- Email: [email protected]
A unique non-Langerhans cell histiocytosis with some features of generalized eruptive histiocytoma
A unique non-Langerhans cell histiocytosis with some features of generalized eruptive histiocytoma Sergij Goerdt, MD, Gisela Bonsmann, MD, Cord Sunderkotter, MD, Stefan Grabbe, MD, Thomas Luger, MD, and Gerhard Kolde, MD Munster, Germany A symmetric eruption of hundreds of coalescentsmall red macules and a fewslightlyelevated papules sparing the flexures was observed in a 73-year-old man. Light microscopicexamination showed loose aggregates of small and large histiocytic cells. Electron microscopy showed an absence of Langerhans cell granules and lipid droplets. Features shared with generalized eruptive histiocytoma were the symmetry of the eruption sparing the flexures, the blue-red coloration, and the absence of lipid-containing foam cells and multinucleated giant cells. However, the primary occurrence of macules rather than papules or nodules, the tendency of the macules to coalesce, and the dimorphic histiocytoid infiltrate are not found in generalized eruptive histiocytoma. Nevertheless, immunohistochemistry confirmed that this unique condition is a form of MS-l+ cutaneous non-Langerhans cell histiocytosis. (J AM ACAD DERMATOL 1994;31:322-6.) Cutaneous histiocytoses are divided into Langerhans cell and non-Langerhans cell groups mainly on the basis of the presence or absence of Birbeck's granules and S-100 and CDla antigens.l-' respectively. Recently we reported that expression ofMS-! antigenv" occurs in a large group of non-Langerhans cell histiocytoses," In contrast, CD34 is predominantly expressed by fibroblast-related lesions such as dermatofibrosarcoma protuberans and fibrous type dermatofibroma. In histiocytoma/cellular type dermatofibroma, CD34 and MS-I expression partially overlap. Among the cases in this previous immunohistologic study, there was a case of generalized macular eruption in which the lesional histiocytes exhibited an antigen expression pattern typically found in non-Langerhans cell histiocytoses (8-100-, CD I a-, MS-I +). In addition, the lesional cells expressed moderate levels of CD34. Some clinical and light and electron microscopic findings were characteristic of generalized eruptive histiocytoma. However, unique features were the occurrence of macules rather than papules, the tendency of the macules to
From the Department of Dermatology, University of Munster. Reprint requests: Sergij Goerdt, MD, Freie Universitat Berlin, Universitiitsklinikum Steglitz, Hautklinikund Poliklinik, Hindenburgdamm 30, 0-12200 Berlin, Germany. Copyright @ 1994 by the Ame rican Academy of Dermatology, Inc.
0190-9622/94 $3.00 + 0
322
16/4/53809
coalesce, the absence of self-healing, and the histologic finding of both small and large lesional histiocytes. We describe this unique case of non-Langerhans cell histiocytosis in greater detail and discuss its classification and histogenesis. CASE REPORT
A 73-year-oldman had a history of developmentof red macules and slightly elevated papules symmetrically on the extensorsurfaces of both arms 4 years previously (Fig. 1). Some of these lesionscoalesced. Slow but progressive development of hundreds of red macules and papules occurred onthe trunk and the extensorsurfaces of the thighs while the face and the distal extremities remained virtually clear. The mucous membranes were unaffected, and results of an ophthalmologic examination were normaL The lesions were neither painful nor itchy. The original lesions did not heal but persistedunchanged for 5 years. Skin biopsy specimens at another institution were interpreted as benign histiocytoma. Examination revealed no lymphadenopathy or hepatosplenomegaly. Bloodglucoseand fasting serum cholesterollevels were elevated to 188 mg/dl (normal, 70 to 110 mg/dl) and 260 rng/dl (normal, <200 mg/dl), respectively. Other laboratory investigations revealed normal erythrocyte sedimentation rate, routine hematology, lymphocyte subpopulations, serum chemistries, and immunoglobulin levels. Chest x-ray, abdominal and lymph nodeultrasonography, and bonescintiscans did not reveal any extracutaneous involvement. Bone marrow smears showed normocellular marrow without histiocytoid infiltration. Light microscopyshoweda slightly acanthotic epider-
Journal of the American Academy of Dermatology Volume 31, Number 2, Part 2
mis overlying loose aggregates of histiocytic cells in the superficial and mid dermis (Fig. 2, A) that were composed of two distinct populations of small and large histiocytes (Fig. 2, B). Histiocytes with two nuclei were found on rare occasions, but multinucleated giant cells were not found. Both small and large histiocytes were characterized by angulated cell borders, more or less abundant eosinophilic cytoplasm, and a round to oval, pale nucleus with prominent nucleoli. Some lymphocytes and occasional mast cells were found intermingled with the histiocytes in a mainly perivascular localization. The lesionswere highly vascularized, whereas the neighboring uninvolveddermis was not. By electron microscopy the histiocytic cells, in particular the larger ones, had an irregular lobulated nucleus and a well-organized, nonlipidized cytoplasm with small dendritic processes. There were numerous lysosomal bodies and, occasionally, comma-shaped cytoplasmic inclusions formed by two closely attached membranes. No Birbeck's granules or cytoplasmic laminated bodies were observed. Immunohistochemical studies were performed on formalin-fixed paraffin-embedded (S-100, Mac-387, and CD34) or fresh-frozen (all other antigens including Mac-387 and CD34) tissue sections as previously described." On fresh-frozen tissue sections, quenching of endogenous peroxidase was achieved with hydrogen peroxide and sodium azide. The sources and specificity of the antibodies used and results of the immunostaining are presented in Table 1. All lesional histiocytes had uniformly positive reactions with monoclonal antibody RM 3/1 (Fig. 3, A), and with monoclonal antibodies directed against CD/Ie, CD34, CD36, and CD68; CD34 staining of lesionalhistiocytes was lessintense than staining of adjacent vascular endothelial cells. Monoclonal antibody MS-l (Fig. 3, B) showed intense cytoplasmic staining of the small lesional histiocytes. In contrast to the other monoclonal antibodies, MS-I staining of the large lesional histiocytes was weaker and restricted to the cell periphery. Monoclonal antibodies 27ElO and Mac-387 and rabbit polyclonal antiserum against the MRP-8/-14 protein heterodimer showed only limited patchy staining. Apart from a few clusters of positivedendritic cells,S-l 00 protein and CD 1a antigen were not expressed by lesional histiocytes.Double-labeling with RM 3/1 (macrophages) and 1FlO (endothelial cells) monoclonal antibodies revealed the extreme degree of vascularization within the lesion, whereas the neighboring dermis was unaffected.
DISCUSSION The cutaneous non-Langerhans cell histiocytoses are rare disorders whose classification is difficult because few of the clinical, histologic, and ultrastructural criteria are absolute.l? When unique features
Goerdt et al. 323
Fig. 1. Symmetric eruption of red macules (A) and rare papules on the extensor surfaces of both arms; lesions on arms show a tendency to coalesce (A) and spare the flexures (B).
are found in a patient with non-Langerhans cell histiocytosis, the question arises whether to group the disorder with the few typical cases or to postulate the existence of a new entity. In general, there is growing conviction that all cutaneous non-Langerhans cell histiocytoses may represent a spectrum of disease rather than discrete entities. Our patient had an unusual combination of both clinical and microscopic features; the primary occurrence of macules rather than papules or nodules is unique among the histiocytic diseases. 1 Nevertheless, we prefer to classify this case as a considerably variant presentation of generalized eruptive histiocytoma. Generalized eruptive histiocytoma was first described as a distinct entity by Winkelmann and Muller in 1963. 13 Since then, some dozen cases have been reported. 13-23 Generalized eruptive histiocytoma is commonly viewed as a nonlipidizing nonLangerhans cell histiocytosis. A relation to classic solitary histiocytoma/dermatofibroma has not been established. In contrast, some authors have sug-
324
Journal of the American Academy of Dermatology August 1994
Goerdt et al.
-.. -
, ,.
Fig. 2. Light microscopy shows loose aggregates of histiocytic cells in papillary and mid dermis (A). Histiocytes are either small or large (B).
Table 1. Antigenic phenotype of lesional histiocytes Antibodies
Specificity
Result
Source
MS-1 RM 3/1 Dako-T6 Antiserum BU15 Qbendla OKM5 KP1 Mac-387 27E10 Antiserum Antiserum DRCI-R3/24 1FIO
Sinusoidal endothelial cells, dendritic cells Monocytes jmacrophages CD1a
+* +
CDllc CD34 CD36 CD68 MRP-8/-14 MRP-8/-14 MRP-8 MRP-14 Follicular dendritic cells Continuous endothelium
+ +
Goerdt et al.4 Zwadlo et al.8 Dakopattsj Immunotech§ Immunotech Immunotech Ortho] Dakopatts Dakopatts Zwadlo et aL9 Odink et aL10 Odink et aL10 Dakopatts Goerdt et aLII
S-100
+ +
-t
*Cytoplasmic staining of srnall lesional histiocytes, peripheral staining of large lesional histiocytes. tHighly increased vascularization within the lesion. :j:Dako Corp., Glostrup, Denmark. §Immunotech S.A., Marseille, France. [Ortho Diagnostic Systems, Inc., Raritan, N.J.
gested that generalized eruptive histiocytoma may have a close relation to classic Langerhans cell histiocytosis,'? to indeterminate cell histiocytosis.P or to lipidizing non-Langerhans cell histiocytoses, such as xanthoma disseminatum'" and multicentric reticulohistiocytosis.Pb 25
According to Winkelmann and Muller.l' the typical diagnostic features of generalized eruptive histiocytoma include the following: (1) widespread, essentially symmetric, multiple lesions, particularly on the trunk and proximal portions of the extremities and, rarely, the mucous membranes; (2) distinct
Journal of the American Academy of Dermatology Volume 31, Number 2, Part 2
flesh-colored to blue-red papules without a tendency to group; (3) progressive development of new lesions without antecedent history of trauma; (4) spontaneous resolution of lesions toward brown macules or complete disappearance; (5) a benign histologic picture of mononuclear histiocytic cells. In several aspects, the eruption in our patient resembles generalized eruptive histiocytoma-symmetric lesions of the trunk and of the extensor surfaces of the proximal portions of the extremities sparing the face and mucous membranes, and progressive development of new lesions without extracutaneous involvement. However, the primary occurrence of macules rather than papules or nodules, the tendency of the macules to coalesce, and the absence of self-healing are not typical of generalized eruptive histiocytoma. In xanthoma disseminatum, the closest differential diagnosis to generalized eruptive histiocytoma.P papular lesions may coalesce, but they then form plaques in a flexural localization not encountered in our patient. Histologically, there were loose aggregates of small and large histiocytes, but no foamy or multinucleated giant cells. Electron microscopy revealed the absence of Birbeck's granules and of lipid in the cytoplasm of the lesional histiocytes . The absence of Birbeck's granules precludes the diagnosis of classic Langerhans cell histiocytoses and self-healing reticulohistiocytosis,2?,28 whereas the absence of foamy and multinucleated giant cells and of cytoplasmic lipid in the lesional histiocytcs is a prerequisite for the diagnosis of generalized eruptive histiocytoma. 13, 26, 29 In contrast, the simultaneous occurrence of both small and large lesional histiocytes is a typical feature of xanthoma disseminatum rather than of generalized eruptive histiocytoma.P With immunohistochemical studies, lesional histiocytes in our patient did not express CDla and 8-100 protein antigens, thus excluding the diagnosis of Langerhans cell histiocytosis.v 28,30,31 but they expressed MS-I high molecular weight protein in a pattern diagnostic for non-Langerhans cell histiocytoses.? However, lesional histiocytes in our case weakly expressed CD34. CD34 was first described as an antigen specific for hemopoietic progenitor cells in bone marrow.P but it has since been shown to be expressed by continuous type endothelial cells,33-35 dermal dendrocytes, perifollicular cells, spindle cells of Kaposi's sarcoma,36 in dermatofibrosarcoma protuberans," 37 and in fibrous type.?
Goerdt et al. 325
of
Fig. 3. Immunohistochemical phenotyping lesional histiocytes with monoclonal antibodies RM 3/1 (A)and MS-I (B). Monoclonal antibody MS-l showed strong cytoplasmic staining of smalliesional histiocytes and weaker peripheral staining of large lesional histiocytes, whereas RM 3/1 antigen was strongly and uniformly expressed in both cell types.
and less consistently, cellular type dermatofibroma.?'3? In contrast, CD34 has been shown not to he expressed by the lesional histiocytes of non-Langerhans cell histiocytoses, such as xanthoma disseminatum.l'' multicentric reticulohistiocytosis, and juvenile xanthogranuloma." Up to now, we have also failed to induce CD34 in cultured human monocytesjmacrophages. Therefore CD34 expression by the lesional histiocytes in our patient is troubling. If confirmed as a marker for classic generalized eruptive histiocytoma, CD34 expression might indicate a closer relation of this condition to fibroblast-related lesions than other non-Langerhans cell histiocytosis syndromes exhibit. To clarify further the classification, histogenesis, and relation of the histiocytoid lesions, we suggest establishment of an international immunohistochemistry reference laboratory for
Journal of the American Academy of Dermatology August 1994
326 Goerdt et al.
non-Langerhans cell histiocytoses and related diseases. REFERENCES 1. Gianotti F, Caputo R. Histiocytic syndromes: a review. J AM ACAD DERMATOL 1985;13:383-404. 2. The Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1987;1:208-9. 3. Fartasch M, Vignesswaran N, Diepgen TL, et al. Immunohistochemical and ultrastructural study of histiocytosis X and non-X histiocytoses. J AM ACAD DERMATOL 1990; 23:885-92. 4. Goerdt S, Walsh LJ, Murphy GF, et al. Identification of a novel high molecular weight protein antigen preferentially expressed by sinusoidal endothelial cells in normal human tissues. J Cell Bio11991;113:1425-37. 5. Walsh LJ, Goerdt S, Pober JS, et al. MS-1 sinusoidal endothelial antigen is expressed by factor XIIla+, HLADR+ dermal perivascular dendritic cells. Lab Invest 1991; 65:732-41. 6. Goerdt S, Bhardwaj R, Sorg C. Inducible expression of MS-1 high molecular weight protein by endothelial cells of continuous origin and by dendritic cells/macrophages in vivo and in vitro. Am J PatholI993;142:1409-22. 7. GoerdtS, KoldeG, Bonsmann G, eta!. Immunohistochemical comparison of cutaneous histiocytoses and related skin disorders: diagnostic and histogenetic relevance of MS-l high molecular weight protein expression. J Pathol 1993; 170:421-7. 8. Zwadlo G, Voegeli R, Schulze-Osthoff K, et al. A monoclonal antibody to a novel differentiation antigen on human macrophages associated with the downregulation phase of the inflammatory process. Exp Cell Bioi 1987;55:295-304. 9. Zwadlo G, Schlegel R, Sorg C. A monoclonal antibody to a subset of human monocytes found only in the peripheral blood and inflammatorytissues. J ImmunolI986;137:512-8. 10. Odink K, Cerletti N, Bruggen J, et al. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 1987;330:80-2. 11. Goerdt S, Steckel F, Schulze-Osthoff K, et al. Characterization and differential expression of an endothelial cellspecific surface antigen in continuous and sinusoidal endothelia, in skin vascular lesions and in vitro. Exp Cell Biol 1989;57:185-92. 12. Coldiron BM, Cruz PD Jr, Freeman RG, et al. Benign non-X histiocytosis: a unique case bridging several of the non-X histiocytic syndromes. J AM ACAD DERMATOL 1988;18:1282-9. 13. Winkelmann RK, Muller SA. Generalized eruptive histiocytoma. A benign papular histiocytic reticulosis. Arch Dermatol1963;88:586-96. 14. Braun-Falco 0, Korting HC, Zienicke H, et al. Eruptive Histiozytome und Xanthoma disseminatum als Manifestationsformen derselben Erkrankung? Hautarzt 1988;39: 652-7. 15. Saijo S, Hara M, Kuramoto Y, et al. Generalized eruptive histiocytoma: a report of a variant case showing the presence of dermalindeterminate cells. J Cutan Pathol1991 ;18: 134-6. 16. Shimizu N, Ito M, Sato Y. Generalized eruptive histiocy-
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
28. 29. 30. 31. 32.
33. 34.
35. 36.
37.
toma: an ultrastructural study. J Cutan Pathol 1987;14: 100-5. Stables GI, Mackie RM. Generalized eruptive histiocytoma. Br J DermatoI1992;126:196-9. Arnold M-L, Wirth H, Anton-Lamprecht I, et al. Generalisierte eruptive Histiozytome, Hautarzt 1982;33:428-37. Caputo R, Alessi E, Allegra F. Generalized eruptive histiocytoma. Arch Dermatol 1981;117:216-21. SohiAS, Tiwari VD, Subramanian CSV, et al. Generalized eruptive histiocytoma. Dermatologica 1979; 159:471-5. Cramer H -J. Multiple Reticulohistiocytome der Haut ohne nachweisbare Zweiterkrankung. Hautarzt 1963; 14:297302. Caputo R, Ermacora E, Gelmetti C, et al. Generalized eruptive histiocytoma in children. JAM ACAD DERMATOL 1987;17:449-54. Winkelmann RK, Kossard S, Fraga S. Eruptive histiocytoma of childhood. Arch Dermato11980;116:565-70. Chevrant-Breton J. Lareticulo-histiocytosemulticentrique: revue de la literature recente (depuis 1969). Ann Dermatol VenereoI1977;104:745-53. Magnin PH, Bomchil G, Cases JG. Reticulohistiocitosis multicentrica e histiocitoma eruptive generalizado. Prensa Med Argentina 1972;59:331-5. Ringel E, Moschella S. Primary histiocytic dermatoses. Arch Dermato11985;121:1531-41. Hashimoto K, Pritzker MS. Electron microscopic study of reticulohistiocytoma: an unusual case of congenital selfhealingreticulohistiocytosis. Arch Dermato11973;107:26370. Divaris DXG, Ling FCK, Prentice RSA. Congential selfhealingreticulohistiocytosis. AmJ Dermatopathol1991; 13: 481-7. Winkelmann RK. Cutaneous syndromes of non-X histiocytosis. Arch DermatolI981;117:667-72. Zeiger B, Cerio R, Orchard G, et al. Histologic and immunohistochemical study comparing xanthoma disseminatum and histiocytosis X. Arch Dermatol 1992;128:1207-12. Kolde G, Brocker E-B. Multiple tumors of indeterminate cells in an adult. J AM ACAD DERMATOL 1986;15:591-7. Civin CI, Strauss LC, Brovall C, et al. Antigenic analysis of hematopoiesis: III. A hemopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-la cells. J Immunol1984;133:157-65. Beschorner WE, Civin CI, Strauss LC. Localization of hemopoietic progenitor cells in tissue with the anti-My-lO monoclonal antibody. Am J PathoI1985;1l9:1-4. Schlingemann RO, Rietveld FJR, de Waal RMW, et al. Leucocyte antigen CD34 is expressed by a subset of cultured endothelial cellsand on endothelial abluminal microprocesses in the tumorstroma. Lab Invest 1990;62:690-6. Fina L, Molgaard HV, Robertson D, et al. Expression ofthe CD34 gene in vascular endothelial cells. Blood 1990;75: 2417-26. Nickoloff BJ. The human progenitor cell antigen (CD34) is localized on endothelial cells, dermal dendritic cells, and perifollicular cells in formalin-fixed normal skin and on proliferating endothelial cells and stromal spindle-shaped cells in Kaposi's sarcoma. Arch Dermatol1991;127:523-9. Aiba S, Tabata N, Ishii H, et al. Dermatofibrosarcoma protuberans is a unique fibrohistiocytic tumor expressing CD34. Br J Dermatol 1992;127:79-84.
From the Department of Dermatology, University of Munster. Reprint requests: Sergij Goerdt, MD, Freie Universitat Berlin, Universitiitsklinikum Steglitz, Hautklinikund Poliklinik, Hindenburgdamm 30, 0-12200 Berlin, Germany. Copyright @ 1994 by the Ame rican Academy of Dermatology, Inc.
0190-9622/94 $3.00 + 0
322
16/4/53809
coalesce, the absence of self-healing, and the histologic finding of both small and large lesional histiocytes. We describe this unique case of non-Langerhans cell histiocytosis in greater detail and discuss its classification and histogenesis. CASE REPORT
A 73-year-oldman had a history of developmentof red macules and slightly elevated papules symmetrically on the extensorsurfaces of both arms 4 years previously (Fig. 1). Some of these lesionscoalesced. Slow but progressive development of hundreds of red macules and papules occurred onthe trunk and the extensorsurfaces of the thighs while the face and the distal extremities remained virtually clear. The mucous membranes were unaffected, and results of an ophthalmologic examination were normaL The lesions were neither painful nor itchy. The original lesions did not heal but persistedunchanged for 5 years. Skin biopsy specimens at another institution were interpreted as benign histiocytoma. Examination revealed no lymphadenopathy or hepatosplenomegaly. Bloodglucoseand fasting serum cholesterollevels were elevated to 188 mg/dl (normal, 70 to 110 mg/dl) and 260 rng/dl (normal, <200 mg/dl), respectively. Other laboratory investigations revealed normal erythrocyte sedimentation rate, routine hematology, lymphocyte subpopulations, serum chemistries, and immunoglobulin levels. Chest x-ray, abdominal and lymph nodeultrasonography, and bonescintiscans did not reveal any extracutaneous involvement. Bone marrow smears showed normocellular marrow without histiocytoid infiltration. Light microscopyshoweda slightly acanthotic epider-
Journal of the American Academy of Dermatology Volume 31, Number 2, Part 2
mis overlying loose aggregates of histiocytic cells in the superficial and mid dermis (Fig. 2, A) that were composed of two distinct populations of small and large histiocytes (Fig. 2, B). Histiocytes with two nuclei were found on rare occasions, but multinucleated giant cells were not found. Both small and large histiocytes were characterized by angulated cell borders, more or less abundant eosinophilic cytoplasm, and a round to oval, pale nucleus with prominent nucleoli. Some lymphocytes and occasional mast cells were found intermingled with the histiocytes in a mainly perivascular localization. The lesionswere highly vascularized, whereas the neighboring uninvolveddermis was not. By electron microscopy the histiocytic cells, in particular the larger ones, had an irregular lobulated nucleus and a well-organized, nonlipidized cytoplasm with small dendritic processes. There were numerous lysosomal bodies and, occasionally, comma-shaped cytoplasmic inclusions formed by two closely attached membranes. No Birbeck's granules or cytoplasmic laminated bodies were observed. Immunohistochemical studies were performed on formalin-fixed paraffin-embedded (S-100, Mac-387, and CD34) or fresh-frozen (all other antigens including Mac-387 and CD34) tissue sections as previously described." On fresh-frozen tissue sections, quenching of endogenous peroxidase was achieved with hydrogen peroxide and sodium azide. The sources and specificity of the antibodies used and results of the immunostaining are presented in Table 1. All lesional histiocytes had uniformly positive reactions with monoclonal antibody RM 3/1 (Fig. 3, A), and with monoclonal antibodies directed against CD/Ie, CD34, CD36, and CD68; CD34 staining of lesionalhistiocytes was lessintense than staining of adjacent vascular endothelial cells. Monoclonal antibody MS-l (Fig. 3, B) showed intense cytoplasmic staining of the small lesional histiocytes. In contrast to the other monoclonal antibodies, MS-I staining of the large lesional histiocytes was weaker and restricted to the cell periphery. Monoclonal antibodies 27ElO and Mac-387 and rabbit polyclonal antiserum against the MRP-8/-14 protein heterodimer showed only limited patchy staining. Apart from a few clusters of positivedendritic cells,S-l 00 protein and CD 1a antigen were not expressed by lesional histiocytes.Double-labeling with RM 3/1 (macrophages) and 1FlO (endothelial cells) monoclonal antibodies revealed the extreme degree of vascularization within the lesion, whereas the neighboring dermis was unaffected.
DISCUSSION The cutaneous non-Langerhans cell histiocytoses are rare disorders whose classification is difficult because few of the clinical, histologic, and ultrastructural criteria are absolute.l? When unique features
Goerdt et al. 323
Fig. 1. Symmetric eruption of red macules (A) and rare papules on the extensor surfaces of both arms; lesions on arms show a tendency to coalesce (A) and spare the flexures (B).
are found in a patient with non-Langerhans cell histiocytosis, the question arises whether to group the disorder with the few typical cases or to postulate the existence of a new entity. In general, there is growing conviction that all cutaneous non-Langerhans cell histiocytoses may represent a spectrum of disease rather than discrete entities. Our patient had an unusual combination of both clinical and microscopic features; the primary occurrence of macules rather than papules or nodules is unique among the histiocytic diseases. 1 Nevertheless, we prefer to classify this case as a considerably variant presentation of generalized eruptive histiocytoma. Generalized eruptive histiocytoma was first described as a distinct entity by Winkelmann and Muller in 1963. 13 Since then, some dozen cases have been reported. 13-23 Generalized eruptive histiocytoma is commonly viewed as a nonlipidizing nonLangerhans cell histiocytosis. A relation to classic solitary histiocytoma/dermatofibroma has not been established. In contrast, some authors have sug-
324
Journal of the American Academy of Dermatology August 1994
Goerdt et al.
-.. -
, ,.
Fig. 2. Light microscopy shows loose aggregates of histiocytic cells in papillary and mid dermis (A). Histiocytes are either small or large (B).
Table 1. Antigenic phenotype of lesional histiocytes Antibodies
Specificity
Result
Source
MS-1 RM 3/1 Dako-T6 Antiserum BU15 Qbendla OKM5 KP1 Mac-387 27E10 Antiserum Antiserum DRCI-R3/24 1FIO
Sinusoidal endothelial cells, dendritic cells Monocytes jmacrophages CD1a
+* +
CDllc CD34 CD36 CD68 MRP-8/-14 MRP-8/-14 MRP-8 MRP-14 Follicular dendritic cells Continuous endothelium
+ +
Goerdt et al.4 Zwadlo et al.8 Dakopattsj Immunotech§ Immunotech Immunotech Ortho] Dakopatts Dakopatts Zwadlo et aL9 Odink et aL10 Odink et aL10 Dakopatts Goerdt et aLII
S-100
+ +
-t
*Cytoplasmic staining of srnall lesional histiocytes, peripheral staining of large lesional histiocytes. tHighly increased vascularization within the lesion. :j:Dako Corp., Glostrup, Denmark. §Immunotech S.A., Marseille, France. [Ortho Diagnostic Systems, Inc., Raritan, N.J.
gested that generalized eruptive histiocytoma may have a close relation to classic Langerhans cell histiocytosis,'? to indeterminate cell histiocytosis.P or to lipidizing non-Langerhans cell histiocytoses, such as xanthoma disseminatum'" and multicentric reticulohistiocytosis.Pb 25
According to Winkelmann and Muller.l' the typical diagnostic features of generalized eruptive histiocytoma include the following: (1) widespread, essentially symmetric, multiple lesions, particularly on the trunk and proximal portions of the extremities and, rarely, the mucous membranes; (2) distinct
Journal of the American Academy of Dermatology Volume 31, Number 2, Part 2
flesh-colored to blue-red papules without a tendency to group; (3) progressive development of new lesions without antecedent history of trauma; (4) spontaneous resolution of lesions toward brown macules or complete disappearance; (5) a benign histologic picture of mononuclear histiocytic cells. In several aspects, the eruption in our patient resembles generalized eruptive histiocytoma-symmetric lesions of the trunk and of the extensor surfaces of the proximal portions of the extremities sparing the face and mucous membranes, and progressive development of new lesions without extracutaneous involvement. However, the primary occurrence of macules rather than papules or nodules, the tendency of the macules to coalesce, and the absence of self-healing are not typical of generalized eruptive histiocytoma. In xanthoma disseminatum, the closest differential diagnosis to generalized eruptive histiocytoma.P papular lesions may coalesce, but they then form plaques in a flexural localization not encountered in our patient. Histologically, there were loose aggregates of small and large histiocytes, but no foamy or multinucleated giant cells. Electron microscopy revealed the absence of Birbeck's granules and of lipid in the cytoplasm of the lesional histiocytes . The absence of Birbeck's granules precludes the diagnosis of classic Langerhans cell histiocytoses and self-healing reticulohistiocytosis,2?,28 whereas the absence of foamy and multinucleated giant cells and of cytoplasmic lipid in the lesional histiocytcs is a prerequisite for the diagnosis of generalized eruptive histiocytoma. 13, 26, 29 In contrast, the simultaneous occurrence of both small and large lesional histiocytes is a typical feature of xanthoma disseminatum rather than of generalized eruptive histiocytoma.P With immunohistochemical studies, lesional histiocytes in our patient did not express CDla and 8-100 protein antigens, thus excluding the diagnosis of Langerhans cell histiocytosis.v 28,30,31 but they expressed MS-I high molecular weight protein in a pattern diagnostic for non-Langerhans cell histiocytoses.? However, lesional histiocytes in our case weakly expressed CD34. CD34 was first described as an antigen specific for hemopoietic progenitor cells in bone marrow.P but it has since been shown to be expressed by continuous type endothelial cells,33-35 dermal dendrocytes, perifollicular cells, spindle cells of Kaposi's sarcoma,36 in dermatofibrosarcoma protuberans," 37 and in fibrous type.?
Goerdt et al. 325
of
Fig. 3. Immunohistochemical phenotyping lesional histiocytes with monoclonal antibodies RM 3/1 (A)and MS-I (B). Monoclonal antibody MS-l showed strong cytoplasmic staining of smalliesional histiocytes and weaker peripheral staining of large lesional histiocytes, whereas RM 3/1 antigen was strongly and uniformly expressed in both cell types.
and less consistently, cellular type dermatofibroma.?'3? In contrast, CD34 has been shown not to he expressed by the lesional histiocytes of non-Langerhans cell histiocytoses, such as xanthoma disseminatum.l'' multicentric reticulohistiocytosis, and juvenile xanthogranuloma." Up to now, we have also failed to induce CD34 in cultured human monocytesjmacrophages. Therefore CD34 expression by the lesional histiocytes in our patient is troubling. If confirmed as a marker for classic generalized eruptive histiocytoma, CD34 expression might indicate a closer relation of this condition to fibroblast-related lesions than other non-Langerhans cell histiocytosis syndromes exhibit. To clarify further the classification, histogenesis, and relation of the histiocytoid lesions, we suggest establishment of an international immunohistochemistry reference laboratory for
Journal of the American Academy of Dermatology August 1994
326 Goerdt et al.
non-Langerhans cell histiocytoses and related diseases. REFERENCES 1. Gianotti F, Caputo R. Histiocytic syndromes: a review. J AM ACAD DERMATOL 1985;13:383-404. 2. The Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1987;1:208-9. 3. Fartasch M, Vignesswaran N, Diepgen TL, et al. Immunohistochemical and ultrastructural study of histiocytosis X and non-X histiocytoses. J AM ACAD DERMATOL 1990; 23:885-92. 4. Goerdt S, Walsh LJ, Murphy GF, et al. Identification of a novel high molecular weight protein antigen preferentially expressed by sinusoidal endothelial cells in normal human tissues. J Cell Bio11991;113:1425-37. 5. Walsh LJ, Goerdt S, Pober JS, et al. MS-1 sinusoidal endothelial antigen is expressed by factor XIIla+, HLADR+ dermal perivascular dendritic cells. Lab Invest 1991; 65:732-41. 6. Goerdt S, Bhardwaj R, Sorg C. Inducible expression of MS-1 high molecular weight protein by endothelial cells of continuous origin and by dendritic cells/macrophages in vivo and in vitro. Am J PatholI993;142:1409-22. 7. GoerdtS, KoldeG, Bonsmann G, eta!. Immunohistochemical comparison of cutaneous histiocytoses and related skin disorders: diagnostic and histogenetic relevance of MS-l high molecular weight protein expression. J Pathol 1993; 170:421-7. 8. Zwadlo G, Voegeli R, Schulze-Osthoff K, et al. A monoclonal antibody to a novel differentiation antigen on human macrophages associated with the downregulation phase of the inflammatory process. Exp Cell Bioi 1987;55:295-304. 9. Zwadlo G, Schlegel R, Sorg C. A monoclonal antibody to a subset of human monocytes found only in the peripheral blood and inflammatorytissues. J ImmunolI986;137:512-8. 10. Odink K, Cerletti N, Bruggen J, et al. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 1987;330:80-2. 11. Goerdt S, Steckel F, Schulze-Osthoff K, et al. Characterization and differential expression of an endothelial cellspecific surface antigen in continuous and sinusoidal endothelia, in skin vascular lesions and in vitro. Exp Cell Biol 1989;57:185-92. 12. Coldiron BM, Cruz PD Jr, Freeman RG, et al. Benign non-X histiocytosis: a unique case bridging several of the non-X histiocytic syndromes. J AM ACAD DERMATOL 1988;18:1282-9. 13. Winkelmann RK, Muller SA. Generalized eruptive histiocytoma. A benign papular histiocytic reticulosis. Arch Dermatol1963;88:586-96. 14. Braun-Falco 0, Korting HC, Zienicke H, et al. Eruptive Histiozytome und Xanthoma disseminatum als Manifestationsformen derselben Erkrankung? Hautarzt 1988;39: 652-7. 15. Saijo S, Hara M, Kuramoto Y, et al. Generalized eruptive histiocytoma: a report of a variant case showing the presence of dermalindeterminate cells. J Cutan Pathol1991 ;18: 134-6. 16. Shimizu N, Ito M, Sato Y. Generalized eruptive histiocy-
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
28. 29. 30. 31. 32.
33. 34.
35. 36.
37.
toma: an ultrastructural study. J Cutan Pathol 1987;14: 100-5. Stables GI, Mackie RM. Generalized eruptive histiocytoma. Br J DermatoI1992;126:196-9. Arnold M-L, Wirth H, Anton-Lamprecht I, et al. Generalisierte eruptive Histiozytome, Hautarzt 1982;33:428-37. Caputo R, Alessi E, Allegra F. Generalized eruptive histiocytoma. Arch Dermatol 1981;117:216-21. SohiAS, Tiwari VD, Subramanian CSV, et al. Generalized eruptive histiocytoma. Dermatologica 1979; 159:471-5. Cramer H -J. Multiple Reticulohistiocytome der Haut ohne nachweisbare Zweiterkrankung. Hautarzt 1963; 14:297302. Caputo R, Ermacora E, Gelmetti C, et al. Generalized eruptive histiocytoma in children. JAM ACAD DERMATOL 1987;17:449-54. Winkelmann RK, Kossard S, Fraga S. Eruptive histiocytoma of childhood. Arch Dermato11980;116:565-70. Chevrant-Breton J. Lareticulo-histiocytosemulticentrique: revue de la literature recente (depuis 1969). Ann Dermatol VenereoI1977;104:745-53. Magnin PH, Bomchil G, Cases JG. Reticulohistiocitosis multicentrica e histiocitoma eruptive generalizado. Prensa Med Argentina 1972;59:331-5. Ringel E, Moschella S. Primary histiocytic dermatoses. Arch Dermato11985;121:1531-41. Hashimoto K, Pritzker MS. Electron microscopic study of reticulohistiocytoma: an unusual case of congenital selfhealingreticulohistiocytosis. Arch Dermato11973;107:26370. Divaris DXG, Ling FCK, Prentice RSA. Congential selfhealingreticulohistiocytosis. AmJ Dermatopathol1991; 13: 481-7. Winkelmann RK. Cutaneous syndromes of non-X histiocytosis. Arch DermatolI981;117:667-72. Zeiger B, Cerio R, Orchard G, et al. Histologic and immunohistochemical study comparing xanthoma disseminatum and histiocytosis X. Arch Dermatol 1992;128:1207-12. Kolde G, Brocker E-B. Multiple tumors of indeterminate cells in an adult. J AM ACAD DERMATOL 1986;15:591-7. Civin CI, Strauss LC, Brovall C, et al. Antigenic analysis of hematopoiesis: III. A hemopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-la cells. J Immunol1984;133:157-65. Beschorner WE, Civin CI, Strauss LC. Localization of hemopoietic progenitor cells in tissue with the anti-My-lO monoclonal antibody. Am J PathoI1985;1l9:1-4. Schlingemann RO, Rietveld FJR, de Waal RMW, et al. Leucocyte antigen CD34 is expressed by a subset of cultured endothelial cellsand on endothelial abluminal microprocesses in the tumorstroma. Lab Invest 1990;62:690-6. Fina L, Molgaard HV, Robertson D, et al. Expression ofthe CD34 gene in vascular endothelial cells. Blood 1990;75: 2417-26. Nickoloff BJ. The human progenitor cell antigen (CD34) is localized on endothelial cells, dermal dendritic cells, and perifollicular cells in formalin-fixed normal skin and on proliferating endothelial cells and stromal spindle-shaped cells in Kaposi's sarcoma. Arch Dermatol1991;127:523-9. Aiba S, Tabata N, Ishii H, et al. Dermatofibrosarcoma protuberans is a unique fibrohistiocytic tumor expressing CD34. Br J Dermatol 1992;127:79-84.