Histiocytic syndromes: A review

JOURNAL

of the

AmeRICaN ACaDemy OF

DerMaTOLOGY VOLUME 13

Continuing

NUMBER 3

SEPTEMBER, 1985

medical education

Histiocytic syndromes: A review Ferdinanda Gianotti, M.D. ,t and Ruggero Caputo, M.D. Milan, Italy Histiocytoses represent a large, puzzling group of rare skin diseases. The purpose of this review is to schematically outline the clinical, histologic, and ultrastructural features of the most important histiocytic syndromes and to provide the pertinent differential diagnoses. For convenience, we have followed the criterion suggested by Winkelmann, I distinguishing these conditions into X and non-X. Among the non-X histiocytoses the self-healing forms have been treated first; the progressive forms follow. (J AM ACAD DERMATOL 13: 383-404, 1985.) Histiocytoses are disorders resulting from proliferation of cells of monocyte-macrophage lineage, Histiocytic syndromes of varying degrees of differentiation, localization, course, and prognosis occur in all age groups. They represent a large, puzzling group of skin diseases. These conditions may be more or less conveniently distinguished into self-healing or progressive disorders (i.e., benign or malignant or, as suggested by Winkelmann, 1· X or non-X histiocytoses). The purpose of this review is to schematically outline the clinical, histologic, and ultrastructural features of the most important histiocytic syndromes on the basis of both our personal experience and an accurate review of the literature and to provide the pertinent differential diagnoses, For convenience we will follow the criteria suggested by Winkelmann, 1 discussing first the clinical forms

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Abbreviations used BCH benign cephalic histiocytosis EG eosinophilic granuloma GEH generalized eruptive histiocytoma HSC Hand-Schiiller-Christian (disease) HX histiocytosis X JXG juvenile xanthogranuloma LG Langerhans granules LSD Letterer-Siwe disease MR multicentric reticulohistiocytosis PX papular xanthoma SHML sinus histiocytosis with massive lymphadenopathy SHR self-healing reticulohistiocytosis

of histiocytosis X and then the non-X histiocytoses. HISTIOCYTOSIS X

The CME articles are made possible through an educational grant from Syntex Laboratories, Inc,

From the Istituta di I Clinica Dermatolagica e Dermatalogia Pediamca, Universitil di Milano. Accepted for publication Nov. 29. 1984. No reprints available.

Histiocytosis X (HX) is a disease of unknown cause and is characterized by a proliferation of a distinct histiocytic cell type (containing Langerhans granules in the cytoplasm). HX includes three clinical forms 2: Letterer-Siwe disease (LSD),

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Fig. 1. Fig. 2. Fig. 3. Fig. 4. Italy.)

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LSD. Characteristic papular eruption on scalp. LSD. Papular, purpuric, crusty eruption on trunk. LSD in octogenarian. EG. Periorificial noduloulcerative lesions. (Courtesy Professor A. Finzi, Milan,

Hand-Schuller-Christian (HSC) disease, and eosinophilic granuloma (EG). These three forms may best be regarded as being, respectively, the acute disseminated, the

chronic progressive, and the benign localized forms of HX. When the disorder involves at least two tissues or organs, the term disseminated histiocytosis X has been proposed. 3

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Letterer-Siwe disease. LSD begins within 6 months of the patient's life in one third of the cases and before 2 years of age in most of the other cases. About twenty congenital cases 4 and thirty adult cases 5-8 have been reported. A familial incidence has been documented. 4 Cutaneous manifestations are present in about half of the cases at the onset, whereas they occur in almost all fatal cases 3,9 and are absent in one fifth of the nonfatal cases. 9 The morphologic features of the cutaneous lesions are characteristic (Figs. 1 to 3); their uniqueness is easily appreciated, and they may represent the earliest sign of disease. The typical lesion is a small, translucent papule (1-2 mm in diameter), slightly raised, roseyellow in color, and generally located on the trunk (Figs. 2 and 3) and on the scalp (Fig. 1). * The lesions may then begin to scale and may become crusty, pustular, and even purpuric (Figs. 2 and 3). On the scalp the lesions tend to merge, displaying a seborrheic-like appearance (Fig. 1). Skin eruptions appear in successive crops. Meanwhile, the general condition may worsen; petechiae may appear On the palms and soles and in nail beds as purpuric striae. Ulcerations of the mucous membranes may also be observed. Occasionally, forms of disseminated HX show xanthomatous cutaneous lesions that clinically and histologically mimic other xanthomatous disorders. These manifestations may be considered a distinct clinicopathologic entity. 10 Pulmonary involvement can be detected in more than half of the affected children and may be asymptomatic. Marked hepatomegaly is a frequent complication and is a prognostically unfavorable sign found in two thirds of the cases, particularly when jaundice and other clinical or biologic signs of hepatic failure appear. 3.9 Less than one third of children with splenomegaly survive. 9 Lymphadenopathy is rarely prominent but has been noted in one fourth 9 to three fourths II of fatal cases. In the later stages of the disease, bone lesions occur in more than 60% of the cases and more frequently affect flat bones, vertebral bones, and

cranial bones. These osteolytic lesions, whose presence can be marked by pain and functional impairment, are generally multiple and appear gradually. Their presence is more frequent in cases with a favorable course. 3 Teeth may be lost precociously. When spontaneous thrombocytopenia and severe anemia occur, death is almost certain,3.12 especially if splenomegaly coexists and osteolytic lesions are absent. Intercurrent infections are frequent. The course is usually fatal; however, some patients have been reported to recover spontaneously.3,11 A very early onset is often indicative of severe disease. 3 •9 . 13 For determination of a reasonable prognosis, several classifications that take into account various parameters have been outlined by Nezelof et aP (prognosis relates to number of organs involved), by Oberman '4 (prognosis relates to bone and soft tissue involvement), and by Lahey l5 (prognosis relates to age of appearance and number of involved tissues). The prognosis of LSD in the adult does not seem to be significantly influenced by treatment. 8 Hand-Schuller-Christian disease. HSC disease begins between the second and sixth years of life in 70% of cases and before the age ano in 91 %. In less than 4% it occurs after the fifth decade. 16 The disorder is characterized by the following three findings: bone lesions, diabetes insipidus, and exophthalmos, *.17 although it is uncommon for aU three manifestations to be seen together in the same patient. Bone lesions are the most frequent manifestations (80% of the cases). They preferentially in-' valve the calvarium, especially in the temporoparietal region, where the infiltrate causes welllimited osteolytic areas that merge to give a typical "map" appearance. Osteolysis of the lower maxillary bones is also frequent, and therefore on xray the teeth appear to be "floating" in the mouth. JR Bone lesions of the mastoidal region may cause otitis media. Diabetes insipidus is present in over 50% of the cases and is easily controlled by vasopressin (Pitressin).

*Gianolli F, Caputo R. Ermacora E: Histiocytose X dans I'enfance: Importance de ses manifestations cutanees. Med et Hyg 33:754757,1975.

*Gianotti F, Caputo R, Ennacora E: Istiocitosi X dell'infanzia: Terapia delle fanne disseminate can vinblastina. Boll 1st Derm S Gallicano 9:111-112, 1974.

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Fig. 5. HX, proliferative stage. Skin biopsy shows large histiocytes with abundant eosinophilic cytoplasm and indented nuclei (HX cells). Some of these cells are distinctly outlined and separated by edema fluid. (x 310.)

Exophthalmos usually appears later on, is present in 10% to 30% of the cases, and may be unilateral or bilateral. In our opinion the infrequency of this sign makes its diagnostic relevance questionable. Cutaneous lesions occur in about one third of the cases. In the early stage the papular manifestations have the same morphologic characteristics as those observed in LSD. In the later phases, skin lesions are fewer in number and are grouped on the medial aspects of the chest, back, and temporoparietal areas. Mucous membranes may be involved. Pulmonary infiltrates can be found in 20% of the cases, whereas hepatomegaly and lymphadenopathy are rare. The clinical course is long term. In the absence of therapy about 50% of the patients die of other causes. The same prognostic evaluation parameters as for LSD can be adopted.3.14.15 Eosinophilic granuloma. EO is the localized, benign form of HX. It occurs between the fifth and thirtieth years of life and is more common in male patients. *The typical granulomatous lesions affect the bones in the following decreasing order of frequency'9.2o: cranial vault, ribs, vertebral col*Gianotti F, Caputo R, Ennacora E: Istiocitosi X dell'infanzia: Terapia delle fonne disseminate can vinblastina. Boll 1st Derm S Gallicano 9: 111-112, 1974.

umn, pelvis, scapulae, and long bones. The lesion is usually single and may go undetected unless spontaneous fracture and/or otitis media occurs. Cutaneous lesions*·B.17.21 are rare but may be of the nodular-ulcerative type and may involve the periorificial region and the mucous membranes (Fig. 4). Lymph nodes may be involved, especially in the laterocervical, submaxillary, axillary, and inguinal regions and may be the first sign of the disease. The lungs may exhibit poorly defined nodules, regressing either spontaneously or with therapy, leaving fibrosis. The course is chronic, but the prognosis is good because the disease responds well to treatment. Histopathologic findings

The histologic features observed in HX are of three types: proliferative, granulomatous, and xanthomatous. 22 Each type of pathologic condition may arise as such, but in the early stage most lesions consist almost exclusively of proliferative histiocytic cells. The xanthomatous and granulomatous forms appear in the subsequent chronic stage. Different types of histologic reactions may be simultaneously found in the same subject. The linking histologic element of these lesions is the *See footnote on opposite page.

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Fig. 6. HX, xanthomatous stage. Skin biopsy shows foamy cells intermingled with HX cells. (x 310.)

Fig. 7. HX, granulomatous stage. Skin biopsy shows extensive aggregation of HX cells and inflammatory cells with some multinucleated histiocytes. (x 310.)

typical "HX cell" (Fig. 5), a cell easily identified and differentiated from the nonspecific elements of the infiltrate by its size and its configuration. This cell is about four to five times larger than small lymphocytes, has an irregular and vesiculated nucleus, is often reniform, and has abundant, slightly eosinophilic cytoplasm. In the upper dermis of the early lesions, HX cells are typically separated by edema (Fig. 5), whereas in the lower dermis their cell membranes

coalesce. Cytologic examination of these cells is easily performed by scraping an early papule. * Lipid accumulation (Fig. 6) in old, persistent lesions appears as sudanophilic intracytoplasmic droplets seen within histiocytes (foam cells) intermingled with HX cells. This lipid accumulation is considered to be a late secondary phenomenon. The granulomatous reactions consist of an ex*See footnote on opposite page.

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Fig. 8. HX. Immunoperoxidase staining with rabbit anticalf-brain 8-100 antibody demonstrates strong and remarkable activity in HX cells. (X 125.)

tensive aggregation of HX cells with some multinucleated histiocytes (Fig. 7), as well as with various numbers of eosinophils, generally in clusters. Neutrophils, lymphocytes, and plasma cells may also appear in the infiltrate. lmmunoperoxidase staining with a rabbit anticalf-brain S-IOO antibody demonstrates strong and remarkable activity in HX cel1s23 (Fig. 8). The xanthomatous lesions (Fig. 9) that appear in clinically cured subjects (Le., after discontinuance of therapy for a long time) do not contain any HX cells or Touton giant cells, but giant cells with vacuolized cytoplasm and occasionally multinucleated cells are present. Anti S-loo staining is negative. These lesions are regarded 10 as a distinct clinical entity and should be differentiated from juvenile xanthogranuloma, papular xanthoma, and xanthoma disseminatum. Ultrastructural findings

Electron microscopic study shows that approximately 50% of the histiocytes of all three forms of HX contain Langerhans granules (LG)24.25.26.27 (Fig. 10; Table I).

The HX cells differ morphologically from the Langerhans cells, as follows: 1. The LG may be long, are more frequently attached to the plasma membrane, and are clustered together. 28 2. The LG may exhibit a fuzzy coat. 26,29 3. The LG may be present within the nuclei as the result of abnormal mitosis. 30 4. In the cytoplasm of HX cells, in addition to LG, comma-shaped bodies have also been found. 28 With the use of monoclonal antibodies, HX cells are OKT6-positive31 .33 (Fig. 10). Treatment

Disseminated HX is usually treated with chemotherapy (vinblastine sulfate), *.34.35 corticosteroids being added in severe cases. Vinblastine is given intravenously, at doses from 0.1 to 0.2 mgt kg once weekly as long as the cutaneous and mucous membrane lesions remain (normally 1 to 3 *Gianotti F, Caputo R, Ermacora E: Istiocitosi X delJ'infanzia: Ter· apia delle forme disseminate can vinblastina. Boll 1st Denn S Gi1Ilicano 9:111-112,1974.

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Fig. 9. HX. Xanthomatous lesions appearing in clinically cured patients do not contain any HX cells, but giant cells with vacuolated cytoplasm are present. (X 125.)

Fig. 10. HX. Immunoelectron microscopy demonstrates dermal OKT6-positive HX cells with LG, which are frequently attached to plasma membrane. (X 15,000.)

months). Readministration of the alkaloid should be instituted only when new skin lesions appear. Of the nineteen children treated by us according to this approach, eighteen presently no longer require therapy. Recently, good results have been obtained with daily injections of crude calf thymus extract. 13 Diabetes insipidus is unaffected by the antineoplastic therapy but is vasopressin (Pitressin) sensitive. Surgery and x-ray therapy are effective on bone and skin lesions of EG.

Differential diagnosis

Skin lesions of disseminated HX are clinically similar to those of seborrheic dermatitis, cutaneous moniliasis, miliaria, Darier's disease, and lichen nitidus. Diagnosis may be promptly confirmed by a cytologic examhlation performed by scraping an early papule. Chronic and xanthomatous lesions of HX differ from nodular urticaria pigmentosa in that the latter lesions become urticarial immediately after rubbing and from benign cephalic histiocytosis

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Table I. Cytoplasmic markers in histiocytic proliferations of skin Lysosomes

LG

HX SHR SHML BCH JXG PX Xanthoma disseminatum GEH MR Progressive nodular histiocytosis

Dense and Regularly Comma- Pleomorphic shaped cytoplasmic multivesicular laminated inclusions bodies bodies bodies

+ +++ + ++ ++ +++ + + -

+++ +++

(BCH), juvenile xanthogranuloma (JXO), sinus

histiocytosis, generalized eruptive histiocytoma (OER) , and papular xanthoma (PX) because of their different localization and their lack of HX cells and negativity with anti-S-lOO staining. Self-healing reticulohistiocytosis (SHR) is distinctive for its firm red-brown large nodules, its short duration, and its confinement to the skin. In granuloma faciale the presence of soft violaceous plaques located on the face distinguishes it from EG. NON-X HISTIOCYTOSIS Self-healing reticulohistiocytosis SHR36.42 is a rare, rapidly self-healing, congenital or perinatal disease described by Hashimoto and Pritzker. 36 SHR is characterized by the appearance, at birth or during the first few days of life,42 of mUltiple disseminated, elevated, firm, red-brown nodules that may be large (Fig. 11). These lesions can grow in size and number in the first few weeks of life and then form brown crusts that peel off and leave whitish atrophic scars. Mucous membranes are always spared and visceral lesions are not detectable. No hematologic abnormalities have been observed except in one case42 (neutropenia, marked lymphocytosis). Spontaneous regression occurs within 2 to 3 months and lesions never recur. Physical and mental development is normal. No therapy is required. Histologically (Fig. 12) the infiltrate appears to

+ +++ + + ++ + + +++ ++ ++

+ +++ -

-

-

-

+++ -

+

Myeloid bodies

+ + + + ++ ++ ++ + +++ +

Fatty droplets without Unique limiting phagosomes membranes -

+++ +++ -

++ +++ +++ +++ + +

consist mostly of large mononucleated or multinucleated cells located in the upper and mid dermis or in the deep dermis. The epidermis is usually infiltrated by these cells and is often ulcerated. The nuclei of the cells forming the infiltrate exhibit irregular contours but may also be kidney-shaped like HX cells. The cytoplasm is either acidophilic or has a ground-glass appearance. Portions of the cells may be positive for periodic acid-Schiff stain and diastase resistant. An admixture of lymphocytes and eosinophils is always present in the infiltrate. Reticulum fibers are increased around the histiocytes. About 20% of the histiocytic cells are positively stained with S-100 antibodies. * Under the electron microscope the infiltrate appears to consist mainly of two cell types (Table I): (1) cells containing LG (10% to 25% of the tumor cells)36.41.42 and (2) large histiocytes containing dense bodies and regularly laminated bodies 28 .41 often clustered together. The presence of S-IOO-positive cells and of cells containing LG may suggese.41 that this disorder belongs to the group of HX. Differential diagnosis. The absence of urtication and, as shown by histological study, of mast cells rules out urticaria pigmentosa. The nodular lesions of JXG can be present at birth. However, they rapidly become yellow, tend not to ulcerate, and heal spontaneously in several years (but never *Unpublished data.

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in a few months). Histologically, the lesions are composed of multinuclear giant cells and foamy cells; S-100 protein-staining cells are absent, and no cells containing LG are detected by electron microscopy. The eruption on BCH generally begins when the patient is 6 to 12 months old and is localized on the head. S-100 protein-staining cells are absent, and no cells containing LG are detected by electron microscopy. The differentiation between SHR and some nodular forms of HX may be difficult, since the two forms are similar histologically, immunohistochemically, and ultrastructurally, both showing the presence of LG and positive S-100 protein staining. SHR is distinctive in that the skin alone is involved, and the lesions are rapidly self-healing. Benign cephalic histiocytosis BCH is a self-limited disease that is preferentially localized on the scalp. It has been observed by Gianotti et a143 -45 and Barsky et al 46 in eight children in the last few years. The eruption generally begins in the second half-year of life with erythematous, yellow, papulonodular lesions that are slightly raised, 2 to 3 mm in diameter, and scattered on the upper part of the face (Fig. 13). Other lesions subsequently appear over the whole head, the auricles (particularly on the posterior side), the occipital region, and the neck; a few other lesions may appear on the shoulders and arms. Mucous membranes are always spared. After a few years (2 to 5) every papulonodular lesion becomes flat, leaving an atrophic, roundish, pigmented macula. Laboratory tests and x-ray investigations never show any remarkable changes. Somatic and mental development is normal. Histologically (Fig. 14), early lesions show a circumscribed infiltrate closely attached to the lower surface of the epidermis, which is thinned and flattened. Most of the cells within the infiltrate are histiocytes having a pleomorphic nucleus, with pale chromatin and light cytoplasm, that is sometimes glassy in appearance. Lymphocytes that are either scattered or grouped among the histiocytes and a few eosinophils may be found. In the dermis, reticular fibers are abundant, whereas no fat, mucopolysaccharide, or lipid is observed in the histiocytes with specific stains. Older lesions con-

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tain a few giant cells with peripheral nuclei and without lipids, and they contain many more lymphocytes. S-100-positive cells are absent. * Under the electron microscope28 the cytoplasm of about 20% of the histiocytes forming the infiltrate contains clusters of comma-shaped bodies (Fig. 15). The comma-shaped bodies are formed by two electron-dense membranes of approximately 60 A, separated by a light space of about 80 A. Where the infiltrate is more dense, desmosome-like junctions may be observed among the histiocytesY These cells always lack fatty droplets, regularly laminated bodies, and LG (Table I). Differential diagnosis. BCH can be differentiated from JXG (particularly the small nodular type), in which the nodules are pleomorphic and not limited to the head and neck. Histologically the latter nodules appear to be composed of many multinucleated giant cells and foamy cells. Electron microscopy demonstrates lipid droplets without limiting membranes in the cytoplasm of the macrophages. The nodular type of urticaria pigmentosa is distinguishable because of the wheal that immediately follows after the lesions are rubbed; mast cells are an obvious histopathologic marker. The lichenoid form of sarcoidosis can be diagnosed by its islands of epithelioid cells permeated and surrounded by reticulum fibers. GEH is distinguishable because of the age of onset (mainly adults) and of the sites involved. Electron microscopy demonstrates many dense and regularly laminated bodies, clustered together in the macrophages. PX can be differentiated because the lesions are widespread and show foamy cells and Touton giant cells even in the early stage. Histiocytosis X, especially the chronic disseminated form (HSC disease), is distinguishable because its papular lesions spread to the scalp and the trunk. Histopathologic study, S100 protein staining, and electron microscopy confirm the diagnosis. Juvenile xanthogranuloma JXG48 is a benign, self-healing disorder of infants, children,49.5o and occasionally adults (twenty-five adult cases collected from the *Unpublished data.

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literature8 ,49). It is characterized by yellowish nodules located in the skin and other organs and consisting of an infiltrate of histiocytes with a progressively greater degree of lipidation in the ab~ sence of a metabolic disorder. JXG may be present at birth (30% of the cases) or may appear within the first 9 months of life (other three fourths of the cases).51,52 Clinically, two forms can be distinguished 51 : a small nodular form and a large nodular form. The small nodular form (Fig. 16) is characterized by numerous (up to 100) firm, hemispheric lesions, 2 to 5 mrn in diameter, that are red-brown at first and then quickly turn yellowish. These lesions are irregularly scattered throughout the skin but are mainly located on the upper part of the body. Mucous membranes are seldom involved. There is a frequent association with cafe au lait spots of neurofibromatosiss 2,s3 (Fig, 16), which may also be present in relatives. 52 In the small nodular form, ocular involvement52 ,54 is the most typical extracutaneous manifestation; it may precede or follow the cutaneous lesions. Nodular lesions on the external portion of the eye lead to hemorrhage (hyphema) and to glaucoma. The large nodular form is less frequent and is marked by one or a few lesions (Fig. 17). The nodules are generally round, 10 to 20 mm in diameter, translucent, red, and show telangiectasias on their surface. The mucous membranes may be involved. The macronodular form of JXG may be related to systemic lesions oflungs, bones, kidneys, pericardium, colon, ovaries, and testes. 45 ,51,52 The nodular lesions of the skin tend to flatten with time, and both the skin and the visceral lesions spontaneously disappear within 3 to 6 years. The patient's general health is not impaired, and physical and mental development is normal. Metabolic disturbances have not been identified. Histologically, early lesions show a monomorphous, nonlipid-containing histiocytic infiltrate. 1,49,SO,51 Mature lesions (Fig. 18) contain foamy cells, foreign body giant cells, and Touton giant cells, mainly distributed in the superficial dermis and on the border of the infiltrate. In addition to histiocytes and foamy cells, there may be eosinophils, plasma cells, and neutrophils scat-

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tered throughout the lesion. Older lesions may show fibrosis. Fat stains are positive, whereas anti-S-100 staining of histiocytes is absent. 23 Under the electron mieroscope28 the histiocytes that characterize the early stage of the disease exhibit irregular nuclei, are rich in pseudopods, and contain many elongated and irregularly shaped dense bodies. Clusters of comma-shaped bodies, but no LG, can occasionally be observed (Table I). In older lesions there is a predominance of foamy cells the cytoplasm of which is completely filled with lipid vacuoles, cholesterol clefts, and myeloid bodies. Differential diagnosis. JXG can be differentiated from nodular urticaria pigmentosa, whose lesions become urticarial immediately after rubbing and which histologically have many mast cells. BCH differs from JXG by its papular lesions, located only on the head and neck. Its infiltrate lacks foamy cells and multinucleated giant cells. GEH is not granulomatous, and lipidation of the cells never occurs; its histiocytes are monomorphous and are rich in dense and regularly laminated bodies on electron microscopic examination. In SHR the cutaneous lesions persist for only the first few months of life, and 10% to 25% of the cells are S-100 protein-positive and show LG. Tuberous xanthoma appears only in hyperlipidemic states. PX is distinguishable from JXG and XD, from a histologic point of view, only because the primitive pure histiocytic phase is lacking. The nodular forms of HX can be differentiated because of the different histologic, immunocytochemical, and ultrastructural characteristics (Le., the presence of HX cells, which are S-l DO-positive and contain LG). Single JXG may be clinically difficult to distinguish from benign juvenile melanoma, which is characterized by the presence of spindle and epithelial nevus cells. Histologically, however, they are distinctly different. Sinus histiocytosis with massive lymphadenopathy Sinus histiocytosis with massive lymphadenopathy (SHML), described by Rosai and Dorf-

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Fig. 11. SHR. Multiple disseminated elevated, firm, red-brown nodules. (From Bonifazi

E, Caputo R, Ceci A, Meneghini C: Arch DermatoI1l8:267-272, 1982. (Copyright 1982, American Medical Association.) Fig. 13. BCH. Papulonodular eruption on upper part of face. (From Gianotti F, Caputo R: Unknown histiocytosis with intracytoplasmic wormlike particles in two children. Proceedings of the Fourteenth International Congress on Dermatology. Amsterdam, 1972, Excerpta Medica.)

Fig. 12. SHR. Cellular infiltrate occupying entire thickness of dermis and invading epi-

dermis. (Original magnification, X 310.) (From Bonifazi E, Caputo R, Ceci A, Meneghini C: Arch DermatoI118:267-272, 1982. Copyright 1982, American Medical Association.)

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characterized by a dermal infiltrate composed predominantly of histiocytes with large vesicular nuclei and abundant pale cytoplasm. Some histiocytes are foamy and/or multinucleated. Lymphophagocytosis has been described. Histiocytes are sometimes aggregated in clusters resembling lymph node sinuses. Lymphocytes and plasma cells are intermixed in the infiltrate. Electron microscopyS8 shows that most histiocytes forming the infiltrate are rich in phagosomes and may contain clusters of comma-shaped bodies. LG are absent (Table 1). Differential diagnosis. Dermatofibroma is distinguishable from SHML by its conspicuous fibroblastic component and the abundance of collagen fibers. The lack of both plasma cells and lymphophagocytosis usually distinguishes PX, JXG, and GEH, from SHML. Unlike SHML, HX shows LG in the histiocytes, and the lesions of Hodgkin's disease contain the typical Reed-Sternberg cells. Generalized eruptive histiocytoma Fig. 14. BCH. Skin biopsy shows circumscribed infil-

trate closely attached to lower surface of epidermis. Most cells within infiltrate are histiocytes having a pleomorphic nucleus and ill-recognizable cytoplasm. (X 310.)

man,5S,56 is a benign, generally self-limited disease characterized by cervical lymphadenopathy. It is usually accompanied by fever, elevated erythrocyte sedimentation rate, leukocytosis with neutrophilia, and polyclonal hypergammaglobulinemia. The cervical lymphadenopathy is often bilateral, painless, and massive. Other lymph nodes (axillary, inguinal, mediastinal), the upper respiratory tract, bones, testes, and skin may also be involved. This disease occurs most frequently in the first or second decade of life, without predilection for either sex. Cutaneous manifestations (Fig. 19) are observed in 10% of patients 57 .58 as isolated or disseminated, red-brown or yellow-brown papules or nodules, without any particular localization. The course of the disease is benign, even though spontaneous resolution may take several years. HistopathologicallyS7,58 (Fig. 20), the skin is

Winkelmann and Muller9 ,60 described GEH as a papular, nonlipidic, self-healing histiocytosis affecting mainly adults. Approximately ten cases have been reported. 61 -66 The skin lesions (Fig. 21) consist of an asymptomatic eruption of discrete papules that are firm, are dark red or dark bluish, and range in size from 3 to 10 rnm. These lesions appear in successive crops, may be numerous (50 to 1,000), and are symmetrically distributed on the face, trunk, and proximal limbs. Rare mucouS membrane lesions are found. The disease lasts for a few years and then subsides spontaneously. General health is always normal. No visceral lesions are observed. Histologically the papular lesion consists of a relatively monomorphous histiocytic infiltrate in the upper and mid dermis (Fig. 22). The histiocytes contain a nucleus with scanty chromatin and abundant, lightly staining, poorly limited cytoplasm. No foamy cells or giant cells are observed, but a few lymphocytes can be seen. Stains are negative for lipids, mucopolysaccharides, and anti-S-lOO. * *Unpublished data.

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Histiocytic syndromes 395

Fig. 15. BCH. Electron micrograph illustrates cluster of comma-shaped bodies. (X 54,000.)

Electron microscopy shows the tumor cells to contain a large amount of dense and regularly laminated bodies, often clustered together. Occasionally, wormlike bodies are found, whereas LG are always absent60 ,63,64 (Table I). Winkelmann l suggests that this syndrome could represent the primitive form of other, more developed, non-X histiocytoses (JXG, BCH, multicentric reticulohistiocytosis [MRJ). Differential diagnosis JXG and PX may be excluded in view of the

color of the lesions and the presence of foamy cells and Touton giant cells. BCH has lesions localized on the face and affects only children. MR may be ruled out because of the absence of arthritis and the lack of multinucleated giant cells. Progressive nodular histiocytosis typically involves the face, which acquires a leonine appearance; the condition is not spontaneously reversible, and pleomorphic cytoplasmic inclusions are found in the histiocytes forming the infiltrate. Forms of HX are easily distinguished by their different clinical, histologic, immunocytochemical, and ultrastructural features. Papular xanthoma

Winkelmann1,8 described PX as a normolipidemic, papular cutaneous xanthomatosis in which a primitive histiocytic phase is lacking. PX is char-

acterized by an eruption of 2 to 15 mm, rounded, yellowish papulonodular lesions occurring on the skin and mucous membranes in a generalized distribution (Fig, 23). The lesions do not form confluent plaques or have the red or brown chronic appearance of xanthoma disseminatum. Diabetes insipidus is absent. Spontaneous involution occurs after a few years, but a progressive course has also been described in several cases. 67,68 Histologically (Fig. 24) the lesion is composed almost entirely of histiocytes, foamy cells, and Touton giant cells, without the mixed features of xanthoma disseminatum or JXG, and is rich in phospholipids. 69 Ultrastructural findings are similar to those of mature JXG (Table I). Differential diagnosis. PX differs from xanthoma disseminatum because the lesions do not tend to merge into plaques and do not turn redbrown, the skinfolds are spared, and there is no diabetes insipidus. Histologically, inflammatory cells are absent. JXG can be recognized by its pure primitive histiocytic phase and, in mature lesions, by the presence of inflammatory cells. BCH differs in localization and never shows lipidation. GEH does not have lipid-containing cells. PX is clinically and histologically difficult to differentiate from the xanthomatous lesions that may appear in HX,IO but history and the absence

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® Fig. 16. JXG. Small nodular fann of JXG associated with cafe au lait spots. Fig. 19. SHML. Red-brown papulonodular lesions on face. Note cervical lymphadenopathy. (Courtesy Dr. M. F. Avril, Villejuif, France.)

Fig. 17. JXG. Macronodular lesions involving scalp.

of lesions typical of HX (S-lOO-positive cells and LO) are discriminating factors.

Xanthoma disseminatum Xanthoma disseminatum, or Montgomery syndrome, J,8,70-73 is a rare, benign form of histiocyto-

xanthomatosis affecting the skin and mucous membranes. It is associated with diabetes insipidus and has a normal lipid profile. The cutaneous manifestations are marked by the eruption of hundreds of papules that are red-brown at first and then become yellowish. They symmetrically involve the trunk, face, and proximal extremities and, in flexures and folds, tend quickly to merge (Fig. 25). The eyelids and conjunctivae may be involved. The lips, pharynx, and larynx are characteristically infiltrated with red or yellow plaques. Vasopressin-sensitive diabetes insipidus is present in half of the cases. 73 In the course of the disease, transitory elevation in serum cholesterol and/or triglyceride values has been reported. 73 In our opinion the disorder is ill defined with respect to the other xanthomatoses. The patients are generally in good health, and no other visceral lesions occur. The skin lesions and diabetes insipidus resolve spontaneously after several years. In the early stage the histopathologic study shows a mixture of histiocytes, foamy cells, and inflammatory cells; later on, foamy cells predominate (Fig. 26). Siderosis is often observed. 71 Ultrastructurally74 the cells are similar to those present in PX and

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Fig. 18. JXG. Skin biopsy shows mature lesion containing foamy cells and Touton giant cells. (X 125.)

Fig. 20. SHMH. Skin biopsy shows dermal infiltrate composed ofhistiocytes with vesicular nuclei and abundant pale cytoplasm. Some histiocytes show lymphophagocytosis. Lymphocytes and plasma cells are intermixed in infiltrate. (Original magnification, X 310.) (Courtesy Dr. M. F. Avril, Villejuif, France.)

JXG, but the plasma membranes of foamy cells show many microvilli (Table I). Differential diagnosis. Xanthoma disseminatum differs from PX as follows: the tendency of its lesions to merge into plaques, the typical mucous membrane involvement, and its associated diabetes insipidus. Moreover, histologic study

shows an inflammatory infiltrate in the early phase. JXG mainly affects children, and lesions do not merge into plaques; there may be visceral involvement, but diabetes insipidus is absent. GEH and BCH never show lipidation. HX is distinguished by the presence of HX cells and their anti-S-lOO staining.

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Fig. 21. GER. Asymptomatic dark red papulonodular eruption affecting a child. Fig. 23. PX. Yellowish papulonodular eruption. Lesions do not form confluent plaques. Fig. 25. Xanthoma disseminatum. Face of patient is characteristically infiltrated with yellow-red plaques. (Courtesy Dr. J. Ferrando, Barcelona, Spain.) Fig. 30. Progressive nodular histiocytosis. Typical involvement of face, where lesions tend to merge, giving patient a leonine appearance.

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Multicentric reticulohistiocytosis MR, or reticulohistiocytoma cutis, 75-82,* is a rare syndrome generally occurring in adults over 40 years of age and clinically characterized by a cutaneous and mucous membrane papulonodular eruption and a severe polyarthritis. The papulonodular lesions (Fig. 27) range in diameter from a few millimeters to 2 cm and are round, translucent, and yellow-rose or yellow-brown in color. They do not tend to ulcerate. They preferentially affect the fingers, the palms and backs of the hands, the juxta-articular regions of the limbs, and the face. Small lesions may be found on the trunk. Oral, nasal, and pharyngeal mucosae are involved in 50% of cases. 7B The mucocutaneous lesions have a highly variable course, Xanthomatous lesions are found in 30% of cases. 76 Osteoarticular manifestations suggest chronic diffuse polyarthritis and have a destructive course. The lesions symmetrically involve the hands (80%), knees (70%), and wrists (65%). The osteoarticular manifestations show a progressive course of several years and then become stable. There is no parallelism between the mucocutaneous and articular course. Ocular, muscular, cardiovascular, and pleuropulmonary manifestations have occasionally been described. 78 ,82 Cases associated with malignant visceral disease have been reported. 79,80 Histologically the early lesions may be composed ofhistiocytes and lymphocytes and therefore may be confused with other histiocytoses of the skin. 1,78,83 Older lesions show the characteristic histologic feature: the presence of numerous large, mononucleated or multinucleated histiocytes (Fig, 28) with an abundance of eosinophilic, homogeneous to finely granular cytoplasm having a ground-glass appearance. The cytoplasm of these cells is strongly positive for periodic acid-Schiff stain and is diastase resistant. Collagen and reticular fibers are often abundant. At times, connective tissue and red blood cell phagocytosis may be seen. 84 Under the electron microscope, about 40% of *Basset A, Malaville J, Bergoend H, et al: Reticlliohistiocytome (reticulomatose a cellules geantes de la pcau et des synoviales. Arch Belg Dermatol SyphiloI26:141-151, 1970,

Fig. 22. GEH. Skin biopsy shows relatively monomorphous histiocytic infiltrate in superficial and mid dermis. (Original magnification, x ~25.) (From Caputo R, Alessi E, Allegra F: Arch Dermatol 117:216-221, 1981. Copyright 1981, American Medical Association.)

the histiocytes contain unique and highly complex structures designated by the term pleomorphic cytoplasmic inclusions85 - 88 (Fig. 29). These granules consist mainly of unit membranes, occasionally limiting electron-dense areas containing vesicles. About 20% of the histiocytes that form the infiltrate and that do not contain any pleomorphic cytoplasmic inclusions show a remarkable collagenophagic activity.88 LG are absent (Table I). Treatment is usually not helpful. 78 ,82 Anti-inflammatory drugs are ineffective. Systemic corticosteroids have a short-lasting favorable effect on articular lesions only. Antimitotic agents have been reported to induce regression of mucocutaneous lesions in only a few cases. 82,87 Differential diagnosis. MR can be distinguished from the other non-X histiocytoses because it occurs in adults over 40 years, is not self-

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Fig. 24. PX. Skin biopsy shows lesion composed almost entirely of histiocytes and foamy cells. (x 3lO.)

Fig. 27. MR. PapUlonodular lesions affecting fingers.

Fig. 26. Xanthoma disseminatum. Histopathologic findings: mixture of histiocytes, foamy ce]]s, Touton giant cells, and inflammatory cells. (X 125.)

limiting, is associated with destructive joint lesions, and is histologically marked by giant cells with ground-glass cytoplasm. According to some authors, however, the histologic findings are not

diagnostic. 76-78 ,83 Magnin et al * and ChevrantBreton78 claim that GEH may tum into MR. Progressive nodular histiocytosis is a histiocytopathy histologically and ultrastructurally similar to MR, but arthropathy, mucosal involvement, and collagenophagocytosis are absent, the face acquires a leonine appearance, and treatment with *Magnin PH, Bamchil G, Casas JG: Reticulohistiocytosis multicen· trica e histiocytoma eruptivo generalizado. Prensa Med Argentina 59:331-335, 1972.

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Fig. 28. MR. Skin biopsy shows numerous large mononucleated or multinucleated histiocytes with ground-glass cytoplasm. (X 125.)

Fig. 29. MR. Electron microscopy. Histiocyte containing pleomorphic cytoplasmic inclusions. These granules consist of unit membrane occasionally limiting electron-dense areas containing vesicles. (X 45,000.)

electron beam and antimitotic agents is highly effective. The lack of neurologic symptoms, laboratory findings, and histologic data easily rule out lepromatous leprosy. Progressive nodular histiocytosis

In our opinion this tenn should be used to describe a non-X histiocytosis clinically characterized by the following:

1. Widespread, essentially symmetrical papulonodular eruption 2. Progressive development of new lesions 3. Typical involvement of the face, where lesions tend to merge, giving the patient a leonine appearance (Fig. 30) 4. Absence of arthritis and of visceral or mucous membrane involvement 5. Good general health In addition to an unpublished case observed by

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Fig. 31. Progressive nodular histiocytosis. Skin biopsy shows massive infiltrate of histio-

cytes intermingled with masses of lymphocytes. Histiocytes show irregular nuclei and granular, slightly eosinophilic cytoplasm. (X 125.)

us, three other cases have been studied ultrastructurally and described under different names (reticulohistiocytome multiple, 197987 ; nodular cutaneous reactive histiocytosis, 197489 ; nodular nonX histiocytosis, 198290 ). Microscopically the lesions are composed of a massive infiltrate of histiocytes intermixed with masses of lymphocytes (Fig. 31). The histiocytes show irregular nuclei and a granular, slightly eosinophilic cytoplasm. Giant cells and mitotic figures are absent or rare. Ultrastructurally, many histiocytes contain pleomorphic cytoplasmic inclusions identical to those found in MR (Table I); collagenophagic cells are absent, however. Chemotherapy90 and electron beam therapy87 lead to a remission of lesions. Differential diagnosis. Progressive nodular histiocy'tosis may represent a form of MR with limited clinical expression,87 a transitional state between GEH and MR,90 or a distinct histiocytopathy. It is distinguishable from MR because of the typical leonine appearance of the face; the lack of involvement of joints, visceral organs, and mucous membranes; the good general health of the patient; and the satisfactory response to chemotherapy or electron beam. In GER, lesions are smaller, do not induce the leonine appearance of the face, re-

solve spontaneously, and do not contain pleomorphic cytoplasmic inclusions. REFERENCES 1. Winkelmann RK: Cutaneous syndromes of non-X histiocytosis. Arch Dennatol 117:667-672, 1981. 2. Lichtenstein L: Histiocytosis X: Integration of eosinophilic granuloma of bones, Letterer-Siwe disease and Schuller-Christian disease as related manifestations of a single nosologic entity. Arch Pathol Lab Med 56:84-102, 1953. 3. Nezelof C, Frileux-Herbert F, Cronier-Sachot J: Disseminated histiocytosis X: Analysis of prognostic factors based on a retrospective study of 50 cases. Cancer 44:1824-1838, 1979. 4. Bingham EA, Bridges JM, Kelly AMT, et al: LettererSiwe disease: A study of thirteen cases over a 21-year period. Br J Dermatol106:205-209, 1982. 5. Chevrant-Breton J: La maladie de Letterer-Siwe de l'adulte: Revue de la litterature. Ann Dermatol Venereol 105:301-305, 1978. 6. Vollum 01: Letterer-Siwe disease in the adult. Clin Exp Dermatol 4:395-406, 1979. 7. Caputo R, Berti E, Monti M, et al: Letterer-Siwe disease in an octogenarian. JAM ACAD DERMATOL 10:226-233, 1984. 8. Winkelmann RK: Adult histiocytic skin diseases. G Ital Dennatol VenereoI115:67-76, 1980. 9. Lycaya J: Histiocytosis X. Am J Dis Child 121:289-295, 1971. 10. Altman J, Winkelmann RK: Xanthomatous cutaneous lesions of histiocytosis X. Arch Dermatol 87:164-170, 1963.

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II. Doede KG, Rappaport H: Long-term survival of patients with acute differentiated histiocytosis (Letterer-Siwe disease). Cancer 20:1782-1795, 1967. 12. Lahey ME: Prognosis in reticuloendotheliosis in children. J Pediatr 51:664-671, 1962. 13. Osband ME, Lipton JM, Lavin P, et al: Histiocytosis X: Demonstration of abnormal immunity, T-cell histamine H,-receptor deficiency, and successful treatment with thymic extract. N Engl J Med 304: 146-153, 1981. 14. Oberman HA: Idiopathic histiocytosis: A clinicopathological study of 40 cases and review of literature on eosinophilic granuloma of bone, Hand-SchUller-Christian disease and Letterer-Siwe disease. Pediatrics 28:307326, 1961. 15. Lahey ME: Histiocytosis X; An analysis of prognostic factors. J Pediatr 87: 184-189, 1975. 16. Dolezal JF, Thomson ST: Hand-SchUller-Christian disease in a septuagenarian. Arch Dennatol 114:85-87, 1978. 17. Fitzpatrick R, Rapaport MJ, Silva DG: Histiocytosis X. Arch Dermatol 117:253-257, 1980. 18. Sigala JL, Silverman S, Brosy HA, et al: Dental involvement in histiocytosis X. Oral Surg 33:42-48, 1972. 19. McGavian MH, Spady HA: Eosinophilic granuloma of bone: A study of 28 cases. J Bone Joint Surg (Am) 42:979-992, 1960. 20. Sparbaro JL, Francis KC: Eosinophilic granuloma of bone. JAMA 178:706-708, 1961. 21. Winkelmann RK: The skin in histiocytosis X. Mayo Clin Proc 44:535-549, 1968. 22. Lever WF, Schaumburg-Lever G: Histopathology of the skin, ed. 6, Philadelphia, 1983, J. B. Lippincott Co., p. 392. 23. Rowden G, Connelly EM, Winkelmann RK: Cutaneous histiocytosis X: The presence of S-100 protein and its use in diagnosis. Arch Dermatol 119:553-559, 1983. 24. Tarnowski W, Hashimoto H: Langerhans' cell granules in histiocytosis X. Arch Dermatol 96:298-304, 1976. 25. Gianotti F, Caputo R: Skin ultrastructure in HandSchUller-Christian disease. Arch Dermatoll00:342-349, 1969. 26. Eady RAJ: Lctterer-Siwe disease in elderly patient: Histological and ultrastructural findings. Clin Exp Dermatol 4:413-421, 1979. 27. Gebhart W, Knobler R, Niebauer G: Langerhans cells in histiocytosis X. Ital Dermatol Venereol 115:121-128, 1980. 28. Caputo R, Gianotti F: Cytoplasmic markers and unusual ultrastructural features in histiocytic proliferations of the skin. G Ital Dermatol Venereal 115: 107-120, 1980. 29. Schuler G, Stingl G, Wolff K: Coated Langerhans cell granules in histiocytosis X cells. J Invest Dermatol 78:331, 1982. (Abst.) 30. Gianotti F, Caputo R: Skin ultrastructure in Letterer-Siwe disease treated with vinblastine: Mode of penetration of Langerhans granules into the nucleus. Br J Dermatol 84:335-345, 1971. 31. Murphy GF, Bhan AK, Sato S, et al: Characterization of Langerhans cells by the use of monoclonal antibodies. Lab Invest 45:465-468, 1981. 32. Berti E, Monti M, Cavicchini S, Caputo R: The avidin

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