Langerhans cell histiocytosis in children: Diagnosis, differential diagnosis, treatment, sequelae, and standardized follow-up

doi:10.1016/j.jaad.2017.05.060

Journal of the American Academy of Dermatology

Volume 78, Issue 6, June 2018, Pages 1047-1056

https://doi.org/10.1016/j.jaad.2017.05.060 Get rights and content

A definitive diagnosis of Langerhans cell histiocytosis (LCH) requires a combination of clinical presentation, histology, and immunohistochemistry. The inflammatory infiltrate contains various proportions of LCH cells, the disease hallmark, which are round and have characteristic “coffee-bean” cleaved nuclei and eosinophilic cytoplasm. Positive immunohistochemistry staining for CD1a and CD207 (langerin) are required for a definitive diagnosis. Isolated cutaneous disease should only be treated when symptomatic, because spontaneous resolution is common. Topical steroids are first-line treatment for localized disease of skin and bone. For multifocal single-system or multisystem disease, systemic treatment with steroids and vinblastine for 12 months is the standard first-line regimen. Current research is seeking more effective regimens because recurrence rates, which increase the risk of sequelae, are still high (30-50%) in patients with multisystem disease. An active area of research is the use of targeted therapy directed at the mitogen-activated protein kinase pathway. Adequate follow-up to monitor for disease progression, relapse, and sequelae is recommended in all patients.

Section snippets

Diagnostic criteria

Key point

•
A definitive diagnosis is made by the combination of clinical presentation, histology, and immunohistochemistry

Obtaining a biopsy specimen is mandatory for a diagnosis of Langerhans cell histiocytosis (LCH), and the skin is an easily accessible site in patients presenting with cutaneous signs; however, because Langerhans cell reactivity is not specific for LCH, the diagnosis should be reserved for the appropriate clinical context. Bone marrow aspiration and biopsy specimens are indicated in

Differential diagnosis

Key points

•
The diverse cutaneous presentation of LCH generates a broad differential
•
Techniques to distinguish LCH from alternative diagnoses include immunohistochemistry, electron microscopy, and cultures

The differential diagnosis of LCH can be broad based on clinical presentation. Histology, immunohistochemistry, electron microscopy, Tzanck preparations, bacterial, viral, and fungal cultures, and serology can be used to distinguish LCH from alternative diagnoses (Table I).

Evaluation at initial presentation, relapse, or progression

Key point

•
A thorough history and physical examination for extracutaneous manifestations is indicated in all patients with LCH

The distinction between single-system and multisystem LCH is essential for prognosis and treatment, yet a physical examination and histology are not sufficient for reliable stratification.² The uncertainty of clinical course based on clinical and histologic findings warrants thorough evaluation and regular follow-up.²⁴

A standardized initial evaluation is mandatory in all patients

Treatment of cutaneous single-system LCH

Key points

•
Topical steroids are first-line therapy for lesions few in quantity
•
Systemic steroids with vinblastine (12 months) are first-line therapy for diffuse disease

There is no treatment protocol for isolated cutaneous disease. Recommendations are mainly based on case series rather than prospective controlled trials. In children with isolated cutaneous LCH, systemic therapy is only indicated for symptomatic or progressive disease, because isolated cutaneous involvement often resolves spontaneously.27, 28

Targeted therapy

Key point

•
Targeted therapy is still an experimental highly individualized treatment option and an area of active research

Considering that the RAS-RAF-MEK-ERK-MAP kinase pathway is activated in all patients with LCH, including those with wild-type BRAF,⁶⁸ pharmacotherapy targeting this pathway in patients with known mutations seems a logical option. In addition, alternative treatments are highly needed, particularly in patients with primary refractory disease and in those with multiple recurrences, and

Sequelae

Key points

•
The most frequent permanent consequences include diabetes insipidus, anterior pituitary hormone deficits, orthopedic problems, hearing loss, and neurodegeneration
•
Long-lasting disease activity and recurrences increase the risk for sequelae

The most frequent sequelae of LCH include diabetes insipidus (24%), orthopedic problems (20%), hearing loss (13%), and neurologic sequelae (11%).⁹² After diabetes insipidus, the second most common neurologic sequela is neurodegenerative LCH, which has a varied

Standardized follow-up recommendations

Key points

•
Isolated cutaneous LCH should be closely monitored (every 2-4 weeks), particularly if left untreated
•
Regular follow-up is recommended in all patients; those with isolated cutaneous LCH should be followed every 6 months for 5 years after complete regression

Observation is recommended in all patients once the diagnosis is clear to monitor for progression to potentially life-threatening, multisystem disease or reactivation of disease that had been responsive to therapy. Eighty-eight percent of

References (95)

Y. Gothelf et al.
A subset of human cord blood mononuclear cells is similar to Langerhans cells of the skin: a study with peanut agglutinin and monoclonal antibodies
Hum Immunol
(1986)
D.C. Pinto et al.
Rosai-Dorfman disease in the differential diagnosis of cervical lymphadenopathy
Braz J Otorhinolaryngol
(2008)
L.J. Margesson et al.
Hidradenitis suppurativa
Best Pract Res Clin Obstet Gynaecol
(2014)
P. Kapur et al.
Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): ten-year experience at Dallas Children's Medical Center
J Am Acad Dermatol
(2007)
J.A. Taverna et al.
Adult cutaneous Langerhans cell histiocytosis responsive to topical imiquimod
J Am Acad Dermatol
(2006)
H. Gadner et al.
Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification
Blood
(2008)
H. Gadner et al.
Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis
Blood
(2013)
H. Gadner et al.
A randomized trial of treatment for multisystem Langerhans' cell histiocytosis
J Pediatr
(2001)
C. Monsereenusorn et al.
Clinical characteristics and treatment of Langerhans cell histiocytosis
Hematol Oncol Clin North Am
(2015)
G. Badalian-Very et al.
Recurrent BRAF mutations in Langerhans cell histiocytosis
Blood
(2010)

N.A. Brown et al.

High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis

Blood

(2014)

R. Chakraborty et al.

Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis

Blood

(2014)

R. Chakraborty et al.

Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis

Blood

(2016)

J. Haroche et al.

Histiocytoses: emerging neoplasia behind inflammation

Lancet Oncol

(2017)

J. Haroche et al.

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation

Blood

(2013)

J. Charles et al.

Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation

J Am Acad Dermatol

(2014)

W. Zhang

BRAF inhibitors: the current and the future

Curr Opin Pharmacol

(2015)

M. Wnorowski et al.

Pattern and course of neurodegeneration in Langerhans cell histiocytosis

J Pediatr

(2008)

D.J. Zinn et al.

Langerhans cell histiocytosis: emerging insights and clinical implications

Oncology (Williston Park)

(2016)

D. El Demellawy et al.

Langerhans cell histiocytosis: a comprehensive review

Pathology

(2015)

M.L. Galluzzo et al.

Bone marrow findings at diagnosis in patients with multisystem langerhans cell histiocytosis

Pediatr Dev Pathol

(2010)

E.K. Satter et al.

Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society

Pediatr Dermatol

(2008)

M. Girschikofsky et al.

Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net

Orphanet J Rare Dis

(2013)

K. Takahashi et al.

Immunohistochemical localization and distribution of S-100 proteins in the human lymphoreticular system

Am J Pathol

(1984)

M. Kassardjian et al.

Congenital self-healing reticulohistiocytosis: an underreported entity

Cutis

(2016)

L. Larsen et al.

Congenital self-healing reticulohistiocytosis: concern for a poor prognosis

Dermatol Online J

(2012)

B. Yağci et al.

Thymic Langerhans cell histiocytosis mimicking lymphoma

Pediatr Blood Cancer

(2008)

K. Querings et al.

Clinical spectrum of cutaneous Langerhans' cell histiocytosis mimicking various diseases

Acta Derm Venereol

(2006)

W.G. Sun et al.

A case of adult generalized cutaneous Langerhans cell histiocytosis

Ann Dermatol

(2016)

S.A. Meehan et al.

Cutaneous Langerhans cell histiocytosis of the genitalia in the elderly: a report of three cases

J Cutan Pathol

(1998)

L. Edsall et al.

Adult onset Langerhans cell histiocytosis mimicking intertrigo

J Cutan Pathol

(2007)

S.L. Stein et al.

Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series

Arch Pediatr Adolesc Med

(2001)

M.L. Price et al.

Lichen aureus: a localized persistent form of pigmented purpuric dermatitis

Br J Dermatol

(1985)

E.M. Grosshans

Lichen aureus masquerading as Langerhans cell histiocytosis

Pediatr Dermatol

(1992)

A.G. Dufresne et al.

Histiocytosis X mimicking the follicular occlusion syndrome: response to local therapy

J Am Acad Dermatol

(1987)

M. Yasuda et al.

Langerhans cell histiocytosis masquerading as hidradenitis suppurativa

J Dermatol

(2016)

H. Isaacs

Cutaneous metastases in neonates: a review

Pediatr Dermatol

(2011)

C.L. Willman

Detection of clonal histiocytes in Langerhans cell histiocytosis: biology and clinical significance

Br J Cancer Suppl

(1994)

V. Broadbent et al.

Histiocytosis syndromes in children: II. Approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Clinical Writing Group of the Histiocyte Society

Med Pediatr Oncol

(1989)

R. Haupt et al.

Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years

Pediatr Blood Cancer

(2013)

C. Titgemeyer et al.

Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study

Med Pediatr Oncol

(2001)

M. Aricò

Langerhans cell histiocytosis in children: from the bench to bedside for an updated therapy

Br J Haematol

(2016)

E. Dodd et al.

Topical Imiquimod for the treatment of childhood cutaneous Langerhans cell histiocytosis

Pediatr Dermatol

(2016)

M.A. Morren et al.

Diverse cutaneous presentations of Langerhans Cell histiocytosis in children: a retrospective cohort study

Pediatr Blood Cancer

(2016)

P.H. Hoeger et al.

Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis

Arch Dis Child

(2000)

D. O'Kane et al.

Langerhans cell histiocytosis associated with breast carcinoma successfully treated with topical imiquimod

Clin Exp Dermatol

(2009)

M. Napolitano et al.

Systemic treatment of pediatric psoriasis: a review

Dermatol Ther (Heidelb)

(2016)

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Childhood langerhans cell histiocytosis: A bizarre thoracic-spine presentation of a multi-organ disease and a narrative review of the literature
2023, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Langerhans cell histiocytosis is a rare disease with diverse clinical presentations. We report a 4-year-old boy with progressive weakness in lower extremities, a large head lump, and inability to walk. On physical examination, bulged scalp, ulcerative skin lesions, engorged veins over the abdomen and chest, and decreased muscle strength were evident. The computed tomography and magnetic resonance imaging revealed lytic lesions on vertebral bodies (T5-T8), resulting in the destruction of T7 vertebra and compression of the spinal cord, along with abnormal meningeal enhancement and multiple enhanced cerebral lesions, mainly at the junction of white and gray matter. Biopsy of T7 vertebra revealed Langerhans cell histiocytosis, confirmed by S-100 and CD1a expression in immunohistochemistry. The clinical team should be vigilant for the insidious development of central nervous system (CNS) symptoms and seek the required neurosurgical interventions to have a timely and definitive diagnosis and tackle the CNS lesions before resulting in permanent deficits.
Craniofacial involvement in Langerhans cell histiocytosis: A review of 44 cases at a single medical center
2023, Journal of Plastic, Reconstructive and Aesthetic Surgery
Craniofacial bones are the most commonly involved site of Langerhans cell histiocytosis (LCH). The main purpose of this study was to clarify the relation between subsites of craniofacial bone and clinical presentation, treatment modalities, outcomes, and permanent consequences (PCs) in patients with LCH.
Forty-four patients diagnosed with LCH involving the craniofacial region presenting at a single medical center during 2001–2019 were collected and divided into four groups: single system with unifocal bone lesion (SS-LCH, UFB); single system with multifocal bone lesions (SS-LCH, MFB); multisystem without risk organ involvement (MS-LCH, RO-); and multisystem with risk organ involvement (MS-LCH, RO+). Data including demographics, clinical presentation, treatments, outcomes, and the development of PC were retrospectively reviewed.
Temporal bone (66.7% versus 7.7%, p = 0.001), occipital bone (44.4% versus 7.7%, p = 0.022), and sphenoid bone (33.3% versus 3.8%, p = 0.041) involvement were more common in SS-LCH, MFB than they were in SS-LCH, UFB. No difference of reactivation rate was noted among the four groups. The most common PC is diabetes insipidus (DI), reported in 9 of the 16 (56.25%) patients with PC. The single system group was reported with the lowest incidence of DI (7.7%, p = 0.035). The reactivation rate was also higher in patients with PC (33.3% versus 4.0%, p = 0.021) or DI (62.5% versus 3.1%, p < 0.001).
An increased risk of multifocal or multisystem lesions was associated with temporal bone, occipital bone, sphenoid bone, maxillary bone, eye, ear, and oral involvement, which may indicate poor outcomes. Longer follow-up may be indicated if there is the presence of PC or DI due to the high risk of reactivation. Therefore, multidisciplinary evaluation and treatment according to risk stratification are vital for patients diagnosed with LCH involving the craniofacial region.
Langerhans cell histiocytosis: a rare case of the multisystemic form in an infant
2023, Anais Brasileiros de Dermatologia
Langerhans cell histiocytosis. Advances in pathogenesis and clinical practice
2022, Anales de Pediatria
La histiocitosis de células de Langerhans (HCL) es un tipo de neoplasia hematológica de origen mieloide, que puede afectar a diferentes órganos o tejidos, con gran variabilidad en la presentación clínica y comportamiento biológico, por lo que puede simular diferentes enfermedades. Se recomienda realizar diversas pruebas clínicas, analíticas y de imagen, para determinar la extensión de la afectación, que puede ser única o multisistémica, y la presencia o no de disfunción en órganos de riesgo como sistema hematopoyético, hígado y bazo. El diagnóstico se debe confirmar mediante biopsia y estudio histológico. Los estudios moleculares han permitido identificar mutaciones en la vía MAPK, lo que han ampliado las opciones terapéuticas. El diagnóstico es complejo y existe controversia en el manejo de ciertos casos. Las recomendaciones terapéuticas dependen de la localización de las lesiones y de la extensión de la afectación. Los estudios colaborativos internacionales han demostrado la efectividad de terapias prolongadas combinadas como vinblastina y prednisona en formas graves o multisistémicas y destaca el papel beneficioso de fármacos antiinflamatorios como indometacina y de otras combinaciones de citostáticos. La HCL representa un buen ejemplo de la importancia de la medicina de precisión y del beneficio de la identificación de dianas moleculares, comunes a diferentes neoplasias, para desarrollar nuevas terapias dirigidas. Los inhibidores de la vía MAPK representan una alternativa terapéutica en casos refractarios y en las formas neurodegenerativas de la HCL. Los estudios moleculares pueden contribuir en el pronóstico, el tratamiento y el seguimiento, especialmente en las formas graves.
Langerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical presentation and biological behaviour, so it may mimic different diseases. Performance of different clinical assessments and laboratory and imaging tests is recommended to determine the extent of involvement, which may be of a single location or multisystemic, and the presence or absence of dysfunction in risk organs, such as the haematopoietic system, liver and spleen. The diagnosis must be confirmed by histological examination of a biopsy sample. Molecular tests have identified mutations in the mitogen-activated protein kinase (MAPK) pathway, which has expanded treatment options. The diagnosis is complex and there is controversy regarding the management of certain cases. Treatment recommendations depend on the location of the lesions and the extent of involvement. International collaborative studies have demonstrated the effectiveness of prolonged combination therapies such as vinblastine and prednisone in severe or multisystemic forms, and anti-inflammatory drugs such as indomethacin and other cytostatic combinations have proven beneficial. LCH is a good example of the importance of precision medicine and the benefit of identifying molecular targets, common to different neoplasms, to develop new therapies. MAPK pathway inhibitors offer an alternative treatment option in refractory cases and neurodegenerative forms of LCH. Molecular testing can contribute to the prognosis, treatment and follow-up of LCH, especially in severe forms of disease.
Characteristics and Treatment Outcomes of Pediatric Langerhans Cell Histiocytosis with Thymic Involvement
2022, Journal of Pediatrics
To evaluate the characteristics and treatment outcomes of patients with pediatric Langerhans cell histiocytosis (LCH) with thymic involvement.
We retrospectively described the clinical, biological, and imaging characteristics of a series of 19 patients with pediatric LCH with thymic involvement in our center between September 2016 and December 2019. We further analyzed the treatment response and outcomes of patients treated with chemotherapy or targeted therapy.
Thymic involvement was found in 4.4% of a 433-consecutive pediatric LCH cohort; all LCH–thymic involvement presented with multisystem disease. Patients with thymic involvement were typically younger, harboring more lung and thyroid involvement and less bone involvement than those without thymic involvement. Most patients with thymic involvement had alteration of immunocompetence with decreased numbers of T-lymphocyte subsets and immunoglobulin G levels. Overall, 47.1% of patients demonstrated a response after 6 weeks of induction therapy, and 92.3% of the patients who did not respond to the first-line treatment had resolution of thymus after the second-line and/or targeted therapy. The progression/relapse rate showed no difference between patients who shifted to second-line therapy and those to dabrafenib (33.3% vs 25%, P = 1.000). The survival for patients with thymic involvement did not differ from those without thymic involvement. More patients treated with second-line chemotherapy had severe adverse events than those given dabrafenib (88.9% vs 0, P < .001).
Thymic involvement was observed rarely in LCH and had specific clinical characteristics. Chemotherapy could resolve most thymic lesions, and BRAF inhibitors might provide a promising treatment option with less toxicity for infants with BRAF-V600E mutation.
http://www.chictr.org.cn, identifier: ChiCTR2000030457 (BCH-LCH 2014 study); ChiCTR2000032844 (dabrafenib study).
Skin-limited Langerhans cell histiocytosis presenting as crusted papules in an acneiform distribution in an adolescent man
2022, JAAD Case Reports
Citation Excerpt :
In our case, the patient's pink-red papular lesion was thought to be acne in an adolescent man by the family and patient's pediatrician. First-line management of skin-limited LCH involves watchful waiting, as lesions may spontaneously resolve, or treatment with topical corticosteroids.10 It is imperative to establish a clear diagnosis of skin-limited versus systemic LCH at the time of diagnosis, as systemic LCH may involve significantly more morbidity.

View all citing articles on Scopus

: Funding sources: None.

: Conflicts of interest: None disclosed.

: Date of release: June 2018

: Expiration date: June 2021

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Continuing medical educationLangerhans cell histiocytosis in children: Diagnosis, differential diagnosis, treatment, sequelae, and standardized follow-up

Section snippets

Diagnostic criteria

Differential diagnosis

Evaluation at initial presentation, relapse, or progression

Treatment of cutaneous single-system LCH

Targeted therapy

Sequelae

Standardized follow-up recommendations

Hum Immunol

Braz J Otorhinolaryngol

Best Pract Res Clin Obstet Gynaecol

J Am Acad Dermatol

J Am Acad Dermatol

Blood

Blood

J Pediatr

Hematol Oncol Clin North Am

Blood

Blood

Blood

Blood

Lancet Oncol

Blood

J Am Acad Dermatol

Curr Opin Pharmacol

J Pediatr

Langerhans cell histiocytosis: emerging insights and clinical implications

Oncology (Williston Park)

Langerhans cell histiocytosis: a comprehensive review

Pathology

Bone marrow findings at diagnosis in patients with multisystem langerhans cell histiocytosis

Pediatr Dev Pathol

Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society

Pediatr Dermatol

Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net

Orphanet J Rare Dis

Immunohistochemical localization and distribution of S-100 proteins in the human lymphoreticular system

Am J Pathol

Congenital self-healing reticulohistiocytosis: an underreported entity

Cutis

Congenital self-healing reticulohistiocytosis: concern for a poor prognosis

Dermatol Online J

Thymic Langerhans cell histiocytosis mimicking lymphoma

Pediatr Blood Cancer

Clinical spectrum of cutaneous Langerhans' cell histiocytosis mimicking various diseases

Acta Derm Venereol

A case of adult generalized cutaneous Langerhans cell histiocytosis

Ann Dermatol

Cutaneous Langerhans cell histiocytosis of the genitalia in the elderly: a report of three cases

J Cutan Pathol

Adult onset Langerhans cell histiocytosis mimicking intertrigo

J Cutan Pathol

Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series

Arch Pediatr Adolesc Med

Lichen aureus: a localized persistent form of pigmented purpuric dermatitis

Br J Dermatol

Lichen aureus masquerading as Langerhans cell histiocytosis

Pediatr Dermatol

Histiocytosis X mimicking the follicular occlusion syndrome: response to local therapy

J Am Acad Dermatol

Langerhans cell histiocytosis masquerading as hidradenitis suppurativa

J Dermatol

Cutaneous metastases in neonates: a review

Pediatr Dermatol

Detection of clonal histiocytes in Langerhans cell histiocytosis: biology and clinical significance

Br J Cancer Suppl

Histiocytosis syndromes in children: II. Approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Clinical Writing Group of the Histiocyte Society

Med Pediatr Oncol

Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years

Pediatr Blood Cancer

Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study

Med Pediatr Oncol

Langerhans cell histiocytosis in children: from the bench to bedside for an updated therapy

Br J Haematol

Topical Imiquimod for the treatment of childhood cutaneous Langerhans cell histiocytosis

Pediatr Dermatol

Diverse cutaneous presentations of Langerhans Cell histiocytosis in children: a retrospective cohort study

Pediatr Blood Cancer

Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis

Continuing medical education
Langerhans cell histiocytosis in children: Diagnosis, differential diagnosis, treatment, sequelae, and standardized follow-up