LANGERHANS CELL HISTIOCYTOSIS: CASE REPORT AND LITERATURE REVIEW - Anais Brasileiros de Dermatologia 1998;73(4):327-332

José Wilson Accioly Filho, MD (1)
Maria Kátia Gomes, MD (1)
Andréia Nogueira, MD (1)
Olga Oiticica Harris, MD (2)
Cristina Maeda Takiya, MD, PhD (3)
Marcia Ramos-e-Silva, MD, PhD (4)

* Trabalho realizado no Curso de Pós-Graduação em Dermatologia, HUCFF-UFRJ, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

1. Aluno do Curso de Pós-Graduação em Dermatologia
2. Professor Assistente - Anatomia Patológica
3. Professor Adjunto - Anatomia Patológica
4. Coordenador Adjunto do Curso e Professor Adjunto - Dermatologia

Resumo
Relato de caso infreqüente de granuloma eosinofílico, a forma localizada da histiocitose de células de Langerhans, em paciente masculino de 24 anos com envolvimento cutâneo e pulmonar.

A síndrome histiocítica é um grupo de alterações proliferativas das células histiocíticas que expressam o fenótipo de células de Langerhans. Varia da forma benigna localizada a fatal e disseminada com envolvimento multicêntrico. Duas categorias foram recentemente estabelecidas: histiocitose de células de Langerhans e histiocitose de células não-Langerhans.

Os autores discutem os aspectos clínicos, histológicos, imunohistoquímicos e ultrastruturais desta forma rara de histiocitose, que pode lembrar várias outras condições, como doença de Darier, dermatite seborréica e psoríase.

Palavras-chave: histiocitose, célula de Langerhans; granuloma eosinofílico; grânulos de Birbeck; cristais de Charcot-Leyden.


Abstract
Report of an unusual case of eosinophilic granuloma, the localized form of Langerhans cell histiocytosis, in a 24-year-old male with cutaneous and pulmonary involvement.

Histiocytic syndrome is a group of proliferative disorders of histiocytic cells expressing the phenotype of Langerhans cells. It ranges from a benign and localized to a fatal and disseminated form with multicentric involvement. Two categories were recently established: Langerhans cell histiocytosis and non-Langerhans cell histiocytosis.

The authors discuss the clinical, histological, immunohistochemical and ultrastructural aspects of this rare form of the histiocytosis that may mimic various other conditions, such as Darier's disease, seborrheic dermatitis and psoriasis.

Key Words: histiocytosis, Langerhans-cell; eosinophilic granuloma; Birbeck granules; Charcot-Leyden crystals.

 

Introduction
Histiocytic syndromes represent a diverse and misunderstood group of diseases with courses that vary from benign and localized to fatal and disseminated form.(1,2,3)

Recently, two greater categories of histiocytic syndromes were established: Langerhans cell histiocytosis (LCH) and non-Langerhans histiocytosis.(1,3)

Langerhans cell histiocytosis, previously designated by the term histiocytosis X,(4) is characterized by the aberrant proliferation of a group of dendritic, bone marrow-derived, monocytic-macrophage(6) system belonging cells (Langerhans cell). These cells can be identified by the presence of a peculiar cytoplasmic organelle, known as Birbeck granule, an endocytic and adsorptive organelle. Although not always demonstrable in the suspected biopsy material, a histiocytic infiltrate containing these granules is usually considered confirmatory evidence to the diagnosis.(1,2,3,5)

Langerhans cell can also be identified by its cytoplasmic enzymatic activity, including adenosine triphosphatase, acid phosphatase and non-specific sterase, and also by the uniform or variable expression of class 1 and 2 alloantigens, T 200, CD1, CD4, S-100 proteins, C3 C3bi and some monocyte/macrophage antigens, such as CDW14, Ki-M1, Ki-M6.(3,6,7,8)

The term Langerhans cell histiocytosis is wide and more adequate than histiocytosis X,(4) because it groups together a series of disorders that are almost equivalent, and have as in common feature a proliferation of Langerhans cells in many tissues:
1. eosinophilic granuloma, a localized and benign accumulation of histiocytes, primarily in bone, and sometimes involving other organs, as skin, lungs and lymphnodes;(9)

2. Hand-Schüller-Christian disease, a chronic and more progressive form, characterized by a triad: skull defects, exophthalmos and diabetes insipidus(10) and

3. Letterer-Siwe disease, an acute disseminated, often fatal disorder, characterized by multiple visceral involvement, including lungs, lymphnodes, liver, spleen, bone marrow, skin and mucous membranes.(11)

Cutaneous involvement in Langerhans cell histiocytosis is frequent and the observed lesions are very variable: papules, desquamative papules, vesicles, seborrheic dermatitis-like lesions, intertrigo, purpuric patches, purpuric nodules, eroded nodules, tumor, eyelid lipoidic infiltration, eruptive xanthoma and even cutaneous ulcerations,(1,2,3) granuloma annular-like lesions,(12) and even a set of symptoms similar to the occlusion follicular syndrome(13) and to mastocytosis.(14)

LCH is primarily a childhood disease(1,2,3,15) but it can also begin in adults.(1,2,3,12,16,17,18,19)

We present a case of Langerhans cell histiocytosis in a 24 year-old young male, discussing the clinical presentation, differential diagnosis, laboratorial aspects, and treatment.

Case report
M.S.E., 24 years-old, white male, married, X-ray technician, born in Rio de Janeiro, Brazil.

The patient reported that five years ago he presented fever and rough cough. At that time a chest X ray revealed bilateral diffuse interstitial infiltrate and a lung biopsy showed a 'lymphocytic pneumonia', which evolved with spontaneous remission of symptoms, despite the maintenance of the radiological image. Two years ago he noted the onset of erythematous skin lesions on the perianal region with progression to the inguinal regions. He used many topical ointments (antibiotics and steroids) with no improvement. After that, papulocrusted and erythematous desquamative lesions on the scalp appeared.

Concerning pathological antecedents, nothing was noteworthy.

When we first examined the patient, erythematous desquamative and papulokeratotic lesions could be seen on his scalp. Erythematous desquamative lesions were noted on the pavillion of the ears and retroauricular regions; fissured erythematous patches, vegetations and exulcerations with abundant secretion; and a characteristic smell were present on the inguinal folds. (Figure 1, 2)

Histopathological examinations with hematoxylin-eosin stain showed an exulcerated epidermis and a dense infiltrate of characteristic cells with lobulated, indented and clear nuclei and eosinophilic cytoplasm in the dermis. Some of these cells were binucleated, while others were multinucleated. There was a large number of eosinophils and smaller quantity of lymphocytes and plasma cells. This infiltrate was limited to the reticular dermis. (Figure 3)

Protein S-100 immunostaining was positive within the dermal infiltrate cells, staining in brown the nucleus and the cytoplasm (immunoperoxidase technique; avidin-biotin technique; revealing substance: diaminobenzidine - DAB). Such cells presented various sizes and were ovoid. (Figure 4)


Under electron microscopy we observed a dense cellular infiltrate of predominantly histiocytic lineage cells with clear and convolute nuclei in the dermis. These cells had abundant cytoplasm containing rod shaped structures, with a fuzzy coat and a vesiculated extremity, tennis racket shaped, the Birbeck granules. (Figure 5) We also noted the presence of numerous highly developed cytoplasmic organelles with membranous structures, called comma shaped bodies and worm bodies. Numerous cytoplasmic processes were seen departing of the free surface of these cells (filopodia). Large number of eosinophils, with characteristic electrondense granules, some degenerated, and lymphocytes were also found. In the extracellular space electron dense crystalloid bodies with hexagonal geometric structure or in fuse, the Charcot-Leyden crystals, were present. (Figure 6)

Laboratorial results were: RBC: 5,360,000/mm3; hemoglobin: 16.6%; hematocrit: 48%; MCV: 89; MCH: 31; MCHC: 34; ESR rate: 90mmHg; WBC: 14,900;, negative anti-HIV, negative VDRL; normal urinary sedimentation elements, feces parasitology and skull tomography, and a chest X-ray with bilateral interstitial diffuse infiltrate.

Spirometry showed a mixed spyrographic pattern, with minimal restriction and moderate obstruction, with no response to the broncodilating proof.

The patient was treated with oral prednisone 60 mg/day and within a month, based on the good clinical response, a reduction scheme was initiated.

Comments
HCL is a heterogeneous group of proliferative disorders of histiocytic cells that express the phenotype of Langerhans cells.(1,2,3,15) Despite its obscure etiopathogeny, the potential pathogenic factors that have received more attention lately can be divided in three categories: immune dysfunction, viral infection and malignancy.(1,3)

It includes a broad spectrum of diseases from cutaneous and/or osseous forms (eosinophilic granuloma) to cases with multicentric involvement, as described in the classical Letterer-Siwe syndrome.(1,2,3,15) Involvement limited to skin has been frequently reported.(15,18,20,21) Although more common in childhood, patients with ages ranging from birth to 91 years have been already described.(13-16,18,19,20,22) In the present case, the patient was 22 years-old when the first lesions appeared. Dermatological examination showed erythematous desquamative lesions on the scalp, ear pavillions and inguinocrural region. It is known that, in Langerhans cell histiocytosis, cutaneous lesions tend to be distributed on seborrheic areas,(1,2,3,15,17,19,22) a fact that imposes differential diagnosis with other disorders that may affect these same sites, as seborrheic dermatitis, Darier's disease and psoriasis.

Pulmonary chaanges in Langerhans cell histiocytosis are more frequent in adults and are characterized by interstitial involvement with several restriction degrees and reduced compliance.(1,3) The chest X-ray and the spirometry of our patient suggested a discrete pulmonary involvement.

In the reported case, the findings on optical microscopy (hematoxylin-eosin) were consonant with the described in the literature about Langerhans cell histiocytosis: we noted the presence of eosinophilic cells (Langerhans cells) and a mixed inflammatory infiltrate, containing lymphocytes, neutrophils, eosinophils and a small number of plasma cells. It is known that the histological pattern of Langerhans cell histiocytosis varies in relation to the age of the lesion and to the site of involvement.(3,5) On the examined sections, the presence of an exulcerated epidermis, due to the aggression to the basal membrane by the cell proliferation from the papillary dermis and the large number of eosinophils in the cell infiltrate suggested an older lesion, since eosinophilic infiltration and necrosis are more prominent in this evolutive phase.(3,5) Helm et al.,(17) in 1993, pointed out that the follicular involvement may be observed in lesions of Langerhans cell histiocytosis located on seborrheic areas rich in appendages. In the present case, such involvement was clinically noted specially on the scalp, which was confirmed by histological sections.

Histiocytic populations on Langerhans cell histiocytosis lesions can be studied by immunohistochemical techniques through a combination of antibodies, including OKT6, S-100, muramidase and a1 antitrypsin, that separates Langerhans cell from other phagocytic histiocytes.(3,7,8) Protein S-100 is a good marker for Langerhans cells and it is the most popular due to its degradation resistance, induced by the conventional fixation and embedding techniques, which allows retrospective study of cases.(3,8) Up to 90% of Langerhans cell histiocytosis lesions are protein S-100 reactive.(23) Immunostaining of the infiltrate cells of our patient was highly positive for a polyclonal S-100 antibody (rabbit).

Concerning the ultrastructural findings, it is usually accepted that Birbeck granules constitute the only unquestionable finding of the disease.(1,2,3,5) Under electron microscopy, numerous Langerhans cells were observed, since they contained the typical granules. These cells, however, showed some peculiarities when compared to the Langerhans cell present in normal epidermis: presence of light and extremely convoluted nuclei; numerous Birbeck granules, closely placed and exhibiting a fuzzy coat; well-developed rough endoplasmic reticulum and many mitochondria, presence of other membranous structures, such as comma shaped bodies and worm bodies, non pathognomonic of the disease, but present in other non Langerhans histiocytosis,(2,3,6) and many filopodia.(2,3,5,6) In general, it is assumed that cellular morphology alterations of Langerhans cells in HCL would be much alike to the ones seen on actinic reticuloid and many other cutaneous disorders.(5) Langerhans cells present in these conditions seem to be normal, activated by the presence of a chronic inflammatory process in skin.(3,5)

It is worthy to point out the observation, in our patient, of many eosinophils in different maturation phases in the cellular infiltrate and of Charcot-Leyden crystals occasionally observed in intercellular disposition. These crystals are microscopic structures extremely electron dense, that resemble two hexagonal pyramids placed base to base, with opposing triangular bases, forming 20o at the apex. They have been detected only in primates (man and monkey),(24,25) in sites where eosinophils concentration occurs. Concerning cutaneous pathology, such crystals were only detected in cases of facial (Lever's) granuloma and in incontinentia pigmenti.(24) Although the precise mechanism of crystal formation remains uncertain, it is usually considered the result of the aggregation of disintegrated eosinophil materials. Recent investigations showed that Charcot-Leyden crystals are composed only by lisophosphatase, a protein of molecular weight 17,400, present in eosinophils.(25,26) On Langerhans cells histiocytosis, Charcot-Leyden crystals have already been observed in eosinophilic granuloma bone lesions, in Hand-Schüller-Christian disease(15) and in cutaneous lesions of a case of Letterer-Siwe disease.(24) Kanitakis et al, in 1986,(24) observed, by electron microscopy, Charcot-Leyden crystals in cutaneous lesions of LCH treated with topical mecloretamine, which favored eosinophilic alterations leading to crystal formation. We believe, nevertheless, that the presence of Charcot-Leyden crystals is not necessarily related to the treatment but is probably linked to the evolutive phase of the biopsed region, considering that the material we used for electronic microscopy was obtained before the treatment of our patient was initiated.

Multiple isolated or combined therapeutical options were proposed for the treatment of Langerhans cells histiocytosis. Risks and potential benefits should be carefully weighed because of the possibility of a benign course and spontaneous remission. Systemic and intralesional corticosteroids,(1,3,15) radiotherapy,(13,18) topical nitrogen mustard,(22,24) immunotherapy,(27,28) PUVA,(29) ciclosporin,(30) etoposide(31) and isotretinoin(21) are some of the most important therapeutical modalities used for the cutaneous disease management whereas for systemic involvement, administration of one or more chemotherapeutic agents is suggested.(1,2,3,15,32) Because of the limited cutaneous and pulmonary involvement observed in our patient, we chose to use oral prednisone, without association with chemotherapy, as preconized, in 1985, by Esterly et al..(15)

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Figure 1. Clinical aspect: inguinal region
Figure 2. Clinical aspect: scalp and ear pavillion
Figure 3. Histopathology: dense infiltrate with eosinophils, lymphocytes and plasmocytes. Bi- and multinucleated Langerhans cells with lobulated, indented, light and large eosinophilic cytoplasm (HE - 100 X).
Figure 4. S-100 protein: Langerhans cell in brown (immunoperoxidase, DAB - 40 X)
Figure 5. Ultrastructure: Langerhans cell with Birbeck granule.
Figure 6. Ultrastructure: Charcot-Leyden crystals in fuse and hexagonal shape in extracellular space.

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ABSTRACT

Background: Histiocytic syndrome is a group of proliferative disorders of histiocytic cells expressing the phenotype of Langerhans cells. It ranges from a benign and localized to a fatal and disseminated form with multicentric involvement. Two categories were recently established: Langerhans cell histiocytosis and non-Langerhans cell histiocytosis.

Observation: An unusual case of granuloma eosinophilic, the localized form of Langerhans cell histiocytosis, in a 24-year-old male, with cutaneous and pulmonary involvement is reported, emphasizing its immunohistochemical and ultrastructural aspects.

Conclusions: Skin lesions may mimic various other conditions, such as Darier's disease, seborrheic dermatitis and psoriasis, and the clinical, histological, immunohistochemical and ultrastructural aspects of this rare disease are very important in establishing the diagnosis. Due to the mild cutaneous and pulmonary involvement improvement was obtained with oral prednisone.