Langerhans Cell Histiocytosis in Taiwan: A Retrospective Case Series in a Medical Center

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1 Original Study Langerhans Cell Histiocytosis in Taiwan: A Retrospective Case Series in a Medical Center Yi-Chin Shih Wan-Lung Lin I-Hsin Shih Background: Langerhans cell histiocytosis (LCH) comprises a diverse group of disorders where pathologic Langerhans cells accumulate in a variety of organs. Objectives: To characterize the disease presentation in Taiwanese, and to analyze the differences of LCH between Taiwanese and western populations. Methods: A retrospective chart review was performed on patients diagnosed with LCH in a medical center in Taiwan between 1990 and Results: diagnosis. The male: female ratio was 3: 2. Multisystemic involvement was found in 15 patients (42.8%) and isolated bone lesions were found in 12 patients (34.2%), 3 patients had isolated cutaneous involvement; the remaining 5 patients had solitary lymph node, lung, thyroid gland, submandibular gland or extraocular soft tissue involvement, respectively. Ten of the 15 patients with multisystemic diseases had skin/mucosal involvement; 10 had bony involvement. All three patients that expired had multisystemic disease. Conclusion: ment (2.8%) in our cohort. Further multi-centered, prospective researches may be needed to better characterize the disease presentation in Asian population. (Dermatol Sinica 27: , 2009) Key words: Langerhans cell histiocytosis, Taiwan INTRODUCTION Langerhans cell histiocytosis (LCH) is caused by the infiltration of bone marrowderived pathological Langerhans cells in one or more organs. The involved organs include bone, skin/mucosa, lung, hypothalamus/posterior pituitary gland, lymph nodes, liver, spleen, bone marrow and various soft tissues. 1 According to the different extent of sentations formerly defined as eosinophilic granuloma, Hand-Schuller-Christian syndrome, Lettere-Siwe disease, and Hashimoto- Pritzker syndrome. The clinical course and outcome of the patients varied in wide range from single system diseases often cured by surgical curettage to generalized and fulminant diseases resulting in life-threatening organ dysfunction. 1 Rarity of the disease have baffled our understanding of it for decades, From the Department of Dermatology, Chang Gung Memorial Hospital, Taipei and Department of Pediatric Dermatology, Chang Gung Children s Hospital, Linkou and Chang Gung University College of Medicine Corresponding author: I-Hsin Shih, 199, Tun-Hua North Road, Taipei, 105, Taiwan TEL: FAX: ma1606@adm.cgmh.org.tw Funding source: none Received: September 03, 2008 Revised: December 30, 2008 Accepted: March 09,

2 Langerhans Cell Histiocytosis however, emerging cross-specialty reports and studies addressing the clinical manifestations and treatment modalities have helped in the understanding of the disease. Among them, most notable is the international registry of Histiocyte Society, 2 which serves as a common platform for clinical evaluation and therapeutic trials. Before the emergence of Histiocyte Society, many of the early studies had marked selection bias and lacked standardized diagnostic and classification criteria. Despite these emerging efforts, until now the majority of the reports were based on western races, and very few reports of- population. 3 To provide an opportunity to compare the natural history, management and outcome between Taiwanese and western population, we reviewed the presentation and course of patients with LCH that were diagnosed pathologically at a medical center in Taiwan between 1990 and MATERIAL AND METHOD Using computer research of database, we were able to identify 50 LCH patients whose pathological diagnoses were made in our institute from 1990 to Data was obtainable in 35 of the patients. A retrospective review of the medical records from the clinical database was performed, along with a review of available photographic documentation of the cutaneous lesions. The following parameters were evaluated: sex, age of initial symptoms/signs, ages of diagnosis, organ involvement, therapy administered, clinical course and outcome. Using criteria developed by the Histiocyte Society (Table 1), 4 23 of 35 meet definitive diagnosis by the demonstration of CD1a antigenic determinants on the surface of lesional cells. In the remaining patients, routine histological analyses were performed erature (Fig. 1, 2). 4 All patients after pathological diagnosis of LCH underwent systemic survey including comprehensive history taking, physical examination and whole body radiographic skeletal survey. The reported sites of characteristic osseous abnormality were regarded positive for LCH. Ear, nose and Dermatol Sinica, Jun

3 Yi-Chin Shih, et al otorrhea and/or mastoid infiltration. Skin/ mucosa involvement was defined by histological criteria or by skin rash/hypertrophic disease location. Liver/spleen involvement was defined by organomegaly. Lymph node tures and/or an increased lymph node size (>2 tern and/or histological confirmation. Pituitary involvement was defined by a growth hormone and/or thyroid stimulating hormone deficiency, and/or diabetes insipidus. Bone marrow involvement was defined by histo- tion or functional bone marrow dysfunction manifested by low blood cell count. were confirmed histologically. Ten patients had multisystemic involvement and three presented purely with cutaneous disease. Skin lesions were the initial presentations in all but two patients. In the eleven patients with follow up, 7 achieved relapse free survival during the period of follow up, 2 had progressive disease, and 2 died despite treatment. Morphologic characters of the skin lesions are listed in Table 3. The most common lesions are pinhead- to pea-sized RESULTS The median age of diagnosis in the 35 patients was 3 years (range, 2 months to 58 years). The male: female ratio was 3:2. Thirty are pediatric patients (i.e. diagnosed at age 18 or under). Multisystemic LCH was found in 15 patients (42.8%). Isolated bone lesions were found in 12 patients (34.2%). Of the remaining 8 patients (22.8%) with nonosseous single system disease, 3 had isolated cutaneous involvement, 1 had lymph node involvement, 1 had lung disease, 1 had thyroid gland infiltration, 1 had submandibular gland involvement and 1 had extraocular soft tissue lesion. Bone and mucocutaneous tissue are the two most commonly involved organs in multisystemic diseases. Of the 15 patients with multisystemic diseases, 10 had skin/ mucosal involvement, 10 had bony involvement. The thirteen patients with cutaneous involvement were further examined in Table 2, including patient characteristics, symptoms at presentation, treatment and clinical courses. All but one of the skin involvements Fig. 1 Langerhans cell histiocytosis: the infiltrate in the upper dermis consists mainly of histiocytes with abundant eosinophilic cytoplasm and vesicular nuclei. Note also epidermotropism and eosinophils. This case is included in Fig. 2 Langerhans cell histiocytosis: tumor cells regularly express CD1a. Same case as in Fig. 1. (CD1a, original mag- 95 Dermatol Sinica, Jun 2009

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5 Yi-Chin Shih, et al erythematous papulopustules, often with certain degree of crust formation (Fig. 3). Another important manifestation is eczematous scaly patches, which are often in seborrhealike distribution and occasionally can cause cluded generalized petechiae, gum hypertrophy (Fig. 4) and nodular/ulcerative lesions. Of the three patients with solitary cutaneous involvement, one was a 4 month-old boy to topical steroid, one was lost to follow up, and the other was a 28 year-old woman presented with multiple pinkish to skin-colored papules on face, upper trunk and arms for 2 months (Fig. 5). Solitary skin involvement was confirmed subsequently. Clearance of skin lesion was noted after treatment with isotretinoin 1.5mg/kg daily for 5 months. Two of the five patients with hepatosplenic involvement received liver biopsy. Both demonstrated sclerosing cholangitis without LCH cells. One of them died shortly after liver transplantation. The other developed late stage liver disease and later received repeated variceal ligations. Vinblastine/vincristine with steroid was the most common regimen when systemic chemotherapy was used (18/35). Pediatric patients with multisystemic diseases were treated according to protocols developed by Taiwan Pediatric Oncology Group (TPOG). 6-mercaptopurine, methotrexate and etoposide were frequently added in the multidrug Histiocyte Society. After treatment, 6 of the 15 patients with multisystemic disease had continuing active disease. All the patients with non-osseous single system disease with follow up (7/7) remained disease free after initial treatment. There were a total of 3 deaths, all of them had multisystemic involvement. Fig. 3 Multiple purpuric papules with ulceration and crusting on the back of a 2 m/o girl. Fig. 4 Hypertrophic gum with hemorrhage of a 15 m/o boy. Fig. 5 Yellow to pinkish papules on the neck of a 28 y/o woman. 97 Dermatol Sinica, Jun 2009

6 Langerhans Cell Histiocytosis DISEASE ASSOCIATION Five patients had an intercurrent disease, including one cancer. In one case the diagnosis of LCH was based on biopsy of mandibular lesion, diabetes insipidus and interventricular brain biopsy. He was disease free for 9 years after craniotomy, chemotherapy and radiotherapy of the head, but died of metastatic sebaceous carcinoma originating in the face. Two patients presented with sclerosing cholangitis. In both patients, liver biopsy failed to identify Langerhans cell with immunohistochemical stain. We also found one case each of diaphragm hernia and recurrent obstructive airway xanthoma. DISCUSSION The clinical presentation and outcome of treatment for Langerhans cell histiocytosis are highly variable, ranging from an isolated spontaneously remitting bone lesion to a multi-system disease with life-threatening organ dysfunction, most notoriously hepatoslpenic, hematopoietic, and lung dysfunction. Since the early 1990 s, international cooperative approaches to LCH have been organized under the support of the Histiocyte Society, an international association of researchers dedicated to clinical and fundamental research into the histiocytic disorders. The successive trials have helped to standardize the initial investigations and have led to the randomized therapy now being tested therapeutic trials. 2 We examined the clinical presentations of our patients by comparing them with western studies. When compared with a large pediatric cohort (n=348) in a French study, 5 no significant trend of difference regarding diversity of organ involvement and disease characteristics was found using our pediatric subgroup (n=30): bone involvement, 81% vs. 76.7%; ENT and/or mastoid, 15.2% vs. 16.7%; skin, 39% vs. 36.7%; liver, 14.4% vs. 16.7%; bone marrow, 11.2% vs.10%; lungs, 12.6% vs. 6.7%; lymph nodes, 10.9% vs. 13.3%; pituitary gland, 15.8% vs. 20%. We further compared our data with a retrospective study of 314 patients performed in Mayo clinic. 6 As shown in Table 4, all 35 patients were categorized into subgroups according to organ(s) involved. The largest difference between two studies lies in the number of patients with isolated lung disease, which consisted of 87 patients (27.7%) in the 314-patient cohort, while we were only able to identify one patient (2.8%) with isolated lung involvement. Due to the limitations of our study design, the true incidence of isolated lung involvement may be underestimated in our population, since an invasive procedure such as lung biopsy is not likely to be performed in all patients with suspected pulmonary LCH, and especially not in those whose disease is asymptomatic or resolves spontaneously. However, in earlier reports, pulmonary LCH was found to occur mainly among white people. 7 Common presenting features Dermatol Sinica, Jun

7 Yi-Chin Shih, et al of pulmonary involvement included progressive dyspnea, spontaneous pneumothorax, chronic cough and abnormal chest X-ray in- and interstitial pattern, with a predominance of middle- and upper-lobe involvement. Isolated pulmonary LCH were almost always found in smoking adults, 2, 6 in fact, in the Mayo study, 83 of the 87 are adults, and 84 of the 87 are smokers. Furthermore, according to data published in International Histiocyte Society Registry, 8 among adult patients, lung is the most commonly involved organ in single system disease (51.1%). In short, the high proportion of cases with pulmonary disease is the most striking difference between children and adults with LCH. Our study did not include solitary lung involvement without pathological proof. Whether the paucity of this presentation in our cohort represents an actual racial difference remains to be answered. In accordance with former studies, 5, 6 bone and mucocutaneous tissue are the two most commonly involved organs in multisystemic diseases. Of the 15 multisystemic cases in our series, 10 had skin/mucosal involvement, 10 had bony involvement. In the study from Mayo clinic, 6 74 and 63 out of the 96 patients in multisystemic group had bone and skin/mucosa involvement, respectively. Cutaneous involvement is traditionally considered to portend a multisystemic involvement and poor prognosis in LCH. 5, 6 Cutaneous LCH may appear as localized or as disseminated lesions. The diverse cutaneous or mucocutaneous lesions, either as curable single organ disease or as part of multisystemic manifestation, are often the first keys to the correct identification of LCH. Since the majority of the patients presented with skin lesions were later found to have multisystemic disease, we argue that a thorough workup and a periodical follow up should ensue to detect possible evolution of systemic disease. As shown in our cases, typical cutaneous lesions of LCH present as scaly, erythematous papules or seborrheic dermatitis-like patches, especially pronounced on the scalp or flexural areas. The eruption is generally not itchy, but some patients may complain of pruritus. 9 LCH can also appear as isolated nodules in the skin. Here, the differential diagnosis should include eruptive xanthoma and granuloma annulare. In children and particularly in patients who are thrombocytopenic, skin eruptions frequently become purpuric. The vulva 99 Dermatol Sinica, Jun 2009

8 Langerhans Cell Histiocytosis is relatively commonly involved in older women 10 who often complain of vulvar irritation or soreness, and examination usually shows vulva ulcers with or without papules or nodules. The differential diagnosis in this setting includes Paget s disease of the vulva, candidiasis and eczema. Involvement of external male genitalia, on the other hand, is unusual. In all, polymorphic cutaneous presentations in children and adults mentioned above are prone to be mistaken for a broad spectrum of more common diseases, so a skin biopsy should be done whenever there is doubt to avoid this clinical pitfall. According to the writing group of the Histiocyte Society, 4 the definitive diagnosis of LCH requires the finding of Birbeck granules in lesional cells by electron microscopy and/or the expression of T6-antigenic determinants (positive staining with CD1a antibodies) on the surface of lesional cells. Anti-S100, langerin (CD207), CD68 and factor XIIIa may be further helpful if LCH is suspected and need to be distinguished from other types of histiocytoses. Langerhans cells usually label for S100 and CD207, not for CD68 and factor XIIIa. 11 As suggested by Lahey, 12 liver, spleen, lungs and hematopoietic were risk organs whose dysfunction portend a poor prognosis. Functional hematological involvement was defined by anemia and/or leukocytopenia and/or thrombocytopenia. Functional pulmonary involvement was defined by dyspnea and/or cyanosis. Functional liver involvement was defined by cholestasis and/or hypoalbuminemia, and/or prolonged prothrombin time. 5 Liver involvement occurs in 16-36% of multisystem LCH and has the clinical, histological and radiological hallmarks of sclerosing cholangitis. In the past, these patients frequently died of hepatic failure. Recently, liver transplantation has been reported as an effectual treatment for end-stage hepatic disease both in children and adults. 13 In the past, treatment for LCH was anecdotal and sporadic; however, within the last 20 years several randomized trials have proach. 14 Optimal treatment of LCH depends on disease severity, ranging from local corticosteroids to multi-drug chemotherapy. The rationale for the multidrug chemotherapeutic regimens for the patient with disseminated LCH, which are conducted through the Histiocyte Society, is based on clinical experience without fundamental background. This has led to a cure rate of approximately 70%. 15 In general, however, a high percentage of cured LCH patients with either localized or disseminated disease, have highly debilitating late sequelae of their disease. 16 Currently, the LCH-III protocol is probably the most common therapeutic strategy used for patients with multiorgan involvement. This protocol has several treatment arms dependent upon the number and type of organ systems involved, as well as whether risk organ 14, 17 dysfunction is present. Clinical trials of the Histiocyte Society do not support further use of etoposide, a drug associated with a remarkably high risk for the development of leukemia, especially in patients who have received multiple treatments due to recurrent disease. 18, 19 Monoclonal antibodies that target tors are among the newer agents currently under investigation. 14 Various therapeutic options are available for cutaneous LCH, including surgical excision, topical steroids, PUVA, topical nitrogen mustard, systemic steroids, radiotherapy, trimethoprim-sulfamethoxazole, thalidomide, isotretinoin, interferon and cyclosproin. 8 Lesion type, lesion number, and natural history of LCH, especially its tendency to regress spontaneously, should be taken into consideration before starting treatment, with the rationale being to start with the easi- Dermatol Sinica, Jun

9 Yi-Chin Shih, et al est treatment with fewest side effects and progress to stronger treatments depending on clinical response. CONCLUSION Despite limitation by the retrospective nature and significant referral bias from a single institution, this descriptive study aspires to provide further disease information regarding Taiwanese. In the small number of patients we collected, we found fewer anticipated cases of adult patient with solitary pulmonary disease. Whether this represented a true racial difference remains to be answered. Further collaborative, prospective researches may be needed to better characterize the disease presentations in Asians. ACKNOWLEDGEMENTS The authors acknowledge Dr. Ya-Ching Chang, Dr. Yea-Huey Chuang, Dr. Ming- Jing Chen and Dr. Chih-Hsun Yang for their contribution to the data collection. We thank Dr. Tseng-tong Kuo for his assistance in dermatopathology. REFERENCES 1. Favara BE, Feller AC, Pauli M, et al.: Contem- WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 29: , Aricò M: Langerhnas cell histiocytosis in adults: more questions than answers? Eur J Cancer 40: , Asamoto H, Kitaichi M, Nagai S, et al.: Pulmonary eosinophilic granuloma-clinical analysis of 17 patients. Jap J Thorac Dis 33: , Chu T, D Angio GJ, Favara B, et al.: Histiocytosis syndromes in children. Writing group of the histiocyte society. Lancet 8526: , Donadieu J, Thomas C, Herbelin C, et al.: A multicentre retrospective survey of Langerhans cell histiocytosis: 348 cases observed between 1983 and The French Langerhans Cell Histiocytosis Study Group. Arch Dis Child 75: 17-24, Howarth DM, Gilchrist GS, Mullan BP, et al.: Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 85: , Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans -cell histiocytosis. New Eng J Med 342: , Aricò M, Girschikofsky M, Généreau T, et al.: Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer 39: , Munn S, Chu AC: Langerhans cell histiocytosis of the skin. Hemato/Oncol Clin Nor Am 12: , Solano T, Espana A, Sola J, et al.: Langerhans cell histiocytosis on the vulva. Gynecol Oncol 78: , Zelger B, Cerio R, Orchard G, et al.: Histologic and immunohistochemical study comparing xanthoma disseminatum and histiocytosis X. Arch Dermatol 128: , Lahey ME: Histiocytosis X- an analysis of prognostic factors. J Pediatr 87: , Griffiths W, Davies S, Gibbs P, et al.: Liver transplantation in an adult with sclerosing cholangitis due to Langerhans cell histiocytosis. J Hepatol 44: , Satter EK, High WA: Langerhans cell histiocytosis: a review of the current recommendations of the histiocyte society. Pediatr Dermatol 25: , Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans cell histiocytosis. J Pediatr 138: , Haupt R, Nanduri V, Calevo MG, et al.: Permanent consequences in Langerhans cell histiocytosis patients. A pilot study from the Histiocyte Society Late Effects Study Group. Pediatr Blood Cancer 1: , Braier J, Chantada G, Rosso D, et al.: Langerhans cell histiocytosis: retrospective evaluation of 123 patients at a single institution. Pediatr Hemato Oncol 16: , Allen CE, McClain KL: Langerhans cell histiocytosis: a review of past, current and future therapies. Drugs Today 43: , Kudo K, Yoshida H, Kiyoi H, et al.: Etoposiderelated acute promyelocytic leukemia. Leukemia 12: , Dermatol Sinica, Jun 2009

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