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Langerhans cell histiocytosis in an adult
CANCER LETTERS Cancer
ELSEVIER
Letters
84 (1994) 173-176
Langerhans cell histiocytosis in an adult Hakan
Sayrak”,
Bilal Dog’an*b, Yavuz Harmanyerib, Hakan Cingil” _
ibrahim
“Department of Pathology. bDepartment of Dermatology, GATA Teaching Hospital, Haydarpap, Received
10 June
1994; accepted
6zteka, Istanbul, Turkey
21 June 1994
Abstract We present the case of a 27-year-old Caucasian woman who suffered from Langerhans cell histiocytosis with axillary and scalp involvement. She also developed diabetes insipidus after 2 years of skin lesions. Topical nitrogen mustard therapy was performed for the skin lesions, but we had to stop this therapy because of severe local irritation and systemic urticaria. Afterwards, we administered etoposide systemically, but no improvement appeared in 6 weeks. Finally we used methotrexate for 3 months and the result was very good at the end of the first month. Keywords:
Langerhams
cell histiocytosis;
Cytokine;
Lesions
1. Introduction Langerhans cell histiocytosis (LCH) is a new term for a disease, described under a variety of names, such as Hand-Schiiller-Christian syndrome, Abt-Letterer-Siwe disease, eosinophilic granuloma, pure cutaneous histiocytosis, type II histiocytosis, self-healing histiocytosis, non-lipid reticuloendotheliosis, Hashimoto Pritzker syndrome, Langerhans cell granulomatosis, and histiocytosis X [3,1 I]. LCH is a reactive condition in which cells with the phenotype of Langerhans cells accumulate in various tissues and cause damage to
* Corresponding author, GATA Haydarpap E&tim Hastanesi, Dermatoloji Klinigi 8 1327, Haydarpap, Istanbul, Turkey. 0304-3835/94/$07.00 0 1994 Elsevier Science SSDI 0304-3835(94)03478-2
Ireland
the tissues which appears to be due, in part, to cytokine production [2]. The disease affects predominantly infants and young children, but infrequently onset may occur in adulthood. The incidence is about 0.2-l per 100 000 children per year. The incidence in adults must be more rare than this rate. The exact etiology of LCH is unknown and the pathogenesis is not understood [2,3]. In a large series of 124 patients, bone, lymph node and skin lesions were the most frequently seen, but 50% of patients showed liver disease and 23% lung disease with frequent hematologic changes [2]. In adults, granuloma annulare-like appearance has been reported [6]. Localized skin ulcers may also occur [lo]. The progress of the disease is unpredictable in any given patient.
Ltd. All rights reserved
H. Savrak et al. /Cancer
174
Lett. 84 (1994)
173-176
2. Case report A 27-year-old Caucasian women had had scaling and crusting of the skin of the scalp and bilateral axillary intertrigo from the age of 5. Her complaints initiated like seborrheic dermatitis of scalp which was erythematous with greasy scales. Lesions of the scalp were treated as seborrheic dermatitis, but the response to therapy was not successful. After 6 months, an erosive lesion appeared on the left axillae and thereafter right axillae (Fig. 1). A biopsy was performed then, but no specific diagnosis was established. Many non-specific therapy schedules were tried in order to improve the condition during this period, but all of them failed. The specific diagnosis was established 4 months after the last biopsy by performing a new biopsy
Fig. 2. Inflamatory cell infiltrate consisting of histiocyter cells and polymorphonuclear leukocytes superficially, lymphocytes and plasma cells more deeply. (H&E; x 200).
Fig. 1. Glazed, partially Nary region.
eroded, ulcerated
erythema
in right ax-
on the suspicion of LCH. Histochemical and immunohistochemical studies of the specimen were done. Histopathologic examination of the scaled, crusted papule on the axillary region showed band like upper dermal cellular infiltration with epiderma1 invasion, disrupted epidermal basal lamina and crusting. In the upper dermis, histiocyter cells with abundant eosinophilic, and also methachromatic cytoplasm and indented nuclei were located separately in the edematous stroma. An accompanying infiltratory cell infiltrate consisted of polymorphonuclear leukocytes superficially, lymphocytes and plasma cells more deeply (Fig. 2). Eosinophils and multinucleated histiocytes were present infrequently. Entire sections were scanned
H. Sayrak
et al. /Cancer
for mast cells and these cells were generally located in the upper reticulary derma, especially in the area which edema was pronounced. No fungi or acid-fast bacteria were detected on specially stained sections. On the biopsy performed in the same region after treatment with MTX, we observed rare histiocyter cells in the upper papillary derma and the fibrosing granulation tissue sustituted histiocyter infiltration. No xanthomatous changes were noticed. Immunohistochemical studies (Strept Avidin Biotin, DAKO) showed intrascytoplasmic positivity for S-100 protein and vimentin, negativity for LCA, which confirm the diagnosis of Langerhans cell histocytosis. Craniography, cerebral computerized tomography, electroencephalography, bone marrow aspiration, chest X-ray, complete blood count, liver function tests, VDRL, HIV, and PPD tests were
Lett. 84 (1994)
173-176
175
performed and no pathological findings were present; X-ray and radionucleotide studies were performed for detecting bone involvement, but nothing pathological was found. As a result of performing vasopressin and thirsting tests because of the symptoms of polyuria and polydipsia, diabetes insipidus (DI), which suggested central nervous system involvement, was established. We planned topical nitrogen mustard therapy for the skin lesions (daily application of an aqueous solution, 20 mg/lOO ml) and desmopressin acetate spray for DI. During the use of topical nitrogen mustard therapy, a moderate improvement was produced in the first 7 days, but thereafter severe irritation and systematic urticaria developed and could not be controlled unless this therapy was stopped. Afterwards, we used etoposide (VP16) 100 mg/m* i.v daily for 3 days every 3 weeks for 6 weeks. Because there was no improvement in skin lesions and DI, and the severe side-effects of the drug, treatment was discontinued. At the end, oral methotrexate (MTX) was tried at 20 mglweek and it produced a very good improvement within 4 weeks, and the axillary ulcers recovered by scarring (Fig. 3). The treatment was continued for 2 months more and then discontinued. Twelve weeks after discontinuing MTX, the disease was in remission. 3. Discussion
Fig. 3. Right axillary
region
after MTX treatment.
The skin lesions in LCH usually involve a seborrheic distribution in adults as in children. However, ulceration in the flexures and in the groin or perianally is a common presentation in adult patients, as in our case. Several dermatologists had seen the patient before the diagnosis was suspected and the diagnosis was confirmed 4 years after the initial symptoms. Because of the rarity of this disease, especially in adults, LCH must be suspected when the flexural ulcerations and erosions fail to respond to conventional treatment. After forming the suspicion, performing a biopsy which is studied with histochemical, immunohistochemical and electromicroscopic assays is enough to form a diagnosis.
176
H. Sayrak et al. /Cancer
Treatment of LCH depends on the extent and the severity of the disease. Patients with single system bone or skin disease have a good prognosis and often require no or only limited treatment [2]. Low dose radiotherapy [8], PUVA, UVB [5], topical nitrogen mustard [lo], systemic chemotherapy with prednisolone 19) and/or vinblastin, MTX, etoposide [1,4], and interferon [7] are the alternative therapies which have been tried in one or more patients for the skin lesions of LCH. Because etoposide has recently shown promising effects in the prevention and treatment of diabetes insipidus [ 11, we prefered to use etoposide before MTX therapy in our case. However, there were various sideeffects and no improvement in ulcerations and DI with etoposide. Therefore, we used MTX and the result was very good for the skin lesions including the scalp. The therapy modalities used with our patient suggest that we cannot predict the result of a therapy unless we use it for the present. Etoposide did not produce any improvement in our case, but might be effective when combined with prednisolone [4]. Even though there were irritation and urticaria with the nitrogen mustard therapy in our patient, the moderate improvement of lesions in the first week encourages its usefulness. Nevertheless, MTX seems as an efficient and relatively safe drug alone in the treatment of skin lesions of LCH.
Let!. 84 (19941 173-176
References [II Broadbent,
[21
[31
141
PI
161
171
181
191
[lOI
[III
V. et al. (1989) Etoposide (VP16) in the treatment of multisystem Langerhans cell histiocytosis (histiocytosisx). Med. Pediatr. Oncol., 17. 97. Chu. A.C. (1992) Histiocytoses. In: Textbook of Dermatology, pp. 2045-2052. Editors: R.H. Champion, J.L. Burton and F.J.G. Ebling. Blackwell Scientific Publications, Turin. Gardner. H. and Grois, N. (1993) The histiocytosis syndromes. In: Dermatology in General Medicine, pp. 2003-2011. Editors: T.B. Fitzpatrick, A.Z. Eisen, K. Wolff, I.M. Freedberg and K.F. Austen. McGraw-Hill, New York. Hocking, W.G. and Swanson, M. (1986) Multifocal eosinophilic granuloma: response of a patient to etoposide. Cancer, 58, 840-842. Ivatsuki, K., Tsugiki. M., Yoshizava, N. et al. (1986) The effect of phototherapies on cutaneous lesions of histiocytosis X in the elderly. Cancer, 57. 1931-1936. Lichtenwald, D.J., Jacubovic, H.R. and Rosenthal, D. (1991) Primary cutaneous Langerhans cell histiocytosis in an adult. Arch. Dermatol., 127, 1545-1548. Lindeliif, B., Forslind, B., Hilliges. M. et al. (1991) Langerhans cell histiocytosis in an adult. Acta Derm. Venereol. (Stockh.), 71, 178-180. Palmieri, G., Stefani, S.. Gridelli. C. et al. (1989) Irradiation of the hypothalamic-hypophyseal area induces complete regression of mucocutaneous lesions in disseminated histiocytosis X. Cancer, 64, 29-31. Wolfson. S.L.. Botero, F., Hurwitz, S. and Pearson, H.A. (1981) ‘Pure’ cutaneous histiocytosis X. Cancer, 48, 2236-2238. Wong, E., Holden, C.A., Broadbent, V. and Atherton, D.J. (1986) Histiocytosis X presenting as intertrigo and responding to topical nitrogen mustard. Clin. Exp. Dermatol., 1I, 183-187. Writing Group of the Histiocyte Society: Histiocytosis syndromes in children. Lancet, 1987, 24, 208.
ELSEVIER
Letters
84 (1994) 173-176
Langerhans cell histiocytosis in an adult Hakan
Sayrak”,
Bilal Dog’an*b, Yavuz Harmanyerib, Hakan Cingil” _
ibrahim
“Department of Pathology. bDepartment of Dermatology, GATA Teaching Hospital, Haydarpap, Received
10 June
1994; accepted
6zteka, Istanbul, Turkey
21 June 1994
Abstract We present the case of a 27-year-old Caucasian woman who suffered from Langerhans cell histiocytosis with axillary and scalp involvement. She also developed diabetes insipidus after 2 years of skin lesions. Topical nitrogen mustard therapy was performed for the skin lesions, but we had to stop this therapy because of severe local irritation and systemic urticaria. Afterwards, we administered etoposide systemically, but no improvement appeared in 6 weeks. Finally we used methotrexate for 3 months and the result was very good at the end of the first month. Keywords:
Langerhams
cell histiocytosis;
Cytokine;
Lesions
1. Introduction Langerhans cell histiocytosis (LCH) is a new term for a disease, described under a variety of names, such as Hand-Schiiller-Christian syndrome, Abt-Letterer-Siwe disease, eosinophilic granuloma, pure cutaneous histiocytosis, type II histiocytosis, self-healing histiocytosis, non-lipid reticuloendotheliosis, Hashimoto Pritzker syndrome, Langerhans cell granulomatosis, and histiocytosis X [3,1 I]. LCH is a reactive condition in which cells with the phenotype of Langerhans cells accumulate in various tissues and cause damage to
* Corresponding author, GATA Haydarpap E&tim Hastanesi, Dermatoloji Klinigi 8 1327, Haydarpap, Istanbul, Turkey. 0304-3835/94/$07.00 0 1994 Elsevier Science SSDI 0304-3835(94)03478-2
Ireland
the tissues which appears to be due, in part, to cytokine production [2]. The disease affects predominantly infants and young children, but infrequently onset may occur in adulthood. The incidence is about 0.2-l per 100 000 children per year. The incidence in adults must be more rare than this rate. The exact etiology of LCH is unknown and the pathogenesis is not understood [2,3]. In a large series of 124 patients, bone, lymph node and skin lesions were the most frequently seen, but 50% of patients showed liver disease and 23% lung disease with frequent hematologic changes [2]. In adults, granuloma annulare-like appearance has been reported [6]. Localized skin ulcers may also occur [lo]. The progress of the disease is unpredictable in any given patient.
Ltd. All rights reserved
H. Savrak et al. /Cancer
174
Lett. 84 (1994)
173-176
2. Case report A 27-year-old Caucasian women had had scaling and crusting of the skin of the scalp and bilateral axillary intertrigo from the age of 5. Her complaints initiated like seborrheic dermatitis of scalp which was erythematous with greasy scales. Lesions of the scalp were treated as seborrheic dermatitis, but the response to therapy was not successful. After 6 months, an erosive lesion appeared on the left axillae and thereafter right axillae (Fig. 1). A biopsy was performed then, but no specific diagnosis was established. Many non-specific therapy schedules were tried in order to improve the condition during this period, but all of them failed. The specific diagnosis was established 4 months after the last biopsy by performing a new biopsy
Fig. 2. Inflamatory cell infiltrate consisting of histiocyter cells and polymorphonuclear leukocytes superficially, lymphocytes and plasma cells more deeply. (H&E; x 200).
Fig. 1. Glazed, partially Nary region.
eroded, ulcerated
erythema
in right ax-
on the suspicion of LCH. Histochemical and immunohistochemical studies of the specimen were done. Histopathologic examination of the scaled, crusted papule on the axillary region showed band like upper dermal cellular infiltration with epiderma1 invasion, disrupted epidermal basal lamina and crusting. In the upper dermis, histiocyter cells with abundant eosinophilic, and also methachromatic cytoplasm and indented nuclei were located separately in the edematous stroma. An accompanying infiltratory cell infiltrate consisted of polymorphonuclear leukocytes superficially, lymphocytes and plasma cells more deeply (Fig. 2). Eosinophils and multinucleated histiocytes were present infrequently. Entire sections were scanned
H. Sayrak
et al. /Cancer
for mast cells and these cells were generally located in the upper reticulary derma, especially in the area which edema was pronounced. No fungi or acid-fast bacteria were detected on specially stained sections. On the biopsy performed in the same region after treatment with MTX, we observed rare histiocyter cells in the upper papillary derma and the fibrosing granulation tissue sustituted histiocyter infiltration. No xanthomatous changes were noticed. Immunohistochemical studies (Strept Avidin Biotin, DAKO) showed intrascytoplasmic positivity for S-100 protein and vimentin, negativity for LCA, which confirm the diagnosis of Langerhans cell histocytosis. Craniography, cerebral computerized tomography, electroencephalography, bone marrow aspiration, chest X-ray, complete blood count, liver function tests, VDRL, HIV, and PPD tests were
Lett. 84 (1994)
173-176
175
performed and no pathological findings were present; X-ray and radionucleotide studies were performed for detecting bone involvement, but nothing pathological was found. As a result of performing vasopressin and thirsting tests because of the symptoms of polyuria and polydipsia, diabetes insipidus (DI), which suggested central nervous system involvement, was established. We planned topical nitrogen mustard therapy for the skin lesions (daily application of an aqueous solution, 20 mg/lOO ml) and desmopressin acetate spray for DI. During the use of topical nitrogen mustard therapy, a moderate improvement was produced in the first 7 days, but thereafter severe irritation and systematic urticaria developed and could not be controlled unless this therapy was stopped. Afterwards, we used etoposide (VP16) 100 mg/m* i.v daily for 3 days every 3 weeks for 6 weeks. Because there was no improvement in skin lesions and DI, and the severe side-effects of the drug, treatment was discontinued. At the end, oral methotrexate (MTX) was tried at 20 mglweek and it produced a very good improvement within 4 weeks, and the axillary ulcers recovered by scarring (Fig. 3). The treatment was continued for 2 months more and then discontinued. Twelve weeks after discontinuing MTX, the disease was in remission. 3. Discussion
Fig. 3. Right axillary
region
after MTX treatment.
The skin lesions in LCH usually involve a seborrheic distribution in adults as in children. However, ulceration in the flexures and in the groin or perianally is a common presentation in adult patients, as in our case. Several dermatologists had seen the patient before the diagnosis was suspected and the diagnosis was confirmed 4 years after the initial symptoms. Because of the rarity of this disease, especially in adults, LCH must be suspected when the flexural ulcerations and erosions fail to respond to conventional treatment. After forming the suspicion, performing a biopsy which is studied with histochemical, immunohistochemical and electromicroscopic assays is enough to form a diagnosis.
176
H. Sayrak et al. /Cancer
Treatment of LCH depends on the extent and the severity of the disease. Patients with single system bone or skin disease have a good prognosis and often require no or only limited treatment [2]. Low dose radiotherapy [8], PUVA, UVB [5], topical nitrogen mustard [lo], systemic chemotherapy with prednisolone 19) and/or vinblastin, MTX, etoposide [1,4], and interferon [7] are the alternative therapies which have been tried in one or more patients for the skin lesions of LCH. Because etoposide has recently shown promising effects in the prevention and treatment of diabetes insipidus [ 11, we prefered to use etoposide before MTX therapy in our case. However, there were various sideeffects and no improvement in ulcerations and DI with etoposide. Therefore, we used MTX and the result was very good for the skin lesions including the scalp. The therapy modalities used with our patient suggest that we cannot predict the result of a therapy unless we use it for the present. Etoposide did not produce any improvement in our case, but might be effective when combined with prednisolone [4]. Even though there were irritation and urticaria with the nitrogen mustard therapy in our patient, the moderate improvement of lesions in the first week encourages its usefulness. Nevertheless, MTX seems as an efficient and relatively safe drug alone in the treatment of skin lesions of LCH.
Let!. 84 (19941 173-176
References [II Broadbent,
[21
[31
141
PI
161
171
181
191
[lOI
[III
V. et al. (1989) Etoposide (VP16) in the treatment of multisystem Langerhans cell histiocytosis (histiocytosisx). Med. Pediatr. Oncol., 17. 97. Chu. A.C. (1992) Histiocytoses. In: Textbook of Dermatology, pp. 2045-2052. Editors: R.H. Champion, J.L. Burton and F.J.G. Ebling. Blackwell Scientific Publications, Turin. Gardner. H. and Grois, N. (1993) The histiocytosis syndromes. In: Dermatology in General Medicine, pp. 2003-2011. Editors: T.B. Fitzpatrick, A.Z. Eisen, K. Wolff, I.M. Freedberg and K.F. Austen. McGraw-Hill, New York. Hocking, W.G. and Swanson, M. (1986) Multifocal eosinophilic granuloma: response of a patient to etoposide. Cancer, 58, 840-842. Ivatsuki, K., Tsugiki. M., Yoshizava, N. et al. (1986) The effect of phototherapies on cutaneous lesions of histiocytosis X in the elderly. Cancer, 57. 1931-1936. Lichtenwald, D.J., Jacubovic, H.R. and Rosenthal, D. (1991) Primary cutaneous Langerhans cell histiocytosis in an adult. Arch. Dermatol., 127, 1545-1548. Lindeliif, B., Forslind, B., Hilliges. M. et al. (1991) Langerhans cell histiocytosis in an adult. Acta Derm. Venereol. (Stockh.), 71, 178-180. Palmieri, G., Stefani, S.. Gridelli. C. et al. (1989) Irradiation of the hypothalamic-hypophyseal area induces complete regression of mucocutaneous lesions in disseminated histiocytosis X. Cancer, 64, 29-31. Wolfson. S.L.. Botero, F., Hurwitz, S. and Pearson, H.A. (1981) ‘Pure’ cutaneous histiocytosis X. Cancer, 48, 2236-2238. Wong, E., Holden, C.A., Broadbent, V. and Atherton, D.J. (1986) Histiocytosis X presenting as intertrigo and responding to topical nitrogen mustard. Clin. Exp. Dermatol., 1I, 183-187. Writing Group of the Histiocyte Society: Histiocytosis syndromes in children. Lancet, 1987, 24, 208.