Refractory Adult-Onset Localized Cutaneous Langerhans Cell Histiocytosis Successfully Treated with Surgical Intervention: Case Report

Abstract

Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disorder that frequently mimics common inflammatory dermatoses, often resulting in delayed diagnosis. We report a highly deceptive clinical presentation. A 36-year-old man presented with a five-year history of painful, refractory ulcerated plaques on his bilateral groins. Previous empirical therapies failed completely. A targeted skin biopsy eventually revealed classic atypical Langerhans cells with reniform nuclei, demonstrating striking immunohistochemical positivity for CD1a and CD207. Comprehensive systemic investigations confirmed isolated cutaneous involvement. Although subsequent trials of systemic agents—including thalidomide, methotrexate, and upadacitinib—were poorly tolerated and offered limited benefit, surgical excision ultimately achieved complete resolution. The patient has not presented recurrence at 18-month follow-up. This case highlights the critical necessity of an early biopsy for chronic intertriginous ulcers. Furthermore, it demonstrates that surgical management serves as a safe and durable definitive strategy for recalcitrant, localized cutaneous LCH.

Introduction

Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disorder characterized by the abnormal accumulation of CD1a+/CD207+ dendritic cells. While it primarily affects children, adult-onset LCH is exceptionally rare, with an estimated annual incidence of only 1–2 cases per million.¹ The disease can present as either a multisystem or single-system disorder. Single‑system LCH is largely confined to skin and generally carries a favorable prognosis, whereas multisystem LCH involves multiple organs and is associated with higher morbidity and mortality, requiring more intensive systemic therapy.² Cutaneous involvement is highly prevalent but notoriously polymorphic, frequently mimicking common inflammatory dermatoses—such as hidradenitis suppurativa, Hailey-Hailey disease, or recalcitrant intertrigo—often leading to significant diagnostic delays.³

From a therapeutic perspective, the management of adult-onset LCH lacks universally standardized guidelines, particularly for refractory, skin-limited disease. While mild localized lesions may respond to topical corticosteroids, nitrogen mustard, or localized radiotherapy, recalcitrant cases conventionally necessitate systemic interventions. Current options include immunosuppressants, chemotherapeutic agents, or targeted therapies directed at MAPK pathway mutations.^1,4 These targeted agents are developed based on the finding that somatic activating mutations in the MAPK signaling pathway constitute the major molecular driver of LCH pathogenesis.⁵ However, navigating these systemic treatments is clinically challenging; many patients experience incomplete responses, disease relapse, or severe adverse effects that lead to treatment discontinuation. Although novel agents like JAK inhibitors have shown theoretical promise in controlling inflammatory neoplastic conditions in non-Langerhans cell histiocytosis, their practical efficacy and tolerability in adult cutaneous LCH remain underexplored and inconsistent.⁶

Herein, we report a highly deceptive case of adult-onset, localized cutaneous LCH presenting as chronic, painful intertriginous ulcers. Crucially, the patient demonstrated profound resistance and intolerance to empirical therapies and multiple systemic agents, including thalidomide, methotrexate, and upadacitinib. Complete clinical resolution was ultimately achieved exclusively through surgical excision. By presenting this case, we aim to emphasize the diagnostic necessity of early biopsy for atypical intertriginous ulcers and highlight surgical management as a definitive, safe, and durable therapeutic strategy for recalcitrant, localized cutaneous LCH when systemic pharmacotherapy fails.

Case Presentation

A 36-year-old man presented to our department with a 5-year history of painful and pruritic lesions on his bilateral groins. The lesions initially appeared as erythematous patches that gradually enlarged and progressed to ulcerated plaques, accompanied by severe pain. The patient had previously received empirical topical glucocorticoids, antifungals, and antibacterials with poor clinical response. No family history of similar dermatological conditions was reported.

Physical examination revealed erythema, ulcerated plaques, and local linear skin atrophy on the bilateral groins without lymphadenopathy (Figure 1A). The patient reported no systemic symptoms, and vital signs were normal. A skin biopsy was obtained from the representative ulcerated plaques on the right groin for histopathological examination. Routine investigations, including a complete blood count (CBC), urinalysis, and a comprehensive biochemical panel, were conducted.

Figure 1.

Clinical and H&E histopathological features. (A), erythema and ulcerated plaques on the groin. (B) Hematoxylin‑eosin stain showed a large number of mononuclear cells with large, round cell bodies, abundant cytoplasm, and notched nuclei distributed in the dermis, accompanied by eosinophilic infiltration.

Histopathologic examination of the skin biopsy showed numerous mononuclear cells with large, round cell bodies, abundant cytoplasm, and characteristic grooved (“coffee-bean”) nuclei distributed throughout the dermis, accompanied by prominent eosinophilic infiltration (Figure 1B). As these morphological features strongly indicated a histiocytic disorder of the Langerhans cell lineage, targeted immunohistochemical staining was subsequently performed. The atypical cells showed striking positivity for CD1a, CD207 (Langerin), CD68, and S-100 (Figure 2), unequivocally establishing the diagnosis of Langerhans cell histiocytosis (LCH).

Figure 2.

Immunohistochemical staining. (A) CD207. (B) S100. (C) CD1a. (D) CD68.

Further comprehensive systemic investigations were initiated to assess the extent of disease involvement. Evaluations including positron emission tomography-computed tomography (PET-CT), brain magnetic resonance imaging (MRI), and high-resolution CT scans of the chest, abdomen, and pelvis revealed no significant abnormalities. Consequently, the condition was staged as an isolated single-system, single-site cutaneous LCH.

Therapeutically, the patient initially commenced on a systemic combination regimen consisting of oral thalidomide (25 mg, three times daily) and methotrexate (15 mg/week). However, this treatment was quickly discontinued due to the onset of severe dizziness. Subsequently, Off-label treatment with upadacitinib (30mg daily) was initiated. After two months of upadacitinib therapy, the patient reported significant relief from pruritus; nevertheless, the ulcerated plaques showed no remarkable morphological improvement. Furthermore, laboratory monitoring revealed a notable elevation in liver transaminases, exceeding four times the upper limit of normal, necessitating the immediate cessation of upadacitinib. Given the highly refractory nature of the lesion and the poor tolerance to systemic pharmacotherapy, definitive surgical excision of the involved cutaneous lesions combined with an advancement flap reconstruction was ultimately performed. The surgical intervention was successful and achieved complete resolution of the recalcitrant plaques. At the 18-month post-operative follow-up, the patient remains strictly recurrence-free (Figure 3).

Figure 3.

Follow-up at 18 months.

Discussion

Cutaneous Langerhans cell histiocytosis (cLCH) is a rare proliferative disorder of histiocytes primarily affecting children; adult-onset cases, particularly those isolated to the skin without systemic involvement, are extremely uncommon.¹ This report describes a highly instructive case of recalcitrant adult cLCH presenting as groin ulcers. The clinical significance of this case lies in its prolonged diagnostic delay, the unique dichotomy of its response to JAK inhibition, and the exploration of surgical excision as a potentially effective therapeutic alternative.

The clinical presentation of cLCH is highly heterogeneous. When lesions manifest in intertriginous areas such as the groins, they closely mimic common dermatoses, including tinea cruris, severe intertrigo, or cutaneous Crohn’s disease.³ In our patient, this morphological ambiguity led to a 5-year delay in diagnosis and prolonged exposure to ineffective empirical treatments. This case underscores a critical clinical caveat: for chronic, refractory, and painful ulcerated plaques in intertriginous regions that fail to respond to standard therapies, an early diagnostic skin biopsy is imperative to rule out underlying histiocytic or neoplastic disorders.

From a therapeutic perspective, managing isolated adult cLCH remains challenging. While systemic agents like methotrexate and thalidomide are frequently utilized, they are often limited by poor tolerability, as seen in our patient’s severe dizziness. Most notably, the off-label application of the JAK-1 inhibitor upadacitinib yielded a fascinating clinical divergence. The striking resolution of severe pruritus suggests that JAK inhibition successfully dampened the reactive, cytokine-driven inflammatory milieu surrounding the LCH lesions.⁶ However, the failure of the ulcers to heal indicates that upadacitinib lacked direct anti-proliferative efficacy against the primary pathogenic Langerhans cell clones. Furthermore, the development of severe hepatotoxicity highlights the critical need for rigorous safety monitoring when repurposing potent immunosuppressants for orphan diseases.

Published cases of isolated adult‑onset cutaneous LCH remain scarce. Available case reports indicate that many patients fail systemic therapies including immunosuppressants and targeted agents, with variable response rates and frequent adverse events. According to current consensus guidelines, topical or local therapies are first‑line for mild localized cutaneous LCH, while systemic therapy is reserved for progressive or multifocal disease.⁷ Surgical excision represents an acceptable therapeutic option for well‑demarcated, localized lesions, though its real‑world application is largely limited to individual case reports, given the rarity of this clinical entity.^8–10

Given the poor tolerance and inadequate structural response to systemic pharmacotherapy, our case advocates for a re-evaluation of treatment strategies in highly selected patients. For localized, single-site cLCH, complete surgical excision combined with appropriate reconstructive techniques (eg, advancement flaps) should be considered a viable and potentially effective therapeutic option. Our patient’s recurrence-free status at 18 months post-surgery suggests that this localized approach can achieve sustained clinical remission while circumventing the toxicities of systemic agents.

Despite the favorable outcome, several limitations in our report must be acknowledged. First, as a single‑case observation, the generalizability of our findings regarding both the limits of upadacitinib and the long‑term efficacy of surgical excision remains constrained. Second, molecular profiling (such as testing for the BRAF V600E mutation) was not performed; identifying specific genetic drivers could have provided a deeper understanding of the disease’s clonal pathogenesis and its resistance to targeted therapies. Third, there are no universally accepted objective and standardized criteria to evaluate treatment response for this rare condition. We also lack detailed information regarding the histological resection margins of the excised specimen, and no control biopsy was performed after medical treatment. Finally, although an 18‑month recurrence‑free period is encouraging, continued longitudinal follow‑up is still warranted to monitor for potential late local relapses or systemic progression.

Conclusion

Localized adult-onset cutaneous LCH may present as chronic ulcerated plaques in intertriginous areas and is easily misdiagnosed. Early skin biopsy is essential for atypical, treatment-refractory lesions. In this case, systemic therapy was limited by poor tolerance and inadequate lesion response, whereas surgical excision achieved durable remission without recurrence at 18 months. Surgical treatment may therefore represent an effective option for selected patients with localized, medically refractory cutaneous LCH.

Funding Statement

There is no funding associated with this work.

Data Sharing Statement

Data sharing does not apply to this article.

Ethical Approval

According to the policy of the Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, formal institutional review board approval was not required for the publication of a single anonymized case report. Written informed consent for publication and accompanying images was obtained from the patient.

Consent to Publish

Consent was obtained from the participant for publication in this report and any accompanying images.

Disclosure

The authors report no conflicts of interest in this work.