Dermatology Online Journal

An unusual case of adult disseminated cutaneous Langerhans cell histiocytosis
Hamideh Moravvej MD¹, Maryam Yousefi MD², Behrooz Barikbin MD¹
Dermatology Online Journal 12 (6): 13

1. Skin research center and department of dermatology, Shohada-e-tajrish hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. bbarikbin@yahoo.com
2. Department of dermatology,Razi hospital, Tehran University of Medical Sciences, Tehran, Iran

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Abstract

Langerhans cell histiocytosis (LCH) represents a group of rare histiocytic syndromes characterized by tissue infiltration with dendritic cells. The management of LCH is difficult because these disorders respond inconsistently to immunosuppressive and chemotherapeutic strategies. We describe a refractory and relapsing case of skin and nail limited LCH in a 27-year-old man. He presented with a 7-year history of an erythematous papular eruption of the scalp, ears, face, trunk, axillae, groins, fingernails, feet, and toenails. Diagnosis of LCH was made based on skin histopathology and immunohistochemical staining. Histological studies of biopsy specimens revealed a dense infiltrate of histiocytic mononuclear cells beneath the epidermis; these cells reacted strongly with anti-S-100 antibodies. In addition, CD1a was positive in most of the infiltrating cells. Extensive investigations failed to detect systemic involvement. The patient's cutaneous eruption did not respond to various therapeutic interventions, including phototherapy with oral psoralen with long-wave UV radiation in the A range (PUVA) and cyclosporine. Marked but temporary clinical improvement was achieved with thalidomide, etoposide with systemic steroid, and total body electron beam radiotherapy. Now the patient is on maintenance therapy with thalidomide and is under acceptable control.

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Introduction

Langerhans cell histiocytosis (LCH) is a clonal proliferative disease of Langerhans cells that express an immunophenotype positive for S100 and CD1a, and which contain cytoplasmic Birbeck granules. LCH occurs worldwide and most commonly develops in children aged 1-3 years, although disease can develop at any age. An annual incidence of at least 5 per million children has been reported for LCH, with the adult incidence suspected to be less than one-third that of children. LCH is more common in boys, with a male:female ratio of nearly 2:1. In adults, there may be a slight female predominance [1].

Langerhans cell histiocytosis most frequently involves bone, but also involves the skin in 40 percent of cases; in 10 percent of patients it is limited to the skin. Cutaneous findings of skin-limited LCH include scaly papules, vesicles, nodules, tumors with erosion, ulceration, crusting, or purpura [2]. Nail involvement in LCH is rare, but findings include paronychia, nail-fold destruction, onycholysis, and subungual expansion with nail plate loss [3].

Adult LCH is much rarer than infant or childhood LCH; the most commonly involved sites are the skin, lung, and bone [1]. Adult LCH is also more difficult to treat. Disseminated multisystem adult LCH has a more benign chronic course; it has a slowly progressive or undulating course in contrast with the childhood type [1, 2].

We report an interesting case of adult skin and nail limited LCH occurred in a 27 year old man.

Clinical synopsis

A 27-year-old man presented with 7-year history of multiple erythematous papules and nodules on the face, scalp, trunk, axillae, hands, and feet. The lesions were very pruritic.

Examination showed symmetrically distributed papules and nodules; some of them were skin colored and some were erythematous and purpuric. The lesions were located on the scalp, forehead, nose and perinasal area, upper lip, chin, cheeks, preauricular areas, ears (conchae and around external auditory meati), retroauricular areas, chest, abdomen, posterior trunk, axillae, and groins (Figs. 1-9). Around the nostrils the papules were confluent. Some of the facial and ear lesions were ulcerated and crusted. Atrophic scars were present at the sites of spontaneously healed lesions (Fig. 10).

Figure 1	Figure 2
Figure 1. Involvement of the face, chest and axillae by cutaneous LCH Figure 2. Papular lesions on and around the nose and upper lip

Figure 3	Figure 4
Figure 3. Papular lesions on the face
Figure 4. Involvement of the ear

Figure 5	Figure 6
Figure 5. Involvement of the retroauricular area
Figure 6. Involvement of the scalp

Figure 7	Figure 8
Figure 7. Papular lesions on the chest and abdomen
Figure 8. Involvement of the posterior upper trunk

Figure 9	Figure 10
Figure 9. Involvement of the axilla
Figure 10. Atrophic scars of the spontaneously healed lesions on the chest

Figure 11
Figure 11. Involvement of the fingernails

Acral involvement also was present in the form of fingernail involvement of the hands and an eczematous like eruption and nail involvement on the feet (Fig. 11). Nail involvement included brittleness, longitudinal ridging, purpuric lines, V-shaped notches, and pterygium formation (Figs. 11-15).

Figure 12	Figure 13
Figure 12. Nail involvement in the forms of brittleness, longitudinal ridging, purpuric lines and V-shaped notch
Figure 13. Pterygium formation

Figure 14	Figure 15
Figure 14. Eczema-like lesions on the dorsum of the feet
Figure 15. Toenail involvement

The patient denied systemic complaints including fever, significant weight loss, vomiting, diarrhea, polyuria, polydypsia, bone pain, fatigue, dyspnea, and jaundice. On physical examination the head and neck area was normal except the skin lesions on the scalp and face. There was no exophthalmia. The oral cavity, teeth, and gingiva were normal. There was no lymphadenopathy and no organomegally. Chest and abdomen examinations were normal. Neurologic examination including sensory and motor function revealed no abnormality.

The clinical differential diagnoses included histiocytosis, Darier disease, sarcoidosis, seborrheic dermatitis, and generalized eruptive histiocytoma. Skin biopsies of the neck and nose lesions showed upper and mid-dermal infiltrates composed of large, rounded cells with indented, kidney-shaped nuclei (Figs. 16 and 17).

Figure 16	Figure 17
Figure 16. Histiocytic infiltration of the upper and mid dermis
Figure 17. Close-up view of fig.16

Immunohistochemistry revealed S-100 protein and CD1a positivity in most of the infiltrating cells. Laboratory tests, PPD skin test, radiologic and ultrasonographic images were all normal. Chest, abdomen and brain CT scans were all normal. A whole body bone scan was normal.

The patient was diagnosed with isolated cutaneous LCH. He received 15 sessions of PUVA therapy with no improvement. He then received thalidomide (100 mg/day for 3 months) with a good response, however, because of occurrence of neuropathy, the drug was stopped and the lesions recurred 1 month later. With the recommendations of oncology department, the patient underwent treatment with etoposide and systemic steroids. He responded with gradual clearing of skin and nail lesions (Figs.18-20).

Figure 18	Figure 19
Figure 18. Clinical improvement after several sessions of chemotherapy with etoposide plus systemic steroid
Figure 19. Clearance of the chest lesions

Figure 20
Figure 20. Improvement of fingernail lesions

The lesions recurred 2 months after termination of treatment. The patient was then treated with total body electron beam radiotherapy and the lesions disappeared again. And again the lesions relapsed 2 months after therapy. Cyclosporine was administered but was completely ineffective. At last, we again started thalidomide with close monitoring for neuropathy and the patient responded well to the drug. At 6 months followup the eruption is under control with maintenance therapy (100 mg twice weekly).

Discussion

LCH is well known in childhood as Abt-Letterer-Siwe disease. The classification of Langerhans-cell histiocytosis and non-Langerhans-cell histiocytosis was established in 1987 by the Histiocyte Society. The group of LCH includes congenital self-healing histiocytosis of the Hashimoto-Pritzker type, Abt-Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma. The latter three were formerly called histiocytosis X, where the X indicated the unknown etiology. These have multiple clinical manifestations, and may also involve lymph nodes and bones as a multifocal disease [4].

Initial symptoms occurring in adulthood as in our case are unusual, but this has been previously reported [4, 15, 18, 19, 20, 21]. Recently, Howarth et al. reported 314 cases of various types of LCH, 114 were osseous, 96 were multisystemic, and 104 were single-system non-osseous in origin [17]. Among 104 cases of single-system non-osseous origins, only 14 cases originated in mucocutaneous tissue [17]. Therefore primary cutaneous LCH as in presented case appears to be rare [16]. Chronic relapse of the disease is often seen, and even after some years patients may progress to a multisystem disease [6].

The therapeutic regimen for LCH depends on the localization and extent of the disease. Spontaneous healing is reported as are therapy-resistant cases [7]. Successful treatment with PUVA [8] , thalidomide [9], low dose methotrexate [15] and interferon-α [2] is reported. Intravenous 2-chlorodeoxyadenosine only showed a transient improvement whereas long-term remission was seen after local radiation [10]. In the case of low-risk LCH in children, effective therapy with oral methotrexate and alternate-day prednisolone has been reported [14]. In our case there were no obvious effects of systemic PUVA therapy administered for a period of 2 months.

Thalidomide is an anti-inflammatory, immunomodulatory, and anti-angiogenic compound. These features allow the use of this drug in inflammatory disorders, neoplasms (including multiple myeloma, prostate cancer, renal cell carcinoma, glioma, and colorectal cancer), and in the dermatological manifestations of sarcoidosis and mucocutaneous LCH [23, 24, 25, 26]. The mechanisms that underlay its properties rely on the modulation of inflammatory cytokines such as TNF-α , interferon-γ, IL-10, IL-12, and the nuclear transcription factor NFkB [23, 24]. In the literature there is also evidence that in LCH not only thalidomide but also agents that selectively neutralizes TNF-α activity (etanercept), proved effective in the control of the disease [27].

This case is unusual for involvement limited to skin, the pattern of nail involvement, the age of the patient. It illustrates the relapsing nature of LCH after using several therapies. The response of this patient suggests that thalidomide may be a valuable therapeutic option in disseminated cutaneous LCH, but close monitoring for neuropathy should be performed.

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