A case report of cutaneous Langerhans cell Histiocytosis in an infant: a therapeutic challenge

Abstract

Langerhans Cell Histiocytosis (LCH) is a rare clonal disorder of immature CD1a-positive dendritic cells, most commonly affecting children, with peak incidence between ages 1 and 3. This report presents a unique case of multifocal cutaneous LCH with cervical lymphadenopathy in a 7-month-old infant. The patient exhibited an unusual pattern of treatment resistance, failing to respond adequately to corticosteroids and vinblastine-prednisone, before achieving remission with methotrexate. This highlights the therapeutic challenges in managing refractory pediatric LCH and the need for alternative treatment approaches in such cases. This case emphasizes the importance of early diagnosis, tailored treatment regimens, and the potential utility of methotrexate in refractory cases. Comprehensive evaluation and multidisciplinary care are critical for managing this rare disease and minimizing its impact on quality of life.

Introduction

Langerhans Cell Histiocytosis (LCH) is a rare clonal disorder characterized by the proliferation of immature CD1a-positive dendritic cells in various organs. It most commonly affects children, with peak incidence between ages 1 and 3, occurring in approximately five cases per million annually, with a higher prevalence in males [1, 2]. The discovery of oncogenic BRAF mutations and the presence of proinflammatory cytokines and chemokines highlight the unique characteristics of this disease [2].

Most patients (70%) present with single-system involvement, whereas others develop multisystem disease, with nearly half of these cases affecting high-risk organs such as the bone marrow, liver, or spleen [3]. The most commonly affected organs are bone (80%) and skin (33%), followed by others. Systemic symptoms such as fever occur in approximately 50% of pediatric cases [1]. Isolated skin involvement is rare (<2%), with more than 90% of patients with cutaneous LCH also exhibiting involvement of other organs [1]. Skin symptoms typically present as red, scaly patches on the scalp, face, and trunk.

Histiocytic diseases, including LCH, result from abnormal accumulation of cells within the mononuclear phagocytic system. They are classified into five groups, with LCH falling under the ‘L’ group. LCH cells, unlike normal Langerhans cells (LCs) found in the skin, exhibit distinct pathological and genetic features. These abnormal cells, found in lesions along with eosinophils and macrophages, retain some characteristics of normal LCs, such as Birbeck granules, but differ significantly in their morphology and behavior [2].

Prognosis depends on risk organ involvement and response to initial therapy. Single-system disease has an excellent prognosis, with nearly 100% survival, whereas multisystem involvement carries a 50% risk of recurrence and long-term sequelae [4].

This report details a distinctive case of multifocal cutaneous LCH accompanied by cervical lymphadenopathy in a 7-month-old infant. The patient demonstrated an atypical pattern of treatment resistance, showing insufficient response to corticosteroids and vinblastine-prednisone, but ultimately achieved remission with methotrexate. This case underscores the therapeutic challenges associated with managing refractory pediatric LCH and emphasizes the necessity for exploring alternative treatment strategies in such situations.

Case presentation

A 7-month-old boy, weighing 9 kg and measuring 71 cm in length, previously healthy with age-appropriate milestones and up-to-date vaccinations, presented to a dermatology clinic in Syria in November 2023 with a maculopapular rash and purpura. Initially diagnosed as eczema, he was treated empirically with topical corticosteroids and antifungals, but symptoms persisted. After six weeks of minimal improvement, he was referred to a pediatrician for further evaluation.

Examination revealed a generalized, non-pruritic maculopapular rash with purpura, predominantly on the trunk and head, sparing the legs and buttocks (Figs 1 and 2). Cervical lymphadenopathy was present, but there were no signs of anemia, hepatosplenomegaly, or fever (temperature: 37.5°C).

Figure 1.

Extensive erythematous, scaly plaques and papules affecting the lower abdomen, groin, and diaper area of an infant, showing a confluent rash with satellite lesions and skin breakdown.

Figure 2.

Close-up image of the patient’s back revealing diffuse erythematous papules and excoriated crusted lesions (black arrow) with interspersed desquamation (red arrow).

Laboratory tests, including liver enzymes, BUN, creatinine, CBC, CRP, immunoglobulin levels (IgA, IgG, IgM), complement levels (C3, C4), and TSH, were all within normal limits. Urinalysis was unremarkable. Given the persistent rash and clinical findings, LCH was suspected. A skin biopsy was performed from papular lesions on the trunk, scalp, and diaper area, with differential diagnoses including diaper rash, seborrheic dermatitis, juvenile xanthogranulomas, and other dermatological conditions.

Histopathological examination revealed moderate acanthosis, focal spongiosis, inflammatory cell exocytosis, parakeratosis, and histiocytic infiltration in the dermis with eosinophils, 6lymphocytes, and neutrophils. The histiocytes exhibited indented, grooved nuclei, and the tissue was highly vascularized with extravasated red blood cells. Immunohistochemistry confirmed LCH, with CD1a and S100 positivity and CD68 negativity. Imaging studies, including cranial X-rays (Fig. 3) and abdominal ultrasound (Fig. 4), ruled out multisystem involvement.

Figure 3.

Frontal skull X-ray.

Figure 4.

Abdominal ultrasound.

Initial treatment with oral corticosteroids (2 mg/kg for four weeks) resulted in minimal improvement. The regimen was escalated to six cycles of vinblastine (6 mg/m²) with prednislone, achieving only a partial response. Following a relapse, methotrexate (500 mg/m²) with leucovorin rescue was initiated in March 2024, leading to significant clinical improvement. The rash resolved, leaving hypopigmented areas (Fig. 5), and lymphadenopathy fully subsided.

Figure 5.

Hypopigmented macules and residual post-inflammatory changes on the back following initial cutaneous lesions.

Despite an attempt to maintain remission with vinblastine in July, another relapse occurred, presenting as a diffuse maculopapular rash on the trunk, buttocks, and head. Methotrexate (intermediate dose monthly) was reintroduced, achieving a four-month remission. The patient has remained lesion-free for two months, even after transitioning back to vinblastine for remission maintenance.

Discussion

This case of multifocal single-system LCH presented with a widespread rash and cervical lymphadenopathy, complicated by treatment resistance and relapses. It underscores the importance of accurate diagnosis through histopathology and immunohistochemistry and the necessity of tailored treatment strategies, often requiring combination therapies and maintenance regimens for sustained remission.

The treatment of LCH poses significant challenges, particularly in cases that are refractory to standard therapies. First-line treatment typically involves vinblastine and prednisone, followed by maintenance therapy for 12 months. However, some patients, including the one described here, may show inadequate responses to these conventional protocols, necessitating alternative treatment strategies.

In our patient’s case, there was minimal improvement with corticosteroids and only a partial response to vinblastine-prednisone, illustrating the complexities of managing LCH in infants. Following a relapse after initial therapy, we transitioned to methotrexate, which ultimately led to complete remission. Methotrexate, an antifolate agent known for its immunosuppressive effects, has been documented as an effective option for refractory LCH [5, 6].

LCH is a rare clonal disorder of the monocyte–macrophage system characterized by uncontrolled proliferation of CD1a+/CD207+ dendritic cells. Its clinical presentation varies widely, from isolated, self-healing skin and bone lesions to life-threatening multisystem disease [7]. Approximately 65% of patients present with single-system disease, with bone lesions being the most common (70–82% of cases), while isolated skin involvement is less frequent (12%) [8]. However, skin lesions occur in 30–60% of cases, particularly in infants, making dermatological evaluation crucial [9, 10].

Methotrexate (MTX) inhibits the proliferation of inflammatory cells associated with rheumatoid arthritis (RA) through a folate antagonism pathway. It also exerts anti-inflammatory effects via the adenosine signaling pathway. Additionally, MTX mitigates inflammation by restraining the NF-κB, JAK/STAT, and p38 MAPK signaling pathways. Furthermore, it protects bone and cartilage in RA by regulating the balance of RANKL/RANK/OPG. Lastly, MTX modulates the autoimmune response by influencing the expression of CD4+ T lymphocyte subsets, including Th1/Th2, Th17/Treg, and CD73 [11].

Several conditions mimic LCH skin lesions, including seborrheic dermatitis, psoriasis, atopic dermatitis, and viral exanthems [12]. In this case, differentiation from eczema and other dermatological conditions was challenging. Lymphadenopathy, present in up to 20% of cases, most commonly affects cervical nodes [1, 8, 13, 14].

Diagnosis relies heavily on histopathology and immunohistochemistry, supported by clinical and imaging findings [5]. Standard treatment includes vinblastine and prednisone for 6–12 weeks, followed by at least 12 months of maintenance therapy [15]. However, emerging evidence suggests that immunosuppressants like low-dose methotrexate, hydroxyurea, or 6-mercaptopurine may be effective for refractory cutaneous or bone disease [6]. This case highlights the diagnostic and therapeutic challenges of LCH, a rare disease with diverse clinical presentations. Definitive diagnosis required histopathological confirmation and immunohistochemistry. The patient exhibited minimal response to corticosteroids and only partial improvement with vinblastine, but achieved remission with methotrexate. A subsequent relapse upon reintroducing vinblastine underscored the need for individualized treatment strategies. Overall, the case emphasizes the importance of tailored therapeutic approaches to achieve and maintain remission in LCH.

Declaration of competing interest

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.

Funding information

This research received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval

Ethical review and approval were waived for this case study.

Consent for publication

The patient’s mother gave written informed consent to the publication of this case report and any accompanying images.

Guarantor

Linda Khanje.