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Wendy Dawber- LCH patient
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Andy Ross - LCH
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LCH in adultsLangerhans Cell Histiocytosis in adults - orphan disease: There have been no population-based studies of LCH in adults. The peak age of presentation in adults is between 20-35 years (range 18-90 years) with multi-system disease reported in 30-70% of cases. Some of the clinical features differ between adults and children. Case control studies exploring risk factors for LCH in children have identified different associations, for example with thyroid disease in their families. Smoking is the only known risk factor for LCH in adults; the majority of patients with pulmonary LCH are smokers. (1) There is a specialist centre at Hammersmith Hospital for adults with LCH. If you need any further information or would like contact details for Dr. Chu, please email us at info@histiouk.net In 2005, a conference was held to discuss LCH in adults, at the Royal College of Physicians. This was organised in association with the Royal College of Paediatrics and Child Health and supported by the Leukaemia Research Fund. For a detailed report from the meeting, please click here There are many problems faced by adults with LCH, these include ; misdiagnosis, the lack of specialist centres in the UK, funding for treatment from a different Primary Health Trust and no guidelines in place for the time between diagnosis and when treatment starts. Histiocytosis UK are working with Rare Disease UK to highlight these problems - If you have a story regarding this, please contact us lisa@histiouk.net
If the pituitary gland has been affected, some adults with LCH have Diabetes Insipidus. - The Pituitary Foundation is a national UK charity, which is working to provide information and support to those living with pituitary disorders, including patients, their relatives, friends and carers. Adults with Diabetes Insipidus can apply for a medical exemption certificate that will allow them to receive prescriptions free of charge. To apply for a medical exemption certificate, ask your docotr for Form FP92A. The form tells you what to do. Please find a detailed paper by Ken McClain below; this includes symptoms, diagnosis and treatment. - Kenneth McClain, M.D., Ph.D., Texas Children's Cancer Center & Hematology Svc., Houston, Texas, USA Introduction Orphan diseases are most often connected with children. However, in the case of Langerhans cell histiocytosis (LCH), the adults are the true orphans. First, adults have difficulty finding a medical "home." If they present to a dermatologist, only skin may be evaluated; pulmonologists often investigate only the lung disease. Far too often, the adult LCH patient cannot find a physician who is aware that LCH can be a systemic disease. Secondly, even for those who are knowledgeable about LCH, the world of adult LCH is full of unknowns, because no organized treatment protocols have been in place to define optimal therapies and natural history of the disease. This article will summarize what is known about adult LCH from the medical literature and the author's own experience, as well as information from a questionnaire mailed in 1998 to adult LCH patients by the Histiocytosis Association of America. Terminology There is confusion in the literature and in the minds of some physicians regarding terminology. This confusion begins with the plethora of terms being used. "Langerhans cell histiocytosis" (LCH) is the preferred term, since the cell of origin, the Langerhans cell, has been known for over 40 years and is increasingly better characterized. (See below.) Historical terms for LCH include "histiocytosis X", "eosinophilic granuloma," "Letterer-Siwe disease," "Hand-Schüller-Christian disease," and others.1 The key issues are whether the disease is unifocal or multifocal in a single-organ system with or without other "nonrisk" organs involved.2 The "risk" organs are liver, spleen, bone marrow, and lungs. Since the lungs in adult patients may be the only organ system involved, the designation as a "risk" organ system takes on a slightly different connotation. It is clear that progressive pulmonary disease is a life-threatening condition; however, it is not clear whether this predisposes to or is closely associated with disease in other organs, as is the case for children.
Langerhans Cell The Langerhans cell (LC) is a member of the dendritic-cell network, derived from blood precursors (stem cells) that originate in the bone marrow. Growth factors (cytokines) from other white blood cells including lymphocytes, macrophages, and the bone marrow stromal cells, direct the stem cells to produce several subtypes of dendritic cells. When the primary cytokines include GM-CSF (granulocyte-macrophage colony-stimulating factor) and TNF-α (tumor necrosis factor alpha), as well as others, the stem cells become LCs, which are found in the skin, lymph nodes, bone marrow, spleen, and probably the brain. Langerhans cells have characteristic surface proteins, which identify them as "immature" or "mature." Within the LC is a five-layered structure, a Birbeck granule, first seen by electron microscopy in 1961.3 The gene coding for this infolded surface protein has been identified and the protein called "langerin."4 Now the diagnosis of LCH can be confirmed by staining biopsy tissue specimens with anti-langerin, as well as the standard marker anti-CD1a. Adult Patient Presentation To date, no epidemiologic studies have been done to provide definitive data regarding the incidence of adult LCH. However, based upon several case series, it is assumed there are one to two cases per million population.5 It is impossible to know what this incidence is from the large published studies, since referral patterns and inherent underdiagnosis of LCH undoubtedly skew any assumptions. Three major reviews of LCH in adults have been published5,6,7 with the largest also including pediatric patients seen at the Mayo Clinic.7 The age at presentation ranges from 15 to 91 years with means of 37 to 49 years. Presenting symptoms from the published studies (in order of frequency, most frequent first) are skin rash, dyspnea, polydipsia and polyuria (diabetes insipidus/DI), bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, and balance and memory problems. A survey conducted in 1998 by the Histiocytosis Association of America had responses from 164 of the 400 patients sent questionnaires. Despite a possible bias in reporting, results of the survey bring some interesting points to light. Among these 164 respondents were 57 males and 107 females. The age range is shown below.
The most frequent presenting symptoms, including single and multiple sites in the same patient, involved bone in 49 patients, skin 42, lung 38, diabetes insipidus 36, fever 30, teeth/gums 28, weight loss 26, ear infections 21, lymph node enlargement 15, eye or vision problems 9, liver abnormalities 6, and single mention of spleen enlargement, swollen fingers, nasal problems, hip pain, headaches, rib pain and a lesion on the tongue. The length of time from presenting symptoms to diagnosis is frustratingly long. Many patients wait one to four years before the correct diagnosis is made, and others have symptoms for five to twenty years. Diabetes insipidus is frequently the initial symptom, sometimes starting in childhood and not recognized as due to LCH until other symptoms occur later. Maghnie and colleagues published an important study showing that 15% of patients with supposedly isolated DI had LCH.8 Eighty percent of these patients had a deficiency in another pituitary hormone within five years. The classic MRI finding of loss of brightness in the pituitary gland is not absolutely diagnostic of LCH. One must be careful that enlargement of the pituitary could also be a sign of a pituitary tumor. An enlarged pituitary may be biopsied for a definitive diagnosis, but total removal should be avoided, since the resultant total dysfunction is an immense problem to manage. In the Mayo Clinic series of children and adults, 42 of 44 patients with DI had other organ systems involved: bone 68%, skin 57%, lung 39%, and lymph nodes 18%.7 Treatment of the pituitary damaged by LCH has not been shown to reverse the DI, although some patients report a need for less DDAVP (vasopressin) after chemotherapy. Patients with isolated DI should be carefully observed for onset of other symptoms characteristic of LCH. Skin LCH Many patients present with a papular rash of brown or red lesions, ranging in size from a pinhead to a dime. In the scalp, the rash is similar to seborrhea. Skin in the groin, genitalia, or around the anus may have open ulcers that do not heal with antibacterial or antifungal therapy. In the mouth, gingival hypertrophy or ulcers on the buccal mucosa, hard or soft palate, or tongue may be signs of LCH. Bones Although the skull is the most frequently involved site, the jaw is especially significant in adults. Pain in the jaw and loose teeth may be presenting symptoms. It is preferable to avoid mutilating surgery to remove teeth or jaw bones. Systemic chemotherapy can cure the disease, and bone lesions can regress so the jaw bone and teeth can return to a normal condition. Of 47 patients in the study by Baumgartner, the primary sites were jaw 30%, skull 21%, extremities 17%, vertebrae 13%, pelvis 13%, and ribs 6%. This is in contrast to children, where the skull is the major bone area involved (40%), and the jaw is involved in only 8% of those patients. Although bone lesions may be asymptomatic in some areas, those in the mouth are especially troublesome because of tooth loss and a high recurrence rate. Lung Pulmonary LCH is slightly more prevalent in males and is clearly more frequent in smokers than in nonsmokers.9 Patients with pulmonary LCH present with cough, dyspnea, or chest pain. Pain may be from a pneumothorax or bone lesions. Nearly 20% of adults with lung involvement have no symptoms.10 Most important is the fact that other sites of LCH involvement can be found: bone 18%, skin 13%, and DI 5%. Pulmonary function studies are quite variable, but the most frequent finding is a reduced carbon monoxide diffusing capacity of the lungs (DLCO) in 70 to 90% of cases.11,12 The most sensitive diagnostic test is a high-resolution CT, which can reveal cysts and nodules characteristic of LCH. Evaluation Regardless of the presentation, patients with LCH should have the following tests done: skeletal survey, skull series, bone scan, complete blood count, sedimentation rate, liver function tests, electrolytes, and urinalysis. If there are symptoms of DI, a water deprivation test should be done. When the bones near the ears or eyes are involved, a head CT should be ordered to evaluate more closely these and other bones in the skull. If large skull lesions exist, or if lesions near the ears or the eyes present, an MRI of the brain is necessary, since such bone lesions are a clue that a patient may be at risk for brain involvement. Therapy No organized series of treatments for adults has been published. In the reports now in the medical literature, the wide diversity of applied treatments makes it impossible to define an optimal strategy, but successful treatment is likely with a variety of chemotherapy regimens. Results from the LCH-I and LCH-II studies in children do give some guidelines. One major revelation is that radiation or single-drug administration is not sufficient for patients with multiple bone lesions. The rate of recurrent disease goes down markedly when patients receive a six-month course of Velban and prednisone. There are reports that 2-chloro-2'-deoxyadenosine (2CdA) is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system disease.13,14 Unfortunately, no studies have been done comparing different treatments in adults with lung disease. It is stated that steroids may help slow or even stop the progression of lung LCH, but without a randomized study comparing no therapy to therapy with steroids or another treatment in a large group of patients, we will never know. In the latter part of 2001, the Histiocyte Society will initiate a protocol for treatment of adults with LCH. Please contact the Histiocytosis Association of America (1-800-548-2758) for information regarding this protocol. We invite all physicians to participate by registering their patients in this study, so that an organized approach can provide answers to the lingering questions regarding optimal treatment and long-term effects of LCH. References Writing Group of the Histiocyte Society. "Histiocytosis Syndromes in Children." Lancet, vol. 1, 1987, pp. 208-209. Gadner H, Grois N, Arico M, et. al. "A Randomized Trial of Treatment for Multisystem Langerhans Cell Histiocytosis." Pediatrics, In press, 2001. Birbeck MS, Breathnach AS, Everall JD. "An Electron Microscope Study of Basal Melanocytes and High-Level Clear Cells (Langerhans cells) in Vitiligo." J Invest Dermat, vol. 37, 1961, pp. 51-63. Valladeau J, Ravel O, Dezutter-Dambuyant C, et. al. "Langerin, a Novel C-Type Lectin Specific to Langerhans Cells is an Endocytic Receptor that Induces the Formation of Birbeck Granules." Immunity, vol. 12, 2000, pp. 71-81. Baumgartner I, von Hochstetter A, Baumert B, Luetolf U, Follath F. "Langerhans Cell Histiocytosis in Adults." Med Ped Oncol, vol. 28, 1997, pp. 9-14. Malpas JS, Norton AJ. "Langerhans Cell Histiocytosis in the Adult." Med Ped Oncol, vol. 27, 1996, pp. 540-546. Howarth DM, Gilchrist GS, Mullan BP, Wiseman GA, Edmondson JH, Schomberg PJ. "Langerhans Cell Histiocytosis: Diagnosis, Natural History, Management and Outcome." Cancer, vol. 85, 1999, pp. 2278-2290. Maghnie M, Cosi G, Genovese E, et. al. "Central Diabetes Insipidus in Children and Young Adults." New Eng J Med, vol. 343, 2000, pp. 998-1007. Schonfeld N, Frank W, Wenig S, Uhrmeister P, Allica E, Pressler H, Grassot A, Loddenkemper R. "Clinical and Radiologic Features, Lung Function and Therapeutic Results in Pulmonary Histiocytosis X." Respiration, vol. 60, 1993, pp. 38-44. Travis WD, Borok Z, Roum JH, Zhang J, Feuerstein I, Ferrans VJ, Crystal RG. "Pulmonary Langerhans Cell Granulomatosis (Histiocytosis X): A Clinicopathologic Study of 48 Cases." Am J Surg Pathol, vol. 17, 1993, pp. 971-986. Delobbe A, Durieu J, Duhamel A, Walleert B. "Determinants of Survival in Pulmonary Langerhans Cell Granulomatosis (Histiocytosis X)." Eur Respir J, vol. 9, 1996, pp. 2002-2006. Crausman RS, Jennings CA, Tuder RM, Ackerson LM, Irvin CG, King TE. "Pulmonary Histiocytosis X: Pulmonary Function and Exercise Pathophysiology." Am J Respir Crit Care Med, vol. 153, 1996, pp. 426-435. Saven A, Foon KA, Piro LD. "2-Chlorodeoxyadenosine-induced Complete Remissions in Langerhans Cell Histiocytosis." Ann It Med, vol. 121, 1994, pp. 430-432. Weitzman S, Wayn AS, Arceci R, Lipton JM, Whitlock JA, De Rossi G. "Nucleoside Analogues in the Therapy of Langerhans Cell Histiocytosis: A Survey of Members of the Histiocyte Society and Review of the Literature." Med Ped Oncol, vol. 33, 1999, pp. 476-48.
Adult Langerhans Cell Histiocytosis (1)
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