Langerhans cell histiocytosis

INTRODUCTION

Histiocytic neoplasm represents a rare tumor arising from clonal myeloid-derived dendritic cells resembling epidermal Langerhans cells with surrounding inflammatory infiltrate. They account for <1% of tumors of soft tissue and lymph nodes. It was initially referred to as histiocytosis X, later in 1987, renamed by the Histiocyte Society as Langerhans cell histiocytosis (LCH). This disorder predominantly affects children and adolescents of Hispanic whites, less commonly in blacks. Its median age of presentation is 3 years, but it rarely manifests in adults in the fourth decade. Its incidence declines from 5 to 9 million in children under 15 years–1 million in adults.^[1]

It is a clinically challenging disorder of any age group manifesting in any system or organ with varied presentation ranging from an indolent, focal mass lesion to widespread, lethal multiorgan involvement. In view of rapid clinical advances and biological understanding, the landmark classification of histiocytic disorders was first published in 2016.^[2] Being predominantly a disease of childhood, the majority of published literature is based on pediatric data. Later, the Histiocyte Society which is the frontline international consortium for clinical trials in pediatric LCH has published guidelines for adult LCH in 2022.^[3]

CLASSIFICATION

The recent 5^th edition of the 2022 World Health Organization (WHO) and International consensus classification (ICC) of hematolymphoid tumors has summarized a holistic, evidence-based, refined, and contemporary diagnostic criteria on myeloid and histiocytic/dendritic tumors.^[4] It encompasses a systematic, hierarchic classification based on clinical, biologic, and lineage attributes, considering therapeutic and actionable prognostic markers contributed by 420 members with multidisciplinary expertise and wide geographical representation.

Accordingly, both LCH and Langerhans cell sarcoma are included as Langerhans cell neoplasm under the combined dendritic/histiocyte cell-driven neoplasm in view of commonly seen driver mutations in the mitogen-activated protein kinase (MAPK) pathway of variable frequency in the current 2022 World Health Organization (WHO) and ICC. In view of a shared, unified genetic and phenotypic landscape that parallels lineage differentiation of dendritic cells, Langerhans cells, monocytes, and macrophages as well as development from common myeloid precursor, they were positioned immediately after myeloid neoplasm in the WHO 2022 classification.^[5]

MOLECULAR ABERRATION

In view of uncertain etiopathogenesis and diverse clinical spectrum, it was initially thought to be an immune-mediated dysregulation but it has now been reclassified as a neoplastic disorder with no causal or etiological agent identified. Somatic mutations involving the mitogen-activated protein (MAP) kinase pathway, leading to changes in RAS(Rat Sarcoma)-RAF(Rapidly Accelerated Fibrosarcoma)-MEK(Mitogen-Activated Protein Kinase)-Extracellular Signal-Regulated Kinase (ERK) signaling and Phosphoinositide 3-Kinase(PIK)-AKT Threonine Kinase 3(AKT3) PIK-AKT3, are commonly noted. This reiterates the misguided myeloid differentiation model where the activating mutation occurring during cell differentiation represents the disease extent in the ontogeny of LCH.

Despite the disparity of the immune versus clonal hypothesis in the origin of LCH, identification of clonal somatic mutations in BRAF-V600E, p53 expression, inflammatory milieu arising from dysregulated IL17A cytokine levels, and misguided myeloid differentiation model emphasizes the neoplastic nature of this disorder.^[6-8]

Both BRAF-V600E and MAP2K1 are mutually exclusive in LCH.^[9] B-Raf Proto-Oncogene, Serine/Threonine Kinase, Valine-to-Glutamic Acid substitution at codon 600. BRAFV600E is mutated in 40–70% pediatric LCH, followed by 10– 30% of mutations in MAP2K1.^[10] Other less common gene mutations include KRAS, NRAS, ARAF, ALK, RAF1, ERBB3, MAP3K1, BRAF duplications, and PIK-AKT3 pathway mutations.

RISK ORGAN (RO) INVOLVEMENT

The terms unifocal and multifocal are referred in the context of bone disease in pediatric LCH. Depending on critical/RO involvement of one or more vital organs such as liver, spleen, central nervous system (CNS), and hematopoietic system, pediatric LCH is further sub-classified into RO+ or RO negative due to the high risk of treatment failure, reactivation, and death.^[11] As an adult LCH usually presents as a multifocal multisystem disease, RO is not classified individually. Low RO includes skin, bone, lymph node, thymus, and mucosal surface of the oral and genitourinary system. Table 1 depicts various manifestations of adult and pediatric LCH.

Either single or multiple organs involving skin (35%), bones (80%), lymph nodes (8%), endocrine organs (25% pituitary), CNS (2–4%), lung, liver, spleen, and hematopoietic system, about 15% in each, were reported.^[12]

CLINICAL HETEROGENEITY

Pulmonary LCH is characterized by multiple granulomas with eosinophils, Langerhans cells in apical and mid lobes, sparing the bases, manifesting as centrilobular nodules or diffuse lesions. This is followed by intralobular cavitation and cystic lesions leading to alveolar dilatation, fibrosis, bronchiectasis, respiratory failure, cough, breathlessness, and pneumothorax ultimately. Isolated lung lesions are commonly noted in chronic smokers.

Bilateral apical and mid-lobe involvement with reticulo-nodular opacities/cystic lesions may be noted. Focal pulmonary LCH may be asymptomatic or may present with cough or dyspnea on exertion. High-resolution computed tomography (CT) along with bronchoscopic biopsy aids in definitive diagnosis. Spirometry may demonstrate a reduction in diffusion capacity with a variable lung function pattern.^[13]

Dermatologic manifestations vary from seborrheic eczema, erythematous papules, crusted nodules, plaques, ulcerated pustules, or vesicles. It may clinically masquerade as neonatal diffuse hemangiomatosis or refractory eczematous lesions in the scalp, genital areas, or intertrigo in adults. Skin involvement is frequently mistaken for psoriasis, candida, and lichen planus.

Skeletal involvement typically manifests in orbital or mastoid bone as lytic, punched-out lesion or vertebral involvement leading to vertebra plana. Bone imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), and radio-isotope studies are useful in defining the extent, response to therapy, and revealing lytic lesions without marginal sclerosis. Permanent sequelae due to vertebral collapse, fractures, facial or limb asymmetry, tooth loss, proptosis resulting in visual impairment may be noted.

Hematologic manifestations include cytopenia such as hemoglobin <10 g%, total count <4000/mm³, and thrombocytopenia (platelet count <1 lakh/mm³) due to bone marrow infiltration by LCH.

Liver infiltration manifests as hepatomegaly, elevated bilirubin level, and rarely sclerosing cholangitis, resulting in liver fibrosis and end-stage hepatic failure. Early identification of dilated or irregular intrahepatic ducts by MRCP or ERCP in patients with cholestatic jaundice and prompt systemic therapy to mitigate the risk of liver failure.

Gastrointestinal (GI) involvement manifests as mucosal ulcerations or polypoid masses in colonic mucosa, hematochezia, abdominal pain, and diarrhea.

CNS is commonly affected in multisystem disease and characterized by a diverse clinical spectrum ranging from focal mass lesions in meninges, parenchyma, choroid plexus to progressive neurodegeneration resulting in irreversible anterior pituitary dysfunction manifesting as growth hormone, thyrotropin, and gonadotropin deficiency, cognitive dysfunction, ataxia, dysarthria, dysphagia, aflexia, tremors, pseudobulbar palsy, and permanent diabetes insipidus (DI).

Magnetic resonance imaging (MRI) shows signal T2 hyperintensity on the pituitary stalk, circumventricular areas, T1 hyperintense in the basal ganglia, cerebellum, and pons. DI is noted in 25–30% cases in LCH at diagnosis, particularly in multisystem disease, usually precedes the diagnosis of LCH or manifests several years after LCH. Around 50–70% develop permanent anterior pituitary hormone deficiency over a period of 5 years following DI, the most common being growth hormone (40–65%), followed by gonadotropin (35–55%) and thyrotropin deficiency (11–30%).^[14-16]

LABORATORY DIAGNOSIS

Langerhans cells consist of large cells with pale cytoplasm, reniform nuclei due to coffee bean nuclear groove, expressing CD1a, more specific CD207 (Langerin) related to Birbeck particle, CD163, CD68, lysozyme, S100 positivity, CD3, and CD79a negativity on immunohistochemistry, and Birbeck granules, which are penta-laminar cytoplasmic rod-shaped crystals on electron microscopy.

Pathological Langerhans cells lack nuclear atypia or high-grade malignancy features and are seen amidst an inflammatory background comprising eosinophils, lymphocytes which are T-regulatory cells, macrophages, and multinucleated giant cells. Combined positivity of CD1a and CD207 distinguishes LCH from indeterminate cell histiocytosis which harbors ETV3 mutation, immunoglobulin G4 disorders, idiopathic retroperitoneal fibrosis, low-grade B cell lymphomas as well as fat necrosis. Definitive diagnosis requires the presence of CD68/163-positive histiocytes showing CD1a and/or Langerin on immunohistochemistry.

Bone marrow biopsy is usually not recommended in LCH except in cases of peripheral cytopenia or cytosis where there is a risk of concomitant myeloproliferative or myelodysplastic syndrome. Electron microscopy is not essential for the diagnosis. Analysis of BRAF-V600E or MAP2K1 in biopsy samples assists in prognostication and treatment decisions.^[17]

Target capture next-generation sequencing or pyrosequencing for molecular typing of MAPK/ERK and Phosphoinositide 3-Kinase/AKT pathway may guide the diagnosis of equivocal or atypical cases on histopathology. French recommendations for molecular studies in LCH include 1. RO involvement, 2. Disease in age <2 years, 3. Pituitary/orbit/skull base involvement, 4. First-line treatment resistance, and 5. Severe complications and sequelae.^[10]

IMAGING

As per National Comprehensive Cancer Network (NCCN) LCH expert consensus, whole-body ¹⁸F-FDG PET/CT with vertex to toe protocol (instead of the conventional skull base to thigh) due to high incidence of extremities involvement is recommended as an imaging modality for pediatric as well as adult LCH during initial diagnosis, to identify target areas for excision biopsy and during response assessment.^[18]

Organ specific imaging to assess disease involvement and to monitor organ tailored response, additional imaging modality such as MRI brain plain/contrast for evaluation of pituitary or parenchymal infiltration (as PET CT shows background metabolic activity in CNS lesion, except in late stages where there are hypometabolic foci due to secondary neuronal loss), CT lung with spirometry for unifocal pulmonary LCH, ultrasonography for hepatosplenic infiltration are recommended.

TREATMENT

In view of variable clinical presentation ranging from single system to multisystem extensive disease, treatment outcomes are inferior though comparatively improved over the decades. Figure 1 depicts the management algorithm of various manifestations of pediatric LCH.

Close

Figure 1: Algorithm showing management of unifocal, multisystem, and neurodegenerative Langerhans cell histiocytosis in childhood. LACS: Langerhans Cell Histiocytosis-Associated Cerebellar Syndrome, BRAF: B-Raf Proto-Oncogene, Serine/Threonine Kinase, MEK: Mitogen-Activated Protein Kinase Kinase, CR: Complete Response, PR: Partial Response, LCH: Langerhans Cell Histiocytosis, LACI: Langerhans Cell Histiocytosis-Associated Cognitive Impairment,

Export to PPT

Cutaneous LCH management includes topical triamcinolone or low-dose oral steroids as per physician preference and patient tolerance. Locally extensive cutaneous LCH is treated with a combination of either topical steroid, 6-mercaptopurine, hydroxyurea, and low-dose methotrexate. If treatment resistant, 20% imiquimod, local irradiation, or topical N-mustard 20% may enhance response.

Pulmonary LCH mandates cessation of smoking, along with inhalational steroid and long-acting beta-2 agonists. As vinblastine has limited efficacy in lung lesions, cladribine is preferred for improvement in pulmonary function. Lung transplantation is recommended for those refractory to systemic therapy.

Multisystem disease Table 2 enumerates the treatment regimen of multifocal, multisystem LCH, refractory disease, and CNS LCH as per recent recommendations.^[3] A combination of vinblastine and prednisolone is the preferred first-line therapy in pediatric LCH. LCH-I, II, and LCH-III initial data compared with the vinblastine + prednisolone combination, with etoposide added to intensification and 6-mercaptopurine added to continuation phase in those with RO involvement.^[19] Both treatment arms showed faster disease resolution in critical organs despite a short duration of 6-month therapy course but a high risk of disease reactivation as compared to other protocols. Addition of methotrexate to initial treatment in those with RO+ in LCH III has led to increased toxicity without improved response or survival benefit.

TARGETED THERAPY

Identification of the MAPK pathway in the pathogenesis of LCH has led to the discovery of targeted agents such as vemurafenib and dabrafenib against BRAF-V600E. They have shown excellent short-term efficacy and tolerability in high-risk and refractory LCH cases; however, treatment cessation led to quick relapses. Table 3 shows various targeted agents in published and ongoing trials.

Although BRAF inhibitors were initially used in metastatic melanoma and other adult BRAF-mutated cancers, they were shown to be ineffective in various studies. They were first reported for off-label clinical use in patients with refractory multisystem Erdheim-Chester disease carrying BRAF- V600E mutation.

In pediatric multisystem LCH data, vemurafenib monotherapy at 20 mg/kg/day had shown 100% overall response rate following 8 weeks of treatment but is associated with 80% risk of reactivation after treatment discontinuation.^[20,21] In a pilot study on RO+ and relapsed RO-negative pediatric LCH, the combination of vemurafenib with cladribine and intermediate dose cytarabine (up to 500 mg/m²) has shown safety and achieved sustained remission.^[22] BRAF inhibitors are less effective in non-V600E-BRAF mutations and are associated with the risk of arthralgia, skin rash, and secondary cutaneous squamous cell carcinoma.

In contrast, dabrafenib monotherapy, a selective BRAF-V600E inhibitor, is associated with notable safety, better response, and fewer adverse events, particularly in refractory disease presenting with HLH and chemo intolerance.^[23] Its association with other malignancies such as lung, thyroid, Hodgkin’s, non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia was well documented in the literature.

Patients harboring class 3 mutations in the MAP2K1 pathway are frequently reported with a variable disease spectrum and frequent involvement of CNS, lymph node, bone, and are resistant to multiple lines of therapy including MEK inhibition, except in few cases, where response to ulixertinib, an ERK inhibitor, was documented.^[24]

The unacceptably high reactivation rate of 30–40% has shown acute worsening as well as long-term neurological deterioration; hence, data from LCH III and other historical populations have shown survival and response benefit after a 12-month treatment course instead of 6 months.^[25] Despite the enhanced cure rate of LCH after the advent of targeted drugs, quality of life is still suboptimal.

RESPONSE ASSESSMENT AND SURVEILLANCE

Surveillance PET CT at first 2 or 3 months of treatment initiation and thereafter at 3–6 months interval with subsequent imaging frequency being tailored as per individual clinical scenario is recommended for the following treatment of adult LCH with multifocal, unifocal, and multisystem disease. Pituitary or hypothalamic assessment is evaluated by annual endocrine function and MRI scan if initially involved. PFT and HRCT thorax are recommended as a surveillance investigation in pulmonary LCH.

PET response criteria in solid tumors (PERCIST) laid down for response monitoring in solid tumors (comprising complete, partial, stable, and progression) had high sensitivity in detecting extra-skeletal and skeletal lesions compared to whole body MRI, bone scan, and skeletal survey, except in CNS, liver, and lungs. It enabled systematic and structured evaluation of involved organs, differentiated treatment-related changes, and active from inactive lesions with low false-positive rates.^[26]

In the previous trials such as LCH-1 (1991–1995), LCH-II (1996–2001), and LCH III (2001–2008) conducted by the International LCH study group as well as the JLCH (Japan LCH) study group (2001–2008), skeletal radiography, ultrasonography, and CT were the imaging modalities implemented for disease response assessment. Considering imaging, laboratory, and clinical findings, the scoring system comprised of bone, soft tissue, CNS, liver, lung, spleen, skin, transfusion requirement, and constitutional symptoms assigning a score from 0 to 5, with score more than 7 being considered poor prognosis and associated with treatment failure.^[27]

Similarly, treatment response was categorized as no active disease, active disease (with better, stable, or progression), and progression depending upon the individual RO involvement in pediatric LCH trials till 2008, whereas recent response assessment is based upon an objective scoring system consisting of the extent and magnitude of individual organ dysfunction at initial diagnosis as well as after 6 weeks following treatment.

BIOMARKERS

Various data have shown BRAF-V600E in association with high-risk disease, multisystem presentation, high chances of reactivation, and treatment failure in LCH. Identification of BRAF V600E in cell-free circulating DNA was proposed as a biomarker to monitor minimal residual disease by digital droplet polymerase chain reaction in LCH, but disease progression was still noted in negative circulating DNA cases too.^[28]

A risk model comprising neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic inflammation response index, systemic immune inflammation index, BRAF-V600E mutation, and MAP2K1 has correlated with liver, spleen, CNS involvement, and predicted poor prognosis in those with a high score in pediatric LCH, reiterating the altered tumor microenvironment and immune dysregulation as seen in other cancers such as breast, lung, and GI cancers.^[29]

Circulating plasma BRAF-V600E allele is seen in LCH with tumor tissue harboring BRAF-V600E allele, multisystem features, RO involvement, high disease activity score, symptomatic disease, and although they have shown sequential reduction following treatment, they remain detectable in these patients. Multisystem/RO dysfunction, age <2 years confer poor prognosis. Disease activity score above 7 at diagnosis as well as following 6 weeks of treatment, is associated with poor prognosis and mortality.^[30]

Serum matrix metalloproteinase-7 and tumor necrosis factor (TNF-alpha) levels have been identified as simple markers of reduced lung function in pulmonary LCH.^[31] Other prognostic markers such as interleukin-17, TNF-alpha, receptor activator of nuclear factor kappa B, receptor activator of nuclear factor kappa B ligand, osteoprotegrin, periostin, sclerostin, alkaline phosphatase in circulation as well as CSF osteopontin and neurofilament light chain protein are sensitive prognostic markers in CNS and neurodegenerative LCH.^[10]

PROGNOSIS

Except for pulmonary unifocal LCH which has an excellent outcome and 5-year overall survival of >90%, other subtypes show variable response.^[32] Respiratory failure is the main cause of death in those with progressive pulmonary disease and requires close lung function monitoring. In the era of targeted therapies, the outcome of neurodegenerative LCH and sclerosing cholangitis is still guarded. Most LCH-related deaths occur within 5 years and carry higher overall mortality compared to the general population.^[31] Non-LCH-related deaths after 5 years are mainly due to chronic obstructive pulmonary disease and secondly, myeloid malignancies. Despite BRAF-V600E being a marker of high-risk disease and treatment resistance in pediatric LCH, such a mutation is noted with increasing age in adults.^[31]

CONCLUSION

Despite being an uncommon disorder, the presence of an isolated cutaneous, pulmonary, or skeletal lesion must raise the suspicion of LCH in any age group. Early detection of critical organ infiltration by appropriate clinical, laboratory, genetic, hormonal, and imaging techniques through multidisciplinary collaboration is mandatory to enhance treatment outcome and limit morbidity. Single-system disease is amenable to local therapy. Treatment failure and refractory disease pose major challenges leading to poor survival. Paucity of data on second-line therapy, efficacy, and long-term safety of targeted agents warrants future prospective multicenter studies in pediatric as well as adult cohorts.