UPDATED JANUARY 2015
1. GENERAL INFORMATION
1.1 Epidemiological data
Most patients diagnosed as having Langerhans cell histiocytosis are children, with a peak between 1-3 years of age. In general, the disease is probably underdiagnosed. In a Swedish population-based study, the incidence of Langerhans cell histiocytosis in children under the age of 15 years was estimated to be around 0.9 cases per 100,000 children per year (Stålemark 2008). It appears to be more common in boys than in girls (1.2-2:1). Incidence in the adult population is difficult to determine, since a variety of organ specialists are involved due to the varied clinical presentation, but it has been reported that one to two adult cases of LCH occur per 1 million population (Baumgartner 1997). Langerhans cell histiocytosis has been reported in several sibships and in twins. Though it is usually sporadic, it has been reported that around 1% of patients have relatives with Langerhans cell histiocytosis, and that this suggests genetic predisposition (Arico 2003).
1.2 Etiologic and risk factors
The aetiology of Langerhans cell histiocytosis is unknown, and neoplastic and inflammatory origins have been debated for decades (Broadbent 1994; Pritchard 1994; Egeler 1995). Except in the single system pulmonary “form”, “LCH cells” (pathological Langerhans cells) are consistently monoclonal, as judged by X-linked polymorphism studies in female patients, but the disease is not usually considered to be a conventional neoplasm and lesions often regress spontaneously (Willman 1994; Willman 1998). However, in 2010 oncogenic BRAF V600E mutations were identified in 35 of 61 archived specimens (57%) (Badalian-Very 2010). The same group later investigated other genetic causes of ERK pathway activation, and identified one patient with compound mutations in the kinase domain of ARAF (Nelson 2014). Subsequently, a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors has been presented. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, the authors propose that LCH should be defined as an inflammatory myeloid neoplasia (Berres 2014). Other researchers consider LCH to be a “reactive inflammatory disease” maybe in response to an inciting event such as an infection (Fadeel 2003). Recently, Merkel cell polyomavirus DNA sequences in peripheral blood and tissues from patients with Langerhans cell histiocytosis were reported, but these findings have so far not been confirmed by other groups (Murakami 2014). There are no well accepted environmental risk factors associated with Langerhans cell histiocytosis. However, in one epidemiological study from Minneapolis an association with infections during the neonatal period and with thyroid disease in general was reported, whereas there was a negative (“protective”) correlation with childhood vaccinations and chicken pox infection prior to Langerhans cell histiocytosis (Willman 1994). Smoking has been shown to increase the number of Langerhans cells in the bronchial epithelium and it seems likely that cigarette smoke contains one or more precipitants of pulmonary Langerhans cell histiocytosis (Novice 1989; Bernstrand 2001). An increased risk of developing severe pulmonary involvement was recently reported in a long-term follow-up study (Bernstrand 2001).
2. PATHOLOGY AND BIOLOGY
2.1 Biological data
The genetic causes of ERK pathway activation represent an interesting novel finding in LCH, including the oncogenic BRAF V600E mutations and the mutations in the kinase domain of ARAF (Badalian-Very 2010; Badalian-Very 2012; Nelson 2014). LCH is clinically characterized by inflammatory features, and as mentioned LCH has been proposed to be defined as an inflammatory myeloid neoplasia (Berres 2014). Hence, numerous studies have focused on inflammatory features of LCH biology, including inflammatory cytokines. Pathological Langerhans Cells (“LCH cells”) have been shown to be involved in a cytokine production loop that also involves T cells and macrophages. Lymphocytes constitutively produce GM-CSF and IL-3 and, to a lesser degree, IL-1, IL-4 and LIF whilst histiocytes produce TNF-alpha, IL-1 beta and GM-CSF (Kannourakis 1994; Egeler 1995; Egeler 1999; Henter 2001). Recent studies have shown that “LCH cells” also synthesize LIF and IL-11 (Calming 2003). This might explain the presence of lymphocytes, macrophages and eosinophils in the lesions and, more specifically, the raised ESR and the thrombocytosis often associated with active disease (Calming 2003). Geissmann et al have reported that LCH cells in the bone and/or chronic forms of the disease accumulate within the tissues in an immature state, and that they may be induced to differentiate toward mature DCs after CD40 “triggering” (Geissmann 2001). Along the same line, it has also been reported, by Annels et al, that “LCH cells” express the immature dendritic cell marker CCR6 but not the mature dendritic cell marker CCR7 (Annels 2003). The “LCH cells” also appear to be the source of a production of the ligand for CCR6 (CCL20/MIP-3alpha), as well as other inflammatory chemokines. It is still not known how these signs of “inflammatory activity” are related to the reports of LCH being a clonal proliferative disease (Willmann 1994). There is an intriguing report that T cell malignancy and LCH in the same patient can carry precisely the same clonal T cell receptor rearrangement (Feldman 2005). Beverley et al have summarized laboratory research in LCH up to 2005 (Beverley 2005). Importantly, Grois et al have reported that the CNS disease appears to be mainly associated with T cell activity (Grois 2005). Moreover, Coury et al reported that the inflammatory cytokine IL-17A can be produced by dendritic cells in LCH patients, and that IL-17A serum levels are increased in LCH patients with active disease (Coury 2008), supporting the view that LCH is an inflammatory disease. However, these findings were questioned since it was reported that neither IL-17A mRNA nor IL-17A protein was detectable in LCH lesions and attempts failed to identify any IL-17A gene expression from CD207(+) dendritic cells or CD3(+) T cells in LCH lesions (Peters 2011). Notably, recently IL-17A-producing peripheral blood monocytes were detected in Langerhans cell histiocytosis patients. These findings also support a role for these cells, the monocytes, in the pathogenesis of LCH (Lourda 2014). The specific cause of LCH still remains to be elucidated.
With haematoxylin-eosin staining, LCH cells have a homogeneously stained pink cytoplasm and lobulated nuclei. In the early destructive phases of the disease, aggregates of LCH cells are admixed with a variable number of macrophages, lymphocytes and eosinophils and occasional giant multinucleated cells. Helpful immuno- and histo-chemical stains include those for ATPase and alpha-D-mannosidase on specially prepared sections, S-100 protein (seen in 50-60% of LCH cells), and binding of the peanut lectin agglutinin (Pritchard 2001). Definitive diagnosis, however, is only provided by either positive staining of frozen tissue sections with anti CD1a antibodies (antibody O-10 is used in formalin-fixed sections) and or positive staining with Langerin (CD207). The expression of CD1a is regarded as a hallmark of this disease; however, it has always been presumed that it was only expressed by pathogenic Langerhans cells but it has recently been shown that polyclonal T-cells also express CD1a in Langerhans cell histiocytosis lesions (West 2014). Langerin (CD207) is a lectin for which antibodies can be used as immunohistochemical markers of Langerhans cells (Chikwava 2004). Electron microscopic demonstration of Birbeck granules was previously one alternative method to make a definitive diagnosis (WGHS 1987; Favara 1997), but since expression of Langerin confirms the presence of Birbeck granules, ultrastructural demonstration of cytoplasmic Birbeck granules is no longer essential.
2.3 Accuracy and reliability of pathological diagnosis
With LCH, the most common type of dendritic cell-related histiocytoses, the first biopsy may not guide the pathologist to a correct diagnosis. Instead, it may suggest a non-specific inflammatory reaction. Moreover, although the clinical picture may be strongly indicative of LCH, it may be difficult to achieve a definitive diagnosis, so a further biopsy may be necessary. One also has to be aware that a lesion may be healing and therefore not providing a typical pathological picture, and that the biopsy may not have been taken in the exact spot of the lesion.
There is no generally accepted pathologic grading system for Langerhans cell histiocytosis. In fact, there is no reliable way to distinguish the histopathologic picture of an isolated eosinophilic granuloma from disseminated disease (Favara 1997).
2.5 Particular histological types considered elsewhere
3.1 Signs and symptoms
Langerhans cell histiocytosis may affect a number of different organs, so signs and symptoms may be extremely variable (Broadbent 1994; Egeler 1995; Arceci 1999; Braier 1999; Willis 1996; Bernstrand 2005).
The organ system most commonly involved in Langerhans cell histiocytosis is the bony skeleton, involving around 85% of children with LCH at diagnosis, causing a spectrum of findings ranging from a painless isolated bone lesion to multiple lesions which might cause dysfunction, pain, fractures, dental problems, compression of vertebral bodies, and deformities (Bernstrand 2005). The skull, ribs, pelvis, vertebrae, mandible and extremities are most commonly affected. Lesions are typically osteolytic with a sclerotic margin around those that are healing. Some bone lesions may invade into adjacent soft tissues and cause swelling and compression of vital structures (e.g. optic nerve, spinal cord).
Cutaneous lesions are the second most common finding in Langerhans cell histiocytosis, usually beginning with a scaly, erythematous seborrhea-like eruption on the scalp, behind the ears and in the axillary, inguinal or perineal areas, less often palms and soles, and sometimes with secondary infection. It reported that some 30-40% of children with LCH have skin involvement at diagnosis (Bernstrand 2005, Ehrhardt 2014). There may also be more discrete lesions with pinkish brown papulas scattered over the trunk, especially in the lower central (suprapubic and dorsal) areas. There may be purpura, petechiae, and also bleeding into the lesions, especially when the patient is thrombocytopenic.
3.1.3 Lymph nodes
Lymph node enlargement most commonly affects the cervical nodes. Rarely, it can be massive and cause upper airways obstruction.
Ear involvement usually appears as an aural discharge, because of otitis externa or polyps of histiocytic tissue. The mastoid is often affected. Hearing loss may follow ossicle or vestibular damage.
3.1.5 Bone marrow
Bone marrow involvement by “LCH cells” may occur with varying degrees of cytopenia. Mild to moderate anaemia and thrombocytopenia may also be associated with hepatosplenomegaly and increased phagocytosis by macrophages activated by the disease process. A transfusion dependent anemia and thrombocytopenia may develop, often in association with a secondary hemophagocytic lymphohistiocytosis.
3.1.6 Liver and spleen
Liver involvement may be severe and associated with hypoalbuminemia, ascites and oedema or with a prolonged prothrombin time. Periportal fibrosis (sclerosing cholangitis), which is likely if transaminases are elevated, may lead to portal hypertension and secondary hypersplenism. Spleen enlargement with “LCH cells” infiltration and phagocytosing histiocytes may also cause hypersplenism.
3.1.7 Respiratory system
Pulmonary involvement in children is usually part of multisystem disease, but in adults the lung may be the only organ involved. Lung parenchymal involvement with “LCH cells” and secondary pulmonary fibrosis, with consequent reduction of lung volume, are the commonest causes of respiratory insufficiency. This may result in tachypnea, dyspnea, recurring episodes of pneumothorax (particularly in older children and smoking adults) and, ultimately, fibrosis, sometimes with respiratory failure (Vassallo 2000; Tazi 2006).
3.1.8 Gastrointestinal tract
Oropharyngeal mucosa infiltration may appear as ulceration of palatal or gingival mucosa and occurs in up to one third of patients (Geissmann 1996). Weight loss or failure-to-thrive may also occur and Langerhans cell histiocytosis of the small bowel may be associated with malabsorption (Shima 2010). Diarrhoea, with blood and/or mucus, suggests colon involvement. Occasionally the pancreas is involved.
3.1.9 Genital tract
Langerhans cell histiocytosis of the female genital tract may involve the vulva (most common), vagina, cervix, endometrium, and ovary. It may occur with or without other organ involvement. Although involvement of the genital tract can occur at any age, it is most common in young adulthood (Axiotis 1991).
Infiltration and dysfunction of the pituitary gland and/or adjacent hypothalamus occurs in between 10-50% of cases with multisystem involvement during the evolution of the disease. The most frequent manifestation is diabetes insipidus (Donadieu 2004). Infiltration of the anterior pituitary is less common but may cause growth retardation and/or panhypopituitarism. More than half of all patients with diabetes insipidus will develop growth hormone deficiency.
Central nervous system involvement may cause symptoms such as ataxia, dysarthria, dysphagia and hyperreflexia, and may develop many years after onset of the disease (Grois 1998). Heightened clinical awareness and the high sensitivity of MRI scanning have led to increasing brain involvement recognition, in particular in patients with patients with craniofacial involvement and those with multisystem disease. Swedish population-based studies indicate a minimum prevalence of radiologically verified neurodegeneration of around 25% in all children with LCH (Laurencikas 2011). The cerebellar white matter is often involved, causing ataxia and tremor, but lesions in the meninges, cerebral hemispheres, hypothalamus, pons and choroid plexus are also described. Recently, cognitive dysfunction has been recognised in long-term survivors (Calming 2002; Nanduri 2003; Mittheisz 2007; Van t Hooft 2008).
3.2 Diagnostic strategy
Langerhans cell histiocytosis may be missed because of failure to consider this diagnosis. If Langerhans cell histiocytosis is suspected, a pathological examination should always be obtained. A biopsy of the bone, skin, of the colon if GI tract involvement is suspected, or virtually any other affected organ can be performed. In “isolated” pulmonary Langerhans cell histiocytosis of adults, confirmation of pulmonary involvement requires biopsy or bronchial washings (bronchial washing should usually be performed first).
3.3 Pathological diagnosis
In Langerhans cell histiocytosis diagnosis rests entirely on pathological examinations. Definitive diagnosis is only provided by either positive staining with anti CD1a antibodies and/or positive staining with Langerin (CD207) (for futher information, see paragraph 2.2). In addition to light microscopy, studies with electron microscopy to search for Birbeck granules can be used as an alternative method to make a “definitive diagnosis” (Réfabert 1996; Favara 1997; Gadner 2001). However, the incidence of positive tests varies in different organ systems. In CNS lesions, for instance, positive staining for CD1a, Langerin, and Birbeck granules may be difficult to detect (Grois 1994; Grois 2005).
Defects in type I cytokine pathway, leading to gamma-interferon deficiency, predispose to atypical Mycobacterial infection which can present with features, including osteolytic, lung and skin lesions, that resemble those of LCH. The pathologic distinction should be evident to experienced pathologists. Gorham’s disease (“vanishing bone disease”) is characterised by osteolytic lesions which, without biopsy, may be mistaken for LCH.
4.1 Staging classifications
The most common staging system for Langerhans cell histiocytosis is to distinguish between single system disease (affecting only one organ/ system) and multisystem disease (with involvement of two or more organ systems) (Gadner 1994; Egeler 1995; Gadner 2001; Gadner 2013). Single system disease of the bone can be separated into single site or multiple site involvement. Out of 170 patients with single system LCH registered in the DAL-HX 83/90 studies, coordinated in Vienna, single bone lesions were most common (68%), followed by multiple bone lesions (19%), isolated skin disease (11%), and isolated lymph node involvement (2%) (Titgemeyer 2001). Multisystem disease can be separated into patients with or without ‘organ dysfunction’ of either liver, lung or hematopoietic system, according to Lahey’s criteria (Lahey 1975). In current international clinical trial (LCH-IV), “risk organ” involvement is defined as involvement of any of the following: hematopoietic system, liver or spleen. Hematopoietic involvement is independent of bone marrow (CD1a) involvement and is present if at least two of the following criteria are met: haemoglobin 3 cm below costal margin (palpation, midclavicular line) and/or liver dysfunction, i.e. protein 2 cm below costal margin (palpation, midclavicular line).
4.2 Staging procedures
When Langerhans cell histiocytosis is suspected, recommended investigations, in addition to a thorough clinical examination, are haemoglobin and/or hematocrit, WBC and differential, platelet count, liver function tests (serum transaminases, alkaline phosphatase, bilirubin, albumin and total protein), coagulation studies (PT, PTT, fibrinogen), urine osmolarity and arginine vasopressin measurement (after overnight water deprivation (Broadbent 1989). Urinary AVP concentration is more informative in the diagnosis of diabetes insipidus than urine osmolarity), chest radiograph (PA and lateral) and a skeletal radiograph survey (isotope bone scan is less informative). In certain patients, in order to determine the extension of the disease, an ultrasound or CT of the abdomen may be indicated and, in others, a CT of the chest, which is more sensitive than plain chest radiographs for quantifying pulmonary involvement. Respiratory tests should be performed routinely in adults and co-operative children. The clinical situation may suggest further studies, such as diagnostic colonoscopy in patients with suspected GI involvement. An MRI of the brain is suggested in patients with CNS involvement, or at increased risk for developing CNS involvement (i.e. patients with visual or neurologic abnormalities, with endocrine deficiencies, or with aural discharge or deafness), and it can also be considered in patients with CNS “risk lesions” (lesions in the orbital, temporal/mastoid, sphenoid, zygomatic, ethmoid bones, maxilla, sinuses or anterior and middle cranial fossa with intracranial soft tissue extension) (Grois 1994; Grois 1998). PET-CT is another radiologic alternative that combines the anatomic detail of CT and the physiologic activity of (18)F-FDG imaging, which can be clinically useful to evaluate disease activity and response to therapy (Kaste 2007). Pathological examinations from more than one organ such as a bone marrow biopsy in case of cytopenias and liver biopsy when liver dysfunction is present, may be necessary to define the number of organs involved.
5.1 Natural history
The course of Langerhans cell histiocytosis may be quite variable. It may resolve spontaneously or have a fatal outcome despite intensive treatment (Lahey 1975; Komp 1980; Broadbent 1994). It may reactivate unpredictably in one or more episodes, that resolve with or without treatment, including very late relapses (twenty years or more from onset). Permanent sequelae are common (Willis 1996; Bernstrand 2005). The clinical course of Langerhans cell histiocytosis localized solely to the bone is generally benign and tends to resolve spontaneously over a period of months to years, although there may be permanent sequelae. These may include compression of vertebral bodies, orthopedic deformities, growth plate involvement with growth impairment and deformities of the cranium, such as destruction around the orbit, loose teeth and hearing impairment. Diabetes insipidus (with a cumulative risk varying between 10-50% in different – institutional or multicentre – series), may pre-date the diagnosis. It occurs more often among patients with multisystem disease and those with cranial bone involvement. Moreover, after a disease course of 10 years with diabetes insipidus, most affected patients may also develop growth hormone deficiency.
In patients with multisystem disease without “organ dysfunction”, around 50% suffer one or more sequelae, including small stature, growth hormone deficiency, diabetes insipidus, partial deafness, cerebellar ataxia, loss of permanent dentition, orthopedic problems, pulmonary fibrosis and/or biliary cirrhosis with portal hypertension and also cognitive dysfunction (Willis 1996; Bernstrand 2005; Nanduri 2003). In adults with Langerhans cell histiocytosis, lung disease may be life-threatening and a mortality of around 25% has been reported (Basset 1978; Novice 1989; Malpas 1996).
5.2 Prognostic factors
High correlation has been observed between the mortality rate and the number of organ/systems involved (Lahey 1975; Komp 1980; Broadbent 1994; Willis 1996). Furthermore, involvement of liver, lungs, hematopoietic system, or spleen is associated with a higher mortality (Gadner 2001). There is also evidence that serious CNS complications are associated with multisystem disease and cranial bone involvement, i.e., lesions in the facial bones and skull base with intracranial soft tissue extension shown to be associated with an increased risk of development of diabetes insipidus (DI) (sometimes known as “CNS risk lesions”) (Grois 1998; Grois 2006). Skin involvement and an age of less than 1 year at diagnosis decrease the chance of prolonged survival, but age per se is no longer considered an independent risk factor. Rather, young age is more often associated with risk organ involvement (Gadner 2001). Older patients tend to have a worse outcome (Novice 1989; Malpas 1996). Early response to therapy appears to be a predictive factor for final outcome. A group of non-responders with a high risk of poor outcome can be identified after the first 6 weeks of systemic treatment (Gadner 1994; Gadner 2001; Gadner 2008).
6.1 Single system Langerhans cell histiocytosis in children
Single system Langerhans cell histiocytosis most often involves the bone, skin or lymph nodes, and lungs. The two major aims of therapy are to provide relief of symptoms and reduce permanent sequelae.
6.1.1 Bone lesions
Treatment options for single bone lesions include wait-and-see, oral indomethacin, curettage, intralesional steroid injections, bisphosphonates or radiation. In case of a bone lesion with mild or no symptoms and without risk of permanent sequelae, wait-and-see or diagnostic curettage (which often is followed by healing) are standard options, on a type C basis. Oral indomethacin, which acts as an analgesic and maybe also “anti-inflammatory” against the Langerhans cell histiocytosis itself, may also be considered suitable for individual clinical use on a type R basis. In case of symptomatic lesions or when there is a risk of permanent damage (growth impairment, fracture, loss of hearing, loss of permanent teeth, other unacceptable dysfunction or deformities), more active therapy may be necessary. Injection of local steroids (preferably >100 mg methyl-prednisolone) is suitable for individual clinical use, on a type 3 level of evidence (Egeler 1992) and is commonly followed by symptomatic relief (Bernstrand 1996). Radiation, which should be given only in low doses (6-10 Gy) to reduce the risk of second tumours, is now rarely used but can be considered suitable for individual clinical use on a type R basis if treatment is important to conserve function, and intralesional therapy is not feasible (Ladisch 1994a). In the present LCH-3 treatment protocol (launched 2011), treatment for CNS risk lesions is also under study.
6.1.2 Multifocal bone disease
In patients with multifocal bone disease, the clinical picture varies considerably, ranging from a few non symptomatic lesions to a large number of lesions, and the treatment approach varies accordingly. Treatment options suitable for individual clinical use on a type R basis include wait-and-see (based on the observation that spontaneous remissions may occur) or local treatments of more symptomatic lesions, including curettage (see above) and intralesional steroids. Radiation, in low doses, can be considered in individual patients where treatment is important to conserve function for whom no other therapy is availalble, but it is rarely used nowadays. Systemic chemotherapy is another option suitable for individual clinical use on a type R basis or patients with several symptomatic lesions supported by recent data suggesting that a more “active” approach may be associated with a lower number of permanent sequelae in these patients (Titgemeyer 2001). Thus, in the current international treatment protocol (LCH-IV) all patients with isolated “CNS risk” or multifocal bone lesions, a two-drug regimen (vinblastine and prednisolone) is suggested (Stratum II, Group B), with the duration randomized to 6 or 12 months.
6.1.3 Skin lesions
In patients with skin involvement only, wait-and-see or local therapy, e.g., with topical steroids, are standard options on a type C basis. Topical nitrogen mustard in a 0.02% aqueous solution can be effective and may be considered suitable for individual non standard clinical use on a type 3 level of evidence (Sheehan 1991). There is no evidence that nitrogen mustard (0.02%) applied topically in this concentration causes skin cancer, or any other skin sequelae (Hoeger 2000).
In the case of lymph node involvement only the standard option, on a type C basis is no treatment at all, since most patients recover spontaneously. However, it is important to search for other organ involvement, causing secondary lymph node involvement. Surgical removal or chemotherapy can be considered suitable for individual clinical use on a type R basis.
If the disease is active with functional impairment, systemic chemotherapy is suitable for individual clinical use, on a type 3 level of evidence, aiming at reducing further parenchymal destruction. In addition, in isolated pulmonary Langerhans cell disease of adults and adolescents, the first step recommended, on a type C basis, is to have smokers quit smoking.
6.2 Multisystem Langerhans cell histiocytosis in children
The major aim of treatment is to increase survival and to accelerate regression of active disease so that late effects are reduced. Recent data indicate that systemic chemotherapy is suitable for individual clinical use on a type 3 level of evidence, since it may increase survival, as well as reduce the number of permanent sequelae (Gadner 1994; Gadner 2001; Gadner 2008; Gadner 2013). Corticosteroids and vinblastine for a period between 6 and 12 months are the most commonly used chemotherapeutic agents, which in combination with 6-mercaptopurine and methotrexate have proved effective in a prospective study (Gadner 1994). However, the addition if methotrexate to standard therapy did not show added value in the LCH-III study, and the use of 6-mercaptopurine is evaluated in the study LCH-IV (Gadner 2013). With regard to the relative efficacy of single drug therapy, an Italian study has suggested the special efficacy of VP-16 (Ceci 1988). However, a randomised study (LCH-I) has shown no significant difference between vinblastine versus VP-16 given as single drug therapy following an initial single pulse of systemic high dose methylprednisolone (Gadner 2001). A subsequent study (LCH-II) showed that intensified treatment significantly increases rapid response and reduces mortality in risk multisystem LCH (Gadner 2008). Thus, multiagent chemotherapy might be considered suitable for individual clinical use on a type 2 level of evidence (Gadner 1994; Ladisch 1994b; Gadner 2001; Gadner 2008; Gadner 2013). In the recent LCH-III study based on vinblastine, prednisolone and oral 6-mercaptoprine, the addition of methotrexate did not improve outcome. However, historical comparisons revealed survival superior in the 12-months study LCH-III to that of identically stratified patients with risk organ involvement treated for 6 months in the predecessor trials LCH-I (62%) or LCH-II (69%, P <0.001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P <0.001) (Gadner 2013). Treatment with cyclosporin A is investigational or suitable for individual clinical use on a type 3 level of evidence (Arico 1995). Another investigational therapeutic option of potential theoretical interest is anti-cytokine therapy (as anti-TNF) (Henter 2001), but recent clinical data has not been as rewarding as initially was anticipated. A new interesting investigational therapeutic option is the use of vemurafenib in patients with Langerhans cell histiocytosis that harbor the BRAF V600E mutation (Haroche 2013). Myeloablative therapy with allogeneic bone marrow transplantation in patients with a suitable donor with refractory aggressive disease can be considered suitable for individual non-standard clinical use on a type 3 level of evidence, and reports indicate that stem cell transplantation with reduced intensity conditioning may prove beneficial (Ringden 1987; Morgan 1994; Cooper 2008). Orthotopic liver transplants and heart-lung transplants have been successfully performed in patients with end stage liver or lung failure. Active disease in other organ systems need not be an absolute contraindication to these procedures. Organ transplants can be considered suitable for individual non standard clinical use on a type 3 level of evidence even though disease may recur in the transplanted organ (Melendez 1996). A combination oral 6-mercaptopurine, low-dose oral methotrexate and intermittent prednisone pulses with or withhold additional vinblastine every third week has been suggested but is still investigational for the treatment of prolonged disease activity. Interestingly, significantly lower 5-year reactivation rates was observed by prolonged treatment to 12-month (37%) compared with 6-month (54%, P = 0.03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P <0.001) (Gadner 2013). The use of 2-chlorodeoxyadenosine (2-CDA) for reactivation of LCH, in particular bone disease, can be considered non-standard clinical use on a type 3 level of evidence (Weitzman 1999). The combination of 2-chlorodeoxyadenosine and ARA-C, investigated in the LCH-S-2005 study, can be considered as a salvage therapy for individual non-standard clinical use on a type 3 level of evidence in severe Langerhans cell histiocytosis that is refractory to standard therapy, but it is associated with extremely high toxicity (Bernard 2005).
6.3 Treatment of Langerhans cell histiocytosis in adults
The published literature on adult LCH cases lacks a comprehensive discussion on the differences between paediatric and adult patients and there are no recommendations for evaluation and comparative therapies. However, consensus recommendations for the management of adult patients with LCH have been developed, including diagnostic work up, therapy, and follow up (Stockschlaeder 2006; Girschikofsky 2013).
6.4 Juvenile xanthogranuloma
Juvenile xanthogranuloma is a benign histiocytic lesion of the skin, commonly located in the skin, that usually occurs in neonates and young children (Weitzman 2005). The lesions usually persist for 1 to 2 years and then spontaneously resolve. Therefore an initial “wait-and-see” approach is standard option, on a type C basis. In patients with more active disease, surgical excision of lesions may be curative and is suitable for individual clinical use on a type R basis. Systemic chemotherapy, or less attractive, radiation therapy are suitable for individual clinical use on a type 3 level of evidence (Freyer 1996). Juvenile xanthogranuloma and LCH can occur in the same patient, suggesting that the pathogenesis of the two conditions may have a common element. One suggestion is that some juvenile xanthogranuloma lesions may represent burnt-out LCH (Hoeger 2001).
7. LATE SEQUELAE
7.1 Treatment of chronic sequelae
Chronic sequelae associated with Langerhans cell histiocytosis are common, and, rather than being the consequence of therapy – as in survivors of child cancer – they are most often the result of the disease activity itself, with tissue destruction and fibrosis or gliosis secondary to the granulomatous involvement of various tissues (Greenberger 1981; Willis 1996; Braier 1999; Bernstrand 2001). Reactivation is a frequent and early event in multisystem LCH, but involvement of risk organs at reactivation is rare and mortality is minimal, but reactivations increase the risk for permanent consequences by about 2-fold (Minkov 2008). In one long-term follow-up study (median follow-up 16 years), late sequelae had developed in 42% of the patients, more frequently in patients with multisystem disease (Bernstrand 2005). Diabetes insipidus was the most common disability (15%), neurological complications affected 10%, and pulmonary fibrosis had developed in 11% (Bernstrand 2005). The CNS symptoms usually manifest many years after the diagnosis of Langerhans cell histiocytosis, and often when the disease is considered quiescent. This neurodegenerative CNS-LCH disease may be progressive, causing severe symptoms, such as ataxia, tremor and dysarthria (Grois 1994; Grois 2010). Changes in personal behavior, judgement and cognitive function may also occur (Calming 2002; Nanduri 2003; Mittheisz 2007;van’t Hooft 2008). Gadolinium-enhanced MRI is the best way to detect CNS and pituitary abnormalities (Grois 1994). There is as yet no established therapy for LCH-CNS disease but it can be speculated that treatment reducing inflammatory activity within the CNS will also reduce the development of secondary gliosis and of functional damage. High dose immunoglobulin (IVIG) has been suggested to reduce the incidence of Langerhans cell histiocytosis-associated CNS neurodegeneration, but further studies are needed to confirm this (Imashuku 2009; Gavhed 2011). Of interest, CSF levels of neurofilament light (NF-L) and tau appear to be elevated in CNS-LCH, and are therefore potential markers for CNS-LCH to monitor disease progression and to evaluate various treatment attempts (Gavhed 2009).
7.2 Related and secondary tumours
A 5% incidence of malignancy in long-term survivors of Langerhans cell histiocytosis has been reported, which is a frequency higher than expected from chance alone (Egeler 1993; Egeler 1994). In a case series of 91 cases of Langerhans cell histiocytosis and a malignant neoplasm, 22 had leukaemia, of whom 16 had acute non-lymphoblastic leukaemia (ANLL). ALL most commonly precedes or coincides with Langerhans cell histiocytosis, whereas Langerhans cell histiocytosis usually precedes ANLL. Some cases of ANLL may have developed as a consequence of Langerhans cell histiocytosis treatment (“secondary leukaemia”) with chemotherapy. In addition, secondary “solid” tumours may arise in irradiated areas. Increased incidence of secondary leukaemia (ANLL) and myelodysplastic syndrome has been reported following the use of epipodophyllotoxin derivatives, such as etoposide (VP-16). The cumulative incidence of secondary leukaemia in patients treated with etoposide for Langerhans cell histiocytosis has been estimated to be around 1%. Solid tumours, particularly sarcoma and brain tumours, may develop in irradiated areas so radiation therapy, even at low doses, is discouraged unless there is no reasonable alternative.
8.1 General principles and objectives
Since the course of Langerhans cell histiocytosis is so variable, with spontaneous remissions as well as early or late reactivations, the main objective in follow-up is to monitor activity. Other tests, such as regular blood counts will, of course, be needed if the patient requires chemotherapy. Even simple “single lesion disease” may evolve into multisystem disease. Unfortunately, there is at present no reliable marker for disease activity, although elevated ESR and/or platelet number may be helpful, except in slowly active disease as in the lung and the CNS (Calming 1998).
8.2 Suggested protocols
Importantly, it is suggested that patients with Langerhans cell histiocytosis are treated and followed according to the Histiocyte Society protocols and guidelines (www.histiocytesociety.org). In addition to clinical examination, a follow-up protocol for Langerhans cell histiocytosis in remission with ESR haemoglobin and/or hematocrit, WBC and differential, platelet counts, albumin and, if previously affected, liver function tests can be planned according to the clinical status (Broadbent 1989). Imaging evaluation of involved organs such as chest X-ray study or skeletal radiograph survey of affected bones is suggested (Bernstrand 2001). In patients with CNS involvement, MRI evaluations are recommended and for patients with pulmonary involvement respiratory function tests and high resolution CT of the lungs may be useful (Grois 1998; Bernstrand 1999).
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Prof. Jan-Inge Henter (Author) Karolinska Hospital – Stockholm, Sweden
Prof. Jon Pritchard (Reviewer) Passed away on January 20th, 2007
Dr. Carlo Tondini (Editor) START Clinical Editor – Ospedali Riuniti – Bergamo, Italy