cytokine perturbation or some degree of peripheral consumption. It has been proposed that LCH induced macrophage activation syndrome may explain this phenomenon. There may be an associated splenomegaly, but again the cause of this may not be LCH infiltration. A recent report has described a case of LCH where an enlarged spleen “unresponsive to treatment” was removed and found to show extramedullary haematopoiesis rather than infiltration. Nevertheless, splenic enlargement or cytopenias generally reflect a poorer prognosis and are regarded as indicating risk organ disease.
Bowel Intestinal involvement is relatively uncommon, but minor degrees of involvement in MS ROþ disease may be missed. When bowel is
Figure 2 (a) Diagnostic image showing lytic lesions in skull. (b) 3D reconstruction of residual bony deformity. (c) Corresponding surface anatomy of b.
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significantly involved protein losing enteropathy is the commonest presentation. Oral mucosal ulceration and even anal excoriation may occasionally be seen as isolated manifestations of LCH.
caution must be exercised, especially when treatment is being considered. Challenging examples include isolated DI or the finding of an osteolytic lesion in the odontoid peg. With the exception of skin and bone, it may not be possible to confirm organ involvement by demonstrating LCH cells in a biopsy specimen. Other indicators of organ involvement are therefore necessary. In the presence of abnormal liver function tests a liver biopsy may show early sclerosing cholangitis or inflammatory changes but may not contain LCH cells. Liver involvement should therefore be suspected in the presence of hepatomegaly or abnormal function. As already discussed, even in the presence of significant cytopenias, marrow examination often does not reveal any LCH cells. Hence “bone marrow/haemopoetic system” involvement is diagnosed by the presence of significant cytopenias. The spleen is considered involved based on size criteria alone. In MS disease lung and gut involvement can be diagnosed on imaging or clinical criteria respectively as biopsies often show profound inflammatory responses without obvious LCH cells. The extent of bone disease (single/multi-focal) is assessed by skeletal survey and may be supplemented by MRI in cases of suspected craniofacial and vertebral lesions. Routine use of functional imaging is not recommended but a recent report found FDG-PET scan evaluation to be a sensitive technique for identifying lesions not found by other imaging modalities. In every case where LCH is suspected or has been confirmed on biopsy a detailed history should be taken and thorough physical examination performed. Depending on these findings, organ system screening investigations should be undertaken as outlined in Table 2. These investigations can be tailored to the age of the patient. For example a young teenager who has a biopsy proven osteolytic lesion does not generally warrant a skeletal survey unless there is a history of other musculoskeletal problems. In this situation, unless there are other clues in the history or examination, a full blood count, biochemical screen, early morning urine osmolality and chest radiograph are normally adequate to exclude significant involvement of other systems.
Lymph node Lymphadenopathy may occur in isolation, or in the nodes draining an affected area and is not associated with a poor prognosis. Endocrine For reasons that are not entirely clear, LCH has a predilection for the hypothalamic-pituitary axis. Involvement usually affects the pituitary stalk leading to irreversible diabetes insipidus (DI). This may present with polyuria and polydipsia as an isolated manifestation at any time before, during or after treatment for LCH. It is more common in children with craniofacial bony involvement (excluding skull vault lesions). Some children may progress to developing anterior pituitary hormone deficiencies. Rarely, LCH presents with a space occupying mass in the hypothalamus. Central nervous system There are two patterns of involvement in the CNS. Space occupying “tumorous” lesions result from infiltration of LCH and tend to affect the meninges, brain parenchyma and choroid plexus. These are seen during the active phase of the disease. Patients may present with symptoms and signs of raised intracranial pressure or seizures. Neurodegenerative lesions, on the other hand, are usually seen as long-term sequelae, although they may rarely arise very early on in the disease process. These changes are bilateral and symmetrical and tend to affect the cerebellum, basal ganglia and pons with characteristic MRI patterns. The brain stem and forebrain may rarely be involved. Patients present with tremor, ataxia, nystagmus or speech problems. Cognition and learning may also be affected and have an impact on quality of life. MRI changes however, may be present with no associated clinical features and this is termed “radiological neurodegeneration”. The natural history of neurodegeneration is not known and patients may remain stable, progress or may even transiently improve without any specific intervention.
Treatment Detailing the list of substances with activity against LCH is beyond the scope of this article, but it ranges from classical chemotherapeutic, through immunosuppressive and anti-inflammatory agents to bisphosphonates and even a reputable report of the efficacy of Mistletoe extract. In some circumstances local therapy may be helpful. Small areas of skin disease can be treated successfully with topical mustine, although a suitable preparation may be difficult to obtain. As discussed above, biopsy and curettage of a bony lesion will often lead to subsequent spontaneous healing e with or without the addition of intralesional steroid injection. However, although MF bony lesions are very responsive to systemic treatment, they commonly recur when therapy is withdrawn leading to a series of disease “reactivations” that may result in a higher prevalence of longterm sequelae or permanent consequences. Two systemic agents, Vinblastine (VBL) and Prednisolone (Pred) have for many years been known to be very effective in LCH and are used upfront in treatment protocols comprising an initial 6e12 week induction followed by a variable time on three weekly maintenance pulses. Given a rare, heterogeneous and usually very drug responsive disease that may spontaneously remit, attempts to establish evidence-based therapies have been fraught with difficulty. Over
Diagnosis In common with malignant diseases there are two components to making the diagnosis of LCH e establishing the pathology and ascertaining which organ systems are involved. Ideally, the pathological diagnosis is made by demonstrating the characteristic morphological appearance and immunophenotype (Langerin/CD207þ, CD1aþ) of LCH cells in a biopsy of lesional tissue. This is relatively straightforward when skin is affected and involvement of other systems can be screened for by investigations as outlined in Table 2. It follows, therefore, that it is not necessary to biopsy an osteolytic lesion found on a skeletal survey in the context of biopsy proven skin disease. On the other hand, if the only disease is a single bony lesion, biopsy should be performed to establish the diagnosis. Biopsy may also trigger spontaneous healing of the lesion. If a presenting lesion is in a difficult site to biopsy, and the differential diagnosis includes LCH, it is reasonable at this stage to see whether other sites or systems are involved that may be more accessible. In cases where there is only a single site and biopsy is not advisable, great
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the last twenty years members of the international Histiocyte Society (HS) have administered a series of three international randomized therapeutic trials, LCH I (1991e95), LCH II (1996e 2000) and LCH III (2001e08). These have shown that in MS ROþ disease there is no benefit of adding Etoposide or Methotrexate to a standard VBL/Pred induction. Additionally, in MS RO- disease the randomized question as to whether 6 months of maintenance is as efficacious as 12 months found a significant decrease in reactivation after the longer period of treatment. LCH IV the next international interventional trial, is due to open in 2012 and it is expected that 23 counties will take part. For the first time a single trial protocol will allow the study of a range of first and second line treatments for multisystem patients and selected single system patients. Newly diagnosed patients will be registered and their treatment stratified according to the disease features at diagnosis, response to treatment and disease features at the time of progression or reactivation. In addition, all patients will undergo long-term follow up in order to study the incidence and nature of permanent consequences. MS patients will receive a standard VBL/Pred induction and poorly responding ROþ patients, who currently have a 66% mortality, will be switched early to an intensive salvage treatment. LCH IV will also investigate the efficacy of protracted maintenance in prevention of reactivations. It is predictable that extending maintenance beyond 12 months will reduce reactivation rates further. The problem is that it is known from LCH III that most children do not require maintenance beyond 12 months to be cured. The challenge is to find a predictive indicator of disease outcome that will identify those who will benefit from more therapy. Parallel biological studies are planned to explore this dilemma and address our limited understanding of the pathogenesis of this disease. Established DI at diagnosis is considered irreversible and requires life-long desmopressin replacement therapy. If the DI presents as part of active MS LCH, systemic treatment is offered in order to address the multisystem nature of the disease. Systemic treatment for patients with isolated established DI, however, is controversial and prospective studies are required to establish if this approach can reduce the incidence of permanent neurological consequences and of developing anterior pituitary deficiency, in particular growth hormone deficiency. So how should UK children with LCH be treated? Clearly, those that fit prescribed eligibility criteria, should be entered into clinical trials. LCH IV is expected to enrol 180 new patients in the UK over a period of 6 years (1770 worldwide). Those who do not fit eligibility criteria should be treated with the help of the regional paediatric oncology team who in turn have access to the current Children’s Cancer and Leukaemia Group Histiocytosis Special Interest Group treatment guidelines and advice from international Histiocyte Society members.
sequelae. However, some children may be left with depressed skull defects, residual proptosis or asymmetry (Figure 2). Only rarely do these need surgical correction. Scarring in areas of severe skin rash may persist, and may cause cosmetic problems. Diabetes insipidus is one of the most common permanent consequences and occurs in 15e50% of patients with MS LCH. DI is irreversible and there is no evidence that early treatment ameliorates the condition. These patients will need life long treatment with desmopressin. Up to 10% of patients may go on to have anterior pituitary deficiencies (APD), growth hormone loss being the most common. It is hoped that early treatment of LCH, and in particular in those children with a thickened pituitary stalk, may reduce the incidence of APD. Panhypopituitarism, though very rare, causes significant problems which need replacement of multiple hormones and can be potentially life threatening. It is essential that therapy and monitoring is supervised by a paediatric endocrinologist. Neurodegeneration is the most significant and devastating of the sequelae and there is currently no treatment that is proven to reverse these changes. Management is currently based on supportive care with physiotherapy, occupational therapy, psychological and educational support. It is hoped that early and prolonged treatment of active LCH may prevent or reduce the incidence of neurodegeneration. The LCH IV trial protocol will offer possible treatment options for patients with clinical neurodegeneration. In adolescents and adults who smoke, pulmonary involvement can cause destruction of alveoli with bullous formation and long-term scarring, with some patients needing a lung transplant. It is important to advise parents of children with LCH to stop smoking and even more important to ensure that adolescents with LCH do not start smoking.
Non-Langerhans cell histiocytoses (non-LCH) As is usual with a “non”-based classification, the label non-LCH includes an apparently heterogeneous group of rare disorders with varied clinical presentations. Nevertheless, they appear for the most part to originate from a common precursor and form a spectrum of disorders relating to whether they exhibit APC or PC functional characteristics and the stage of maturity at which the histiocyte has become dysregulated. Histologically they can be divided into those that have cells typically found in Juvenile Xanthogranuloma (JXG) lesions e“JXG family” e or not. Clinically, they can then be further subdivided into those that affect predominantly skin, other organ systems or both. Treatment depends on making an accurate diagnosis, which is especially important as spontaneous regression may occur in many of these conditions. Juvenile xanthogranuloma (JXG) family The usually purely cutaneous form of this rare disorder presents at birth or during infancy. It is occasionally found in conjunction with neurofibromatosis type 1 and juvenile myelomonocytic leukaemia. Lesions may be solitary or appear in multiple crops as shown in Figure 3. Initially, the lesions appear rather violaceous and grow in size. Then, presumably as a result of the infant immune system maturing, become yellowish brown and spontaneously resolve. Depending on the site and size of the lesion there may be residual scarring or a degree of subcutaneous pitting. In children, less than 5% of cases develop systemic lesions affecting the liver, spleen, eye or CNS.
Permanent consequences For a disease that can potentially “burn itself out” and remit with little or no treatment, in some organs, LCH can result in significant long-term sequelae which affect the “quality of life” of survivors. A recent UK long-term follow up study found that up to 75% of children treated successfully for LCH had permanent sequelae. However, not all sequelae are clinically significant. Although the skeleton is most commonly involved in LCH, bony lesions tend to heal in the majority and do not result in clinically significant
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Haemophagocytic lymphohistiocytosis (HLH)
In contrast Xanthoma Disseminatum is a disease of young adult males with brownish red papules and, characteristically, systemic involvement of the mucous membranes of the oropharynx, eyes and transient diabetes insipidus. Depending on the aggressiveness of progression, chemotherapeutic agents may be required to prevent significant morbidity before spontaneous regression can occur. Finally, Erdheim Chester Disease, a primarily systemic disease, has been described as a macrophage disorder, but has abnormal cells that are indistinguishable from those found in other members of the JXG family. The disease affects adults and characteristically involves osteosclerosis of long bones with over half of patients having additional organ involvement. Standard therapy for this disease has not been defined but response to treatment with interferon-a was recently identified as an independent predictor of survival in a large multi-centre cohort. This is the first time a treatment has been shown to improve survival in this multi-system disease with high mortality.
The term haemophagocytosis describes a form of immune dysregulation where phagocytic histiocytes engulf and destroy normal peripheral blood, immune system or bone marrow precursor cells. This is seen in some of the non-LCH above, but can also be regarded as a separate clinical entity when it presents as a familial abnormality due to an inherited genetic defect or as a secondary phenomenon in a variety of inflammatory, infectious or malignant diseases. Interestingly, in this condition the primary defect is in the cells regulating histiocytic functioning rather than in the histiocytes per se. Familial HLH Familial HLH is a rare autosomal recessive disorder with an annual incidence of around 1.2 per million children. The true incidence is almost certainly higher as first affected infants in a family may die without the diagnosis being established. It is caused by immune dysregulation at the level of cellular cytotoxicity. Cytotoxic lymphocytes kill virally or malignantly transformed cells by attaching to them and inserting connecting membrane pores through which a variety of cytotoxic protein granules can be injected into the target cell. This mechanism also comes into play killing autologous cells as an immune response is dying down. The defect was first recognized in HLH in 1984 as an in vitro impairment of natural killer cell cytotoxicity. It was later found that in some patients this is caused by a lack of the pore forming protein perforin. Since then several other genes have been identified as crucial in this cytolytic pathway which, if non-functional, can cause a similar clinical picture. At a cellular level impaired cytotoxicity allows uncontrolled proliferation of immune cells and production of abnormal amounts of cytokines leading to, among other things, extensive haemophagocytosis. This translates into the clinical picture, typically seen in the first year of life, of fever and hepatosplenomegaly with associated laboratory findings of peripheral blood cytopenias, abnormal liver function tests, hypertriglyceridaemia, hypofibrinogenaemia and raised ferritin levels. If there is significant CNS involvement children may present with irritability, seizures and even cranial nerve palsies. It is important to note that the onset of familial HLH symptoms and signs may be triggered by an infection. Treatment is aimed at turning off the immune dysregulatory process in the shorter term whilst planning for an allogeneic bone marrow transplant as a form of gene therapy to replace the defective alleles, thereby allowing development of a normal immune system. Currently either chemotherapy or immunotherapy strategies are used in initial treatment with encouraging results in a previously fatal condition. Genetic counselling is also an important consideration for affected families and survivors of the disease.
Non-juvenile xanthogranuloma (non-JXG) family Solitary reticulohistiocytomas are benign lesions that tend to resolve spontaneously. Surgical excision biopsy is successful for lesions causing local problems. Multicentric Reticulohistiocytosis is a very rare and aggressive condition which characteristically presents with arthritis, cutaneous papules and nodules and mucosal lesions. It usually arises in middle-aged women of whom over half present with arthritis. The disease may be self limiting, especially in the rare childhood cases, or progress to a disabling and deforming polyarthritis. There is no evidence for any particular therapeutic modality, but a stepwise approach using steroids and methotrexate or cyclophosphamide has been proposed, with a possible role for infliximab in refractory cases. Finally in the non-JXG family, RosaieDorfman disease presents with massive painless lymphadenopathy, typically in the cervical region. The nodes have a characteristic appearance of sinus invasion by large histiocytes which commonly contain ingested whole erythrocytes or small lymphocytes. There may be associated systemic upset, vital organ involvement and occasionally CNS involvement. Spontaneous regression is common but in persistent cases steroids may accelerate a response.
Secondary HLH Secondary HLH may occur during an immune response to an infection or accompany a variety of underlying disorders that are associated with immune dysregulation. These include a number of congenital immune deficiencies (other than familial HLH), autoimmune diseases and malignancies. These conditions and infections must be carefully looked for while molecular testing is undertaken to identify those who have one of the known familial HLH defects. In patients with no family history of HLH, no known genetic defects and no underlying disorder, it remains
Figure 3 Lesions of juvenile xanthogranuloma.
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SPECIFIC AREAS Abla O, Weitzman S, Minkov M, et al. Diabetes insipidus in Langerhans cell histiocytosis: when is treatment indicated? Pediatr Blood Cancer 2009 May; 52: 555e6. Badalian-Very G, Vergilio JA, Degar BA, Rodriguez-Galindo C, Rollins BJ. Recent advances in the understanding of Langerhans cell histiocytosis. Br J Haematol 2011 Oct 24. doi: 10.1111/j.1365-2141.2011. 08915.x. [Epub ahead of print]. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010 16 Sep; 116: 1919e23. Haupt R, Nanduri V, Egeler R. Late effects of Langerhans cell histiocytosis and its association with malignancy. In: Weitzman S, Egeler M, eds. Histiocytic disorders of children and adults. Cambridge: Cambridge University Press, 2005; 272e292. Jaffe R. Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol 2004; 7: 214e25. Minkov M. Multisystem Langerhans cell histiocytosis in children: current treatment and future directions. Pediatr Drugs 2011; 13: 75e86.
difficult to definitively distinguish between secondary and familial HLH at their first presentation. Secondary HLH can be as severe as familial HLH and may require similar initial nonspecific immunotherapy directed at turning off the immune response. Treatment should however, also be directed at the underlying condition, and any immunotherapy tailored according to the underlying disorder.
Histiocyte lineage-related malignancies Leukaemias Acute myelomonocytic (M4) and monocytic (M5) leukaemias typically present with pancytopenia and the clinical signs of bone marrow failure. In addition, these two particular subtypes of myeloid leukaemia may present with solid lumps of disease described as chloromas or in infants “blueberry muffin” spots. In the UK these are currently treated on MRC protocols for 4e5 months with intensive cyclical chemotherapy resulting in survival rates in excess of 65%. Chronic myelomonocytic leukaemias are rare, clonal, myeloproliferative stem cell disorders that behave differently in children and adults. In children the disease has been known as monosomy 7, but is currently called juvenile myelomonocytic leukaemia. This may initially present with an indolent course that can be stayed with AML type chemotherapy. Unfortunately, relapse is inevitable and the only potentially curative treatment is bone marrow transplantation.
RESEARCH AND SUPPORT Histiocytosis Association https://www.histio.org. Histiocytosis Research Trust http://www.hrtrust.org. Macmillan http://www.macmillan.org.uk/Cancerinformation/Cancertypes/ Childrenscancers/Typesofchildrenscancers/Langerhanscellhistio cytosis.aspx.
Practice points
Sarcomas There are a variety of extremely rare sarcomas potentially of histiocytic lineage. These include interdigitating and follicular dendritic cell tumours and monocytic and histiocytic related sarcomas. Treatment is anecdotal but can include surgery and potentially adjuvant chemotherapy.
LCH C Consider the diagnosis in infants with widespread or resistant eczema and young children with persistent, localized musculoskeletal aches and pain. C Take a very detailed current and past medical history to establish whether multiple organs systems may be involved. C Establish a tissue diagnosis and undertake appropriate investigation of other potentially involved systems. C Seek expert advice on treatment. C Facilitate patient and parent contact with other similarly affected families and support groups.
Conclusion Histiocytoses are rare disorders that often develop and respond to therapy in an unpredictable way. The key to successful therapy is accurate identification at tissue level and appropriate staging. Eligible children and adults should be entered on to available trials. Patients should be observed and monitored to assess long-term morbidity from disease and drug related toxicities. Patients and families should have access to advice from experienced doctors and support groups such as the Histiocytosis Association, or in the UK members of the Histiocytosis Research Trust. A
Non-LCH C Seek dermatological advice for unusual skin lesions in children HLH C Consider in any systemically unwell infant with unexplained hepatic, haematological or neurological problems. C Refer HLH cases to a secondary or tertiary unit with experience in dealing with severely ill children requiring intensive systemic therapy. C HLH presenting in infancy is usually the familial form. check for any history of non-SUDI infant deaths. stem cell transplant is necessary for cure. facilitate access to genetic counselling and contact with other similarly affected families and support groups.
FURTHER READING GENERAL Arceci RJ, Henter JI. The histiocytoses: the fall of the Tower of Babel. Eur J Cancer 1999; 35: 747e69. Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011; 96: 688e93. NCI. Adult LCH. Available from: http://www.cancer.gov/cancertopics/pdq/ treatment/lchistio/HealthProfessional/page10; 2011. Weitzman S, Egeler RM. Histiocytic disorders of children and adults. Cambridge: Cambridge University Press, 2005. Weitzman S, Jaffe R. Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses. Pediatr Blood Cancer 2005; 45: 256e64.
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Histiocyte lineage-related malignancies C Consider in the differential diagnosis of acute leukaemia, especially in the presence of skin or superficial mass lesions. C Refer all cases to a secondary or tertiary centre for precise diagnosis and treatment.
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Advances in the management of histiocytic disorders 2011
Langerhans in 1868, who because of their dendritic processes, thought they were part of the nervous system. Whilst this did not prove to be the case, these epidermal APC were called Langerhans cells (LC). Other histiocytic cells have a primary role as tissue phagocytic cells (PC), cleaning up damaged or inflamed areas by ingesting and recycling foreign material and cellular debris. As with many rare diseases, the nomenclature for histiocytic disorders and their classification is complex and continually evolving as a result of increasingly sophisticated phenotypic, genotypic and functional analyses. There are various sub-classifications relating to function and morphology. For the purposes of this article Table 1 is based on the current clinical terms in common usage. Whilst this article will focus on Langerhans cell histiocytosis, significant progress in the understanding and treatment of other histiocytoses will be discussed.
Kevin Windebank Johannes Visser Vasanta Nanduri
Abstract Childhood histiocytoses span a range of illnesses that can present with a small skin or single bony lesion that may spontaneously regress or a systemic disease resulting in multiorgan failure and death. For practical purposes they can be classified into four groups: Langerhans cell histiocytosis (LCH), Non-Langerhans cell histiocytoses (Non-LCH), Haemophagocytic lymphohistiocytoses (HLH) and Histiocyte lineage-related malignancies. The establishment of diagnostic, staging and response criteria for LCH has enabled a series of international randomized clinical trials to be conducted that are the basis of current evidence based treatment. However, as with non-LCH, individual cases are often difficult to manage and require expert advice. Although in most cases the disease responds to treatment many children are left with significant permanent consequences commonly affecting the skeleton and endocrine system. Familial HLH is an inherited disease in which initial remission can be gained by chemotherapeutic or immunological strategies, but then requires allogeneic stem cell transplant for cure. There are a variety of leukaemias and sarcomas that are phenotypically derived from the histiocytic lineage. Treatment and outcomes for these are generally similar to those of the wider malignant spectrum.
Langerhans cell histiocytosis Pathology and classification In 1953, having identified similar abnormal histiocytic cells in € llereChristian eosinophilic granuloma, LetterereSiwe and Schu disease, Lichtenstein grouped them together under the single name of Histiocytosis X. Subsequently it was found that these abnormal histiocytes closely resembled epidermal Langerhans cells (LC) and the name Langerhans cell histiocytosis (LCH) was adopted. Although pathological LCH cells do share many features in common with normal epidermal LC, recent experimental findings suggest that they may result from oncogenic mutations in APC precursors of similar but distinct lineage. In particular, Rollins’ group has reported finding mutations in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in nearly 60% of a series of LCH cases tested. Interestingly so far, the presence of mutations has not correlated with the severity of the disease.
Keywords classification; complications; diagnosis; epidemiology; Langerhans cell histiocytosis; physiopathology; therapy
non-Langerhans
cell
histiocytosis;
Introduction
Classification of histiocytic disorders
The term histiocyte was first used to describe a type of tissue macrophage, but in time has taken on a broader meaning which embraces a wide variety of cells of monocyte/macrophage lineage including dendritic and phagocytic cells. Dendritic cells are antigen presenting cells (APC) that ingest foreign material, process their antigens and present them to lymphocytes thereby initiating an immune response. Characteristic APC populations are found in many organs but were first described in skin by Paul
Langerhans cell histiocytosis Non-Langerhans cell histiocytoses C Juvenile xanthogranuloma Family Cutaneous Juvenile xanthogranuloma Cutaneous and systemic Xanthoma disseminatum Systemic Erdheim Chester disease C Non-juvenile xanthogranuloma family Cutaneous Solitary reticulohistiocytoma Cutaneous and systemic Multicentric reticulohistiocytosis Systemic RosaieDorfman disease Haemophagocytic lymphohistiocytoses C Familial C Secondary (reactive) Histiocyte lineage-related malignancies C Leukaemias Acute myelomonocytic and monocytic Chronic myelomonocytic/juvenile myelomonocytic leukaemia C Monocytic and histiocytic sarcomas
Kevin Windebank DM MA BMBCh FRCP FRCPCH is a Senior Lecturer in Child Health at Newcastle University & Honorary Consultant in Paediatric and Adolescent Oncology at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Conflict of interest: none. Johannes Visser MBChB MMed(Paed) FCPaed(SA) FRCPCH is a Consultant Paediatric Oncologist at the University Hospitals of Leicester, UK. Conflict of interest: none. Vasanta Nanduri MBBS MRCP FRCPCH MD is a Consultant Paediatrician at Watford General Hospital, UK. Conflict of interest: none.
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Table 1
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Thus LCH appears not to be due to “reactive” epidermal LC responding to an inflammatory stimulus and migrating to and causing problems in other organs, but in many cases may be due to “oncogenic” transformation in precursors of related APC lineages. Does this mean LCH is cancer? The answer as so often with this disease is ‘yes’ and ‘no’. There are such wide variations in the natural history of LCH, from unresponsive, rapidly progressive and fatal disease to cases of spontaneous remission that it is clearly not a malignancy in the same way as acute leukaemia. It is perhaps best regarded as a proliferative process that may have some malignant characteristics. LCH may involve skin, bone, lung, bone marrow, spleen, liver, bowel, lymph nodes and the central nervous system. Depending on organ involvement, staging distinguishes between single system (SS) and multisystem (MS) disease. MS disease involving bone marrow, spleen or liver is associated with a worse prognosis and is designated risk organ positive (ROþ). Multisystem patients without involvement of these systems are designated risk organ negative (RO). In cases of SS, bony or nodal disease, several sites may be involved, which is then described as multifocal (MF) disease.
Presentation and investigation of organ involvement in LCH Presentation
Investigation
Skin
Odd rash Unresponsive eczema Cradle cap Chronic otitis externa Anal excoriation Visible swelling Proptosis Floating teeth Bone/joint pain Fracture Breathlessness Pneumothorax
Biopsy
Bone
Lung
Epidemiology and aetiology LCH is a rare disease. The British Paediatric Surveillance Unit study in conjunction with Newcastle University during 2003/5 revealed an incidence of 4 per million children (age 0e15 years) in UK & Ireland. More than half the patients presented with SS, single site, bony disease e or as previously classified, “isolated eosinophilic granuloma”, whilst a quarter of the cases had MS disease (ROþ: RO, 1:2). During the period of the study three deaths were identified, all of which occurred in infants with MS ROþ disease. Twin studies and familial clustering suggest the possibility that a genetic predisposition may exist in some cases. There is no convincing evidence to implicate specific environmental factors or infectious agents. An association between malignancies and LCH has been described in many reports and a Malignancy Registry established by the Histiocyte Society in 1991 has identified over 150 cases world wide e an association greater than would be expected by chance alone. In some cases the malignancy develops after treatment for LCH suggesting the possibility of therapy induced “second” malignancy. In others it is possible that LCH develops as a paraneoplastic phenomenon. Adults can be affected by the same spectrum of disorders as children. Their predicament is that there is no adult multidisciplinary service equivalent of paediatric oncology that cares for adults with LCH. They therefore tend to be seen in multiple clinics by different subspeciality teams depending on which system is causing their predominant symptoms. Efforts are underway to remedy this situation, including provision of information (written and electronic), organizing clinical meetings and development of adult protocols.
Lymph node Liver
Swollen gland Acute hepatitis Chronic sclerosing cholangitis
Spleen Bone marrow
Splenomegaly Cytopenias
Posterior pituitary Gastrointestinal tract
Polydipsia Polyuria Weight loss Malabsorption
Skeletal survey Consider PET scan
Chest Xray High resolution CT scan Lung function tests Bronchoalveolar lavage Biopsy Biochemical screen Clotting screen Ultrasound Biopsy Ultrasound FBC and film Bone marrow aspirate & trephine MRI of brain Water deprivation test Biochemical screen Biopsy
Table 2
dermatitis. It is only when it becomes more florid or waxes and wanes for months despite “appropriate” treatment that referral to specialist services results in the correct diagnosis. The rash is very characteristic and if untreated excoriated and ulcerated lesions may develop in skin creases (Figure 1). Bone Single or multifocal osteolytic lesions can occur at any age, in any part of the skeleton and may present with pain or an obvious bony mass. Small lesions in long bones have a typical radiographic appearance as do multiple skull vault lesions that present as lumps on the head (Figure 2). Base of skull and membranous bone lesions may have very dramatic imaging appearances that often lead to referral and investigation for suspected bone tumour. Lesions in the jaw may present with “floating teeth”. Lung SS lung disease is rare in children, but is well recognized in adults with LCH who smoke. Lung involvement is often asymptomatic in children and found as part of screening for MS disease. Initially appearing as generalized reticulonodular shadowing, it may progress to so-called honeycomb lung with an inherent risk of pneumothorax. Although previously considered a “risk organ” in childhood LCH, it is now recognized that lung
Presentation Children present with a variety of symptoms and signs depending on which organ systems are involved as outlined in Table 2. Skin The rash often appears shortly after birth and if this is the only manifestation of LCH it is often diagnosed as eczema or allergic
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Figure 1 (a) Widespread distribution of active skin LCH. (b) Axilla, showing typical excoriated and exudative appearance seen in skin creases.
Liver Whilst the liver is considered a risk organ different patterns of hepatic dysfunction may be present. LCH cells may invade and damage larger bile drainage ducts causing cholestasis eventually resulting in sclerosing cholangitis. Children with this type of damage are generally older and have less widespread, less aggressive LCH. Although they are likely to be long-term survivors they are at a high risk of developing cirrhosis. Alternatively, as part of MS LCH, children may present with hepatomegaly and some impairment of liver synthetic function without evidence of obstruction to bile drainage. These children tend to be younger and have widespread multisystem involvement with a relatively poor survival rate. This inflammatory process is probably driven by the inappropriate release of cytokines and if the LCH is successfully treated this type of liver dysfunction often resolves without long-term consequences.
involvement does not confer a worse outcome and therefore is no longer classified as such. Bone marrow and spleen Cytopenia of one or more of the bone marrow produced cell lineages may occur. Fascinatingly, even in the presence of very low circulating levels of blood cells the marrow may appear relatively normal with little or no evidence of infiltration by LCH cells. This suggests that the effect may be mediated by cytokine perturbation or some degree of peripheral consumption. It has been proposed that LCH induced macrophage activation syndrome may explain this phenomenon. There may be an associated splenomegaly, but again the cause of this may not be LCH infiltration. A recent report has described a case of LCH where an enlarged spleen “unresponsive to treatment” was removed and found to show extramedullary haematopoiesis rather than infiltration. Nevertheless, splenic enlargement or cytopenias generally reflect a poorer prognosis and are regarded as indicating risk organ disease.
Bowel Intestinal involvement is relatively uncommon, but minor degrees of involvement in MS ROþ disease may be missed. When bowel is
Figure 2 (a) Diagnostic image showing lytic lesions in skull. (b) 3D reconstruction of residual bony deformity. (c) Corresponding surface anatomy of b.
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significantly involved protein losing enteropathy is the commonest presentation. Oral mucosal ulceration and even anal excoriation may occasionally be seen as isolated manifestations of LCH.
caution must be exercised, especially when treatment is being considered. Challenging examples include isolated DI or the finding of an osteolytic lesion in the odontoid peg. With the exception of skin and bone, it may not be possible to confirm organ involvement by demonstrating LCH cells in a biopsy specimen. Other indicators of organ involvement are therefore necessary. In the presence of abnormal liver function tests a liver biopsy may show early sclerosing cholangitis or inflammatory changes but may not contain LCH cells. Liver involvement should therefore be suspected in the presence of hepatomegaly or abnormal function. As already discussed, even in the presence of significant cytopenias, marrow examination often does not reveal any LCH cells. Hence “bone marrow/haemopoetic system” involvement is diagnosed by the presence of significant cytopenias. The spleen is considered involved based on size criteria alone. In MS disease lung and gut involvement can be diagnosed on imaging or clinical criteria respectively as biopsies often show profound inflammatory responses without obvious LCH cells. The extent of bone disease (single/multi-focal) is assessed by skeletal survey and may be supplemented by MRI in cases of suspected craniofacial and vertebral lesions. Routine use of functional imaging is not recommended but a recent report found FDG-PET scan evaluation to be a sensitive technique for identifying lesions not found by other imaging modalities. In every case where LCH is suspected or has been confirmed on biopsy a detailed history should be taken and thorough physical examination performed. Depending on these findings, organ system screening investigations should be undertaken as outlined in Table 2. These investigations can be tailored to the age of the patient. For example a young teenager who has a biopsy proven osteolytic lesion does not generally warrant a skeletal survey unless there is a history of other musculoskeletal problems. In this situation, unless there are other clues in the history or examination, a full blood count, biochemical screen, early morning urine osmolality and chest radiograph are normally adequate to exclude significant involvement of other systems.
Lymph node Lymphadenopathy may occur in isolation, or in the nodes draining an affected area and is not associated with a poor prognosis. Endocrine For reasons that are not entirely clear, LCH has a predilection for the hypothalamic-pituitary axis. Involvement usually affects the pituitary stalk leading to irreversible diabetes insipidus (DI). This may present with polyuria and polydipsia as an isolated manifestation at any time before, during or after treatment for LCH. It is more common in children with craniofacial bony involvement (excluding skull vault lesions). Some children may progress to developing anterior pituitary hormone deficiencies. Rarely, LCH presents with a space occupying mass in the hypothalamus. Central nervous system There are two patterns of involvement in the CNS. Space occupying “tumorous” lesions result from infiltration of LCH and tend to affect the meninges, brain parenchyma and choroid plexus. These are seen during the active phase of the disease. Patients may present with symptoms and signs of raised intracranial pressure or seizures. Neurodegenerative lesions, on the other hand, are usually seen as long-term sequelae, although they may rarely arise very early on in the disease process. These changes are bilateral and symmetrical and tend to affect the cerebellum, basal ganglia and pons with characteristic MRI patterns. The brain stem and forebrain may rarely be involved. Patients present with tremor, ataxia, nystagmus or speech problems. Cognition and learning may also be affected and have an impact on quality of life. MRI changes however, may be present with no associated clinical features and this is termed “radiological neurodegeneration”. The natural history of neurodegeneration is not known and patients may remain stable, progress or may even transiently improve without any specific intervention.
Treatment Detailing the list of substances with activity against LCH is beyond the scope of this article, but it ranges from classical chemotherapeutic, through immunosuppressive and anti-inflammatory agents to bisphosphonates and even a reputable report of the efficacy of Mistletoe extract. In some circumstances local therapy may be helpful. Small areas of skin disease can be treated successfully with topical mustine, although a suitable preparation may be difficult to obtain. As discussed above, biopsy and curettage of a bony lesion will often lead to subsequent spontaneous healing e with or without the addition of intralesional steroid injection. However, although MF bony lesions are very responsive to systemic treatment, they commonly recur when therapy is withdrawn leading to a series of disease “reactivations” that may result in a higher prevalence of longterm sequelae or permanent consequences. Two systemic agents, Vinblastine (VBL) and Prednisolone (Pred) have for many years been known to be very effective in LCH and are used upfront in treatment protocols comprising an initial 6e12 week induction followed by a variable time on three weekly maintenance pulses. Given a rare, heterogeneous and usually very drug responsive disease that may spontaneously remit, attempts to establish evidence-based therapies have been fraught with difficulty. Over
Diagnosis In common with malignant diseases there are two components to making the diagnosis of LCH e establishing the pathology and ascertaining which organ systems are involved. Ideally, the pathological diagnosis is made by demonstrating the characteristic morphological appearance and immunophenotype (Langerin/CD207þ, CD1aþ) of LCH cells in a biopsy of lesional tissue. This is relatively straightforward when skin is affected and involvement of other systems can be screened for by investigations as outlined in Table 2. It follows, therefore, that it is not necessary to biopsy an osteolytic lesion found on a skeletal survey in the context of biopsy proven skin disease. On the other hand, if the only disease is a single bony lesion, biopsy should be performed to establish the diagnosis. Biopsy may also trigger spontaneous healing of the lesion. If a presenting lesion is in a difficult site to biopsy, and the differential diagnosis includes LCH, it is reasonable at this stage to see whether other sites or systems are involved that may be more accessible. In cases where there is only a single site and biopsy is not advisable, great
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the last twenty years members of the international Histiocyte Society (HS) have administered a series of three international randomized therapeutic trials, LCH I (1991e95), LCH II (1996e 2000) and LCH III (2001e08). These have shown that in MS ROþ disease there is no benefit of adding Etoposide or Methotrexate to a standard VBL/Pred induction. Additionally, in MS RO- disease the randomized question as to whether 6 months of maintenance is as efficacious as 12 months found a significant decrease in reactivation after the longer period of treatment. LCH IV the next international interventional trial, is due to open in 2012 and it is expected that 23 counties will take part. For the first time a single trial protocol will allow the study of a range of first and second line treatments for multisystem patients and selected single system patients. Newly diagnosed patients will be registered and their treatment stratified according to the disease features at diagnosis, response to treatment and disease features at the time of progression or reactivation. In addition, all patients will undergo long-term follow up in order to study the incidence and nature of permanent consequences. MS patients will receive a standard VBL/Pred induction and poorly responding ROþ patients, who currently have a 66% mortality, will be switched early to an intensive salvage treatment. LCH IV will also investigate the efficacy of protracted maintenance in prevention of reactivations. It is predictable that extending maintenance beyond 12 months will reduce reactivation rates further. The problem is that it is known from LCH III that most children do not require maintenance beyond 12 months to be cured. The challenge is to find a predictive indicator of disease outcome that will identify those who will benefit from more therapy. Parallel biological studies are planned to explore this dilemma and address our limited understanding of the pathogenesis of this disease. Established DI at diagnosis is considered irreversible and requires life-long desmopressin replacement therapy. If the DI presents as part of active MS LCH, systemic treatment is offered in order to address the multisystem nature of the disease. Systemic treatment for patients with isolated established DI, however, is controversial and prospective studies are required to establish if this approach can reduce the incidence of permanent neurological consequences and of developing anterior pituitary deficiency, in particular growth hormone deficiency. So how should UK children with LCH be treated? Clearly, those that fit prescribed eligibility criteria, should be entered into clinical trials. LCH IV is expected to enrol 180 new patients in the UK over a period of 6 years (1770 worldwide). Those who do not fit eligibility criteria should be treated with the help of the regional paediatric oncology team who in turn have access to the current Children’s Cancer and Leukaemia Group Histiocytosis Special Interest Group treatment guidelines and advice from international Histiocyte Society members.
sequelae. However, some children may be left with depressed skull defects, residual proptosis or asymmetry (Figure 2). Only rarely do these need surgical correction. Scarring in areas of severe skin rash may persist, and may cause cosmetic problems. Diabetes insipidus is one of the most common permanent consequences and occurs in 15e50% of patients with MS LCH. DI is irreversible and there is no evidence that early treatment ameliorates the condition. These patients will need life long treatment with desmopressin. Up to 10% of patients may go on to have anterior pituitary deficiencies (APD), growth hormone loss being the most common. It is hoped that early treatment of LCH, and in particular in those children with a thickened pituitary stalk, may reduce the incidence of APD. Panhypopituitarism, though very rare, causes significant problems which need replacement of multiple hormones and can be potentially life threatening. It is essential that therapy and monitoring is supervised by a paediatric endocrinologist. Neurodegeneration is the most significant and devastating of the sequelae and there is currently no treatment that is proven to reverse these changes. Management is currently based on supportive care with physiotherapy, occupational therapy, psychological and educational support. It is hoped that early and prolonged treatment of active LCH may prevent or reduce the incidence of neurodegeneration. The LCH IV trial protocol will offer possible treatment options for patients with clinical neurodegeneration. In adolescents and adults who smoke, pulmonary involvement can cause destruction of alveoli with bullous formation and long-term scarring, with some patients needing a lung transplant. It is important to advise parents of children with LCH to stop smoking and even more important to ensure that adolescents with LCH do not start smoking.
Non-Langerhans cell histiocytoses (non-LCH) As is usual with a “non”-based classification, the label non-LCH includes an apparently heterogeneous group of rare disorders with varied clinical presentations. Nevertheless, they appear for the most part to originate from a common precursor and form a spectrum of disorders relating to whether they exhibit APC or PC functional characteristics and the stage of maturity at which the histiocyte has become dysregulated. Histologically they can be divided into those that have cells typically found in Juvenile Xanthogranuloma (JXG) lesions e“JXG family” e or not. Clinically, they can then be further subdivided into those that affect predominantly skin, other organ systems or both. Treatment depends on making an accurate diagnosis, which is especially important as spontaneous regression may occur in many of these conditions. Juvenile xanthogranuloma (JXG) family The usually purely cutaneous form of this rare disorder presents at birth or during infancy. It is occasionally found in conjunction with neurofibromatosis type 1 and juvenile myelomonocytic leukaemia. Lesions may be solitary or appear in multiple crops as shown in Figure 3. Initially, the lesions appear rather violaceous and grow in size. Then, presumably as a result of the infant immune system maturing, become yellowish brown and spontaneously resolve. Depending on the site and size of the lesion there may be residual scarring or a degree of subcutaneous pitting. In children, less than 5% of cases develop systemic lesions affecting the liver, spleen, eye or CNS.
Permanent consequences For a disease that can potentially “burn itself out” and remit with little or no treatment, in some organs, LCH can result in significant long-term sequelae which affect the “quality of life” of survivors. A recent UK long-term follow up study found that up to 75% of children treated successfully for LCH had permanent sequelae. However, not all sequelae are clinically significant. Although the skeleton is most commonly involved in LCH, bony lesions tend to heal in the majority and do not result in clinically significant
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Haemophagocytic lymphohistiocytosis (HLH)
In contrast Xanthoma Disseminatum is a disease of young adult males with brownish red papules and, characteristically, systemic involvement of the mucous membranes of the oropharynx, eyes and transient diabetes insipidus. Depending on the aggressiveness of progression, chemotherapeutic agents may be required to prevent significant morbidity before spontaneous regression can occur. Finally, Erdheim Chester Disease, a primarily systemic disease, has been described as a macrophage disorder, but has abnormal cells that are indistinguishable from those found in other members of the JXG family. The disease affects adults and characteristically involves osteosclerosis of long bones with over half of patients having additional organ involvement. Standard therapy for this disease has not been defined but response to treatment with interferon-a was recently identified as an independent predictor of survival in a large multi-centre cohort. This is the first time a treatment has been shown to improve survival in this multi-system disease with high mortality.
The term haemophagocytosis describes a form of immune dysregulation where phagocytic histiocytes engulf and destroy normal peripheral blood, immune system or bone marrow precursor cells. This is seen in some of the non-LCH above, but can also be regarded as a separate clinical entity when it presents as a familial abnormality due to an inherited genetic defect or as a secondary phenomenon in a variety of inflammatory, infectious or malignant diseases. Interestingly, in this condition the primary defect is in the cells regulating histiocytic functioning rather than in the histiocytes per se. Familial HLH Familial HLH is a rare autosomal recessive disorder with an annual incidence of around 1.2 per million children. The true incidence is almost certainly higher as first affected infants in a family may die without the diagnosis being established. It is caused by immune dysregulation at the level of cellular cytotoxicity. Cytotoxic lymphocytes kill virally or malignantly transformed cells by attaching to them and inserting connecting membrane pores through which a variety of cytotoxic protein granules can be injected into the target cell. This mechanism also comes into play killing autologous cells as an immune response is dying down. The defect was first recognized in HLH in 1984 as an in vitro impairment of natural killer cell cytotoxicity. It was later found that in some patients this is caused by a lack of the pore forming protein perforin. Since then several other genes have been identified as crucial in this cytolytic pathway which, if non-functional, can cause a similar clinical picture. At a cellular level impaired cytotoxicity allows uncontrolled proliferation of immune cells and production of abnormal amounts of cytokines leading to, among other things, extensive haemophagocytosis. This translates into the clinical picture, typically seen in the first year of life, of fever and hepatosplenomegaly with associated laboratory findings of peripheral blood cytopenias, abnormal liver function tests, hypertriglyceridaemia, hypofibrinogenaemia and raised ferritin levels. If there is significant CNS involvement children may present with irritability, seizures and even cranial nerve palsies. It is important to note that the onset of familial HLH symptoms and signs may be triggered by an infection. Treatment is aimed at turning off the immune dysregulatory process in the shorter term whilst planning for an allogeneic bone marrow transplant as a form of gene therapy to replace the defective alleles, thereby allowing development of a normal immune system. Currently either chemotherapy or immunotherapy strategies are used in initial treatment with encouraging results in a previously fatal condition. Genetic counselling is also an important consideration for affected families and survivors of the disease.
Non-juvenile xanthogranuloma (non-JXG) family Solitary reticulohistiocytomas are benign lesions that tend to resolve spontaneously. Surgical excision biopsy is successful for lesions causing local problems. Multicentric Reticulohistiocytosis is a very rare and aggressive condition which characteristically presents with arthritis, cutaneous papules and nodules and mucosal lesions. It usually arises in middle-aged women of whom over half present with arthritis. The disease may be self limiting, especially in the rare childhood cases, or progress to a disabling and deforming polyarthritis. There is no evidence for any particular therapeutic modality, but a stepwise approach using steroids and methotrexate or cyclophosphamide has been proposed, with a possible role for infliximab in refractory cases. Finally in the non-JXG family, RosaieDorfman disease presents with massive painless lymphadenopathy, typically in the cervical region. The nodes have a characteristic appearance of sinus invasion by large histiocytes which commonly contain ingested whole erythrocytes or small lymphocytes. There may be associated systemic upset, vital organ involvement and occasionally CNS involvement. Spontaneous regression is common but in persistent cases steroids may accelerate a response.
Secondary HLH Secondary HLH may occur during an immune response to an infection or accompany a variety of underlying disorders that are associated with immune dysregulation. These include a number of congenital immune deficiencies (other than familial HLH), autoimmune diseases and malignancies. These conditions and infections must be carefully looked for while molecular testing is undertaken to identify those who have one of the known familial HLH defects. In patients with no family history of HLH, no known genetic defects and no underlying disorder, it remains
Figure 3 Lesions of juvenile xanthogranuloma.
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SPECIFIC AREAS Abla O, Weitzman S, Minkov M, et al. Diabetes insipidus in Langerhans cell histiocytosis: when is treatment indicated? Pediatr Blood Cancer 2009 May; 52: 555e6. Badalian-Very G, Vergilio JA, Degar BA, Rodriguez-Galindo C, Rollins BJ. Recent advances in the understanding of Langerhans cell histiocytosis. Br J Haematol 2011 Oct 24. doi: 10.1111/j.1365-2141.2011. 08915.x. [Epub ahead of print]. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010 16 Sep; 116: 1919e23. Haupt R, Nanduri V, Egeler R. Late effects of Langerhans cell histiocytosis and its association with malignancy. In: Weitzman S, Egeler M, eds. Histiocytic disorders of children and adults. Cambridge: Cambridge University Press, 2005; 272e292. Jaffe R. Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol 2004; 7: 214e25. Minkov M. Multisystem Langerhans cell histiocytosis in children: current treatment and future directions. Pediatr Drugs 2011; 13: 75e86.
difficult to definitively distinguish between secondary and familial HLH at their first presentation. Secondary HLH can be as severe as familial HLH and may require similar initial nonspecific immunotherapy directed at turning off the immune response. Treatment should however, also be directed at the underlying condition, and any immunotherapy tailored according to the underlying disorder.
Histiocyte lineage-related malignancies Leukaemias Acute myelomonocytic (M4) and monocytic (M5) leukaemias typically present with pancytopenia and the clinical signs of bone marrow failure. In addition, these two particular subtypes of myeloid leukaemia may present with solid lumps of disease described as chloromas or in infants “blueberry muffin” spots. In the UK these are currently treated on MRC protocols for 4e5 months with intensive cyclical chemotherapy resulting in survival rates in excess of 65%. Chronic myelomonocytic leukaemias are rare, clonal, myeloproliferative stem cell disorders that behave differently in children and adults. In children the disease has been known as monosomy 7, but is currently called juvenile myelomonocytic leukaemia. This may initially present with an indolent course that can be stayed with AML type chemotherapy. Unfortunately, relapse is inevitable and the only potentially curative treatment is bone marrow transplantation.
RESEARCH AND SUPPORT Histiocytosis Association https://www.histio.org. Histiocytosis Research Trust http://www.hrtrust.org. Macmillan http://www.macmillan.org.uk/Cancerinformation/Cancertypes/ Childrenscancers/Typesofchildrenscancers/Langerhanscellhistio cytosis.aspx.
Practice points
Sarcomas There are a variety of extremely rare sarcomas potentially of histiocytic lineage. These include interdigitating and follicular dendritic cell tumours and monocytic and histiocytic related sarcomas. Treatment is anecdotal but can include surgery and potentially adjuvant chemotherapy.
LCH C Consider the diagnosis in infants with widespread or resistant eczema and young children with persistent, localized musculoskeletal aches and pain. C Take a very detailed current and past medical history to establish whether multiple organs systems may be involved. C Establish a tissue diagnosis and undertake appropriate investigation of other potentially involved systems. C Seek expert advice on treatment. C Facilitate patient and parent contact with other similarly affected families and support groups.
Conclusion Histiocytoses are rare disorders that often develop and respond to therapy in an unpredictable way. The key to successful therapy is accurate identification at tissue level and appropriate staging. Eligible children and adults should be entered on to available trials. Patients should be observed and monitored to assess long-term morbidity from disease and drug related toxicities. Patients and families should have access to advice from experienced doctors and support groups such as the Histiocytosis Association, or in the UK members of the Histiocytosis Research Trust. A
Non-LCH C Seek dermatological advice for unusual skin lesions in children HLH C Consider in any systemically unwell infant with unexplained hepatic, haematological or neurological problems. C Refer HLH cases to a secondary or tertiary unit with experience in dealing with severely ill children requiring intensive systemic therapy. C HLH presenting in infancy is usually the familial form. check for any history of non-SUDI infant deaths. stem cell transplant is necessary for cure. facilitate access to genetic counselling and contact with other similarly affected families and support groups.
FURTHER READING GENERAL Arceci RJ, Henter JI. The histiocytoses: the fall of the Tower of Babel. Eur J Cancer 1999; 35: 747e69. Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch Dis Child 2011; 96: 688e93. NCI. Adult LCH. Available from: http://www.cancer.gov/cancertopics/pdq/ treatment/lchistio/HealthProfessional/page10; 2011. Weitzman S, Egeler RM. Histiocytic disorders of children and adults. Cambridge: Cambridge University Press, 2005. Weitzman S, Jaffe R. Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses. Pediatr Blood Cancer 2005; 45: 256e64.
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Histiocyte lineage-related malignancies C Consider in the differential diagnosis of acute leukaemia, especially in the presence of skin or superficial mass lesions. C Refer all cases to a secondary or tertiary centre for precise diagnosis and treatment.
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