Multisystem Langerhans cell histiocytosis in adults: the significance of cutaneous manifestations in early diagnosis

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INTRODUCTION

General Information

Langerhans cell histiocytosis (LCH) is an extremely rare disorder characterized by abnormal infiltration of various organs and tissues by cells phenotypically similar to normal Langerhans cells (CD1a+/CD207+). Disease severity is primarily determined by the extent and nature of organ involvement and the number of affected systems. LCH can involve any organ or system, but most commonly affects the bones, skin, lungs, and pituitary gland [1].

The first reports of this disease date back to the early 1900s, when cases of rapidly progressive and often fatal diseases in children with involvement of the bones, skin, liver, and spleen were described. Later, based on similar histologic features, these conditions were grouped by American pathologist Louis Lichtenstein under the term histiocytosis X, where “X” denoted the unknown nature of the cells [1, 2]. In the 1970s, French pathologist Christian Nezelof demonstrated that the pathological cells resembled intraepidermal macrophages—Langerhans cells [3]. Today, the term Langerhans cell histiocytosis is universally used to encompass all clinical manifestations of this Langerhans cell pathology.

LCH is a very rare disorder that can present at any age. The incidence in children is approximately 4–5 cases per million per year, whereas in adults it is even lower: 1–2 cases per million [4, 5].

Etiology and Pathogenesis

The etiology and pathogenesis of LCH remain incompletely understood. Recent investigations have shown that the precursor cell is a myeloid dendritic cell rather than a differentiated epidermal Langerhans cell. Significant progress in understanding the disease pathogenesis has been made with the discovery of mutations in genes of the MAPK signaling pathway, most frequently BRAF V600E and MAP [1, 2, 5]. It has also been established that smoking plays a key role in the development of isolated pulmonary LCH [6, 7].

Classification

LCH belongs to the group of histiocytic disorders. The classification of histiocytic disorders is extraordinarily complex, and its evolution reflects both advances in medical science and a deeper understanding of these disorders. The first classification of histiocytoses, proposed by the Histiocyte Society in 1987, divided them into Langerhans cell and non–Langerhans cell histiocytoses, based on the presence or absence of specific Langerhans cells [8]. Current classification of histiocytic disorders incorporates not only morphological and immunohistochemical characteristics, but also phenotypic, molecular, genetic, and clinical features. In 2016, the Histiocyte Society revised the classification, which now includes five groups:

1. Group L: LCH and Erdheim–Chester disease.
2. Group C: cutaneous and mucocutaneous non–LCH (including juvenile xanthogranuloma).
3. Group M: malignant histiocytoses.
4. Group R: Rosai–Dorfman disease and various noncutaneous histiocytoses.
5. Group H: hemophagocytic lymphohistiocytosis and macrophage activation syndrome [9].

An alternative classification by the WHO (2016) categorizes LCH under “Tumors of histiocytes and dendritic cells”. This classification includes eight major disease areas [10].

Considering the significant variability of clinical manifestations, LCH is further classified according to the extent of disease involvement:

• Unifocal (a single lesion in any organ);
• Multifocal single-system (multiple lesions within a single organ system);
• Multisystem (involvement of more than two organs or systems);
• Isolated pulmonary LCH (confined to the lungs, more frequently associated with smoking) [11].

DIAGNOSIS

Diagnosis of LCH is challenging and requires a comprehensive approach, including clinical evaluation, histologic analysis, immunohistochemical studies, radiologic methods, and molecular genetic testing. The primary diagnostic criterion is the identification of Langerhans cells in biopsy specimens expressing surface markers CD1a, langerin (CD207), CD68, and S100 protein [11]. Langerin (CD207) is a component of Birbeck granules, which are characteristic cytoplasmic inclusions in Langerhans cells that can be identified by electron microscopy, representing a pathognomonic feature of LCH [12]. Additionally, somatic mutations in the MAP kinase signaling pathway are detected in approximately half of cases, most frequently BRAF V600E (50%) and MAP2K1 (25%) [10].

Owing to the wide variety of clinical manifestations of cutaneous involvement in LCH, disease diagnosis is often challenging, and patients may receive prolonged treatment for other dermatoses.

Clinical Presentation

Cutaneous manifestations in LCH are one of the most prominent symptoms, ranking second in frequency only after bone lesions [13]. Cutaneous manifestations are usually associated with multisystem disease [14]. In a retrospective analysis by Li et al. [15] encompassing 918 cases of LCH in China (from neonates to patients aged 65 years), 510 patients (56%) had cutaneous involvement, and in 106 cases (12%) skin eruptions were the initial manifestation of the disease.

Cutaneous manifestations of LCH are diverse and nonspecific, presenting as small erythematous or flesh-colored papules and pustules that may be well-defined or widespread, solitary or multiple, complicating accurate diagnosis. Clinically, these lesions can resemble seborrheic dermatitis or eczematous rash, sometimes accompanied by petechiae or purpura, scales, and crusts. Lesions most commonly involve the skin of the face, scalp, and upper trunk [16].

Clinical manifestations of LCH in other organs and systems are nonspecific and may mimic more common diseases. Bone involvement occurs in approximately 75% of patients and can affect any bone, most frequently the skull, spine, ribs, and long bones of the upper and lower extremities. Symptoms include pain and swelling at the affected site. Pituitary gland dysfunction occurs in 50% of patients, with diabetes insipidus often serving as a predictor of disease and potentially presenting long before other organs or systems are affected. Interestingly, among major causes of diabetes insipidus, 10% of cases are attributable to LCH.

In addition to antidiuretic hormone deficiency, patients may exhibit impaired synthesis of growth hormone, thyrotropin, gonadotropins, and corticotropin. Even with successful LCH treatment, patients require lifelong hormone replacement therapy. Symptoms of pituitary involvement include excessive thirst and urination, fatigue, thyroid enlargement, metabolic syndrome, menstrual irregularities in women, and decreased libido or erectile dysfunction in men.

Pulmonary manifestations occur in 40%–50% of cases, most commonly as isolated pulmonary disease associated with smoking, though they may also be part of multisystem process. Mutations in the BRAF gene and other genes implicated in lung cancer have also been identified in isolated pulmonary LCH, supporting an oncogenic theory of disease pathogenesis. Clinical manifestations related to pulmonary involvement include chest pain, dyspnea, and cough, with spontaneous pneumothorax possible in advanced stages.

Hepatic involvement occurs in 10%–30% of cases and may present either as mass lesions or hepatomegaly with sclerosing cholangitis, potentially progressing to end-stage cirrhosis. Common symptoms include epigastric pain, jaundice, nausea, and vomiting.

Less common manifestations include involvement of the spinal cord, lymph nodes, gums, and genitourinary system¹ [4, 17].

CASE DESCRIPTION

Patient Information

A 28-year-old female patient M., was admitted to the Rakhmanov Clinic of Skin and Venereal Diseases, Sechenov University (hereinafter referred to as the Rakhmanov Clinic of Skin and Venereal Diseases), with complaints of skin eruptions on the face, scalp, trunk, and upper extremities.

Anamnesis morbi. The patient had considered herself ill for the past five years, when she first noted the appearance of skin eruptions on the scalp accompanied by pruritus. The lesions regressed spontaneously but recurred later. She was followed up at her local dermatovenerologic dispensary with a diagnosis of seborrheic dermatitis and received topical corticosteroid therapy with only a short-term positive effect. Due to exacerbation of the skin process in April 2023, the patient was hospitalized at the Rakhmanov Clinic of Skin and Venereal Diseases. Darier disease was initially considered, but histologic examination ruled out this diagnosis. The working diagnosis was atopic dermatitis with secondary pyoderma, for which the patient received antibacterial, antihistamine, and immunosuppressive therapy with glucocorticoids (prednisolone at a dose of 40 mg/day). During treatment, improvement of the skin condition was observed as the daily dose was reduced to 10 mg over two months; however, the skin process subsequently progressed again, and the patient developed a marked iatrogenic Cushing syndrome. Since 2021, in addition to cutaneous manifestations, the patient began experiencing dyspnea when climbing to the 4th–5th floor. She was twice hospitalized in specialized departments with a diagnosis of cystic and bullous lung changes. In 2022, she repeatedly developed spontaneous pneumothorax and was treated in a thoracic surgery department, where she underwent pleural cavity drainage, partial pleurectomy, and wedge resection of segments VII, VIII, and IX of the right lung and segments IV and V of the left lung, followed by silicone glue application. Histologic examination yielded inconclusive results, the patient’s condition did not improve, and a definitive diagnosis was not established. Considering complaints of persistent thirst and polyuria, diabetes insipidus was diagnosed in November 2022, and desmopressin therapy was initiated (Fig. 1).

 

Fig. 1. Timeline of symptom onset in patient M. with a diagnosis of Langerhans cell histiocytosis. Skin involvement was the first symptom, appearing in 2018, but the diagnosis was only confirmed in September 2023. From the archive of the Department of Dermatology and Venereology named after V.A. Rakhmanov, head O.Yu. Olisova, 2025; published for the first time.

 

In October 2023, the patient was admitted to the Rakhmanov Clinic of Skin and Venereal Diseases in severe condition and transferred to the intensive care unit.

Diagnostic Assessment

General status. Severe condition. Body temperature 36.6 °C. Conscious, oriented, answers questions appropriately, insight preserved, emotionally labile. Lies with head of bed elevated. Cushingoid obesity with fat deposition in the abdomen and trunk; extremities are thin. The face is edematous, moon-shaped.

Local status. Chronic inflammatory skin process. Multiple papular and occasional pustular lesions with firmly adherent serous crusts are observed on the skin of the face, trunk, upper and lower extremities. Papules are 2–3 mm in size, pink, rounded, hemispherical, and tend to group. Multiple bluish-pink striae up to 30 cm long are noted on the chest, abdomen, and extremities. In the right submammary area, two erosions measuring 1 cm and 4 cm are visible with erythema, and in the left area, two erosions measuring 1 cm each (Fig. 2). Nail plates are altered, with purplish-brown inclusions.

 

Fig. 2. Multiple papular and isolated pustular lesions with tightly adherent serous crusts, pink in color, prone to grouping. Numerous striae up to 30 cm in length, bluish-pink in color. Photo from the archive of the Department of Dermatology and Venereology named after V.A. Rakhmanov, head O.Yu. Olisova, 2025; published for the first time.

 

Respiratory system. Respiratory rate 28/min; oxygen saturation 87%. Breath sounds harsh, reduced at the lung bases. Crepitations and a moderate number of nonmusical fine moist rales auscultated in the scapular angles.

Cardiovascular system. Heart sounds muffled, rhythmic. Accentuated second heart sound over the pulmonary artery; systolic murmur at the apex and at the Erb point. Heart rate and pulse: 98 bpm. Blood pressure 135/95 mmHg. Electrocardiogram shows sinus tachycardia.

Laboratory tests. Complete blood count: white blood cells 15.9 × 10⁹/L (4.0–10.0), absolute neutrophils 14.8 × 10⁹/L (2.0–5.5), absolute lymphocytes 0.4 × 10⁹/L (1.2–3.0). Blood chemistry: C-reactive protein 326 mg/L (normal ≤5), alanine aminotransferase 92 U/L (0–32), aspartate aminotransferase 58 U/L (0–31), alkaline phosphatase 204 U/L (30–120), gamma-glutamyl transferase 452 U/L (0–38). Coagulation profile: fibrinogen 8 g/L (1.8–4).

Instrumental diagnostics. Chest computed tomography (CT) (Fig. 3): signs of cystic-bullous lung changes, pulmonary fibrosis, and active chronic bronchitis; post-surgical changes; no pneumothorax.

 

Fig. 3. Instrumental diagnostics: a, b ― chest computed tomography (CT signs of cystic-bullous lung transformation, silicone glue application at the lung resection sites); c ― magnetic resonance imaging of the brain (pituitary involvement ― thickening of the pituitary stalk, a characteristic feature of Langerhans cell histiocytosis). Photo from the archive of the Department of Dermatology and Venereology named after V.A. Rakhmanov, head O.Yu. Olisova, 2025; published for the first time.

 

Pituitary magnetic resonance imaging (MRI) with contrast (Fig. 3): Thickening of the pituitary stalk, absent signal from posterior lobe, contrast accumulation in the pineal gland; small foci in the brain, active lesion in the pons and medulla; signs of histiocytosis (thickened mammillary bodies); bilateral otitis media; pathological component in the right maxillary sinus.

Echocardiography: tachycardia; right ventricular enlargement; bilateral hydrothorax; ejection fraction 65%.

Low-dose skeletal CT: focal-confluent destructive changes in the right mandible, compatible with histiocytosis; chronic inflammatory-specific changes in the right maxillary sinus; diffuse osteoporosis; degenerative-dystrophic changes in the sacroiliac joints (more pronounced on the left); post-infarction changes in the medullary canals of the femurs and tibias.

Magnetic resonance imaging (MRI) of the hips and femurs: detected bone changes in the scanned area, likely chronic proliferative in nature, corresponding to those observed in LCH.

Spirometry: severe ventilatory impairment; forced vital capacity 1.78 L (49% predicted); forced expiratory volume in 1 second 1.34 L (43% predicted).

Histologic examination of skin biopsies (Fig. 4): skin in the affected areas shows massive overlays of necrotic masses and leukocytes (scabs), beneath which regenerating epidermis with lymphohistiocytic infiltration is observed. Infiltrating cells have irregular nuclear contours with grooves, without distinct nucleoli or clear cytoplasmic borders, characteristic of Langerhans cells.

 

Fig. 4. Histological examination. Skin: a ― skin with extensive necrotic debris and leukocyte crusts, beneath which regenerating epidermis with lymphohistiocytic infiltration is observed (hematoxylin and eosin staining, ×150); b ― immunohistochemistry, positive staining of cells with CD1a (immunohistochemical reaction, ×250); c ― immunohistochemistry, positive staining of cells with Langerin (CD207) (immunohistochemical reaction, ×250). Lungs: d ― alveolar spaces filled with clusters of cells displaying histiocytic morphology (hematoxylin and eosin staining, ×150); e ― immunohistochemistry, cells in the alveolar spaces showing diffuse positive staining with CD1a (immunohistochemical reaction, ×200). Photo from the archive of the Department of Dermatology and Venereology named after V.A. Rakhmanov, head O.Yu. Olisova, 2025; published for the first time.

 

Immunohistochemistry of skin and lung specimens (Fig. 4): In skin tissue, CD68 (+++) and CD1a (+++) positive cells in the infiltrate. In lung tissue, positively stained cells are primarily located in alveolar spaces and lumens of individual bronchi.

BRAF V600E mutation analysis: no BRAF V600E mutated cells detected in the specimens.

Specialist consultations. Neurologist: encephalopathy of mixed origin. Endocrinologist: diabetes insipidus, medically controlled; iatrogenic Cushing syndrome; secondary hypocorticism. Psychiatrist: monitored for affective disorders. Pulmonologist: given severe bullous-cystic lung changes, transplant consultation recommended.

Multidisciplinary team comprising pulmonologists, intensivists, hematologists, endocrinologists, and dermatovenereologists: based on the patient’s history, laboratory and instrumental examinations, and immunohistochemical analysis of skin and lung biopsy specimens, a diagnosis of Langerhans cell histiocytosis was established.

Final Diagnosis

Multifocal and multisystem (disseminated) Langerhans cell histiocytosis.

Outcomes and Prognosis

On October 19, 2023, for further evaluation and treatment, the patient was transferred to the Department of Orphan Diseases, National Medical Research Center for Hematology. At present, the patient remains under the supervision of a hematologist and pulmonologist and is receiving biologic therapy with trametinib at a dose of 1 mg daily; desmopressin 120 µg twice daily; ursodeoxycholic acid 500 mg daily; and, as recommended by a psychiatrist, venlafaxine 37.5 mg twice daily.

The addition of a mitogen-activated protein kinase inhibitor (trametinib) to therapy produced a positive effect, including regression of papulopustular eruptions on the scalp, face, and upper trunk; epithelialization of erosive submammary skin lesions; decreased severity of respiratory insufficiency; and partial regression of focal brain lesions (Fig. 5).

 

Fig. 5. Clinical presentation at the time of examination in October 2024: significant regression of lesions, with almost complete disappearance of papular-pustular elements. Photo from the archive of the Department of Dermatology and Venereology named after V.A. Rakhmanov, head O.Yu. Olisova, 2025; published for the first time.

 

DISCUSSION

LCH is a rare disorder characterized by proliferation of Langerhans cells in various organs and tissues, including the skin, bones, lungs, and pituitary gland. It is not uncommon for a patient’s initial consultation to be with a dermatologist. This is because skin lesions mimicking more common conditions, such as seborrheic dermatitis, eczema, atopic dermatitis, Darier disease, and other dermatoses, frequently result in ineffective treatment and a delayed correct diagnosis. The management of LCH depends on the extent of systemic involvement and disease severity and may include both immunosuppressive therapy and targeted treatment, particularly with MEK1/2 kinase inhibitors.

There are reports of cases in which LCH was initially misdiagnosed as other dermatologic disorders, leading to treatment resistance. For example, one patient with papular facial eruptions was misdiagnosed with rosacea for two years despite the lack of response to standard treatment [18]. In another case, LCH was mistaken for Hailey–Hailey disease, and the patient suffered from extensive bullous eruptions for three months before the correct diagnosis was established [19].

Similar to these examples, our case illustrates the diagnostic challenges of cutaneous LCH, emphasizing the importance of a thorough diagnostic evaluation. The patient in this report was initially treated for seborrheic dermatitis, resulting in only transient improvement; subsequently, the disease progressed with systemic manifestations. The inadequate response to systemic glucocorticoids, including the rapid (within two months) development of Cushing syndrome at a low dose of prednisolone (10 mg) accompanied by the appearance of striae, prompted reconsideration of the diagnosis. Careful clinical assessment, evaluation of comorbidities, and immunohistochemical studies ultimately enabled the establishment of the correct diagnosis—multisystem Langerhans cell histiocytosis.

Thus, this case underscores the importance of early recognition of cutaneous manifestations of LCH, particularly when associated with systemic symptoms. Early diagnosis and timely initiation of appropriate therapy, including targeted agents, can significantly improve the prognosis and disease outcome.

CONCLUSION

LCH is a rare disorder that may present with polymorphic cutaneous eruptions resembling other dermatologic conditions, which greatly complicates early diagnosis. A comprehensive diagnostic approach, including histologic and immunohistochemical evaluation, is essential for accurate diagnosis and prevention of inappropriate treatment. The presence of systemic manifestations such as diabetes insipidus due to pituitary involvement and pulmonary changes, together with the described cutaneous lesions, may serve as important diagnostic clues suggesting LCH. The presented case demonstrates that early recognition and accurate diagnosis of LCH can substantially influence disease outcomes and improve the patient’s quality of life.

ADDITIONAL INFORMATION

Authors' contributions. O.V. Grabovskaya, N.P. Teplyuk ― article concept, introducing significant (important) edits to the manuscript in order to enhance the scientific value of the work, preparing and writing the article; A.S. Tertychny ― conducting histological examination of the skin and lungs, preparing and writing the article; O.Yu. Kiseleva ― examination and treatment of the patient, writing the article; D.V. Ignatiev ― treatment of the patient, preparing and writing the article; E.Yu. Dzhakhaya ― collection and processing of material, analysis of literary data, preparing and writing the article. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consent for publication. The patient gave her written voluntary informed consent for the publication of the clinical case and photographic materials in this journal (date of signing 20.10.2024). The scope of the published data has been agreed with the patient.

Funding sources. No funding.

Disclosure of interests. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Statement of originality. In conducting the research and creating this work, the authors did not use previously published information (text, illustrations, data).

Data availability statement. Access to the data obtained in this study is restricted due to the confidentiality of information containing the patient's personal data.

Generative AI. Generative AI technologies were not used for this article creation.

Provenance and peer-review. This paper was submitted to the journal on an unsolicited basis and reviewed according to the usual procedure. Two external reviewers and the scientific editor of the publication participated in the review.

 

¹ Histiocytosis Association [Internet]. Langerhans cell histiocytosis in adults. Histiocytosis Association, Inc.; 2024 [cited 2025 Jan 15]. Available from: https://histio.org/langerhans-cell-histiocytosis-in-adults/

About the authors

Natalia P. Teplyuk

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: teplyukn@gmail.com
ORCID iD: 0000-0002-5800-4800
SPIN-code: 8013-3256

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Moscow

Olga V. Grabovskaya

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: olgadoctor2013@yandex.ru
ORCID iD: 0000-0002-5259-7481
SPIN-code: 1843-1090

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Moscow

Alexander S. Tertychnyy

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: atertychnyy@gmail.com
ORCID iD: 0000-0001-5635-6100
SPIN-code: 5150-0535

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Moscow

Olga Yu. Kiseleva

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: oyukisa@mail.ru
ORCID iD: 0000-0001-8630-3616
Russian Federation, Moscow

Dmitry V. Ignatiev

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: dmitrywork@list.ru
ORCID iD: 0000-0001-8751-3965
SPIN-code: 6743-7960
Russian Federation, Moscow

Elizaveta Yu. Djahaia

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: elizaveta_djahaia@mail.ru
ORCID iD: 0009-0002-3741-6619
Russian Federation, Moscow

References

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