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Print version ISSN 0365-0596On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.78 no.1 Rio de Janeiro Jan./Feb. 2003
Histiocytes and non-Langerhans cell histiocytoses in dermatology*
Flávio Barbosa LuzI; Antônio Pedro GasparII; Neide Kalil-GasparIII; Márcia Ramos-e-SilvaIV
Degree in Dermatology - UFF, doctoral candidate in Dermatology - UFRJ
IIAdjunct Professor - Dermatology Service, HUAP-UFF
IIIProfessor - Dermatology Service, HUAP-UFF
IVAdjunct Professor - Dermatology Service, HUCFF-UFRJ
Histiocytes are no longer recognized as singular cells. The term histiocyte now refers to a heterogeneous group of cells with unique histologic morphology, but with singular functions and characteristics. Histiocytoses are a group of different diseases caused by proliferative histiocytes. Such diseases are rare and their study usually tends to be difficult. The objective of this paper is to simplify the study of these diseases under the novel paradigm of histiocyte heterogeneity.
Key words: Histiocytosis; non-Langerhans cell histiocytoses; histiocytes; macrophages.
Histiocytoses are a group of extremely rare diseases that are poorly understood. So few studies have been made of these entities that only a bare minimum of questions about them may be answered easily. For the most part, information is isolated. Prospective double-blind, controlled, randomnized or comparative studies are virtually impossible to perform. Experimental animal models are unknown. Etiopathogenic and therapeutic investigations especially suffer from the obliquity of extremely reduced samples.
Innumerable advances have been made in the field of skin immunology, in particular in what relates to the monocytic-macrophagic system and to cutaneous dendritic cells. Understanding the histiocyte - albeit as a large family of cells, and not a single cell - is fundamental for the broader grasp of the aforementioned histiocytic diseases.
Establishing an overview of this disease under the paradigm of histiocyte heterogeneity is one of the guidelines used for this work.
This study contains a bibliographical review, in which information may be found on histiocytes and non-Langerhans histiocytoses that should be of dermatological interest.
In 1913, Aschoff and Kiyono1 described large mononuclear phagocytic cells found in the tissues as histiocytes. In 1924, Aschoff 2 used the same term to denominate determined cells of conjunctive tissue, having a number of morphological characteristics in common, considering them as pertaining to the reticuloendothelial system, with a phagocytic function. In May 1986, Headington3 called attention to the fact that the histiocytic term really referred to cells having morphological characteristics in common, but with very distinct origins and functions. He recommended the term histiocyte be abandonned due to the heterogeneity of this cellular group. Yet Wood and Haber4 currently use the term histiocyte to refer to all of the types of macrophages that are derived from the bone medula and other dendritic cells related to the immune system.
Perception of the heterogeneity of histiocytes does not appear to bear witness against the existence of the term, provided that one consider there is no other term available to substitute it adequately.
Moreover, histiocytoses end up having greater identity among themselves under the context of various subgroups of histiocytic cells. When used to morphologically refer to a cellular group, the name histiocyte seems to be valid and appropriate. In this paper the term histiocyte will be employed in accordance with Wood and Haber.4
The problem with defining terms such as macrophage and histiocyte is significant, and many authors disagree on its uses. In his book, Histologic Diagnosis of Inflammatory Skin Diseases, Ackerman5 prefers to stay away from this discussion. He considers macrophage and histiocyte as synonyms, defining them from the purely morphological point of view. Parish6 also considers macrophage and histiocyte as synonyms, emphasizing that the term histiocyte is usually reserved for macrophages that are bound to tissue. Citing Aschoff 2 again, histiocytes would be cells of the reticuloendothelial system that are located in conjunctive tissues. Morphologically, such cells show an oval or reniform nucleus with a cellular diameter varying from 10 to 25 mm, and a nucleo/cytoplasm ratio of 1:1. Macrophages, according to Doval and Toribio,7 are cells derived from the monocyte which leave the blood circulation. Through the process of differentiation they aquire a large phagocytic capacity.
In 1990, Foucar and Foucar8 used the expression Mononuclear phagocyte and immunoregulatory effector system (M-PIRE) to refer to the conjunction of mononuclear cells of the immune system, previously called the reticuloendothelial system.2 M-PIRE would consist of macrophages and dendritic cells (or acessory immune cells). The term histiocyte was used in reference to cells pertaining to the M-PIRE system (macrophages and dendrocytes).
The definition of terms adopted for histiocytic cells is found in summarized form in box 1.
Macrophages may be indistinguishable, by routine staining, from fibroblasts and endothelial cells, except for their location and phagocytic activity. Their diameters vary from 20 to 80 mm, and they have a vesicular nucleus, light pink and elongated, with the nuclear membrane clearly visible.9 Among the antibodies reacting with macrophages, Doval and Toribio7 cite MAC 387, CD11c (Ki-M1), CD68 (Ki-M1P, Ki-M6, Ki-M8, Kp-1, PG-M1), Max.1, Max.2, Max.3, Max.11 and HAM56. According to Wallace and Smoller,10 macrophages also react with the vimentine antibodies, factor XIIIa (only the alveolar macrophages) and CD4. The main function of macrophages is the phagocytosis of foreign bodies, possibly performing as cells showing antigens.7
Dendritic skin cells
Langerhans dendritic cells were identified in 1868 by Paul Langerhans and considered neural cells. Their histiocytic origin and immunological role related to skin have only recently been evidenced (Silberg-Sinakin et al., 1976, apud Teunissen et al., 1997).11
In 1982, the Nomenclature Committee of the Reticuloendothelial Society (Comitê de Nomenclatura da Sociedade Reticuloendotelial) (Tew et al., 1982, apud Wood et al., 1985)12 considers the dendritic cells of human beings as indeterminate cutaneous cells, intradigital paracorticals, folicular dendrites and Langerhans cells.
In 1975, Steinman, apud Doval and Toribio,7 identified a group of dintinct macrophage and lymphocyte cells in the epidermis of a rat with dendritic morphology, a low capacity for phagocytosis and a high power for activating native T-lymphocytes, named dendritic cells. According to Wood et al.,12 the dendritic cells probably share a common origin with macrophages and monocytes. In 1986, Headington13 identified a dermal cell in human beings with characteristics that suggest they hold an important immunological and phagocytic function, naming it dermal dendrocyte. Under the optical microscope, such a cell cannot be distinguished from a fibroblast, but immunophenotypically, it resembles the cells of the monocytic-macrophagic system.
Ever since then, many authors have studied dermal dendrocytes and their role in skin immunology.11,14-28
Doval and Toribio7 assume that such cells represent a single cell with various subtypes as well as distinct cells. According to the same authors, there exist various types of dendritic cells apart from Langerhans cells, namely type I (factor XIIIa+) and type II (CD34+) dermal dendrocytes and other extracutaneous cells, like folicular dendritic cells (S-100- and CD1a-, located in the lymphatic folicules), intradigital cells (S-100+ and Cdla-, located in the paracortical regions of the lymphnodes), splenic, synovial, thyrodial, cardiac, pulmonary and circulating (i.e. present in the blood) lymphoid cells, and those that are located in afferent lymphatic vessels, i.e. veiled cells.
More recently, Cuzzi-Maya et al.29 have described a novel type of dendritic skin cell, immuno-histochemically characterized by the expression of thrombomodulin and by the absence of markers for CD68, CD34 and factor XIIIa. Studying these cells in normal and psoriatic skin, the authors have suggested that the cells participate in the reparational process of tissues, jointly performing with type I dermal dendrocytes in the homeostatic regulation of the extravascular thrombin, under normal and pathological conditions.
Non Langerhans histiocytoses
Various names and definitions have been adopted for histiocytoses. The broadest ones consider the term histiocytosis as identifying a group of diseases characterized by the proliferation of cells of the mononuclear-fagocytic and dendritic system (van Furth, 1970, apud Goyal et al., 1998).30 Gianotti and Caputo,31 and Ringel and Moschella,32 among others, name them histiocytic syndromes and primary histiocytic dermatoses, respectively, limiting histiocytoses to those whose cause is unknown. Even adopting this more restricted concept, a few contradictions remain, because such distinct diseases, like dermatofibroma and sarcoidosis, fulfill the criteria for inclusion in the group, provided that the diseases included differ widely amongst themselves.
In accordance with the consensus reached by the Histiocytic Society, three groups of histiocytoses are separated,33 including those consisting of Langerhans cells, malignant cells and non Langerhans cells. In this paper, non Langerhans histiocytoses of particular interest for the dermatologist are examined (Box 2).
In these histiocytosis
groups, perhaps the most intriging, controversial and unknown ones are non Langerhans
histiocytoses. Various diseases fit this category. Most of them are rare, while
many others are dubiously confirmed, though all are considered idiopathic. Currently,
the following diseases with a predominantly cutaneous manifestation are accepted
into this group:31
- juvenile xanthogranuloma
- disseminated xanthoma
- papulous xanthoma
- reticulohistiocytoma and its systemic form, multicentric reticulohistiocytosis
- benign cephalic histiocytosis
- generalized eruptive histiocytosis
- progressive nodular histiocytosis
- sinus histiocytosis with massive lymphadenopathy
Dermatofibroma itself shows similarities with these diseases. However, it is thus classified to be better accepted as a benign tumor.
In spite of neither being idiopathic nor having rare cutaneous manifestations, Chu et al.33 include (familiar and reactive) erythrophagocytic lymphohistiocytosis in this group.
Ringel and Moschella32 propose another classification for the histiocytoses, in which three other groups are considered, including malignant, pseudomalignant and benign strains (Box 3). While having great prognostic use, this classification does not consider the nature of these diseases. It maintains diseases within a single group which are distinct from the point of view of their immunophenotypic origin.
The authors go on to propose classification based on its clinical manifestations (Box 4), maintaining the same problem found in the previously cited classification, i.e. bringing together diseases whose immunophenotypic origins and distinct etiologies are filed within a single group. By contrast, the latter is extremely useful to aid in formulating different diagnoses.
In spite of having only limited value for research ends and the study of the diseases, the two classifications remain very useful for investigating and conducting one case in particular.
Burgdorf 34 developed his own classification (Box 5), based on the Histiocytic Society Writing Group,33 which considers two additional groups, namely: the disease group related to indeterminate dendritic cells - indeterminate cell histiocytosis (S-100+, CD+ without Birbeck granules) - and the disease group related to antigen-processing dendritic cells in the lymphnodes - sinusal histiocytosis with soft lymphadenopathy (S-100+, CD1- without Birbeck granules).
More recently, Zelger et al.35 proposed a subclassification for non Langerhans histiocytoses, based on the histological, immunophenotypic and electron microscope aspects of the lesions (Box 6). This classification seems useful from the point of view of the histopathologic diagnosis differential as well as from the point of view of the study, owing to the correlation found by the authors between the optical microscope aspects and the electron microscope and immuno-histochemical findings.
Benign cephalic histiocytosis
Originally decribed by Gianotti et al.,36 this is a self-limiting disease clinically characterized by papulonodular, erythematous brownish lesions, varying from two to three millimeters in diameter. It especially affects children in their first year of life. Its lesions are commonly located on the scalp, possibly progressing in a descending movement until reaching the shoulders and upper limbs (MMSS), while always sparing the mucoses (Figure 1). Histologically, there is a predominance of vacuolated histiocytes and sparse lymphocytes, given that in older lesions the quantity of lymphocytes increases and some giant cells form. The infiltrate is well circumscribed and intimately related to the epidermis.37 In spite of differing from xanthogranuloma by the lack of lipids within its cells, Zelger et al.35 believe that benign cephalic histiocytes are a variant of the latter.
Described in 1905 by Adamson,38 xanthoganuloma is considered to be more common than non Langerhans histiocytoses, according to Hernandez-Martin et al.39 Most xanthogranulomas arise during the first year of life, albeit its observation upon birth is not rare. More rarely, its appearance during adult age may be observed, with a peak of incidence occurring between the third and fourth decades of life. Usually, xanthogranuloma appears as a well-delimited, unique or multiple yellow cupuliform papule with a diameter varying from five to 20 mm. As time passes, it becomes yellow-brownish with telangiectasias on its surface (Figure 2). The most common sites are the head and throat, despite of already being described over practically the whole body. It rarely affects the mucoses. In most case, xanthogranuloma is an exclusively cutaneous disease. Extracutaneous lesions are located, above all, in the eyes, lungs and liver.
Zvulonov et al.40 have confirmed the observation of the not unseldom association between xanthogranuloma, neurofibromatosis type I and chronic juvenile myeloid leukemia, a situation indicative of the need to investigate the possible underlying leukemia in children with xanthogranuloma and stigmas or family history of neurofibromatosis. Xanthogranuloma lesions usually regress after a period varying from three to six years, leaving an atrophied and hyperchromic scar. From the histopathologic point of view, xanthogranuloma is considered to be the standard for non Langerhans histiocytoses, appearing as a dense pleomorphic histiocytic infiltrate, with a predominance of vacuolated cells in the initial and later xanthomatoses. As the lesions grows older, it gets easier to identify characteristics, though non specific, of Touton-type multinuclear xanthomatosis cells in a crest-like disposition of its nuclei.
Newman et al.41 histopathologically and immuno-histochemically characterize a variety of non lipid xanthogranuloma that may be confused with melanocytic nevus or Langerhans histiocytosis. They concluded that, beyond the histopathology and S-100 proteine, the presence of auxiliary factor XIIIa assists in the differentiation between xanthogranuloma and these other entities.
Zelger et al.42 have not observed significant differences from the histologic point of view nor from the immuno-histochemical point of view, which would justify considering them as being distinct diseases.
Generalized Eruptive Histiocytoma
In 1963, Winkelmann and Muller43 described a histiocytosis that appeared as firm erythematous hyperchromic papules, dispersed over the trunk, face and surfaces close to the limbs, which measured from 3 to 10 mm, emerging through eruptive outbreaks. The mucoses are usually spared, as are the viscera. The disease tends to last several years and disappears spontaneously. Histopathologically, monomorphic histiocytic infiltrate may be observed in the superior and middle dermis, without spumous or gigantic cells, but with a few lymphocytes. Zelger et al.35 and Winkelmann44 consider the generalized eruptive histiocytoma as the initial undifferentiated state of various histiocytic syndromes, which may precede the classic presentation of xanthogranuloma, disseminated xanthoma, progressive nodular histiocytosis, reticulohistiocytosis or indeterminate cell histiocytosis. Padilla and Sierra45 consider multicentric reticulohistiocytosis and generalized eruptive histiocytoma as variants of a single entity.
Sinusal histiocytosis with massive lymphadenopathy
Described in 1969 by Rosai and Dorfman46 as a benign and self-limiting disease, characterized by cervical lymphadenopathy usually accompanied by fever, neutrophil leukocytosis and polyclonal hypergammaglobulinemia. The lymphadenopathy is bilateral, painless and massive, which can also affect other lymphatic chains. Cutaneous manifestations occur in 10% of cases, usually with erythematous brownish or erythematous yellowish papules, localized or disseminated, with no fixed site (Figure 3).47 It is rarely observed after the second decade of life and has no predilection for any given sex. In spite of the fact that most cases have been observed in poorer areas of the planet, no etiological agent has been isolated. Spontaneous resolution usually occurs within a few years, in spite of certain cases being chronic and fatal. Optical microscopy of the skin lesions reveals dense dermal infiltrate with histiocytes mixed with plasmocytes and lymphocytes. Histiocytes usually have a spumous appearance that can be multinucleated and effect emperipolesis. In emperipolesis, as opposed to lymphophagocytosis, the lymphocytes are captured but not digested by histiocytes and are found intact within the latter. Lymphnodes show capsular fibrosis and dilated nodal sinuses filled with spumous histiocytes.
Both its immunohistochemical and ultramicroscopic profile (S-100+, CD1- without Birbeck granules) and primordial (lymphnode) site lead one to believe that massive lymphadenopathy sinus histiocytosis is a proliferation of intradigital dendritic cell processors of antigens in the lymphnodes.34 Nonetheless, this is not a definite conclusion. As suggested by Perrin et al.48 and Paulli et al.49 in their papers, its origin overlap with Langerhans histiocytosis and dermal dendrocytes, respectively.
Described in 1980 by Winkelmann,50 it is identified by papulous, plane and yellowish lesions, occuring more frequently on the forearms, neck, trunk and extremities of normolipidemic individuals. Initially considered specific to adults, papulous xanthoma may be observed in children as well, especially from the age of five onward.37 From the histopathologic point of view, the lesions show an abundance of xanthomized histiocytes from the very onset of disease, located perivascularly without fibrosis or giant cells. Its course is typically chronic and always benign.31
Chen et al.51 have detected the presence of the CD68 marker in xanthomatous cells and an absence of S-100 protein, CD1a, CD56, lysozyme, alpha-1 antitrypsine and factor XIIIa.
Winkelmann44 believes that papulous xanthoma could represent a variety of adult xanthogranuloma.
According to Magnin et al.,52 some cases were associated with disproteinemias, leukemias, multiple mieloma or MR.
It was described in 1938 by Montgomery and Osterberg53 as a rare and benign form of lymphocytosis affecting the skin and mucoses. The lipid profile was unchanged (in spite of a transitory increase in cholesterol and triglycerid serum values that may be observed). It is associated with insipid diabetes in 39% of cases.54 According to Caputo et al.,55 the eruption of hundreds of papules, erythematous brownish at the start, which evolve into very yellow lesions, symmetrically spreading on the trunk, face, proximal extremities and folds. They show the typical appearance of this disease. Forearms, conjunctivas, lips, pharynx and larynx may be infiltrated by yellow or erythematous plaques, though other organs are rarely affected. Notwithstanding the fact that the disease may occur at any age, 60% of cases appear prior to the age of 25. Cutaneous lesions as well as insipid diabetes are spontaneously resolved over a few years time. The initial histopathological aspect consists of histiocytic infiltrate with spumous and inflammatory cells, with spumous cells predominating later. Its immuno-histochemical profile consists of xanthomatose cell factor XIIIa and CD68 positive, and CD68 positive giant cells, both of the CD68 cells are also negative for protein S-100, MAC387, lysozyme, alpha-1 antitripsine, CD34 and LN3 (HLA-DR).56
Initially described by Zak57 in 1950, this disease consists of small, usually solitary papules that are never eruptive. It is clinically similar to a dermatofibroma and shows a histologic condition considered as indistinguishable from MR. Internal organs are not affected, nor is there an association with malignant neoplasias or other diseases.
Zelger et al.58 have noted a series of differences between reticulohistiocytoma and MR. Reticulohistiocytoma commonly affects young men, with no preference for a site on the body. Histologically, infiltrate can be denser and more circumscribed than for MR, which is an immunohistochemical marker due to factor XIIIa and muscular actine (HHF35), in general negative in MR. These authors have concluded that reticulohistiocytoma is closely related if not identical to xanthogranuloma disseminatum.
Snow and Muller59 found similar histopathologic and immuno histochemical results when comparing the solitary reticulohistiocytoma with MR. They concluded that the opposing poles of a single nosologic spectrum end up corresponding.
(generalized cutaneous reticulohistiocytosis)
According to Gianotti and Caputo,31 this expression should be used to describe a disease limited to the skin, and characterized by symmetrical and disseminated papulonodular eruption, (Figure 4), which shows progressive lesion development, typically involving the face and converging to give an aspect of facies leonina. Notwithstanding the credit Caputo gives to Taunton et al.60 for having been the first to provide a description of the disease, four years earlier Rodríguez et al.61 had extensively but unsucessfullly sought an etiological agent for a case fitting this definition. They had named it nodular cutaneous reactive histiocytosis. Meanwhile, the first case had been described by three Brazilians, namely Absalom Lima Filgueira, Sylvio Fraga and Antônio de Souza Marques in 1969, under the heading of rheumatoid histioytomatosis.61b While studying a novel case, Piette et al.62 considered this entity as an exclusively cutaneous variety of MR, naming it multiple reticulohistiocytoma. In 1982, Winkelmann et al.63 reported a similar case, considering it as an intermediary stage between generalized eruptive histiocytoma and MR. In his book, Text Atlas of Histiocytic Syndromes. A Dermatological Perspective, Caputo37 considers progressive nodular histioctyoma as an entity apart from generalized cutaneous reticulohistiocytosis, in relation to which it is classified as a variety of MR.
Multicentric reticulohistiocytosis (MR)
Multicentric reticulohistiocytosis is a proliferative idiopathic histiocytosis disease, usually characterized by severe cutaneous-articular affliction. It customarily disappears spontaneously in the course of six to eight years. Sequelae are frequent after its cure. Its onset is generally insidious and progressive. Following periods of aggravation and improvement, rapid progression in severity of articular inflation frequently reaches an incapacitating athritis, which may be considered one of the characteristic aspects of the disease. Apart from the articular symptoms oscillating during the disease course, a severe deforming arthritis, known as mutilating arthritis, becomes the prominent disease manifestation in almost half of all cases (45%), according to Barrow and Holubar,64 and in 11% of cases, according to Luz.65
Since Weber and Freudenthal 66 first described MR in 1937, less than 200 cases have been published in worldwide literature. A few cases are believed to have been diagnosed but not published. An unknown though significant number of cases certainly fail to be diagnosed, mainly in Third World countries. This is believed so because most cases published stem from developed countries. According to the alternative hypothesis, i.e. in which MR is a consequence of poor social development, supporting evidence is simply lacking despite the fact that it cannot be dismissed. The observation of the growing number of cases described, mainly in Third World countries, shows diverse racial and social origins. This sustains the possibility of there being a relevant contingency of MR carriers whose diagnosis is confirmed, especially in the most impoverished areas of the world.
The identification of the reticuloendothelial nature of MR by Caro and Senear notwithstanding, eight year earlier three Brazilians, Hildebrando Portugal, Francisco Fialho and A. Milano, had defined the reticuloendothelial origin of MR through confirmation of the phagocytic capacity of its cells. It is interesting to note that given the fact that this article had been published in an Argentine review, authorship of the paper is still at times credited to neighboring country researchers, instead of to Brazilians.
Small papules arranged in linear order around the nails appears as the beaded neckless (Figure 5), initially observed by Barrow. The high frequency of this appearance in MR and lack of knowledge as to the presence of these lesions in other diseases justifies the impression made of them as being MR pathognomic.69 The presence of this pattern must always be search for in patients suspected of carrying MR. Until otherwise disproved, its presence seems to be a sure indicator of this diagnosis.
It is interesting to report that some authors, who prefer to consider MR, progressive nodular histiocytosis and solitary reticuloendothelial histiocytosis as part of the spectrum of a single disease, are of the opinion that reticulohistiocytosis would only differ in its proportion of afflictions, that is, its systemic cutaneous form, generalized and isolated, respectively.70,71
A more complete revision of multicentric reticulohistiocytosis was already published in this review.
Other correlated or disputedly histiocytic diseases included as non Langerhans histiocytoses
Self-healing congenital reticulohistiocytosis
This variant was originally described by Hashimoto and Pritzker in 1973.72 They characterized it as histopathology as well as an acumulation of mono- and multinucleaded cells with cytoplasm showing the ground glass aspect in the middle and superior dermis, and invading the epidermis. This affection is characterized by asymptomatic, firm, erythematous brownish papules, dispersed over the skin, but breaking out on the face and scalp. They are present ever since birth and regress in turn at one year of age (Figure 6).73 Despite what its name may suggest, the presence of typical granules of Langerhans cells revealed by the electron microscope, i.e. Birkbeck granules, and of S-100 protein revealed by the immunohistochemical test, classifies the self-healing congenital reticulohistiocytosis as Langerhans Cell Histiocytosis.
Indeterminate cell histiocytosis
It appears clinically and histopathologically indistinguishable from generalized eruptive histiocytosis. Nonetheless, immunohistochemically it evidenced positivity for S-100 and CD-1. This is one aspect among others that led Sidoroff et al.76 to consider it as being a proliferative disease of indeterminate cells, imprisoned locally as veiled cells prior to migrating from the skin toward the paracortical areas of the lymphnodes. The description of the first case is attributed to Wood et al.76 Indeterminate cell congenital histiocytoma seems to represent the congenital variant of indeterminate cell histiocytosis. Levisohn et al.77 also attribute its origin to indeterminate cells, recalling that they may represent either precursors of Langerhans cells or its more mature forms.
Non Langerhans histiocytosis with defined causes
- Familiar histiocytic dermatoarthritis
In 1973, Zayid and Farraj78 described a syndrome clinically appearing to be indistinguishable from MR from the cutaneous-articular point of view. On the other hand, it differed from MR by the presence of ocular lesions and the absence of typical multinuclear cells with material resembling ground glass, by its onset during infancy or adolescence and mainly by its familiar characteristics. In a manner similar to the next two diseases described, its (autosomic dominant) hereditary nature excluded it from the histiocytosis group when the idiopathic character of the latter is taken into consideration.
Based on the clinical, histopathological and similar ultra-structural aspects observed in two cases of familiar histiocytic dermatoarthritis with MR, Valente et al.79 suggest that these diseases explain a single entity.
- Familiar dermochondrocorneal distrophy
According to Ringel and Moschella,32 this was described by François in 1949. It is characterized by the presence of cutaneous nodules on the nose, ears and hands, and associated with arthritis and corneal opacities. It is autosomal recessive.
- Familiar erythrophagocytic lympho-histiocytosis
According to Roper and Spraker,80 this is an autosomic recessive disease that customarily affects children during the first three years of life. Clinically, it resembles malignant histiocytosis. Similar to the latter, it generally occurs with fever, irritability, hemorrhages, heptomegaly and laboratorial evidence of hepathic dysfunctioning. Hypertriglyceridemy with a lack of alpha-lypoprotein may also be found. According to Ansbacher et al. (1983), apud Ringel and Moschella,32 this finding may serve as a marker of early disease. Association with humoral and cellular immunity defects is common.81 Death tends to occur within two months through diffuse infiltration of the reticuloendothelial organs by histiocytic cells with phagocytic activity and cytologic benignity. On the skin, it may be manifested by generalized erythematous eruptions with papules and vesicles.82
- Erythrophagocytic lympho-histiocytosis associated with the virus
This is clinically and histologically similar to familiar erythrophagocytic lympho-histiocytosis, though differing from the latter by its benign course, broader age range (affecting even adults) and its frequent association with viral agents. Non-viral infections may also be complicated by an erythrophagocytic syndrome.83 Similar to the aforementioned three hereditary entities, the presence of a defined etiology excludes it from the primary histiocytosis group.
Histiocytoses controversially accepted as autonomous entities
- Macrophage activation syndrome
Despite being unrelated in any way with a histiocytosis, the concept of this syndrome may facilitate the understanding of the latter. In a review of the topic by Béraud et al.,84 macrophage activation syndrome is clinically expressed by a continuously high feverish condition, a decrease of the general state with asthenia and anorexia, hepatoesplenomegaly, lymphadenopathy and generalized edema, which may disguise weight-loss. Cytophagic paniculitis represents its specific manifestation (described below). Macrophage activation syndrome may occur as complication of a series of diseases, such aa AIDS, lymphomas and leukemias, erythematous lupus and chronic juvenile arthritis, diverse infections and immunosuppressive treatments. Macrophage activation appears to result from the release of diverse cytocines produced by defective or reactional lymphocyte-T in an infectious process. Tumoral necrosis factor alpha appears to occupy a significant place in the induction of characteristic anomalies of this syndrome.
- Cytophagic paniculitis
Described in 1980 by Winkelmann and Bowie, apud Winkelmann,44 this syndrome is characterized by a condition manifesting fever, pancytopenia, subcutaneous nodules and severe hepathic dysfunctioning, usually resulting in hemorrhagic diasthesis. The histological test of these nodules evidenced profound paniculitis with cytologically benign and phagocytically active histiocytes, beside lymphocytes and plasmocytes. Despite the fact that the often fatal course of the disease and the substitution and non-infiltration of the reticuloendothelial organs by histiocytes justify the idea that a malign entity is being dealt with, the lack of atypical cytologic traits would exclude it from the malignant histiocytosis group. Its nosological position remains controversial, as well as its acceptance as an autonomous entity.
- Necrobiotic xanthogranuloma
In accordance with Johnston et al.,85 Kossard and Winkelmann described this chronic and progressive process in 1980 as characterized by papules and nodules, varying from purple to skin-color and progressing slowly through infiltrated plaques measuring from 0.3 to 25 cm in diameter. Its most common site is the periorbital region. The mature aspect of the lesion is quite similar to that of lipoidic necrobiosis lesion, with central atrophy, telangiectasias and yellow coloring. The histopathologic condition is also quite similar to lipoidic necrobiosis, differing from the latter mainly by its higher amount of spumous cells. Most cases of necrobiotic xanthogranuloma is associated with paraproteinemia, especially mieloma, amiloidosis and macroglobulinemia. Discussion continues as to whether necrobiotic xanthogranuloma represents a specific type of non Langerhans cell histiocytosis, a mere variation of classic xanthogranuloma or, as prefered by Johnston et al.,085 the severest pole of a spectrum of diseases stretching from anular granuloma to necrobiotic xanthogranuloma, including lipoidic necrobiosis.
With the exception of Langerhans cell histiocytoses, whose origins are well documented, histiocytoses consist of a confused and peculiar group of heterogenic diseases that show a common non neoplastic proliferation of histiocytes. For a better understanding of these entities, it is necessary that the origin of every single disease belonging to this large nosologic group be precisely determined. The immunohistochemical test seems to be a useful technique for identifying the proliferative cell that causes each of these histiocytes. It is quite probable that some histiocytes do not represent autonomous entities, but mere variants. The identification of the proliferative histiocyte type in each of the histiocytes allows them to be correctly positioned nosologically, thereby opening a space for elucidating its etiological mechanisms and, consequently, for directed and more efficient therapies. It is in this sense that the present authors are continually working, hoping as they are that other medical professionals will become interested in trying to elucidate this intricate and fascinating field of study.
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Flávio Barbosa Luz
Rua Desembargador Izidro, 28 sala 606 - Tijuca
Rio de janeiro RJ 20521-160
Telefone (21) 2298-2013
Received in January, 02nd of 2002.
Approved by the Consultive Council and accepted for publication in July, 31st of 2002.
* Work done at Dermatology Service of "Universidade Federal Fluminense" and "Universidade Federal do Rio de Janeiro".