Adult multisystem Langerhans cell histiocytosis with cutaneous involvement manifesting as extensive flexural erosions

Abstract

Langerhans cell histiocytosis is a great imitator of other diseases with an often-delayed diagnosis leading to a concerning delay in commencing treatment. We present the case of a male who was previously diagnosed with Hailey-Hailey disease, in whom several treatment options had failed, was referred to the dermatology team for evaluation of a 3-month atypical, extensive, painful and pruritic cutaneous flexural eruption. On systems review, he reported a 2-year history of polyuria and polydipsia. Repeat skin biopsy revealed a prominent histiocytic infiltrate on histopathology with corresponding positive expression of Langerin (CD207), S100, CyclinD1 and p-ERK on immunohistochemistry staining. An MRI of the brain demonstrated posterior pituitary enhancement. The clinical presentation, biopsy and investigations confirmed a diagnosis of a multisystem Langerhans cell histiocytosis, which resulted in longstanding patient morbidity. With considerable multidisciplinary teamwork, a gradual and sustained resolution of his lesions, pain, polyuria and polydipsia was achieved.

Background

Langerhans cell histiocytosis (LCH) is a rare neoplastic clonal proliferation of myeloid dendritic cell precursors leading to focal infiltration of single or multiple organ systems. It is often accompanied by significant morbidity and carries unfavourable mortality if left untreated.¹ Manifestations are highly varied and have been well documented in the paediatric population with very few cases described in adults.¹ Physicians should be aware of the heterogeneous cutaneous manifestations of LCH, particularly in adults, and early clinical suspicion should be raised in patients with atypical dermatologic presentations to ensure a timely diagnosis and appropriate treatment.

Hailey-Hailey disease, also known as familial benign chronic pemphigus, is an autosomal dominant blistering disease that typically presents in the fourth decade of life.² It is characterised by recurrent vesicles, erosions and macerated plaques with a predilection for the intertriginous areas such as the neck, axillae and groin.² It is frequently associated with severe discomfort and chronic relapses, therefore, can be easily mistaken with the similar clinical features of LCH.² We describe an adult multisystem LCH with significant cutaneous involvement manifesting as atypical, extensive flexural erosions, that was initially misdiagnosed as Hailey-Hailey disease leading to significant delay in appropriate treatment with ongoing morbidity.

Case presentation

A male in his 50s presented with a generalised flare of pruritic and painful erosive plaques extending beyond the flexures. This was on the background of a diagnosis of Hailey-Hailey disease 8 years earlier by an external dermatologist based on clinical morphology of small axillary plaques and biopsy findings demonstrating full thickness acantholysis. These initial skin lesions failed to respond to treatment trials of tildrakizumab and baricitinib. Further, he had no known family history of Hailey-Hailey disease and no genetic testing was performed.

In the 3-month period leading up to his presentation, there was progressive cutaneous involvement, debilitating pain and pruritus, with a significant impact on function leading to the inability to dress, toilet or mobilise independently. On systems review, there was a 2-year history of polydipsia and polyuria.

Physical examination revealed sharply demarcated, violaceous, erythematous, confluent plaques and crusted papules with linear erosions and fissures in the intertriginous areas. The plaques extended from his bilateral axilla to his trunk, chest, abdomen and upper and lower limbs (figure 1A–C) with scattered focal spots of active bleeding and seropurulent discharge. There was sparing of the head and neck, umbilicus, no mucosal involvement, no vesicles, no lymphadenopathy and no organomegaly.

Figure 1.

Multiple extensive confluent erythematous erosive plaques of the (A) bilateral axilla and sacrum extending beyond the flexure margins, (B) across the abdomen with active bleeding and periumbilical sparing and (C) across the torso with yellow crusted scale.

Investigations

Given the atypical presentation and extent of disease, repeat biopsies were performed. Histopathological examination of the repeat specimen demonstrated prominent aggregations of histiocytic infiltrate mixed with eosinophils and neutrophils within the epidermis and superficial papillary dermis, staining positive for CD1a on immunohistochemistry (figure 2A,B). Supportive confirmatory staining suggested the atypical CD1a cells showed positive expression of Langerin (CD207), S100, CyclinD1 and p-ERK. No features of acantholysis were observed. Consistent with this, the original biopsy from 8 years earlier was reviewed and confirmed to similarly exhibit large collections of Langerhans cells in the epidermis and superficial dermis with positive CD1a stain. Importantly, to guide therapeutic options and as a marker of disease severity, BRAF molecular testing of the tissue returned negative. All other routine laboratory studies and wound swab results were unremarkable.

Figure 2.

Dermatopathology images showing (A) aggregations of histiocytic infiltrate within the dermis (B) staining positive for CD1a on immunohistochemistry.

Since the tissue specimen findings were suggestive of LCH, this prompted an investigation for multi-organ involvement. A whole-body PET-CT (positron emission tomography-computed tomography) scan and bone marrow aspirate and trephine biopsy did not show evidence of metabolically significant internal organ or bone involvement; however, an MRI of the brain was performed showing posterior pituitary enhancement. Through shared care with the endocrinology team, a completed arginine-stimulated copeptin study with a level of 2.3 pmol/L (<3.8 pmol/L cut-off) was consistent with a diagnosis of central diabetes insipidus. Given the histopathological findings, clinical symptoms and radiographic evidence, a diagnosis of multisystem LCH was confirmed.

Treatment

In line with a working diagnosis of LCH, he was prescribed topical betamethasone dipropionate 0.05% two times per day, methylprednisolone 0.1% to the flexures two times per day and oral prednisolone up to 25 mg daily while investigating for multi-organ involvement. Following confirmation of a multisystem LCH, concomitant management from the haematology team with low dose cytarabine, dexamethasone 2 mg daily, methotrexate 10 mg once weekly and nicotinamide 500 mg two times per day was commenced, and desmopressin 100 μg two times per day was commenced with input from the endocrinology team for his diabetes insipidus.

Outcome and follow-up

During his first month of treatment, we observed a gradual and sustained reduction of his skin lesions and associated pain, and his polyuria and polydipsia resolved. He returned to his usual baseline level of independence and function.

Discussion

LCH is a rare neoplastic clonal proliferation of myeloid dendritic cell precursors that is predominantly observed in the paediatric population but also infrequently occurs in adults within their 40s.^{1 3} Depending on the extent of tissue infiltration, it may be classified into single or multi-organ system LCH with the latter conferring a poorer prognosis, especially if the liver, spleen or bone marrow are involved.¹ A systemic screen for multi-organ system involvement should be considered using a whole-body PET CT in the first instance, with further organ-specific imaging guided by radiological or clinical evidence of other organ dysfunction, in particular, bone, pituitary gland, liver, spleen or lung.³

Cutaneous manifestations are highly variable, including erythematous, painful and pruritic papules, intertrigo or erosions frequently accompanied by overlying scale and crust of the scalp, trunk, limbs or genitalia.^{3 4} Involvement of the mucosa demonstrates localised gingival swellings with painful ulceration.⁵ As there exists a large spectrum of clinical presentations, there is frequently a delay in diagnosis or misdiagnosis, therefore, leading to a significant delay in commencing treatment. Common misdiagnoses for cutaneous lesions include seborrhoeic dermatitis, eczema, psoriasis and candidal intertrigo, so high clinical suspicion for LCH is critical for a timely diagnosis.⁶

Dermatologic manifestations are often the initial presentation and are potentially a leading marker for multifocal disease.⁷ In our case, the unusual cutaneous progression beyond the flexures prompted a concern for re-evaluating his past diagnosis of Hailey-Hailey disease. The repeat skin biopsy and re-analysis of the old biopsy with immunohistochemistry staining positive for CD1a, Langerin (CD207) and S100 was supportive of LCH masquerading initially as a misdiagnosis of Hailey-Hailey disease. This case highlights adult LCH as a differential for clinicians to consider in an atypical extensive flexural eruption.

An oncogenic mutation of BRAF V600E is reported in 40%–70% of cases and has been shown to correlate with poorer prognosis and more aggressive disease than compared with BRAF wild type.⁸ More recently, MAP2K1 mutations have been reported in a large portion of BRAF negative cases.⁹ While there is no guideline for therapy at this stage, consensus recommends that adult multisystem LCH involving the brain parenchyma should be treated with chemotherapy agents of either cytarabine or cladribine.¹⁰ Targeted therapy are options for systemic disease without central nervous system involvement or disease which is chemo-refractory; however, treatment must be balanced with patient tolerability and medication toxicity.

In summary, physicians should recognise atypical and extensive flexural eruptions as a cutaneous presentation of adult LCH to achieve a timely diagnosis. It is prudent to consider a systemic screen with whole body imaging and tissue analysis for testing of the BRAF mutation to anticipate prognosis and guide systemic therapy choices.

Learning points.

• A high index of suspicion for Langerhans cell histiocytosis (LCH) should be raised where there is atypical, extensive and erosive flexural eruptions.

• Multiple skin biopsies may be necessary to prevent diagnostic delay or misdiagnosis.

• Molecular analysis of tissue for BRAF and MAPK-ERK pathway mutations is useful for prognostication and guiding therapeutic options.

• A careful history, whole body PET CT and further organ-specific investigations or imaging are indicated in LCH as it frequently presents with cutaneous signs followed by insipient underlying multi-organ disease.

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