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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.4 Rio de Janeiro July/Aug. 2009
Leonardo Mello FerreiraI; Paulo Sergio EmerichII; Lucia Martins DinizIII; Luciene LageIV; Isabella RedighieriV
Student, Department of Dermatology, School of Medicine of Santa Casa de Misericórdia
de Vitória (EMESCAM) Vitória (ES), Brazil
IIDermatology Specialist, Brazilian Society of Dermatology. Dermatology Preceptor of Pediatrics Residents, Hospital Infantil Nossa Senhora da Glória (HISNG) Vitória (ES), Brazil
IIIDermatology Specialist, Brazilian Society of Dermatology. Assistant Professor, Dermatology Residence Program, School of Medicine of Santa Casa de Misericórdia de Vitória (EMESCAM) Vitória (ES), Brazil
IVPathologist at Hospital da Santa Casa de Misericórdia de Vitória (EMESCAM) and Hospital Infantil Nossa Senhora da Glória (HISNG) Vitória (ES), Brazil
VStudent of the fifth year of Medicine, School of Medicine of Santa Casa de Misericórdia de Vitória (EMESCAM) Vitória (ES), Brazil
Langerhans cell histiocytosis is defined as a clonal proliferation of Langerhans phenotypic-like cells. Letterer-Siwe disease is the most common and serious of these entities, affecting mainly infants up to two years of age. We present two cases of this rare disease, diagnosed after dermatological examination, highligthing its typical aspects.
Keywords: Antigen-presenting cells; Etoposide; Immunohistochemistry; Microscopy, electron; Vinblastine
Histiocytoses are proliferative diseases related to histiocytes, which are cells derived from the bone marrow.1 The term histiocyte includes all types of macrophages and other dendritic cells (antigen-presenting cells: dermal dendrocytes, Langerhans cells (LC), and undetermined cells).2
Electronic microscopy and immunohistochemistry (IHC) have led to the classification of histiocytoses into: Langerhans cell histiocytoses (LCH), non Langerhans cell histiocytoses, and malignant histiocytoses.1,3
LCH is the clonal proliferation of cells phenotypically similar to LC that express a positive immunophenotype for CD1a and/or have Birbeck cytoplasmatic granules visible to the electronic microscope (EM); they have a racket shape pathognomonic of LC.1,4 The presence of additional markers like S100, CD 207 (Langerin), CD68 and factor XIIIa may help in the differential diagnosis with other histiocytoses.4
LCH is a spectral disease, with four syndromes recognized: Letterer-Siwe disease (LSD) or disseminated acute LCH occurring up to two years of age; Hand-Schüller-Christian disease or chronic multifocal LCH occurring between two and six years of age; eosinophilic granuloma or chronic focal LCH affecting people from five to 30 years of age; and Hashimoto-Pritzker disease a self-limited congenital variant.1,2,5
The most frequent LCH occurs in children between 1 and 3 years of age, although it may occur at any age. Its annual incidence seems to be between 2 to 5 cases per million children. It is twice more frequent among males.1,3
Its pathogenesis remains unknown. Its reactional or neoplastic nature is still debated, although there are more arguments favoring the first option.3,4
As a spectral disease, the clinical features of the four well-defined variants of LCH may overlap.1 More than 50% of the patients initially present skin manifestations of the disease, which sounds natural, considering that LCs, although originated in the bone marrow, physiologically belong to the skin immune system.4
LCD occurs more frequently in children under one year of age. The skin is involved in most patients as rosy, yellowish or normal skin color papules, 1 to 2 millimeters wide, pustules and/or vesicles on the scalp and skin folds on the neck, axillae, perineum, and trunk. Lesions tend to coalesce and become firmer. Flaking, erosion, ulceration, and crusts, with secondary infection, and the emergence of petechias and purpuras are common. In some cases there may be nodules that may ulcerate. It may affect the nose and the palmar-plantar regions. 1,2
During the course of the disease, there is fever and weight loss,2 and many organs like the lungs, liver, lymph nodes, and bones can be infiltrated by LC clones. The hematopoietic system can also be involved with thrombocytopenia and anemia.1
Prognosis is poor. Children with less than two years of age, with involvement of the hematopoietic system, liver, lungs, and spleen, even with aggressive treatment, may have mortality greater than 50%.1,6
In the typical papule, there is LC proliferation on the papillary dermis. These cells are wide, with a reniform nucleus. There is usually some degree of epidermal infiltration. The dermal infiltrate frequently includes eosinophils, neutrophils, lymphocytes, plasmocytes, and mastocytes. Old non-proliferative lesions may look granulomatous, xantomatous, or fibrotic.1,7
Treatment varies depending on the extension and severity of the case.1 Recent studies suggest treatment should be made with vinblastine or etoposides, associated to steroids, instead of the multi-drug therapy used in the past (DALHX 83-90), although this last regimen has a smaller relapse rate after treatment. The failure to have therapeutic response after six weeks of treatment is a sign of worst prognosis and the need of treatment with more aggressive combinations regimens.1,3,6
Case 1: Female patient, fourteen months of age, was admitted to a pediatric reference center, with 30-day history of jaundice, choluria, fecal acholia, and abdominal distension, with a palpable mass on the left, inguinal lymphadenopathy, and skin lesions.
Abdominal ultrasound showed hepatosplenomegalia and empirical antibioticotherapy started without changes in her status.
A dermatologic examination was then ordered, showing erythematous-vesical-squamous-crusty lesions on the scalp, inguinal region (Figure 1), neck and trunk, associated to purpuras, especially in the palmar-plantar regions (Figure 2). She also presented some erythematous papules on the lower abdomen and a nodular lesion on the scalp that was biopsied. The diagnostic hypothesis was LCH, confirmed by the histopathological (Figure 3) and immunohistochemical examinations (Figure 4). The myelogram did not show medullar involvement.
Treatment consisted of systemic chemotherapy with vimblastine associated to prednisone, with a favorable evolution of the disease. Other hospitalizations were necessary a few months later because of complications, especially pulmonary. The patient was later lost to follow up.
Case 2: Male patient, eight months of age; two months before had presented edema on the lower limbs, occasional fever and symptoms similar to seborrheic dermatitis that evolved to otalgia, dry cough, dyspnea, and jaundice. He progressively worsened and was then admitted to a pediatric reference center. He had a general poor status, hypocolored mucosas, anasarca, hypotension, tachycardia, abdominal distension, hepatomegalia of difficult palpation, melena, visible collateral circulation, oliguria, choluria, and oral lesions.
Lab tests showed severe liver failure, anemia, and thrombocytopenia.
The diagnostic hypothesis of the pediatric clinic included sepsis and severe malnutrition, fulminating hepatitis, calazar, leucosis, and many other conditions.
Without a favorable response to broad spectrum antibiotics, a dermatologic examination was ordered. The examination showed anasarca, jaundice, widespread petechias, telangiectasias, small erythematous papules on the trunk, ulcerative-necrotic lesion on the left axilla and erythematous-vesical-crustry-flaky-purpuric lesions on the scalp, extremities of upper limbs (especially palmar region) and diaper area (Figure 5). There was also a necrotic lesion on the palate and purpuric-hemorrhagic lesions on the oral cavity. The diagnostic hypothesis was LCH.
The skin lesion histopathological test and myelogram were inconclusive. The patient evolved to death due to multiple organ failure.
The autopsy concluded: multisystem LCH, affecting the skin (Figure 6), bone marrow, liver, spleen, and lungs, with later immunohistochemical confirmation.
The age, dermatologic symptoms, histopathological test, degree of system involvement, and the rapid progression of the disease led to the classification of these two cases as LSD.
The dermatological symptoms were typical in both cases, presenting lesions that could be called purpuric eczema. Other elements were also present, such as the eruption of erythematous papules on the trunk, on the second case, and the nodule on the scalp, on the first patient.
Secondary features like crusts, pustules, hemorrhage, and necrosis may darken the typical LCH1 infiltrate, as in the histopathological examination of the skin biopsy of the second case.
With the aid of IHC, EM has become increasingly less necessary for a definitive diagnosis,1 as in these two cases: CD1A, CD68 antigens and protein S100 were positive.
The degree of liver involvement, on the second patient, explained the extensive hemorrhage and edema. There were also signs of medullar infiltration, like anemia and thrombocytopenia (factor that contributed to the hemorrhage).
Osteolytic lesions of the mastoid process of the temporal bone lead to otitis media8, which was seen in both cases at an early stage, showing it is an important feature for the diagnosis of the disease.
The first patient responded to the treatment with vimblastine and prednisone, although other subsequent hospitalizations suggested relapses, which is more frequent with less aggressive regimens. Treatments associating vinblastine and etoposides with or without other medications are promissing.6
The second patient met several criteria for a poor prognosis but, probably the main factor that led to early death was the delay in the diagnosis.
The anomalous response to viral challenges (HHV6, CMV, Epstein Barr, HIV), immunological changes in T-lymphocytes and cytokines or abnormalities typical of LCs are hypothesis that are being studied about the pathogenesis of this disease.1,9
One example may be the hypothetic model involving all these points. Considering the existence of documented family cases,1,3 genetically predisposed individuals would have abnormal LCs (ALC). The stimulation of ALCs by an immune or inflammatory reaction would lead to the clonal expansion of that cell, and also non-clonal and potentially functional cells deriving from normal LCs. This population of LCs would induce a tissue reaction leading to LCH lesions. The degree of such lesions would be determined by the balance between LC aggressiveness and the competence of the regulation immune system, thus explaining the different forms and clinical course of LCH.3
The two cases herein were diagnosed after dermatologic examinations, in spite of the knowledge and diagnostic hypothesis of the specialized service.
The authors have concluded the LSD is a rare condition, but, due to its severity, dermatologists should be able to recognize its typical dermatological signs, which may be decisive to define the treatment and prognosis of patients affected.
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Leonardo Mello Ferreira
Av. Governador Lindenberg 1066 / 3ºAndar Centro
CEP: 29900-202 - Linhares - ES
Tel./Fax: 27 32641908
Conflict of interest:
Financial funding: None
How to cite this article: Ferreira LM, Emerick PS, Diniz LM, Lage L, Redighieri I. Histiocitose de células de Langerhans: doença de Letterer-Siwe importância do diagnóstico dermatológico em dois casos. An Bras Dermatol. 2009;84(4):405-9.