Periodic
svnopsis
This report reflects the best data available at the time the report was prepared, but caution should he exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report.
Mononuclear phagocytic and dendritic cell systems Samuel L. Moschella, MD, and Thomas G. Cropley, MD Boston, Massachusetts The subsets of cells of macrophage lineage are the macrophage and the dendritic cells, that is, the indeterminate cells, interdigitating dendritic cells, the Langerhans cells, and the dermal dendrocyte. The use of heteroantisera and mononuclear antibodies for cellular antigens and enzyme histochemistry has allowed us to identify these cells more easily. The disorders involving these cells can be divided into benign reactive, malignant reactive, and malignant disorders. The current laboratory techniques have helped us identify the histiocytic malignancies that have included other unrelated malignancies. The purpose of this review is to provide the most current and informative references that will provide a better understanding of the histiocyte, an overview of the benign histiocytoses and of the benign histiocytic-associated disorders of children and adults, an update of the diseases caused by the proliferation of Langerhans cells, a definition and description of the eruptions caused by the proliferation of the indeterminate cells and dermal dendrocytes, and the current status of the fatal histiocytoses characterized by cytophagia with or without panniculitis and malignant histiocytic proliferative disorders. BASIC PRINCIPLES
Key points 1. The cellsof the mononuclear phagocytic system are widespread. They originate in the bone marrow, pass through an intermediate stage in the blood,and deposit in tissue as macrophages (histiocytes). Macrophages function as phagocytes,antigen-presenting cells,and secretory cells; they interact with the afferent arm of the immune system by modulating lymphocyte function and with the effector arm as microbicidal agents and modulators of inflammation. 2. Historically, so-called histiocytes were identified From Lahey Clinic Medical Center and Massachusetts General Hospital. Reprint requests: Samuel L. Moschella, MD, Lahey Clinic Medical Center, Departments of Allergy and Dermatology, 41 Mall Road, Burlington, MA 0 \805. 16/1/17988
cytomorphologically. Through the use of heteroantisera and mononuclear antibodies for selected cellular antigens and enzyme histochemistry, the following mononuclear cells in the skin have been identified: the macrophages (described earlier) and the dendritic cells, which include Langerhans cells and dermal dendrocytes. 3. Dendritic cells in general are derived from the bone marrow, present antigens, do not function as phagocytic cells, and are found in blood, lymph, skin, and peripheral lymphoid organs. They have variable Fe receptor activity, adenosine triphosphatase (ATPase) activity, S·IOO protein expression, presence of human lymphocyte antigen (HLA)-DR and T6 antigen, and weak acid phosphatase and nonspecific esterase activity, but they do not contain peroxidases or C3 receptors. Ultrastructurally, Langerhans cells have Birbeck granules. With a better understanding of tissue-associated dendritic cells, the list of tissue-associated histiocytic disorders should diminish. 4. The dermal dendrocyte is the interstitial cell indigenous to the human dermis that has been described erroneouslyas a fibroblast. This bone marrow-derived dermal cell has an extensive phagocytic function and is an important effector cell in the afferent limb of the normal immune response of the dermis. This dendritic cell is identified by demonstration of enzyme factor X IlIa positivity and cytochemical and immunocytochemical characteristics. Ultrastructurally, no Birbeck granules are seen.The dermal dendrocyte is probably the cell of origin for some localized benign proliferative reactions, such as fibrous papule of the nose, dermatofibroma, angiofibroma, and probably atypical fibroxanthoma; malignant fibrous histiocytoma is a malignant homologue. 5. The disorders of these cells can be categorized as benign reactive, malignant reactive, and malignant. Benign reactive disorders include the mucocutaneous histiocytoses,characterized by macrophage and dendritic cell infiltration, and the granulomatous diseases. Reactive disorders with fatal outcomes include hemocytophagic histiocytosis, which includes the familial type and the socalled cytophagic panniculitis. Malignant disorders are histiocytosis X, malignant histiocytosis, and histiocytic lymphoma. Immunologic and enzymatic techniques have shown the so-called histiocytic malignancies to be a heterogeneous group that includes the histiocytic malignan-
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1092 Moschella and Cropley des, some T cell lymphomas, and primitive hematopoietic malignancies.
References HeadingtonJT. The histiocyte. In memoriam [Editorial]. Arch Dermatol 1986;122:532-3. "Heretical as it may appear, it is time to expose the histiocyte and its mastery of cellular disguise for the mononuclear imposter that it is." (page 534) Dr. Headington emphasizes the histiocyte's capacity to resemble other mononuclear cells and the overwhelming pathologic evidence that no longer supports the generic concept of the histiocyte as a specific differentiated cell that has diverse precursors. With the "explosion" of immunobiology, the concepts of the nature of the histiocyte are being challenged. The cutaneous mononuclear cells identified and studied have been the Langerhans cells, the indeterminate cells, the interdigitating dendritic cells, the macrophages, and the dermal dendrocytes. Subsets of T and B lymphocytes are sometimes mistakenly identified as histiocytes. Wood GS, Turner RR, Shiurba RA, et al. Human dendritic cells and macrophages. In situ irnmunophenotypic definition ofsubsets that exhibit specific morphologic and microenvironmental characteristics. Am J Pathol 1985;119:73-82. The authors used immunohistiocytic techniques to demonstrate the immunophenotypic heterogeneity of dendritic cells and macrophages in tissues. Turner RR, Wood GS, Beckstead JH, et a1. Histiocytic malignancies. Morphologic, immunologic, and enzymatic heterogeneity. Am J Surg Pathol 1985;8:485500. The authors studied 14 patients with hematopoietic malignancies that exhibited histologic features of histiocyticdifferentiation. The authors concluded that"the so-called histiocytic malignancies comprise a diverse clinicopathologic group, ranging from malignant histiocytosis with differentiation toward subsets of histiocytes and dendritic cells to localized true histiocytic "large-cell lymphomas." Some T cell lymphomas and primitive hematopoietic malignancies have been included in this heterogeneous group in the past. Edwards L, Goldberg G , Bangert J, et a1. Benign neoplasms, premalignant conditions and malignancy. In : Schachner LA, Hansen RC, eds, Pediatric dermatology. New York: Churchill-Livingstone, 1988:1055118. This chapter provides a good review of the histiocytosis syndromes in children. A concise and informative table describes the clinical features, skin findings, pathologic features, prognosis, and treatment of these disorders . This section lists 76 references.
Dermatology
Greaves MW. Histiocytic proliferative disorders. In: Rook A, Wilkinson DS, Ebling FJG, et al ., eds. Textbook of dermatology, vol. 2 . 4th ed. London: Blackwell , 1986:1699-711. This section discusses histiocytic proliferative disorders by dividing them into histiocytosis X and non-histiocytosis X groups. Granulomatous and malignant histiocytic proliferative diseases are not included. Moschella SL. Diseases of the mononuclear phagocytic system (the so-called reticuloendothelial system). In: Moschella SL, Hurley HJ, eds. Dermatology, vol. 1. 2nd ed. Philadelphia: WB Saunders, 1985:890-1000. This chapter, like that by Greaves earlier, discusses as a group the cutaneous conditions that are characterized by proliferation of dendritic cells or cells that cytomorphologically are or resemble histiocytes. Lasser A. The mononuclear phagocytic system: a review. Hum Patho11985;14:108-26. The mononuclear phagocytic system is reviewed in depth, and more than 300 articles are referenced. The roles of the macrophage described are the phagocytic, microbicidal, tumoricidal, immunoregulatory, hematopoietic, coagulative, and atherogenic, as well as that in wound healing and tissue remodeling. Unanue ER, Allen PM. The immunoregulatory role of the macrophage. HospPract [Off] 1987;22:87-98,102, 4. This article reviews of the phagocytic, antigen-presenting, and secretory functions of the macrophage in its immunoregulatory role. Knowledge about antigen presentation has two potential therapeutic implications: (1) a more specific and rational approach to vaccine production and immunization against bacterial infections and (2) the synthesis of modified nonimmunogenic peptide antagonists that competitively complex to Ia as therapy for autoimmune disease. Gianotti F, Caputo R. Histiocytic syndromes: a review. J AM ACAD DERMATOL 1985 ;13:383-404. The authors describe the clinical, histologic, and ultrastructural features of the most important histiocytic syndromes and their differential diagnosis. Roper SS, Spraker MK. Cutaneous histiocytosis syndromes. Pediatr DermatoI1985;3:19-30. The authors divide cutaneous histiocytosis into two principal forms: a benign proliferative process and a relentless one with a poor prognosis. Published guidelines for the evaluation of patients with histiocytosis are reviewed and modified. Ringel E, Moschella A. Primary histiocytic dermatoses. Arch DermatoI1985;121 :1531-41.
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The physiologic role of the histiocyte (macrophage) in health and diseaseis reviewed briefly. An archaicoverview of the so-called primary benign and malignant histiocytic disorders, excluding histiocytosis X, is presented.
tein that exhibit lymphocytophagocytosis. The disease bas a broad clinical spectrum characterized by cases that undergo spontaneous remission to those with lethal infiltration of vital organs.
Winkelmann RK. Cutaneous syndromes of non-X histiocytosis. A review of the macrophage-histiocyte diseases of the skin. Arch DermatoI1981;1l7 :667-72. The morefamiliarand clinically appreciated macrophage-histiocytic diseases of the skin are reviewed. All descriptions of the syndromes are based on clinical, histologic, biochemical, immunologic, and ultrastructural findings.
C. Progressive nodular histiocytoma BurgdorfWH, Kusch SL, Nix TE Jr, et al. Progressive nodular histiocytoma. Arch Dermatol 1981;117:644-9. A clinically distinctvariant of the so-called normolipemic histiocytic proliferationis characterized by superficial yellow-brown papules and deep nodules, which histologically have fibrous and cellularpatterns that resemble thoseseenin dermatofibromas. Ultrastructurally, the lesions exhibit a strikingdegree of lipid phagocytosis.
HISTIOCYTIC DISORDERS References I. Benign histiocytic-associated disorders of children and infants A. Benigncephalichistiocytosis BarskyBL, Lao I, BarskyS, et al. Benign cephalic histiocytosis. Arch Dermatol 1985;120: 650-5. The first American case of benign cephalic histiocytosis is reported-a 2-year-old boywithextensive asymptomatic papular eruption of the face,neck, andshoulders of 18months' duration. A skin biopsy specimen revealed a predominantly histiocytic cellinfiltrate. Electronmicroscopyrevealed "comma-shaped" inclusions in the cytoplasm of histiocytes. Such cases have mistakenly been diagnosed as an atypical micronodular form of juvenile xanthogranuloma. B. Sinus histiocytosis with massive lymphadenopathy 1. Lazar AP, Esterly NB, Gonzales-Crussi F. Sinus histiocytosis clinically limited to the skin. Pediatr DermatoI1987;4:247-53. A 15-year-old girl had cutaneousnodules as the only manifestation of sinushistiocytosis, which is a rare entity identified by massive lymphadenopathy with characteristic histopathologic changes in children and young adults. Extranodalinfiltrates occurin the orbits, skin, upper respiratory tract, and bone. Approximately 10%of patientshaveskininvolvement, but few have only skin involvement. 2. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. Current status and future directions. Arch DermatoI1988;124:121l-4. The authors caution that diagnosis be based primarilyon the finding of a certaincytologic subtypeof histiocytes positive for S-100 pro-
II. Benign histiocytic-associated disorders of adults A. Normolipemic cutaneous xanthomatosis Sanchez RL, Raimer SS, Peltier F, et al. Papular xanthoma: a clinical, histologic and ultrastructural study. Arch DermatolI985;121 :62331. The patient had papulonodular lesions on the scalp, thorax,and extremities. Histologically, the lesions showed an infiltratemainly of foam cells and Touton giant cells and an absence of primitive primary nonlipidized histiocytes. On electron microscopy, numerous laminated bodies were seen in the cytoplasm of macrophages. LynchP J, WinkelmannRK. Generalizedplane xanthoma andsystemicdisease. Arch Dermatol 1966;93:639-46. A "classic"review article callsattention again to the planexanthoma and its association with malignantlymphoproliferative diseaseand multiple myeloma. Sonoda T, Hashimoto H, Enjoji M. Juvenile xanthogranuloma. Clinicopathologic analysis and immunohistochemical study of 57 patients. Cancer 1985;56:2280-6. Fifty-seven cases of the two forms of juvenile xanthogranuloma (the infantile and adolescent formand the adult form) withclassicclinical and histologic features werestudied clinicopathologically and immunochemically. Finan MC, Winkelmann RK. Necrobioticxanthogranuloma with paraproteinemia. A review of 22 cases. Medicine 1986;65:376-88. Cutaneous nodules and plaques that have an erythematous and xanthomatous hue; a predilection for the face, especially the periorbitalre-
1094 Moschella and Cropley gion, the trunk, and extremities; and a tendency to ulcerate are characteristic of necrobiotic xanthogranuloma. Histologically, the lesions reveal an inflammatory granuloma with xanthomatosis and a "Touton cell panniculitis." This condition is associated with various types ofparaproteinemia and malignant lyrnphoproliferative and plasmacytic disorders. Localized cutaneous disease responds to localized radiation; extensive cutaneous involvement is best treated by chemotherapy. Kumarkiri M, Sudoh M, Miura Y. Xanthoma disseminatum. Report of a case, with histological and ultrastructural studies of skin lesions. JAM ACAD DERMATOL 1981;4:291-9. The case of a patient with the typical xanthomatous lesions on flexural surface and diabetes insipidus is reported. Elastic tissue and occasionally cholesterol crystals were found to be engulfed by the macrophages. No Langerhans cell granules were found in any dermal macrophages. The authors suggest that autophagocytosisof tissue components is one of the pathologic features in cutaneous lesions of xanthoma disseminatum. Fleischmajer P, Schaefer EJ, Gal AE, et al. Normolipemic subcutaneous xanthomatosis. Am J Med 1983;75:1065-70. Multiple subcutaneous plaques and several superficial papules of the skin of the chest and back and plaques on the vocal cords and around the eustachian tubes developed in a 62-year-old man with diabetes mellitus. Dyslipidemia was not present. Results of lipid and enzyme analysis of the subcutaneous xanthomas were similar to those of xanthomas in patients with diabetes mellitus and type V hyperlipidemia. B. Multicentric reticulohistiocytosis Lesher JL Jr, Allen BS. Multicentric reticulohistiocytosis. J AM ACAD DERMATOL 1984; 11:713-23. Multicentric reticulohistiocytosis is described and the historic, clinicopathologic, radiologic, etiologic, therapeutic, and prognostic aspects of the disease are reviewed. This multisystem disorder is characterized by a papulonodular eruption of the face, neck, arms, and hands. The associated polyarthritis can result in a severe disabling arthritis with appreciable deformity. Histologically, infiltration of tissue by histiocytes and multinucleated giant cells with eosinophilic, finely granulated, ground-glass cytoplasm are
Journal of the American Academy of Dermatology
seen. Approximately 25% of patients have an underlying malignancy. C. Generalized eruptive histiocytoma Caputo R, Alessi E, Allegra F. Generalized eruptive histiocytoma. A clinical, histologic, and ultrastructural study. Arch Dermatol 1981; 117:216-21. The authors present a case with characteristic features: clinically, an eruption of several hundred symmetrically arranged papules on the trunk and proximal parts of the extremities with spontaneous resolution of the lesions;histopathologically, a predominant benign mononuclear histiocytic infiltrate intermixed with fibroblasts and few lymphocytes; and ultrastructurally, dense intracytoplasmic bodies showing myelinlike laminations. The authors speculate on the possible importance of cytoplasmic markers in histiocytic proliferations of the skin and present a detailed table of cytoplasmic markers. D. Nodular cutaneous reactive histiocytosis (nodular non-X histiocytosis, progressive nodular histiocytosis) Winkelmann RK, Hu C-H, Kossard S. Response of nodular non-X histiocytosis to vinblastine. Arch DermatoI1982;118:913-7. A 28-year-old woman had progressivecutaneous papulonodular non-X histiocytosis of the face and proximal parts that showed lymphocytes and masses of bening, periodic acid-Schiff (PAS)-positive histiocytes containing diastaseresistant cytoplasmic polysaccharide. The eruption responded to low-dose intravenous vinblastine sulfate. III. Lesions caused by proliferation of Langerbans cells A. Self-healing reticulohistiocytosis Hashimoto K, Griffin D, Kohsbaki M. Selfhealing reticulohistiocytosis: a clinical, histologic,and ultrastructural study ofthe fourth case in the literature. Cancer 1982;49:331-7. The fourth case of self-healing reticulohistiocytosis is reported, with previously reported hematologic abnormalities. The patient had jaundice, neutropenia, and a palpable liver. All these clinical and laboratory changes cleared spontaneously after a 4Y2-month follow-up.
B. Solitary Langerhans cell histiocytoma Berger TG, Lane AT, Headington JT, et al. A solitary variant of congenital self-healing reticulohistiocytosis: solitary Hashimoto-Pritzker disease. Pediatr Dermatol 1986;3:230-6.
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The authors report four neonates with solitary, congenital, rapidlygrowing, ulceratingtumorsof the face, trunk, and extremitiesand no extracutaneous involvement. These tumors contained Langerhans cells and involuted spontaneously.
C. Histiocytosis X Pujol RM, Moreno A, LopezD, et al. Childhood self-healing histiocytosis X. Pediatr Dermatol 1988;5:97-102. The case of an infant with histiocytosis X that waslimitedto the skinand oral mucosaand that regressed spontaneously is discussed. The autoinvolutive subsets of histiocytosis X limited to skin and mucosal membranes involvement are reviewed. The authors emphasize that childhood self-healing histiocytosis should be differentiated from self-healing reticulohistiocytosis (Hashimoto-Pritzker type). Osband ME, Pochedly C. Histiocytosis X: an overview. Hematol Oncol Clin North Am 1987;1:1-7. This article reviews the six themes repeatedly encountered in the study of histiocytosis X: (1) problems with nomenclature, (2) Langerhans cells as the consistent pathognomonic cells, (3) the immune system dysfunction as an important part of the disease, (4) an extremely heterogeneousdisease, (5) improved therapy needed,and (6) slow progress in research. Berry DH, Becton DL. Natural history of histiocytosis X. Hematol Oncol Clin North Am 1987;1:23-24. When the disease is limited to one site, it tends to be self limiting. When more than one site is involved, the disease appears to smolder and be more chronic, with appreciable morbidity and disabilitybut no mortality. When it is acute, it is associated with substantial morbidity and early death. Bingham EA, Bridges JM, Kelly AM, et a1. Letterer-Siwe disease: a study of thirteen cases over a 21-year period. Br J Dermatol 1982; 106:205-9. This is a retrospective study of 13 cases of the acute and usually fatal form of histiocytosis X, Letterer-Siwe disease. The presentation, therapy, and mortality associated with these cases are reviewed and compared with those reported in the literature. Nine children (69%) died, with an average survival time of 5.3 months; four
Phagocytic and dendritic cell systems 1095 children survived 16, 7, 5, and 5.75 years after diagnosis. IV. Lesionscaused by proliferationof indeterrninate cells A. Solitary lesions Berti E, Gianotti R, AlessiE. Unusual cutaneous histiocytosis expressingan intermediate immunophenotype betweenLangerhans cellsand dermal macrophages, Arch Dermatol 1988;124: 1250-3. A red, asymptomatic, 1 em nodule on the right arm of a man wasexcised.No relapse or visceral involvement occurred during a 2-year follow-up. This benign solitary tumor of the skin was reported as an immunophenotype intermediate between Langerhans cells and dermal macrophages.
B. Multiple lesions Wood GS, Hu C-H, Beckstead JH, et at The indeterminate cell proliferative disorder: report of a case manifesting as an unusual cutaneous histiocytosis. Dermatol Surg Oncol 1985;11: 1111-9. A woman had symmetric, slightly erythematous papules and nodules on the face, forearms, legs, and thighs, which, on the basis of morphologic, antigenic, and enzymatic studies, were proliferations of cutaneous indeterminate cells. This disorder appears to be chronic, limited to the skin, and responsive to intravenous vinblastine. Kolde G, Brocker E-B. Multiple skin tumors of indeterminate cells in an adult. J AM ACAD DERMATOL 1986;15:591-7. A man had widespread and symmetric nodules of circumscribed proliferations of indeterminate cells. Acute mast cell leukemia developed and the patient died. The skin lesions had disappeared during chemotherapy. The authors suggest that this skin disease may represent a paraneoplastic syndrome.. V. Malignant proliferative histiocytic disorders Immunologicand enzymatic techniques have shown the so-called histiocytic malignancies to be a heterogeneous group that includes the histiocytic malignancies, some T cell lymphomas, and primitive hematopoietic malignancies. Among the rare fatal histiocytoses are malignant histiocytosis and reactive hemocytophagic histiocytosis. The clinical and histologic differences between malignant histiocytosis andhemocytophagichistiocytosisand itsvariants are notalwaysdistinct. They have many clinicalfeatures
Journal of the
1096 Moschella and Cropley in common, including hyperpyrexia, lymphadenopathy, hepatosplenomegaly, and pancytopenia. The skin lesions in approximately 10%to 20% of patients with malignant histiocytosis are variable and have been described as purpura, petechiae, papules, nodules, ulcerative lesions,necrotic plaques, and eschars, Although reactive histiocytosis usually has a more immediate favorable prognosis, it is ultimately fatal, like malignant histiocytosis.In some patients, a clear differentiation of malignant from reactive histiocytosis will. not be possible until a clonal marker for malignant histiocytosis is found. A. Reactive process 1. Hemocytophagic histiocytosis and the familial variant (familial hemophagocytic lymphohistiocytosis [FHLH]) Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine 1988; 67:369-88. The clinical and laboratory features of patients with the syndrome of hemocytophagic histiocytosis are reviewed. The clinical course is generally fulminant and may be complicated by coagulation abnormalities, hepatic dysfunction, and renal failure. The syndrome is usually self limited. It usually occurs in patient who have immunologicabnormalities or neoplasms and in whom infections, especially viral infections (viral-associated hemocytophagic syndrome [VAHSD, develop. Soffer D, Okon E, Rosen N, et al. Familial hematophagocytic lymphohistiocytosis in Israel. II. Pathologic findings. Cancer 1984;54:243- 31. Eleven patients from four affected families were studied, with special attention to pathologic findings. Familial hemophagocytic lymphohistiocytosis (FHLH) has been regarded as a distinct disease because of young age at onset, family history, and clinical and pathologic findings. Central nervous system involvement is common. Phagocytosis of erythrocytes and other blood elements by blandappearing histiocytes is striking. 2. Histiocytic cytophagic panniculitis Willis SM, Opal SM, Fitzpatrick JE. Cytophagic histiocytic panniculitis: systemic histiocytosis presenting as chronic, nonhealing, ulcerative skin lesions. Arch Dermatol 1985;121:910-3. The case of a patient who had systemic histiocytosis and chronic, nodular, ulcerative skin lesions is reported.
American Academy of Dermatology
Alegre VA, Winkelmann RK. Histiocytic cytophagic panniculitis. J AM ACAD DERMATOL 1989;20:177-85. The authors reviewed 19 cases of histiocytic cytophagic panniculitis from the literature. They described the clinical and histopathologic features of these cases and reviewed the cases of Weber-Christian disease with features of histiocytic cytophagic panniculitis. The clinical features were inflammatory panniculitis, fever, serositis, reticuloendotheliomegaly, and coagulative defects associated with terminal purpuric episodes. The skin lesions were large hemorrhagic subcutaneous nodules and plaques, which were occasionally ulcerated. The microscopic findings were benign histiocytosis with phagocytosis of erythrocytes, leukocytes, especially lymphocytes, and platelets. At autopsy, "bean-bag" cytophagic cells were seen in bone marrow, liver, spleen, and lymph nodes. The authors advocate aggressive polychemotherapy when there is systemic involvement and large ecchymotic cutaneous plaques.
B. Neoplastic process 1. Malignant histiocytosis Dodd HLJ, Stansfeld AG, Chambers TJ. Cutaneous malignant histiocytosis-a clinicopathological review of five cases. Br J DermatoI1985;1l3:455-61. Malignant histiocytosis, which is rare and fatal, may involve the skin (in 13.1% of patients) and may be the initial symptom in a small number (6.9%) of patients. The authors describe fivepatients with a distinct cutaneous form of malignant histiocytosis who experienced prolonged remissions and survival. Spontaneous resolution of the skin lesions was a feature of two cases. The authors suggest that patients with malignant histiocytosis confined to the skin have a more favorable prognosis. Ducatman BS, Wick MR, Morgan TW, et al. Malignant histiocytosis: a clinical, histologic, and immunohistochemical study of 20 cases. Hum PathoI1985;145:368-77. A correct diagnosis before death was made in only 50% of patients. The mean survival in 17 cases was 7.6 months; three of the seven patients treated aggressively with chemotherapy had complete remission of the disease. Those with initial confinement of the disease to the skin and with an absence of cytopenia and abnormal liver function survived for a
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longerperiod. Autopsies showed that the organsinvolved differed from thosereportedin the past. The histologic appearance of the cells rangedfrom benignto highlyanaplastic; hemophagocytosis was best appreciated and prominentin areas that appeared bland histologically. Because of the accelerated progression of this disease and its potential response to current chemotherapeutic regimen, a rapid diagnosis is imperative. 2. Regressing atypical histiocytosis (RAH) Headington JT, Roth MS, Schnitzer B. Regressing atypical histiocytosis: a review and critical appraisal. Semin Diagn Pathol 1987;4:28-37. The histiocytic origin of regressing atypical histiocytosis (RAH) must now be considered questionable becauseof the results of immunologic phenotyping and the description of the rearrangement of the T-eeIl receptor (jand'Y-chain genes in the newly studiedcases. These studies indicate that this previously considered, primary, cutaneous, histiocytic neoplasm is most likely of T cell lineage. Weiss LM, Trela MJ, Cleary ML, et al. Frequent immunoglobulin and T-cell receptorgenerearrangementsin "histiocytic" neoplasms. Am J Pathol1985;121:369-73. The authors analyzedthe DNA ofimmunoglobulin and T-cellreceptor genes in a series ofsix malignancies that werejudgedto be of histiocytic derivation on the basis of morphology. The results of these studies, in conjunction with the authors' previous observations, suggest that many presumed histiocytic malignancies actually represent T cel11yrnphomas. The authors alsostate alternatively that (j-chain T-cellreceptorgenerearrangement may be a cornmon feature of tumorsthat show monocyteor histiocyte differentiation. SUMMARY
This review presents a classification scheme for disorders of the mononuclear phagocyte and dendritic cell systems. Previous classifications, based primarily on cytomorphology, are now obsolete. Electron microscopy, enzyme histochemistry, and, especially, immunocytochemistry have revealed the histiocyte identified by hematoxylin-and-eosin staining to be not one but several cell types. Currently, two broad groups of histiocytic cells are recognized,
Phagocytic and dendritic cell systems 1097 the monocyte-macrophage group and the dendritic cells. Dendritic cells are further subclassified as Langerhans cells, indeterminate cells, interdigitating cells, and dermal dendrocytes. Many disorders of the skin and other organs are characterized by proliferation of "histiocytic"-appearing cells. Some of these diseases clearly behave in a malignant fashion, whereas others follow a benign or variable course. At present, the proliferating cell type has been identified in only a few of these disorders by ultramicroscopy and cytochemical and immunocytochemical methods. Nevertheless, the pieces of the puzzle are beginning to fall into place. In general, those disorders that typically behave in a malignant fashion have been more extensively studied. The benign histiocytic disorders of children and adults are a heterogeneous group of diseases. Currently, some of these disorders are unclassified or classified with uncertainty. For example, how should severe histiocytosis with massive lymphadenopathy be classified? There is a proliferation of nonlymphoid mononuclear cells that are positive for S-100 protein and negative for CDl and that exhibit lymphophagocytosis. Is this then a mononuclear phagocytic or dendritic celldisorder? Juvenile xanthogranuloma is a disorder of macrophages. Self-healing reticulohistiocytosis and solitary Langerhans cell histiocytoma are benign proliferative disorders of Langerhans cells. Two cases of multiple, cutaneous, nodular proliferations of indeterminate cells have been reported. Because of their rarity and the lack of more complete laboratory studies, the other benign histiocytic disorders have not been studied adequately to permit a clear identification of the putative proliferating cell type. Of the malignant disorders, histiocytosis X is now fairly well established as a disorder of Langerhans cells. Several malignant or ultimately malignant disorders characterized by proliferation of macrophages are known. All these diseases (hemocytophagic histiocytosis and its familial variant, histiocytic cytophagic panniculitis, and malignant histiocytosis) are characterized histologically by erythrophagocytosis and varying cellular atypia. Malignant histiocytosis has been well characterized immunocytochemically as adisordered proliferation ofmonocyte-macrophage cells. Histiocytic lymphoma and monocytic leukemia are distinct clinically, cytomorphologically, and immunocytochemically from malignant histiocytosis.
svnopsis
This report reflects the best data available at the time the report was prepared, but caution should he exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report.
Mononuclear phagocytic and dendritic cell systems Samuel L. Moschella, MD, and Thomas G. Cropley, MD Boston, Massachusetts The subsets of cells of macrophage lineage are the macrophage and the dendritic cells, that is, the indeterminate cells, interdigitating dendritic cells, the Langerhans cells, and the dermal dendrocyte. The use of heteroantisera and mononuclear antibodies for cellular antigens and enzyme histochemistry has allowed us to identify these cells more easily. The disorders involving these cells can be divided into benign reactive, malignant reactive, and malignant disorders. The current laboratory techniques have helped us identify the histiocytic malignancies that have included other unrelated malignancies. The purpose of this review is to provide the most current and informative references that will provide a better understanding of the histiocyte, an overview of the benign histiocytoses and of the benign histiocytic-associated disorders of children and adults, an update of the diseases caused by the proliferation of Langerhans cells, a definition and description of the eruptions caused by the proliferation of the indeterminate cells and dermal dendrocytes, and the current status of the fatal histiocytoses characterized by cytophagia with or without panniculitis and malignant histiocytic proliferative disorders. BASIC PRINCIPLES
Key points 1. The cellsof the mononuclear phagocytic system are widespread. They originate in the bone marrow, pass through an intermediate stage in the blood,and deposit in tissue as macrophages (histiocytes). Macrophages function as phagocytes,antigen-presenting cells,and secretory cells; they interact with the afferent arm of the immune system by modulating lymphocyte function and with the effector arm as microbicidal agents and modulators of inflammation. 2. Historically, so-called histiocytes were identified From Lahey Clinic Medical Center and Massachusetts General Hospital. Reprint requests: Samuel L. Moschella, MD, Lahey Clinic Medical Center, Departments of Allergy and Dermatology, 41 Mall Road, Burlington, MA 0 \805. 16/1/17988
cytomorphologically. Through the use of heteroantisera and mononuclear antibodies for selected cellular antigens and enzyme histochemistry, the following mononuclear cells in the skin have been identified: the macrophages (described earlier) and the dendritic cells, which include Langerhans cells and dermal dendrocytes. 3. Dendritic cells in general are derived from the bone marrow, present antigens, do not function as phagocytic cells, and are found in blood, lymph, skin, and peripheral lymphoid organs. They have variable Fe receptor activity, adenosine triphosphatase (ATPase) activity, S·IOO protein expression, presence of human lymphocyte antigen (HLA)-DR and T6 antigen, and weak acid phosphatase and nonspecific esterase activity, but they do not contain peroxidases or C3 receptors. Ultrastructurally, Langerhans cells have Birbeck granules. With a better understanding of tissue-associated dendritic cells, the list of tissue-associated histiocytic disorders should diminish. 4. The dermal dendrocyte is the interstitial cell indigenous to the human dermis that has been described erroneouslyas a fibroblast. This bone marrow-derived dermal cell has an extensive phagocytic function and is an important effector cell in the afferent limb of the normal immune response of the dermis. This dendritic cell is identified by demonstration of enzyme factor X IlIa positivity and cytochemical and immunocytochemical characteristics. Ultrastructurally, no Birbeck granules are seen.The dermal dendrocyte is probably the cell of origin for some localized benign proliferative reactions, such as fibrous papule of the nose, dermatofibroma, angiofibroma, and probably atypical fibroxanthoma; malignant fibrous histiocytoma is a malignant homologue. 5. The disorders of these cells can be categorized as benign reactive, malignant reactive, and malignant. Benign reactive disorders include the mucocutaneous histiocytoses,characterized by macrophage and dendritic cell infiltration, and the granulomatous diseases. Reactive disorders with fatal outcomes include hemocytophagic histiocytosis, which includes the familial type and the socalled cytophagic panniculitis. Malignant disorders are histiocytosis X, malignant histiocytosis, and histiocytic lymphoma. Immunologic and enzymatic techniques have shown the so-called histiocytic malignancies to be a heterogeneous group that includes the histiocytic malignan-
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1092 Moschella and Cropley des, some T cell lymphomas, and primitive hematopoietic malignancies.
References HeadingtonJT. The histiocyte. In memoriam [Editorial]. Arch Dermatol 1986;122:532-3. "Heretical as it may appear, it is time to expose the histiocyte and its mastery of cellular disguise for the mononuclear imposter that it is." (page 534) Dr. Headington emphasizes the histiocyte's capacity to resemble other mononuclear cells and the overwhelming pathologic evidence that no longer supports the generic concept of the histiocyte as a specific differentiated cell that has diverse precursors. With the "explosion" of immunobiology, the concepts of the nature of the histiocyte are being challenged. The cutaneous mononuclear cells identified and studied have been the Langerhans cells, the indeterminate cells, the interdigitating dendritic cells, the macrophages, and the dermal dendrocytes. Subsets of T and B lymphocytes are sometimes mistakenly identified as histiocytes. Wood GS, Turner RR, Shiurba RA, et al. Human dendritic cells and macrophages. In situ irnmunophenotypic definition ofsubsets that exhibit specific morphologic and microenvironmental characteristics. Am J Pathol 1985;119:73-82. The authors used immunohistiocytic techniques to demonstrate the immunophenotypic heterogeneity of dendritic cells and macrophages in tissues. Turner RR, Wood GS, Beckstead JH, et a1. Histiocytic malignancies. Morphologic, immunologic, and enzymatic heterogeneity. Am J Surg Pathol 1985;8:485500. The authors studied 14 patients with hematopoietic malignancies that exhibited histologic features of histiocyticdifferentiation. The authors concluded that"the so-called histiocytic malignancies comprise a diverse clinicopathologic group, ranging from malignant histiocytosis with differentiation toward subsets of histiocytes and dendritic cells to localized true histiocytic "large-cell lymphomas." Some T cell lymphomas and primitive hematopoietic malignancies have been included in this heterogeneous group in the past. Edwards L, Goldberg G , Bangert J, et a1. Benign neoplasms, premalignant conditions and malignancy. In : Schachner LA, Hansen RC, eds, Pediatric dermatology. New York: Churchill-Livingstone, 1988:1055118. This chapter provides a good review of the histiocytosis syndromes in children. A concise and informative table describes the clinical features, skin findings, pathologic features, prognosis, and treatment of these disorders . This section lists 76 references.
Dermatology
Greaves MW. Histiocytic proliferative disorders. In: Rook A, Wilkinson DS, Ebling FJG, et al ., eds. Textbook of dermatology, vol. 2 . 4th ed. London: Blackwell , 1986:1699-711. This section discusses histiocytic proliferative disorders by dividing them into histiocytosis X and non-histiocytosis X groups. Granulomatous and malignant histiocytic proliferative diseases are not included. Moschella SL. Diseases of the mononuclear phagocytic system (the so-called reticuloendothelial system). In: Moschella SL, Hurley HJ, eds. Dermatology, vol. 1. 2nd ed. Philadelphia: WB Saunders, 1985:890-1000. This chapter, like that by Greaves earlier, discusses as a group the cutaneous conditions that are characterized by proliferation of dendritic cells or cells that cytomorphologically are or resemble histiocytes. Lasser A. The mononuclear phagocytic system: a review. Hum Patho11985;14:108-26. The mononuclear phagocytic system is reviewed in depth, and more than 300 articles are referenced. The roles of the macrophage described are the phagocytic, microbicidal, tumoricidal, immunoregulatory, hematopoietic, coagulative, and atherogenic, as well as that in wound healing and tissue remodeling. Unanue ER, Allen PM. The immunoregulatory role of the macrophage. HospPract [Off] 1987;22:87-98,102, 4. This article reviews of the phagocytic, antigen-presenting, and secretory functions of the macrophage in its immunoregulatory role. Knowledge about antigen presentation has two potential therapeutic implications: (1) a more specific and rational approach to vaccine production and immunization against bacterial infections and (2) the synthesis of modified nonimmunogenic peptide antagonists that competitively complex to Ia as therapy for autoimmune disease. Gianotti F, Caputo R. Histiocytic syndromes: a review. J AM ACAD DERMATOL 1985 ;13:383-404. The authors describe the clinical, histologic, and ultrastructural features of the most important histiocytic syndromes and their differential diagnosis. Roper SS, Spraker MK. Cutaneous histiocytosis syndromes. Pediatr DermatoI1985;3:19-30. The authors divide cutaneous histiocytosis into two principal forms: a benign proliferative process and a relentless one with a poor prognosis. Published guidelines for the evaluation of patients with histiocytosis are reviewed and modified. Ringel E, Moschella A. Primary histiocytic dermatoses. Arch DermatoI1985;121 :1531-41.
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Phagocytic and dendritic cell systems 1093
The physiologic role of the histiocyte (macrophage) in health and diseaseis reviewed briefly. An archaicoverview of the so-called primary benign and malignant histiocytic disorders, excluding histiocytosis X, is presented.
tein that exhibit lymphocytophagocytosis. The disease bas a broad clinical spectrum characterized by cases that undergo spontaneous remission to those with lethal infiltration of vital organs.
Winkelmann RK. Cutaneous syndromes of non-X histiocytosis. A review of the macrophage-histiocyte diseases of the skin. Arch DermatoI1981;1l7 :667-72. The morefamiliarand clinically appreciated macrophage-histiocytic diseases of the skin are reviewed. All descriptions of the syndromes are based on clinical, histologic, biochemical, immunologic, and ultrastructural findings.
C. Progressive nodular histiocytoma BurgdorfWH, Kusch SL, Nix TE Jr, et al. Progressive nodular histiocytoma. Arch Dermatol 1981;117:644-9. A clinically distinctvariant of the so-called normolipemic histiocytic proliferationis characterized by superficial yellow-brown papules and deep nodules, which histologically have fibrous and cellularpatterns that resemble thoseseenin dermatofibromas. Ultrastructurally, the lesions exhibit a strikingdegree of lipid phagocytosis.
HISTIOCYTIC DISORDERS References I. Benign histiocytic-associated disorders of children and infants A. Benigncephalichistiocytosis BarskyBL, Lao I, BarskyS, et al. Benign cephalic histiocytosis. Arch Dermatol 1985;120: 650-5. The first American case of benign cephalic histiocytosis is reported-a 2-year-old boywithextensive asymptomatic papular eruption of the face,neck, andshoulders of 18months' duration. A skin biopsy specimen revealed a predominantly histiocytic cellinfiltrate. Electronmicroscopyrevealed "comma-shaped" inclusions in the cytoplasm of histiocytes. Such cases have mistakenly been diagnosed as an atypical micronodular form of juvenile xanthogranuloma. B. Sinus histiocytosis with massive lymphadenopathy 1. Lazar AP, Esterly NB, Gonzales-Crussi F. Sinus histiocytosis clinically limited to the skin. Pediatr DermatoI1987;4:247-53. A 15-year-old girl had cutaneousnodules as the only manifestation of sinushistiocytosis, which is a rare entity identified by massive lymphadenopathy with characteristic histopathologic changes in children and young adults. Extranodalinfiltrates occurin the orbits, skin, upper respiratory tract, and bone. Approximately 10%of patientshaveskininvolvement, but few have only skin involvement. 2. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. Current status and future directions. Arch DermatoI1988;124:121l-4. The authors caution that diagnosis be based primarilyon the finding of a certaincytologic subtypeof histiocytes positive for S-100 pro-
II. Benign histiocytic-associated disorders of adults A. Normolipemic cutaneous xanthomatosis Sanchez RL, Raimer SS, Peltier F, et al. Papular xanthoma: a clinical, histologic and ultrastructural study. Arch DermatolI985;121 :62331. The patient had papulonodular lesions on the scalp, thorax,and extremities. Histologically, the lesions showed an infiltratemainly of foam cells and Touton giant cells and an absence of primitive primary nonlipidized histiocytes. On electron microscopy, numerous laminated bodies were seen in the cytoplasm of macrophages. LynchP J, WinkelmannRK. Generalizedplane xanthoma andsystemicdisease. Arch Dermatol 1966;93:639-46. A "classic"review article callsattention again to the planexanthoma and its association with malignantlymphoproliferative diseaseand multiple myeloma. Sonoda T, Hashimoto H, Enjoji M. Juvenile xanthogranuloma. Clinicopathologic analysis and immunohistochemical study of 57 patients. Cancer 1985;56:2280-6. Fifty-seven cases of the two forms of juvenile xanthogranuloma (the infantile and adolescent formand the adult form) withclassicclinical and histologic features werestudied clinicopathologically and immunochemically. Finan MC, Winkelmann RK. Necrobioticxanthogranuloma with paraproteinemia. A review of 22 cases. Medicine 1986;65:376-88. Cutaneous nodules and plaques that have an erythematous and xanthomatous hue; a predilection for the face, especially the periorbitalre-
1094 Moschella and Cropley gion, the trunk, and extremities; and a tendency to ulcerate are characteristic of necrobiotic xanthogranuloma. Histologically, the lesions reveal an inflammatory granuloma with xanthomatosis and a "Touton cell panniculitis." This condition is associated with various types ofparaproteinemia and malignant lyrnphoproliferative and plasmacytic disorders. Localized cutaneous disease responds to localized radiation; extensive cutaneous involvement is best treated by chemotherapy. Kumarkiri M, Sudoh M, Miura Y. Xanthoma disseminatum. Report of a case, with histological and ultrastructural studies of skin lesions. JAM ACAD DERMATOL 1981;4:291-9. The case of a patient with the typical xanthomatous lesions on flexural surface and diabetes insipidus is reported. Elastic tissue and occasionally cholesterol crystals were found to be engulfed by the macrophages. No Langerhans cell granules were found in any dermal macrophages. The authors suggest that autophagocytosisof tissue components is one of the pathologic features in cutaneous lesions of xanthoma disseminatum. Fleischmajer P, Schaefer EJ, Gal AE, et al. Normolipemic subcutaneous xanthomatosis. Am J Med 1983;75:1065-70. Multiple subcutaneous plaques and several superficial papules of the skin of the chest and back and plaques on the vocal cords and around the eustachian tubes developed in a 62-year-old man with diabetes mellitus. Dyslipidemia was not present. Results of lipid and enzyme analysis of the subcutaneous xanthomas were similar to those of xanthomas in patients with diabetes mellitus and type V hyperlipidemia. B. Multicentric reticulohistiocytosis Lesher JL Jr, Allen BS. Multicentric reticulohistiocytosis. J AM ACAD DERMATOL 1984; 11:713-23. Multicentric reticulohistiocytosis is described and the historic, clinicopathologic, radiologic, etiologic, therapeutic, and prognostic aspects of the disease are reviewed. This multisystem disorder is characterized by a papulonodular eruption of the face, neck, arms, and hands. The associated polyarthritis can result in a severe disabling arthritis with appreciable deformity. Histologically, infiltration of tissue by histiocytes and multinucleated giant cells with eosinophilic, finely granulated, ground-glass cytoplasm are
Journal of the American Academy of Dermatology
seen. Approximately 25% of patients have an underlying malignancy. C. Generalized eruptive histiocytoma Caputo R, Alessi E, Allegra F. Generalized eruptive histiocytoma. A clinical, histologic, and ultrastructural study. Arch Dermatol 1981; 117:216-21. The authors present a case with characteristic features: clinically, an eruption of several hundred symmetrically arranged papules on the trunk and proximal parts of the extremities with spontaneous resolution of the lesions;histopathologically, a predominant benign mononuclear histiocytic infiltrate intermixed with fibroblasts and few lymphocytes; and ultrastructurally, dense intracytoplasmic bodies showing myelinlike laminations. The authors speculate on the possible importance of cytoplasmic markers in histiocytic proliferations of the skin and present a detailed table of cytoplasmic markers. D. Nodular cutaneous reactive histiocytosis (nodular non-X histiocytosis, progressive nodular histiocytosis) Winkelmann RK, Hu C-H, Kossard S. Response of nodular non-X histiocytosis to vinblastine. Arch DermatoI1982;118:913-7. A 28-year-old woman had progressivecutaneous papulonodular non-X histiocytosis of the face and proximal parts that showed lymphocytes and masses of bening, periodic acid-Schiff (PAS)-positive histiocytes containing diastaseresistant cytoplasmic polysaccharide. The eruption responded to low-dose intravenous vinblastine sulfate. III. Lesions caused by proliferation of Langerbans cells A. Self-healing reticulohistiocytosis Hashimoto K, Griffin D, Kohsbaki M. Selfhealing reticulohistiocytosis: a clinical, histologic,and ultrastructural study ofthe fourth case in the literature. Cancer 1982;49:331-7. The fourth case of self-healing reticulohistiocytosis is reported, with previously reported hematologic abnormalities. The patient had jaundice, neutropenia, and a palpable liver. All these clinical and laboratory changes cleared spontaneously after a 4Y2-month follow-up.
B. Solitary Langerhans cell histiocytoma Berger TG, Lane AT, Headington JT, et al. A solitary variant of congenital self-healing reticulohistiocytosis: solitary Hashimoto-Pritzker disease. Pediatr Dermatol 1986;3:230-6.
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The authors report four neonates with solitary, congenital, rapidlygrowing, ulceratingtumorsof the face, trunk, and extremitiesand no extracutaneous involvement. These tumors contained Langerhans cells and involuted spontaneously.
C. Histiocytosis X Pujol RM, Moreno A, LopezD, et al. Childhood self-healing histiocytosis X. Pediatr Dermatol 1988;5:97-102. The case of an infant with histiocytosis X that waslimitedto the skinand oral mucosaand that regressed spontaneously is discussed. The autoinvolutive subsets of histiocytosis X limited to skin and mucosal membranes involvement are reviewed. The authors emphasize that childhood self-healing histiocytosis should be differentiated from self-healing reticulohistiocytosis (Hashimoto-Pritzker type). Osband ME, Pochedly C. Histiocytosis X: an overview. Hematol Oncol Clin North Am 1987;1:1-7. This article reviews the six themes repeatedly encountered in the study of histiocytosis X: (1) problems with nomenclature, (2) Langerhans cells as the consistent pathognomonic cells, (3) the immune system dysfunction as an important part of the disease, (4) an extremely heterogeneousdisease, (5) improved therapy needed,and (6) slow progress in research. Berry DH, Becton DL. Natural history of histiocytosis X. Hematol Oncol Clin North Am 1987;1:23-24. When the disease is limited to one site, it tends to be self limiting. When more than one site is involved, the disease appears to smolder and be more chronic, with appreciable morbidity and disabilitybut no mortality. When it is acute, it is associated with substantial morbidity and early death. Bingham EA, Bridges JM, Kelly AM, et a1. Letterer-Siwe disease: a study of thirteen cases over a 21-year period. Br J Dermatol 1982; 106:205-9. This is a retrospective study of 13 cases of the acute and usually fatal form of histiocytosis X, Letterer-Siwe disease. The presentation, therapy, and mortality associated with these cases are reviewed and compared with those reported in the literature. Nine children (69%) died, with an average survival time of 5.3 months; four
Phagocytic and dendritic cell systems 1095 children survived 16, 7, 5, and 5.75 years after diagnosis. IV. Lesionscaused by proliferationof indeterrninate cells A. Solitary lesions Berti E, Gianotti R, AlessiE. Unusual cutaneous histiocytosis expressingan intermediate immunophenotype betweenLangerhans cellsand dermal macrophages, Arch Dermatol 1988;124: 1250-3. A red, asymptomatic, 1 em nodule on the right arm of a man wasexcised.No relapse or visceral involvement occurred during a 2-year follow-up. This benign solitary tumor of the skin was reported as an immunophenotype intermediate between Langerhans cells and dermal macrophages.
B. Multiple lesions Wood GS, Hu C-H, Beckstead JH, et at The indeterminate cell proliferative disorder: report of a case manifesting as an unusual cutaneous histiocytosis. Dermatol Surg Oncol 1985;11: 1111-9. A woman had symmetric, slightly erythematous papules and nodules on the face, forearms, legs, and thighs, which, on the basis of morphologic, antigenic, and enzymatic studies, were proliferations of cutaneous indeterminate cells. This disorder appears to be chronic, limited to the skin, and responsive to intravenous vinblastine. Kolde G, Brocker E-B. Multiple skin tumors of indeterminate cells in an adult. J AM ACAD DERMATOL 1986;15:591-7. A man had widespread and symmetric nodules of circumscribed proliferations of indeterminate cells. Acute mast cell leukemia developed and the patient died. The skin lesions had disappeared during chemotherapy. The authors suggest that this skin disease may represent a paraneoplastic syndrome.. V. Malignant proliferative histiocytic disorders Immunologicand enzymatic techniques have shown the so-called histiocytic malignancies to be a heterogeneous group that includes the histiocytic malignancies, some T cell lymphomas, and primitive hematopoietic malignancies. Among the rare fatal histiocytoses are malignant histiocytosis and reactive hemocytophagic histiocytosis. The clinical and histologic differences between malignant histiocytosis andhemocytophagichistiocytosisand itsvariants are notalwaysdistinct. They have many clinicalfeatures
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1096 Moschella and Cropley in common, including hyperpyrexia, lymphadenopathy, hepatosplenomegaly, and pancytopenia. The skin lesions in approximately 10%to 20% of patients with malignant histiocytosis are variable and have been described as purpura, petechiae, papules, nodules, ulcerative lesions,necrotic plaques, and eschars, Although reactive histiocytosis usually has a more immediate favorable prognosis, it is ultimately fatal, like malignant histiocytosis.In some patients, a clear differentiation of malignant from reactive histiocytosis will. not be possible until a clonal marker for malignant histiocytosis is found. A. Reactive process 1. Hemocytophagic histiocytosis and the familial variant (familial hemophagocytic lymphohistiocytosis [FHLH]) Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine 1988; 67:369-88. The clinical and laboratory features of patients with the syndrome of hemocytophagic histiocytosis are reviewed. The clinical course is generally fulminant and may be complicated by coagulation abnormalities, hepatic dysfunction, and renal failure. The syndrome is usually self limited. It usually occurs in patient who have immunologicabnormalities or neoplasms and in whom infections, especially viral infections (viral-associated hemocytophagic syndrome [VAHSD, develop. Soffer D, Okon E, Rosen N, et al. Familial hematophagocytic lymphohistiocytosis in Israel. II. Pathologic findings. Cancer 1984;54:243- 31. Eleven patients from four affected families were studied, with special attention to pathologic findings. Familial hemophagocytic lymphohistiocytosis (FHLH) has been regarded as a distinct disease because of young age at onset, family history, and clinical and pathologic findings. Central nervous system involvement is common. Phagocytosis of erythrocytes and other blood elements by blandappearing histiocytes is striking. 2. Histiocytic cytophagic panniculitis Willis SM, Opal SM, Fitzpatrick JE. Cytophagic histiocytic panniculitis: systemic histiocytosis presenting as chronic, nonhealing, ulcerative skin lesions. Arch Dermatol 1985;121:910-3. The case of a patient who had systemic histiocytosis and chronic, nodular, ulcerative skin lesions is reported.
American Academy of Dermatology
Alegre VA, Winkelmann RK. Histiocytic cytophagic panniculitis. J AM ACAD DERMATOL 1989;20:177-85. The authors reviewed 19 cases of histiocytic cytophagic panniculitis from the literature. They described the clinical and histopathologic features of these cases and reviewed the cases of Weber-Christian disease with features of histiocytic cytophagic panniculitis. The clinical features were inflammatory panniculitis, fever, serositis, reticuloendotheliomegaly, and coagulative defects associated with terminal purpuric episodes. The skin lesions were large hemorrhagic subcutaneous nodules and plaques, which were occasionally ulcerated. The microscopic findings were benign histiocytosis with phagocytosis of erythrocytes, leukocytes, especially lymphocytes, and platelets. At autopsy, "bean-bag" cytophagic cells were seen in bone marrow, liver, spleen, and lymph nodes. The authors advocate aggressive polychemotherapy when there is systemic involvement and large ecchymotic cutaneous plaques.
B. Neoplastic process 1. Malignant histiocytosis Dodd HLJ, Stansfeld AG, Chambers TJ. Cutaneous malignant histiocytosis-a clinicopathological review of five cases. Br J DermatoI1985;1l3:455-61. Malignant histiocytosis, which is rare and fatal, may involve the skin (in 13.1% of patients) and may be the initial symptom in a small number (6.9%) of patients. The authors describe fivepatients with a distinct cutaneous form of malignant histiocytosis who experienced prolonged remissions and survival. Spontaneous resolution of the skin lesions was a feature of two cases. The authors suggest that patients with malignant histiocytosis confined to the skin have a more favorable prognosis. Ducatman BS, Wick MR, Morgan TW, et al. Malignant histiocytosis: a clinical, histologic, and immunohistochemical study of 20 cases. Hum PathoI1985;145:368-77. A correct diagnosis before death was made in only 50% of patients. The mean survival in 17 cases was 7.6 months; three of the seven patients treated aggressively with chemotherapy had complete remission of the disease. Those with initial confinement of the disease to the skin and with an absence of cytopenia and abnormal liver function survived for a
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longerperiod. Autopsies showed that the organsinvolved differed from thosereportedin the past. The histologic appearance of the cells rangedfrom benignto highlyanaplastic; hemophagocytosis was best appreciated and prominentin areas that appeared bland histologically. Because of the accelerated progression of this disease and its potential response to current chemotherapeutic regimen, a rapid diagnosis is imperative. 2. Regressing atypical histiocytosis (RAH) Headington JT, Roth MS, Schnitzer B. Regressing atypical histiocytosis: a review and critical appraisal. Semin Diagn Pathol 1987;4:28-37. The histiocytic origin of regressing atypical histiocytosis (RAH) must now be considered questionable becauseof the results of immunologic phenotyping and the description of the rearrangement of the T-eeIl receptor (jand'Y-chain genes in the newly studiedcases. These studies indicate that this previously considered, primary, cutaneous, histiocytic neoplasm is most likely of T cell lineage. Weiss LM, Trela MJ, Cleary ML, et al. Frequent immunoglobulin and T-cell receptorgenerearrangementsin "histiocytic" neoplasms. Am J Pathol1985;121:369-73. The authors analyzedthe DNA ofimmunoglobulin and T-cellreceptor genes in a series ofsix malignancies that werejudgedto be of histiocytic derivation on the basis of morphology. The results of these studies, in conjunction with the authors' previous observations, suggest that many presumed histiocytic malignancies actually represent T cel11yrnphomas. The authors alsostate alternatively that (j-chain T-cellreceptorgenerearrangement may be a cornmon feature of tumorsthat show monocyteor histiocyte differentiation. SUMMARY
This review presents a classification scheme for disorders of the mononuclear phagocyte and dendritic cell systems. Previous classifications, based primarily on cytomorphology, are now obsolete. Electron microscopy, enzyme histochemistry, and, especially, immunocytochemistry have revealed the histiocyte identified by hematoxylin-and-eosin staining to be not one but several cell types. Currently, two broad groups of histiocytic cells are recognized,
Phagocytic and dendritic cell systems 1097 the monocyte-macrophage group and the dendritic cells. Dendritic cells are further subclassified as Langerhans cells, indeterminate cells, interdigitating cells, and dermal dendrocytes. Many disorders of the skin and other organs are characterized by proliferation of "histiocytic"-appearing cells. Some of these diseases clearly behave in a malignant fashion, whereas others follow a benign or variable course. At present, the proliferating cell type has been identified in only a few of these disorders by ultramicroscopy and cytochemical and immunocytochemical methods. Nevertheless, the pieces of the puzzle are beginning to fall into place. In general, those disorders that typically behave in a malignant fashion have been more extensively studied. The benign histiocytic disorders of children and adults are a heterogeneous group of diseases. Currently, some of these disorders are unclassified or classified with uncertainty. For example, how should severe histiocytosis with massive lymphadenopathy be classified? There is a proliferation of nonlymphoid mononuclear cells that are positive for S-100 protein and negative for CDl and that exhibit lymphophagocytosis. Is this then a mononuclear phagocytic or dendritic celldisorder? Juvenile xanthogranuloma is a disorder of macrophages. Self-healing reticulohistiocytosis and solitary Langerhans cell histiocytoma are benign proliferative disorders of Langerhans cells. Two cases of multiple, cutaneous, nodular proliferations of indeterminate cells have been reported. Because of their rarity and the lack of more complete laboratory studies, the other benign histiocytic disorders have not been studied adequately to permit a clear identification of the putative proliferating cell type. Of the malignant disorders, histiocytosis X is now fairly well established as a disorder of Langerhans cells. Several malignant or ultimately malignant disorders characterized by proliferation of macrophages are known. All these diseases (hemocytophagic histiocytosis and its familial variant, histiocytic cytophagic panniculitis, and malignant histiocytosis) are characterized histologically by erythrophagocytosis and varying cellular atypia. Malignant histiocytosis has been well characterized immunocytochemically as adisordered proliferation ofmonocyte-macrophage cells. Histiocytic lymphoma and monocytic leukemia are distinct clinically, cytomorphologically, and immunocytochemically from malignant histiocytosis.
