Langerhans cell histiocytosis in monozygotic twins

Langerhans cell histiocytosis in monozygotic twins

I I IIIII I I II Langerhans cell histiocytosis in rnonozygotic twins Arnon M. Katz, M D , a Donald Rosenthal, MD, FRCPC, a H e n r y R. Jakubovi...

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Langerhans cell histiocytosis in rnonozygotic twins Arnon M. Katz, M D , a Donald Rosenthal, MD, FRCPC, a H e n r y R. Jakubovie, MD, F R C P C , c R. K. Mohan Pal, MD, FRCPC, b Guillermo E. Quinonez, M D , F R C P C , d and Daniel N. Sauder, MD, F R C P C a

Hamilton and Toronto, Ontario; Winnipeg, Manitoba, Canada Langerhans cell histiocytosis, one of a group of histiocytosis syndromes characterized by Langerhans ceil infiltration, has many clinical manifestations. In the past 30 years, numerous cases of presumed Letterer-Siwe disease, the acute multiorgan variant, have been reported in twins and siblings. Only recently has the Histiocyte Society established a criterion for a "definitive diagnosis" of Langerhans cell hisfiocytosis--the presence of Birbeck granules within the cells of the histiocytic infiltrate. We report the fatal outcome of Langerhans cell histiocytosis in monozygotic twin infants. There is no satisfactory explanation why Langerhans cell histiocytosis occurs concurrently in twins. We suggest that cytokines may provide an endogenous signal that triggers the pathologic proliferation of Langerhans cells. (J AM ACAD DERMATOL 1991;24:32-7.) Langerhans cell histiocytosis ( L C H ) , also termed

histiocytosis X, is characterized by the pathologic proliferation of histiocytes.l-3 It is one of a group of disorders collectively known as the histiocytosis syndromes t, 4, 5 (Table I). The cause of L C H is unknown. Although the role of heredity in the transmission of the disease is not known, there have been reports of abnormal histiocytic proliferations in sibships and even kindreds that were diagnosed as variant forms of LCH. 6tt None of the earlier reports used highly specific diagnostic methods of electron microscopy or monoclonal staining; in retrospect, therefore, it is unclear whether they were actually L C H or another of the histiocytic disorders. W e report a case of monozygotic twins who simultaneously had L C H . In each instance the diagnostic findings met the criteria for a "definitive diagnosis" as established b y the Histiocyte Society1, 4 (Table II). CASE REPORTS Case 1 The first of a pair of monozygotic twin boys was born prematurely at 32 weeks' gestation to a healthy 21-yearFrom theDivisionofDermatologya and the Departmentof Pediatrlcs,b McMaster University Medical Center, Hamilton; University of TorontoC;and the Universityof Manitoba.d Acceptedfor publication May 2, 1990. Reprint requests: Arnon M. Katz, MD, MUMC DermatologyClinic 3V2, 1200Main St. West, Hamilton, Ontario L8N 3Z5, Canada. 16/1/222iS 32

old mother, gravida 1, para 0. There was no family history of histiocytic disease. The pregnancy and delivery were otherwise uneventful. The patient's birth weight was 1610 gm; results of the initial physical examination were unremarkable. A right inguinal hernia was repaired when the infant was 6 weeks old. The patient was then well until 8 months of age when an eczematous eruption of the diaper area and trunk was noted. This eruption was refractory to local treatment. Shortly thereafter, asymptomatic bilateral cervical adenopathy, hepatosplenomegaly, and iron-deficiency anemia were noted. At 1189 months of age he was admitted to the McMaster University Medical Center. A skin biopsy specimen was diagnostic of LCH (see "Histopathology" and "Electron microscopy"). On admission, the serum electrolyte levels and WBC count were normal, as were results of prothrombin and partial thromboplastin times, urinalysis, and microbiologic studies. Chest and skull x-ray films and skeletal survey were normal; results of tests for liver, kidney, and thyroid function were also normal. A bone marrow aspirate revealed decreased iron stores but was otherwise unremarkable. Immunologic studies showed an absolute lymphocyte count of 3.0 X 109/L, with subsets as follows: B cells, 25.4%;Ttotal, 65.3%; T4, 53.4%; TS, 12.0%; T4/T8, 4.4. The phytohemagglutinin response and immunoglobulin levels were normal. HLA typing was not performed. The clinical course during the next 30 months ,r characterized by progressive deterioration despite treatment. Intermittent fever, painful ulcerative cervical lymphadenopathy, recurrent pneumonia, chronic unremitting purulent otitis media and otitis externa, and hepatosplenomegaly were present. The cutaneous findings included scattered peteehiae and a persistent eczem-

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Langerhans cell histiocytosis in twins 33

Fig. 1. Case 1. Bilaterally symmetric eruption consists of confluent, scaly purpuric papules on lower abdomen and smooth, shiny erythema in the inguinal creases. Note increased abdominal girth. Table I. Histiocytosis syndromes LC histiocytosis Histiocytoses of mononuclear phagocytes other than LC Hemophagocytic lymphohistiocytosis Infection-associated hemophagocytic syndrome Sinus histiocytosis with massive lymphadenopathy Xanthogranuloma Reticulohistiocytoma Other unclassified Malignant histiocytic disorders Monocytic leukemia Malignant histiocytosis True histiocytic lymphoma

Table II. Confidence levels for diagnosis of L C H in children Level



Adapted from Favara BE, Jaffe R. Hematol Oncol Clin North Am 1987; 1:92.

III atous eruption on the scalp and diaper area that resembled seborrheic dermatitis (Fig. 1). Developmental delay was prominent by 18 months of age. Neither bone lesions nor diabetes insipidus were detected. The following treatments were given with varying intervening intervals: Therapy was started with vinblastine (0.5 mg/kg daily for the first 3 days of every month) and prednisone (1 mg/kg daily). This regimen was continued for 3 months without improvement. Subsequently, etoposide (100 mg/m 2, administered once a week) was given for four cycles (12 weeks in total) without improvement. Interferon-o~ (10 million U administered intravenously twice weekly) for 10 weeks was of no benefit. Fifteen intramuscular injections of thymosine extract (1 mg/kg) with prednisone (ultimately increased to 4 mg/kg/day) were administered without response. The eruption had


Lowest level--"presumptive diagnosis" Diagnosis based on study of conventionally processed tissue when findings are consistent with criteria defined in the literature Intermediate level--"diagnosis" Diagnosis based on findings that, in addition to I, lesional cells show at least two of the following characteristics: stain positive for S-100 protein, a-mannosidase, or ATPase, or peanut agglutinin binding Highest level--"definitive diagnosis" Diagnosis based on finding that lesional cells show presence of Birbeck granule

Adapted from the Writing Group of the Histiocyte Society. Lancet 1987;1:208. ATPase, Adenosine triphosphatase.

generalized to form large, erythematous, scaly plaques and extensivecrusts of older lesions on the scalp and in the flexural areas. A temporary response, consisting of decreased adenopathy, organomegaly, and improvement in the cutaneous eruption was achieved with total body irradiation given as 10 fractions of 20 rad. Congestive heart failure, hypoproteinemia, and anasarca were prominent before death. At 38 months of age, the patient died of pulmonary edema. Consent for postmortem examination was not obtained.


Journal of the American Academy of Dermatology

K a t z et al.

Fig. 2. Casel. Photomicrograph of skin biopsy specimen shows dermal perivascular and lichenoid infiltrate of histiocytes with scattered involvement of epidermis. (Hematoxylin-eosin stain; Xl0.)

Case 2

The second twin, admitted to the hospital concurrently with his brother, had an essentially parallel course. His' birth weight was 1300 gm. L C H was also definitively diagnosed and the clinical extent of disease was similar. Immunologic findings were also similar: absolute lymphocyte count, 1.9 • 109/L; B cells, 23.4%; Ttota|, 69.4%; T4, 48.2%; T8, I5.2%; T4/T8, 3.2; phytohemagglutinin response and immunoglobulin levels were normal. Therapeutic trials of vinblastine, prednisone, etoposide, interferon-a, and thymosine extract were ineffective. Local radiotherapy for superior vena eava syndrome was only temporarily effective. The patient died of pulmonary edema at 41 months of age. Consent for postmortem examination was not obtained. HISTOPATHOLOGIC FINDINGS A punch biopsy specimen of skin (Fig. 2) revealed a superficial, perivascular, and lichenoid infiltrate of histiocytes with lobulated, pale-staining nuclei and an abundant eosinophilic cytoplasm. Scattered multinucleated histiocytes and eosinophils were also present in the dermis. T h e epidermis contained scattered histiocytes and eosinophils, and focal parakeratosis and scale-crust were evident. These histologic features were essentially identical in both patients. ELECTRON MICROSCOPY The electron microscopy findings for both patients were the same. The dermal infiltrate consisted of histiocytes. These cells contained large nuclei with

a thin rim of peripherally clumped nuclear chromatin. Occasional prominent nucleoli were present. The nuclei were deeply indented and reniform. The cytoplasm contained numerous Birbeck granules (Fig. 3). DISCUSSION L C H is one of the histiocytic disorders. It is the only such disorder in which the predominant pathologic histiocyte is the Langerhans cell (LC). 1, 3, 4 A demonstration that the histiocytic infiltrate consists of LCs, as was the case here, is therefore diagnostic of LCH. The pathogenesis of L C H remains enigmatic. No evidence has been found of an exogenous (i.e., infectious) stimulus to LC proliferation. 12 Moreover, there is little evidence of LC atypia in LCH. 13 The LCs in L C H appear to be morphologically normal,14 but they proliferate and migrate in a pathologic manner. The disease was previously thought to be a neoplastic process. More recently it has been suggested that the pathologic behavior of the LCs may be attributed to an immunologic derangement.14, is Where the putative immune defect lies is unknown. Various immunologic abnormalities have been noted in patients with LCH, including low suppressor T cell numbers, increased immunoglobulins, high T 4 / T8 ratio, defective in vitro monocyte cytotoxicity, and thymus gland disorders such as dysplasia and dysmorphia.16, 17 However, no consistent immuno-

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Langerhans cell histiocytosis in twins 35

Fig. 3. A, Case 1. Electron micrograph shows detail of the histiocyte. Many Birbeck granules (arrows) are present in cytoplasm. B, Case 2. Electron micrograph of Birbeck granule shows typical "zipper-like" structure (arrow) and terminal vesicle (asterisk). (A, X 14,000; B, X80,000.)

logic disorder has been demonstrated in all patients with L C H that could imply a particular endogenous signal that triggers the abnormal behavior of LCs. The twins reported herein died of a fulminant, disseminated form of LCH. In general, however, L C H has many clinical presentations. The disease can involve a single organ, a few organs, or multiple organs. Its course can be progressive and fatal or chronic and resolving. Letterer-Siwe disease is the multiple-organ acute variant of LCH, such as the

cases presented here. Hand-Schfiller-Christian disease is the oligo-organ variant that classically displays the triad of bone lesions, exophthalmos, and diabetes insipidus. Eosinophilic granuloma is a form of L C H that involves a single organ, usually bone, with an often spontaneously remitting course. Although there are no reports of familial cases of the more benign forms of L C H (Hand-SchiillerChristian disease and eosinophilic granuloma), numerous reports, mostly from the 1950s and 1960s,


Katz et aL

describe sibships and kindreds who had what appeared to be Letterer-Siwe disease. 71~ It is difficult to interpret these cases retrospectively because the diagnosis relied on clinical observations and only routine histopathologic evidence of a histiocytic infiltrate. To our knowledge, none of the previous reports demonstrated specifically an LC infiltrate by means of monoclonal antibody stains, electron microscopy, or other conclusive techniques. In addition, many of the cases reported as Letterer-Siwe disease did not have cutaneous manifestations, although it is now well known that most cases of this type of L C H have skin involvement. TM Therefore it is likely that some of the previous reports of Letterer-Siwe disease in sibships may actually have been describing other non-LCH reticulohistiocytic disorders. Certain reticulohistiocytoses, such as familial reticuloendotheliosis with eosinophilia (Omenn's syndrome), hemophagocytic reticulosis, and others, clearly demonstrate familial incidence.a, 6, 18 The exact relation between those disorders and LCH is unclear. A greater understanding may be gained when the histiocytes in these diseases are more specifically identified. The cases reported herein are to our knowledge the first in which a definitive diagnosis of L C H was established in monozygotic twins. There are no reports of cases in which only one twin had LCH. The mechanism that triggers the onset of LCH is unknown. Given the absence of any direct evidence of a genetic or infectious cause, the concurrent occurrence of the disease in fwins and siblings is even more baffling. The possibility that cytokines contribute to the pathogenesis of L C H has been raised by Favara and Jaffe.1 Cytokines are thought to be involved in both normal homeostasis and the pathogenesis of cutaneous diseases19-21; they can exert potent effects of LCs. Granulocyte macrophage-colony-stimulating factor (GM-CSF) has been shown to enhance LC viability in vitro, induce LC differentiation, and stimulate LC function. 22, 23 No cytokine has so far been found to have a proliferative effect on LCs. In fact, there is conflicting evidence as to whether LCs normally proliferate in response to foreign antigen recognition. 24 Nevertheless, it may be conceptually attractive to postulate the existence of a particular cytokine that has a direct proliferative action on LCs or, alternatively, a relative deficiencyof a differentiating cytokine (such

Journal of the American Academy of Dermatology

as GM-CSF) producing a similar result, the abnormal proliferation of LCs. The same theory could explain the presence of eosinophils in LCH, if they respond to the same humoral factor. Such a putative cytokine would be expected to produce a polyclonal LC response. A demonstration that the LCs in LCH are of polyclonal origin may lend support to this hypothesis and may point to an endogenous factor responsible for triggering a pathologic proliferation of LCs. REFERENCES 1. Favara BE, Jaffe R. Pathology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1987;1:75-97. 2. Osband ME, Pochedly C. Histiocytosis-X: an overview. Hematol Oncol Clin North A m 1987;hi-7. 3. Favara BE, McCarthy RC, Mierau GW. Histiocytosis X. Hum Pathol 1983;14:663-76. 4. Chu T, D'Angio G J, Favara B, et al. Histioeytosis syndromes in children. Lancet 1987;1:208-9. 5. Gianotti F, Caputo R. Histiocytic syndromes: a review. J AM AChO DnRMATOL 1985;13:383-404. 6. Omenn GS. Familial reticuloendotheliosis with eosinophilia. N Engl J Med 1985;273:427-32. 7. Juberg RC, Kloepfer W, Oberman HA. Genetic determination of acute disseminated histioeytosis X (Letterer-Siwe syndrome). Pediatrics 1970;45:753-65. 8. Miller DR. Familial retieuloendotheliosis: concurrence of disease in five siblings. Pediatrics 1966;38:986-95. 9. Bierman HR, Lanman JT, Dod KS, et al. The ameliorative effect of antibiotics on nonfipoid reticuloendotheliosis (Letterer-Siwe disease) in identical twins. J Pediatr 1952;40: 269-84. 10. Schoeck VW, Peterson RDA, Good RA. Familial occurrence of Letterer-Siwe disease. Pediatrics 1963;32:1055-63. 11. Nelson P, Santamaria A, Olson RL, et al. Generalized lymphohistiocytic infiltration. Pediatrics 1961;27:931-50. 12. McLelland J, Pritchard Jr, Chu AC. Histiocytosis X: current controversies. Hematol Oncol Clin North Am 1987;1:147-63. 13. Risdall RJ, Dehner LP, Duray P, et al. Histiocytosis X (Langerhans cell histiocytosis). Arch Pathol Lab Med 1983;107:59-63. 14. Ishii E, Watanabe S. Biochemistry and biology of the Langerhans cell. Hematol Oncol Clin North Am 1987;1: 99-117. 15. Broadbent V, Pritchard J. Histiocytosis X---current controversies. Arch Dis Child 1985;60:605-7. 16. Leildn SL. Imrnunobiology of histiocytosis X. Hematol Oncol Clin North Am 1987;1:49-61. 17. Osband ME. Immunotherapy of histioeytosis-X. Hematol Oncol Clin North Am 1987;1:131-45. 18. Esterly NB, Maurer HS, Gonzalez-Crussi F. Histioeytosis X: a seven-year experience at a children's hospital. J" AM ACAD DE~MATOL1985;13:481-96. 19. Kupper TS. Production of cytokines by epithelial tissues. A new model for cutaneous inflammation. Am J Dermatopathol 1989;11:69-73. 20. Sauder DN. Interleukin-1. Arch Dermatol 1989;125:67982.

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Langerhans cell histiocytosis in twins

21. Kupper TS. Mechanisms of cutaneous inflammation. Arch Dermatol 1989;125:1406-12. 22. Witmer-Pack MD, Oliver W, Valinsky J, et al. Granuloeyte/macrophage colony-stimulating factor is essential for the viability and function of murine cultured epidermal Langerhans cells. J Exp Med 1987;166:1484-98. 23. Heufler C, Koch F, Schuler G. Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the


maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med 1988;167:700-5. 24. Rosen K, JonteU M, Mobacken H, et al. Epidermal Langerhans cells in chronic eczematous dermatitis of the palms treated with PUVA and UVB: Acta Derm Venereol (Stoekh) 1989;69:200-5.




Allergic contact dermatitis to two antioxidants in latex gloves: 4,4'-thiobis(6-tert-butyl-meta-cresol) (Lowinox 44S36) and butylhydroxyanisole Allergen alternatives for glove-allergic patients Phoebe Rich, MD, Mary Lou Belozer, BS, Patti Norris, MA, and Frances J. Storrs, MD

Portland, Oregon Allergic contact dermatitis developed on the hands and/or face of two patients after exposure to latex examination gloves. Both patients were patch test negative to the usual rubber allergens, but both had a positive patch test reaction to 4,4'-thiobis(6-tert-butyl-m.cresol) (Lowinox 44S36). Patient 2 was also patch test positive to butylhydroxyanisole. The patients were tested with other gloves, to find gloves that they could safely use. Glove manufacturers were queried to ascertain the occurrence of Lowinox 44S36 and butylhydroxyanisolein different brands of latex and vinyl examination gloves. A list of gloves and their associated allergens was generated and is provided to assist dermatologists in helping patients choose gloves free of specific allergens. (J AM ACADDERMATOL1991;24:37-43.) Seven to eight billion gloves are used annually in the United States. Gloves can be allergenic. 1,2 Antioxidants and accelerators added to rubber in the manufacturing process are the major allergens) We describe two patients with allergic contact dermatitis to 4,4'-thiobis(6-tert-butyl-m-cresol) (Lowinox 44S36), the antioxidant in Perry latex examination gloves. The second patient was coincidentally allergic to butylhydroxyanisole (BHA), an antioxidant that is used in the manufacture of some brands of latex gloves. From the Department of Dermatology,The Oregon Health Sciences University. Accepted for publication May 10, 1990. Reprint requests:Frances J. Storrs, MD, Department of Dermatology, The Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd. L468, Portland, OR 97201


Dermatologists are often asked to recommend gloves for patients with glove allergies. Many brands of latex examination gloves are available, and it is useful to know the allergens present in specific brands so that patients can be advised. CASE REPORTS Case 1

A pruritic dermatitis developed in a 48-year-old nurse's aide on the back of the hands and on the forearms, cheeks, and neck. The reaction first occurred on a hot sunny day, and the patient believed the dermatitis was light-related. The eruption cleared when she was away from work and recurred when she returned to her job. She was not atopic.* *In this article an atopic person is defined as one who has a personal history of or a first-degree relative with asthma, allergic rhinitls, and/or eczema.