Langerhans Cell (Eosinophilic) Granulomatosis

Lang~rhans Cell (Eosinophilic) Granulomatosis

PHILIP H. LIEBERMAN, M.D., CHARLES RAY JONES, M.D., AND DANIEL A. FILIPPA, M.D. Surgical Pathology Service and Department of Pediatrics, M emorial Hospital for Cancer and Allied Diseases, N ew York, N ew York, U.S.A.

Eosinophilic granuloma (Langerhans cell granuloma neoplasms characterized principally by the presence of histio tosis) is the only basically nondermatological disorder cytic elements. consistently associated with the Langerhans cell. Its clin ical manifestations are protean. There is much circum CLINICAL ASPECTS OF EOSINOPHILIC stantial evidence to suggest that this disease is funda (LANGERHANS CELL) GRANULOMAS [13] mentally immunologic. This is consistent with current Eosinophilic granuloma is a disorder readily recognizable by concepts about the Langerhans cell. light microscopy. It is found either in a unifocal or multifocal state and consists of admixtures of eosinophils and mononuclear cells (the latter cells in large part are Langerhans cells). Varying In view of the enormous body of dermatological literature degrees of necrosis and fibrosis are present, as well as multi concerning the Langerhans cell [1-4], it is not smprising that nucleated giant cells and foamy histiocytes; the latter are pres most of the pathologic changes related to these cells are found ent especially in areas of suppuration. Healing of the lesions is in skin disorders. It was of great interest, therefore, when Basset by fibrosis. The classical sites for the granulomas are bones, but and Turiaf [5] described in 1965 the presence of Langerhans soft tissues such as skin, gingiva, lymph nodes (Fig. 1) , and lung cells in "histiocytosis X" of the lung. Since that discovery, the may be involved. Most of the statistical facts about the disease presence of Langerhans cells (identified by the presence of are derived from bone cases since the lesions are most com Birbeck granules [6]) has been found in a host of disorders monly found in bone. Symptoms in unifocal cases are pain and primarily dermatological, occasionally lymph nodal, rarely neo swelling; fractmes are not uncommon. Multifocal lesions may plastic [7]. Most of the instances in which Langerhans cells include various bony sites, lymph nodes, and lungs. Many have been found in human lymph nodes have involved persons patients have otitis externa, otitis media, and mastoiditis (note with reactive nodes, e.g., with dermatopathic lymphadenitis the relationship to squamous epithelium). Ulcerating gingival and subacute sclerosing panencephalitis. Only one nonderma lesions and loosening of teeth are not uncommon. Patients with tological disease process has been consistently linked to the multifocal eosinophilic granuloma may have protracted ill Langerhans cell, and that is eosinophilic granuloma. Indeed, nesses, with recrudescence of lesions, fever, and organomegaly since the Langerhans cell is the most important feature of for many years. eosinophilic granuloma, rather than the eosinophil itself, it The prognosis is very good, especially if appropriate and might not be amiss to take Dr. Wolffs suggestion and rename modest therapeutic measures are taken by physicians skilled in the process "Langerhans cell granulomatosis" [2]. treating these patients. Orthopedic, dental, or pulmonary prob lems often mar the recovery state. Diabetes insipidus, probably CLARIFICATION OF TERMINOLOGY due to granulomatous involvement of the hypothalamic area, is The study of eosinophilic granuloma has been complicated often transient, but occasionally may be permanent. by a complex jargon. Histiocytosis X, or more recently histio Laboratory findings have been disappointing. Despite the cytosis, refers to a spectrum of diseases encompassing both the great incidence of allergic histories, tests of cellular and non benign disorder, eosinophilic granuloma, and malignant lym cellular immunity have been unrewarding. Parasitic and bac phomatous diseases [8]. We have challenged this concept on terial. agents have not been found to be clinically important. clinical, historical, and histological grounds [9]. Hand-Schi.iller Christian disease has been redefined over the years and, as used today, is probably synonymous with multifocal eosinophilic granuloma. Letterer-Siwe syndrome (disease) as formally de fined by Abt and Denenholz [10) is characterized by (a) hepa tosplenomegaly, (b) hemorrhagic diathesis, (c) lymphadenop~ thy, (d) localized tumefactions over bones, (e) secondary anemia and normal differential and platelet counts, (0 increased num bers of non-lipid-containing macrophages in the splenic aspi rate, (g) no familial or hematological disposition, (h) ~ccurr~nce exclusively in infants, (i) acute onset, unrelated to mfectwns, and a downhill course for weeks to several years, (j) unknown etiology, and (k) generalized hyperplasia of non-lipid-containing macrophages in various organs. The redefinition of these non specific criteria by various investigators has caused much con fusion. The terms reticuloendotheliosis and reticulosts are also unsuitable for modern usage, as discussed elsewhere [11]. If we eliminate infectious disorders, nonspecific case reports, hemo phagocytic reticulosis probably due to maternal hematopoietic grafts [12], graft-versus-host disease, and combined immuno deficiency syndromes, we are left with a group of malignant

Reprint requests to: Philip Lieberman, M.D., Surgical Pathology Service, Memorial Hospital for Cancer and Allied Diseases, New York, FrG I. Langerhans cell granulomatosis involving lymph node (he New York 10021. matoxylin and eosin, reduced from X 630).

71 72 LIEBERMAN, JONES, AND FILIPPA Vol. 75, No. 1

conditions in which eosinophils are a prominent featUJ·e but Langerhans cells are lacking. Eosinophilic cystitis, enteritis, and lymphadenitis are often confused with this disorder. ETIOLOGY The pathogenesis of eosinophilic granuloma is unknown. In almost all cases of eosinophilic granuloma, it has been possible to identify the Langerhans cell by electron microscopy. The characteristic Birbeck granules in this disorder seem to arise from the plasmalemma (Fig 2). It is possible the Bii·beck granules represent structural membrane alterations secondary to antigenic challenge. The presence ofLangerhans cells (Fig 3) [14,15], eosinophilia, a high frequency of allergic backgrounds, and the response of the lesions to therapeutic agents used both clinically and experimentally to suppress eosinophilia all sug gest that the disease is reactive rather than neoplastic and may have an immunologic basis. REFERENCES 1. Breathnach AS: The cell of Langerhans. Int Rev Cytol 18:1-28, FIG 2. Electron micrograph showing a Langerhans cell from a per 1965 son with Langerhans cell granulomatosis. Arrow indicates a Birbeck 2. Wolff K: The Langerhans cell. Curr Probl Derma tot 4:79-145, 1972 granule (reduced from X 10,800). Inset, Birbeck granule (reduced from 3. Riley P A: The Langerhans cell, The Physiology and Pathophysi X 128,000). ology of the Skin. Edited by A Jarrett. New York, Academic Press, 1974, pp 1199-1218 4. Shelley WB, Juhlin L: The Langerhans cell: Its origin, nature and function. Acta Derm Venereol [Suppl 79] (Stockh) 58:7-22, 1978 5. Basset F, Tw·iaf J: Identification par Ia microscopic electronique de particules de nature probablement virale dans les lesions granulomateuses d'une histiocytose-X pulmonaire. C R Acad Sci . .. (Paris) 261:3701-3703, 1965 ' 6. Birbeck MSC, Breathnach AS, Everall JD: An electron microscopic .. .. study of basal melanocyte and high level clear cell (Langerhans ... cell) in vitiligo. J Invest Dermatol 37:51- 63, 1961 . 7. Vernon ML, Fountain L, KJ·ebs HM, Horta-Bru·bosa L, Fuccillo DA, Sever JL: Birbeck granules (Langerhans' cell granules) in human lymph nodes. Am J Clin Pathol 60:771-779, 1973 8. Lichtenstein L: Histiocytosis X. Integration of eosinophilic granu loma of bone, "Letterer-Siwe disease," and "Schi.iller-Christian , disease" as related manifestations of a single nosologic entity. ,t Arch Pathol 56:84- 102, 1953 9. Lieberman PH, Jones CR, Dru·geon HWK, Begg CF: A reappraisal of eosinophilic granuloma of bone, Hand-Schi.iller-Christian syn drome and Letterer-Siwe syndrome. Medicine 48:375-400, 1969 • 10. Abt AF, Denenholz EJ: Letterer-Siwe's disease. Splenohepatome • galy associated with widespread hyperplasia of nonlipoid storing ' macrophages; discussion of the so-called reticuloendothelioses. I' Am J Dis Child 51:499-522, 1936 I 11. Symmers WSC: The lymphoreticular system, Systemic Pathology vol I. Edited by GP Wright, WSC Symmers. London, Longmans: Green and Company, 1966, pp 195-274 12. Blennow G, Berg B, Brandt L, Messeter L, Low B, Soderstrom N: FIG 3. Dendritic ATPase-positive ceLls cu.l tured from a person with Haemophagocytic reticulosis. A state of chimerism? Arch Dis Langerhans cell granulomatosis. Courtesy of Drs. K. Lele and G. Potter Child 49:960-962, 1974 (reduced from x 450). 13. Lieberman PH: Eosinophilic granuloma and related synd.J·omes Cecil Textbook of Medicine, 15th edition, section 8. Edited by PB Beeson, W McDermott, JB Wyngaru·den. Philadelphia, WB Viral studies, particularly studies on slow virus infections, have Saunders Company, 1979, pp 1848-1851 been woefully lacking. 14. Silberberg-Sinakin I, Baer RL, Thorbecke GJ: Langerhans cells. A review of their nature with emphasis on their immunologic func IMPROPER USE OF THE TERM EOSINOPHILIC tions. Prog Allergy 24:268-294, 1978 GRANULOMA 15. Sting! G, Katz SI, Shevach EM, Rosenthal AS, Green I: Analogous functions of macrophages and Langerhans cells in the initiation Many pathologists use the term eosinophilic granuloma for of the immune response. J Invest Derma to! 71:59-64, 1978