Introduction
Langerhans cell histiocytosis (LCH) is a rare clonal disease of the monocyte–macrophage system characterised by uncontrolled proliferation of CD1a+/CD207+ dendritic cells. LCH is so named due to its morphological and immunophenotype resemblance to Langerhans cells, which are phagocytic cells located in the skin and mucosa.Reference Favara, Feller, Pauli, Jaffe, Weiss and Arico1 Previous epidemiological studies in the United States (US) have estimated that the annual incidence of LCH is 1–2 per million children per year.Reference Gulati and Allen2 LCH has a heterogeneous clinical presentation. It may involve the skin, bones, intra-abdominal organs, lungs, lymph nodes, thyroid and central nervous system.Reference Grois, Pötschger, Prosch, Minkov, Arico and Braier3 The disease is broadly classified into three main categories: unisystem unifocal (which is also known as eosinophilic granuloma), unisystem multifocal and multisystem disease.Reference Bezdjian, Alarfaj, Varma and Daniel4 The severity of this disease varies widely. It may present as a relatively asymptomatic localised non-invasive lesion with good prognosis or as a life-threatening, multisystemic refractory disease.Reference Gulati and Allen2 As such, early recognition, biopsy and appropriate treatment are essential for favourable outcomes. The aetiology and exact pathogenesis of LCH remains controversial, with some authors believing it to be a neoplastic process whilst others suggest an autoimmune mechanism involving cytokine dysregulation.Reference Egeler and Willman5, Reference Willman, Busque, Griffith, Favara, McClain and Duncan6 Despite these controversies, there is consensus that LCH is more common in the paediatric population and more commonly affects males.Reference Nicholson, Egeler and Nesbit7, Reference Salotti, Nanduri, Pearce, Parker, Lynn and Windebank8
Although several studies and case reports have described LCH, there remains a paucity of literature specifically summarising and discussing the breadth of otolaryngological (head and neck) involvement. A recent systematic review by Chen et al. examined the otologic manifestations of LCH; however, they included both adults and children and did not encompass non-otology manifestations.Reference Chen, Ashman, Bojrab, Johnson, Benson and Hong9 Such involvement may mimic benign otolaryngologic conditions such as otitis media or sinusitis, delaying diagnosis and treatment.Reference Smoler, Rivera-Camacho, Vivar-Mejia and Levy-Pinto10 This review consolidates current knowledge on head and neck manifestations of paediatric LCH, compares these findings with a statewide case series and explores implications for investigations and treatment.
Materials and methods
Search strategy
Eligible articles were identified through a comprehensive search of four electronic databases: PubMed, Ovid Medline, Ovid EMBASE and Cochrane Library. Articles written between 1980 and June 2025 and written in English (or with an English translation available) were considered. The search was restricted to paediatric populations only. A search of reference lists from appropriate studies was also performed, and these were included. The search parameters included subject headings, subheadings and text words including “Langerhans Cell Histiocytosis”, “Histiocytosis”, “LCH”, “Histiocytosis X”, “Otolaryngology”, “Otorhinolaryngology”, “ENT”, “Head and Neck”, and “Paediatric” “Children” “infant” and “juvenile”. The full electronic search strategy for all databases is provided as Supplementary Material 1 (online only).
Inclusion and exclusion criteria
Studies which described cases of LCH in paediatric patients presenting with otolaryngology – head and neck presentations were included in the study. Studies which described multiple different types of head and neck masses in children without separating aetiology from manifestation were excluded. If heterogenous studies had granular data suitable for extracting LCH cases, they were included in our review. Studies that did not mention a specific location of LCH manifestation were excluded. Studies involving patients greater than 18 years old at the time of diagnosis were excluded. When the same data were present in multiple studies, only one data set was extracted. Finally, letters, commentaries and abstracts were not included in this study. Studies which did not include treatments and outcomes but included presentation were still included to establish a broader case base of LCH presentation patterns, this will be discussed further in the limitations section.
Study selection
A total of 205 articles were identified through the combined database search, which resulted in 188 articles after duplicates and non-English studies were excluded. Following review of the titles and abstracts of these results, 121 articles were selected for full-article review. Seventy-threeReference Li, Wu, Huang and Wang11–Reference Cunningham, Curtin, Jaffe and Stool84 of these were then chosen for data extraction, from which 713 paediatric patients were identified with otolaryngologic manifestations of LCH. The study selection process is demonstrated in Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
Figure 1 Long description
The flowchart illustrates the PRISMA process for selecting studies. The identification stage shows records identified through Medline (10), PubMed (173), Cochrane (1) and EMBase (21), totaling 205 articles. An additional 23 records were identified through other bibliographic searches. After duplicates were removed, 188 records remained. The screening stage shows these 188 records screened, with 67 excluded based on title and abstract. The eligibility stage shows 121 full-text articles assessed, with 48 excluded. Finally, the inclusion stage shows 73 studies included in the literature review.
Statistical analysis
Descriptive statistics were used to summarise the data. Categorical variables were reported as frequencies and percentages, while continuous variables were summarised using means, medians and ranges, as appropriate. Data analysis was conducted using SPSS v25.0., no inferential statistics were performed due to the descriptive nature of this study.
Results
Patient characteristics
Seventy-threeReference Li, Wu, Huang and Wang11–Reference Cunningham, Curtin, Jaffe and Stool84 studies were chosen for data extraction in which 713 patients were included in the review. Mean age at diagnosis was 6.6 ± 4.9 years old. There were approximately twice as many males as females in our review, with 447 males (62.7%) and 226 females (31.7%) which is in keeping with other studies.Reference Bezdjian, Alarfaj, Varma and Daniel4 Category of disease (single system unifocal, single system multifocal or multisystem) was reported in 612 patients (85.8% of total patients). Of the reported cases, 317 (51.8%) were single system unifocal, 98 (16.0%) were single system multifocal and 197 (32.1%) were multifocal disease, with 39 cases (5.5%) demonstrating intra-cranial involvement. Median time to presentation was four weeks (interquartile range [IQR] 3–10 weeks), with a range of 3 days to one year.
The most frequent presenting symptom was head and neck swelling of the scalp or skull (57.4%), followed by pain and swelling (21%), cervical lymphadenopathy (14.4%), otorrhea (9.8%), head and neck cutaneous involvement (10.3%), middle ear effusion (7.2%) and external auditory canal (EAC) mass (4.6%). Whilst 58 per cent of patients presented with a bone or skull mass, nearly all patients were found to have a head and neck mass on examination (88%). Of these patients with a head and neck mass, the most common locations of bone lesions found on examination were the calvarium (55.8%); the temporal bone (20.5%), of which 10.2 per cent were in the EAC specifically; the orbit (9.8%); the mandible (5.3%); the maxilla (4.3%); and the cervical spine (3.1%). There were three cases of isolated maxillary sinus LCH, two cases of isolated sphenoid disease and three cases each of isolated ethmoidal sinus and frontal sinus disease. Patient demographic and clinical presentation information is summarised in Table 1.
Patient demographics and clinical presentation information
Table 1 Long description
The table presents demographic and clinical data for 713 patients, highlighting gender distribution, age, disease categories, symptoms, and lesion locations. Male patients constitute 62.7% of the cohort, and the mean age is 6.6 years with a standard deviation of 4.9 years. Disease categories show 51.8% of patients have single system unifocal disease, while 32.2% have multisystem disease. Scalp or skull swelling is the most prevalent symptom, affecting 57.8% of patients. Bony lesions are most commonly located in the calvaria, accounting for 55.8% of cases. The median time to presentation is 4 weeks, with an interquartile range of 0.4 to 52 weeks. The data suggests a predominance of single system unifocal disease and highlights the need for timely diagnosis given the wide range in presentation time.
IQR = interquartile range; SD = standard deviation.
Investigations, management and recurrences
Of all cases included in this literature review, pathological evidence from biopsies was used to confirm a diagnosis of LCH in 65 per cent of patients prior to commencing treatment. A total of 35 per cent of patients were diagnosed by clinical presentation and radiographic evaluation. Whilst most patients received multiple imaging modalities, the distribution of all radiographic investigations for all patients included computed tomography (CT) scans (53%), skeletal surveys (37%), magnetic resonance imaging (MRI) (30.7%), nuclear bone scans (14%) and positron emission tomography (PET) scanning (5.3%). Of the 465 patients in which biopsy was used to confirm diagnosis, 304 (65%) patients had a specified route of biopsy documented, with the most common being excisional biopsy (n = 189; 62%), followed by incisional biopsy (n=103, 34%) followed by fine-needle aspiration or core biopsy (n = 12; 4%).
Most patients underwent systemic treatment (n = 369; 51.8%). This group of systemically treated patients included several treatment modalities including primary chemotherapy (n = 262), resection and adjuvant chemotherapy (n = 88), systemic steroid therapy (often in combination with chemotherapy, n = 273) and indomethacin (n = 7).
The second category of treatment offered was local treatment (n = 316; 32%), which was comprised of surgical excision (n = 162; 22.7%) and curettage (n = 66; 9.3%) and radiotherapy (n = 88; 12.3%). Lastly, a minority of selected cases, which were all unifocal single system disease, were observed (n = 28; 3.9%).
There were 109 recurrences of 713 patients (15.3%) in total documented throughout the studies included. Of these 109, 31 occurred in single system unifocal disease from a total of 317 patients (9.8%), 19 in single system multifocal disease from a total of 98 patients (19.4%) and 58 recurrences were reported in multisystem disease, from a total of 197 patients (29.4%). Median time to recurrence was 10.7 months (IQR = 5.1 – 18.8 months). The above information is summarised in Table 2.
Investigations, treatment modalities, outcomes and recurrences
Table 2 Long description
The table details investigations, treatment modalities, outcomes, and recurrences in a medical study. Biopsy confirmed diagnosis in 65% of cases, with excisional biopsy being the most common at 26.5%. CT was the most utilized imaging modality at 53%. Systemic treatment was administered to 51.8% of patients, with primary chemotherapy being the most frequent. Local treatment was used in 44.3% of cases, with surgical excision being the most common. Outcomes showed 84.7% had no recurrence, while 15.3% experienced recurrences, predominantly in multisystem cases. The median time to recurrence was 10.7 months, with an interquartile range of 5.1 to 18.8 months.
CT = computed tomography; IQR = interquartile range; MRI = magnetic resonance imaging; PET = positron emission tomography
Institutional case series
Methods
A retrospective review of paediatric patients diagnosed with head and neck LCH was performed at our quaternary paediatric centre, which receives all referrals for paediatric suspected malignancies in the state of Victoria, Australia. These cases are discussed and managed through the statewide tumour multidisciplinary team meetings conducted through the Royal Children’s Hospital in Melbourne, Australia. A review (Institutional Research Ethics Approval number 4023) was conducted from January 2019 until December 2024. Data variables extracted included age, sex, presenting symptoms, histology findings, imaging, biopsy techniques, treatments, complications, recurrences, outcomes and follow-up time. Inclusion criteria comprised studies involving paediatric patients (<18 years) with confirmed LCH and otolaryngological manifestations, including otologic (chronic otitis media, mastoiditis, otorrhea, external auditory canal masses), sinonasal (chronic sinusitis, nasal polyps, skull base involvement) or craniofacial and head and neck involvement, including cervical lymphadenopathy, laryngeal and tracheal pathology. Exclusion criteria included systemic symptoms (weight loss or skin involvement) unless directly related to head and neck disease (facial or pinna skin for example).
Results
A total of 25 patients were identified throughout our electronic medical records from January 2019 until December 2024 as having an otolaryngological manifestation of LCH. The mean age was 8.4 ± 5.2 years, with a subtle male predominance (13 male, 12 female). A total of 18 of 25 (72%) patients had single system unifocal disease, 4 of 25 (16%) patients had single system multifocal disease and 3 of 25 (12%) patients had multifocal disease. All patients in our series underwent histological confirmation with biopsies and CD1a testing before treatment commencement, with 10 patients undergoing incisional biopsy (including two external auditory canal biopsies and two nasal cavity biopsies), nine patients undergoing excisional biopsy and 6 patients undergoing ultrasound guided core needle biopsy. Treatment modalities are likewise summarised in Table 3, with 13 patients receiving a chemotherapy course of Vinblastine and prednisolone for a total of 12 months, and 13 patients being observed post either excisional or incisional biopsies. The decision of whether to observe or commence chemotherapy post excisional biopsy was discussed by the multi-disciplinary team meeting and was determined based on either multifocality or multisystem involvement of disease or impression of aggressive growth patterns based on clinical history, with smaller and slower growing unifocal lesions being observed. Of the 12 patients that had no systemic treatment (all unifocal disease, nine of which had excisional biopsies, two of which had incisional biopsies and one of which had a core biopsy) all resolved without progression or recurrence with an average surveillance period of 27 months. Of the 13 patients who were treated with systemic chemotherapy (vinblastine and prednisolone), two patients demonstrated partial response at 12 months and were scheduled for another 12 months of ongoing treatment, two patients demonstrated progression on treatment and were changed to dabrafenib which resulted in remission but requires ongoing maintenance treatment and two patients experienced recurrence two years post completion of vinblastine/prednisolone, with one patient experiencing a small local recurrence which resolved spontaneously, and the other was commenced on trametinib. Complications were not common, with two patients developing bilateral mild avascular hip necrosis which resolved and recovered post treatment completion and one patient with temporal bone LCH developed mastoiditis which was managed with intra-venous antibiotics.
Institutional case series patient information
Table 3 Long description
This table presents detailed information on 25 pediatric patients, focusing on their age, sex, presenting symptoms, disease type, imaging methods, biopsy methods, management strategies, treatment duration, outcomes, subsequent treatments, and complications. Most patients achieved remission, particularly those with unifocal disease types. Two patients experienced bilateral avascular hip necrosis, and one had mastoiditis managed with antibiotics. Treatment durations varied, with some patients requiring ongoing treatment. The table highlights the use of imaging techniques like CT, MRI, and PET, and management strategies including Indomethacin, Cytarabine, Vinblastine, and Prednisolone. The data suggests a trend towards successful remission in unifocal cases, while multisystem cases showed more varied outcomes.
Discussion
This review presents the most comprehensive literature review to date focussing on the otolaryngological manifestations of paediatric LCH, synthesising data from 73 published studies encompassing 713 patients, alongside a contemporary institutional case series of 25 paediatric patients. The findings demonstrate that the head and neck region is a significant site of involvement and may be site of initial presentation in paediatric LCH. The clinical variability and often non-specific symptoms of presentation with regards to the head and neck mean that otolaryngologists are well positioned to recognise this disease and facilitate early diagnosis.
Our findings show that the temporal bone, calvarium, mandible and cervical lymph nodes are among the most frequently involved sub-sites in the head and neck. Of the disease types, unifocal disease accounted for 62 per cent of cases and experienced the lowest rates of recurrence (9.8%), whilst 23 per cent of patients presented with multisystemic disease and experienced a significantly higher recurrence rate (29.4%). Presenting symptoms in all of these patients were diverse, but otorrhea, neck masses and bony swelling were the most common. Misdiagnosis at first presentation was not uncommon both in the literature review and our institutional data, reinforcing the need for vigilance and low threshold for imaging and biopsy in the case of persistent or atypical otologic and cervical presentations. Given the breadth of different presentations demonstrated in this study, it stands to reason that paediatric LCH should be part of the differential diagnosis when symptoms fail to resolve or clinical imaging demonstrates suspicious features. Several cases were unfortunately delayed as patients underwent several courses of antibiotics and tympanostomy tube insertion before eventual diagnosis via biopsy.
In terms of investigation, imaging played a pivotal role. CT and MRI were used in many cases, particularly for bony or CNS-adjacent disease. Histopathologic confirmation, while standard, was not universally performed, particularly in cases with classical imaging features. Recent studies, however, highlight the importance of biopsy in establishing a definitive diagnosis and guiding management, particularly with the emergence of molecular diagnostics such as BRAF V600E testing which have been linked to disease relapse.Reference Ozer, Sevinc, Ince, Yuzuguldu and Olgun85 PET scans were infrequently used but may offer additional utility in staging and post-treatment surveillance.Reference Phillips, Allen, Gerson and McClain86
Management strategies varied considerably across disease categories. Unifocal disease was often managed with surgical curettage or intra-lesional steroids alone, with high rates of disease control. Multifocal and multisystem disease required systemic therapy in most cases, commonly prednisolone in combination with chemotherapy agents such as vinblastine or cytarabine. There is an emerging body of evidence supporting the use of targeted agents (e.g., BRAF or MEK inhibitors), particularly in refractory or recurrent disease with known molecular drivers.Reference Whitlock, Geoerger, Dunkel, Roughton, Choi and Osterloh87 Notably, our review observed increased recurrence rates in multifocal and multisystemic disease, consistent with the progressive nature of systemic involvement.Reference Bezdjian, Alarfaj, Varma and Daniel4 The higher recurrence in multisystem disease aligns with its inherently aggressive biology and the need for systemic immune modulation.Reference Whitlock, Geoerger, Dunkel, Roughton, Choi and Osterloh87
Our institutional series provides valuable insight into the modern treatment paradigm. Over half of the patients demonstrated single system unifocal disease and were managed with observation or local excision, reflecting a selective approach consistent with published guidelines.Reference Gulati and Allen2, Reference Goyal, Tazi, Go, Rech, Picarsic and Vassallo88 In contrast, patients with multifocal or systemic disease required systemic therapy, including vinblastine and prednisolone, and in some cases a BRAF or MEK inhibitor—targeted therapy not yet widely described in the otolaryngology literature. The integration of molecular diagnostics and precision therapy into the LCH management algorithm represents a significant advancement in care, particularly in patients with BRAF V600E mutations or MAPK pathway activation.Reference Lin, Batajoo, Peckham-Gregory, Zinn, Eckstein and El-Mallawany89, Reference McClain and Chakraborty90 These cases demonstrate the shift toward molecularly guided therapy and reflect an emerging modern treatment paradigm. Such therapies may alter the disease trajectory and reduce the long-term morbidity associated with traditional chemotherapeutic regimens, although more data are needed to evaluate durability of remission.Reference Whitlock, Geoerger, Dunkel, Roughton, Choi and Osterloh87
Whilst unifocal single system disease typically follows an indolent course, our review confirms a non-negligible risk of recurrence in these patients. Multifocal and multisystem disease were more strongly associated with recurrence, likely reflecting both underlying disease biology and the complexity of achieving complete disease clearance across multiple sites. Recurrence in ENT-involved disease carries unique considerations. Lesions in the temporal bone or within nasal sinuses may recur with symptoms (hearing loss, imbalance, facial nerve palsy or rhinorrhoea and nasal congestion) or may be asymptomatic. Several cases of recurrence were detected on imaging rather than clinical examination, underscoring the importance of structured follow-up with radiological surveillance in higher-risk cases.Reference Vosoghi, Rodriguez-Galindo and Wilson50, Reference Davidson, McComb, Bowen and Krieger60
This study has several strengths and makes several important contributions to the LCH literature. It is the largest literature review on paediatric LCH to date and specifically outlines the incidence of ENT manifestations, helping to characterise disease patterns, anatomical sides and treatment modalities. Our case series also offers more modern granular patient-level data with well documented diagnostic and therapeutic pathways. Furthermore, we provide treatment data for newer therapeutic agents such as BRAF and MEK inhibitors in ENT-specific disease—which is a contribution not yet reflected in earlier case series or literature reviews.
There are several limitations to this study. The primary limitations of the literature review stem from the variability and heterogeneity of the included studies. The majority were single-patient case reports or small case series, with inconsistent reporting of disease subtypes, treatments or recurrence rates. Studies were often presented as grouped data; hence, it is impossible to stratify treatment type by disease subtype and quantify outcomes statistically. Follow-up durations were often unclear or absent, and recurrence data were frequently incomplete or omitted altogether, potentially leading to underestimation of long-term morbidity and relapse rates. Furthermore, many studies predate the widespread adoption of molecular diagnostics and targeted therapies, limiting their relevance to modern clinical paradigms. These inconsistencies precluded formal meta-analysis and complicated direct comparisons across cohorts. While our own case series was more granular in its data collection and relatively complete in follow-up, it remains limited by sample size and institutional context. Nonetheless, this study provides the most comprehensive ENT-focused synthesis of paediatric LCH to date and serves as a valuable reference point for clinicians managing children with atypical head and neck presentations.
The implications of this study for otolaryngologists remain clear. ENT specialists must maintain vigilance when managing paediatric patients with refractory otorrhea, middle ear effusion, external ear masses, head and neck lumps or persistent cervical lymphadenopathy. Early imaging and consideration of biopsy in atypical cases are critical to establishing diagnosis. Awareness of the LCH spectrum of disease can reduce diagnostic delay and avoid mismanagement.
This study highlights the need for prospective, multicentre registries with standardised data collection to further refine diagnostic and treatment pathways. The integration of molecular testing and targeted therapy will likely expand, and future reviews should include recurrence rates, complications, long-term follow-up and outcomes based on BRAF/MAPK status. ENT-specific clinical guidelines and diagnostic algorithms may also aid in earlier identification and better outcomes in paediatric LCH.
• Langerhans cell histiocytosis (LCH) is a rare clonal disorder of the monocyte–macrophage lineage with highly variable clinical presentations, including otolaryngologic (ENT) involvement
• ENT manifestations of LCH can mimic common paediatric conditions such as otitis media, mastoiditis and chronic sinusitis, contributing to diagnostic delay
• The existing literature is dominated by small series and case reports with heterogeneous reporting, limited follow-up and inconsistent definitions of recurrence and disease extent
• This study presents the most comprehensive review to date of ENT manifestations in paediatric LCH, synthesising data from 81 studies comprising 713 patients
• The paper includes a novel statewide case series, highlighting real-world diagnostic and management pathways in contemporary practice
Conclusion
Paediatric Langerhans cell histiocytosis involving the head and neck presents a diverse and often deceptive clinical spectrum. This comprehensive review confirms that unifocal disease predominates and is associated with favourable outcomes, whilst multisystem involvement significantly raises the risk of recurrence. Our accompanying case series reinforces these findings and contributes new data on the modern diagnostic and therapeutic landscapes including the use of targeted therapies. Early biopsies, multidisciplinary input and tailored treatment remain key. Greater awareness of ENT-specific presentations and standardised reporting will be essential to improving outcomes in this rare but impactful disease.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S0022215126104514.
Ethical statement
Ethical approval was not required for our literature review. Institutional ethics board approval was sought for the case series.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this study.
Disclosure of funding
None.
