The natural history of disease in adult Langerhans cell histiocytosis (LCH), with the exception of pulmonary LCH, is unknown. It is unclear whether there are significant differences from childhood LCH, although it appears that multisystem-risk LCH is less aggressive than childhood high-risk disease. The risk of reactivations is unknown.
A consensus group reported on the evaluation and treatment of adult patients with LCH. However, discussion continues, particularly regarding optimal first-line therapy.
It is estimated that one to two adult cases of LCH occur per 1 million population. The true incidence of this disease is not known, however, because published studies are mostly nonpopulation based and the disorder is likely to be underdiagnosed. A survey from Germany reported that 66% of the patients with LCH were women, with an average age of 43.5 years for all patients.
Presentation of adult LCH by organ, site, or system
Adult patients with LCH may have symptoms and signs for many months before a definitive diagnosis and treatment. LCH in adults is often similar to that in children, and appears to involve the same organs, although the proportions may be different. There is a predominance of lung disease in adults, usually occurring as single-system disease and closely associated with smoking and with some unique biologic characteristics. Most adult lung LCH cases are polyclonal and possibly reactive, while the minority of lung LCH cases are monoclonal. A German registry with 121 registrants showed that 62% had single-organ involvement and 38% had multisystem involvement, while 34% of the total had lung involvement. The median age at diagnosis was 44 years ± 12.8 years. The most common organ involved was lung followed by bone and skin. All organ systems found in childhood LCH were seen, including endocrine and central nervous system, liver, spleen, bone marrow, and gastrointestinal tract. The major difference is the much higher incidence of isolated pulmonary LCH in adults, particularly in young adults who smoke. Other differences appear to be the more frequent involvement of genital and oral mucosa. There may possibly be a difference in the distribution of bone lesions, but both groups suffer reactivations of bone lesions and progression to diabetes insipidus, although the exact incidence is unknown in adults.
Presenting symptoms from published studies are (in order of decreasing frequency) dyspnea or tachypnea, polydipsia and polyuria, bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, ataxia, and memory problems. The signs of LCH are skin rash, scalp nodules, soft tissue swelling near bone lesions, lymphadenopathy, gingival hypertrophy, and hepatosplenomegaly. Patients who present with isolated diabetes insipidus should be carefully observed for onset of other symptoms or signs characteristic of LCH. At least 80% of patients with diabetes insipidus had involvement of other organ systems, including bone (68%), skin (57%), lung (39%), and lymph nodes (18%).
Skin and oral cavity
Thirty-seven percent of adults with LCH have skin involvement which usually occurs as part of multisystem disease. Skin-only LCH occurs but it is less common in adults than in children. The prognosis of adults with skin-only LCH is excellent, with 100% probability of 5-year survival. The cutaneous involvement is clinically similar to that seen in children and may take many forms. Infra-mammary and vulvar involvement may be seen in adult women with skin LCH.
Many patients have a papular rash with brown, red, or crusted areas ranging from the size of a pinhead to a dime. In the scalp, the rash is similar to that of seborrhea. Skin in the inguinal region, genitalia, or around the anus may have open ulcers that do not heal after antibacterial or antifungal therapy. The lesions are usually asymptomatic but may be pruritic or painful. In the mouth, swollen gums or ulcers along the cheeks, roof of the mouth, or tongue may be signs of LCH.
Diagnosis of LCH is usually made by skin biopsy performed for persistent skin lesions.
The relative frequency of bone involvement in adults differs from that in children: mandible (30% vs. 7%) and skull (21% vs. 40%).[2-5] The frequency of vertebrae (13%), pelvis (13%), extremities (17%), and rib (6%) lesions in adults are similar to those found in children.
Pulmonary LCH in adults is usually single-system disease, but in a minority of patients other organs may be involved, including bone (18%), skin (13%), and diabetes insipidus (5%).
Pulmonary LCH is more prevalent in smokers than in nonsmokers and the male to female ratio may be near unity depending on the incidence of smoking in the population studied.[7,8] Patients with pulmonary LCH usually present with a dry cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms.[9,10] Chest pain may indicate a spontaneous pneumothorax (10%–20% of adult pulmonary LCH cases). Pulmonary LCH can be diagnosed by bronchoscopy in about 50% of adult patients, as defined by characteristic CD1a immunostaining cells of greater than or equal to 5% of cells observed.
The LCH cells in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike Langerhans cells (LCs) found in other lung disorders. In addition, pulmonary LCH in adults appears to be primarily a reactive process, rather than a clonal proliferation as seen in childhood LCH. However, BRAF V600E mutations have been demonstrated in pulmonary LCH lesions in adults, suggesting a clonal process in a significant proportion (25%–30%) of patients.
The course of pulmonary LCH in adults is variable and unpredictable. Fifty-nine percent of patients do well with either spontaneous remission with cessation of smoking, or with some form of therapy. Adults with pulmonary LCH who have minimal symptoms have a good prognosis, although some have steady deterioration over many years. Age older than 26 years and lower forced expiratory volume/forced vital capacity (FEV1/FVC) ratio and higher residual volume/total lung capacity (RV/TLC) ratio are adverse prognostic variables. About 10% to 20% have early severe progression to respiratory failure, severe pulmonary hypertension, and cor pulmonale. Adults who have progression with diffuse bullae formation, multiple pneumothoraces, and fibrosis have a poor prognosis.[16,17] The remainder have a variable course, with stable disease in some patients and relapses and progression of respiratory dysfunction in others, some after many years. One study reported that smoking cessation did not increase the longevity of adults with pulmonary LCH, apparently because the tempo of disease is so variable. Patients receiving lung transplantation for treatment of pulmonary LCH have a 77% survival rate at 1 year and 54% survival rate at 10 years, with a 20% chance of LCH recurrence.
The most frequent pulmonary function abnormality finding in patients with pulmonary LCH is a reduced carbon monoxide diffusing capacity in 70% to 90% of cases.[15,20] A high-resolution computed tomography (CT) scan, which reveals a reticulonodular pattern classically with cysts and nodules, usually in the upper lobes and sparing the costophrenic angle, is characteristic of LCH. Despite the typical CT findings, most pulmonologists agree that a lung biopsy is needed to confirm the diagnosis. The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease. A study correlating lung CT findings and lung biopsy results in 27 patients with pulmonary LCH has shed some light on pulmonary LCH. Thin-walled and bizarre cysts had active LCs and eosinophils. Fifty-two percent of patients improved, most with smoking cessation, and some with steroid treatment within 14 months of diagnosis. Four patients (15%) were stable, and nine patients (33%) progressed over 22 months.
Liver involvement in adults has been reported in 27% of a series of adult patients with LCH and multiorgan disease. Hepatomegaly (48%) and liver enzyme abnormalities (61%) were present. CT and ultrasound imaging abnormalities are often found. The early histopathologic stage of liver LCH includes infiltration of CD1a+ cells and periductal fibrosis with inflammatory infiltrates with or without steatosis. The late stage is biliary tree sclerosis and treatment with ursodeoxycholic acid is suggested.
In a large series of patients from the Mayo Clinic, 31% had multisystem LCH compared with 69% registered on the Histiocyte Society adult registry; this likely reflects referral bias.[6,25] In the adult multisystem patients, the organs involved included the following:
- Skin (50%).
- Mucocutaneous (40%).
- Diabetes insipidus (29.6%).
- Hepatosplenomegaly (16%).
- Hypothyroidism (6.6%).
- Lymphadenopathy (6%).
- Girschikofsky M, Arico M, Castillo D, et al.: Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 8: 72, 2013. [PUBMED Abstract]
- Baumgartner I, von Hochstetter A, Baumert B, et al.: Langerhans'-cell histiocytosis in adults. Med Pediatr Oncol 28 (1): 9-14, 1997. [PUBMED Abstract]
- Götz G, Fichter J: Langerhans'-cell histiocytosis in 58 adults. Eur J Med Res 9 (11): 510-4, 2004. [PUBMED Abstract]
- Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980. [PUBMED Abstract]
- Kaltsas GA, Powles TB, Evanson J, et al.: Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment. J Clin Endocrinol Metab 85 (4): 1370-6, 2000. [PUBMED Abstract]
- 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 (16): 2341-8, 2003. [PUBMED Abstract]
- Vassallo R, Ryu JH, Schroeder DR, et al.: Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med 346 (7): 484-90, 2002. [PUBMED Abstract]
- Schönfeld N, Frank W, Wenig S, et al.: Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 60 (1): 38-44, 1993. [PUBMED Abstract]
- Travis WD, Borok Z, Roum JH, et al.: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 17 (10): 971-86, 1993. [PUBMED Abstract]
- Tazi A, Moreau J, Bergeron A, et al.: Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 163 (6): 3511-5, 1999. [PUBMED Abstract]
- Baqir M, Vassallo R, Maldonado F, et al.: Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol 20 (4): 309-12, 2013. [PUBMED Abstract]
- Yousem SA, Colby TV, Chen YY, et al.: Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 25 (5): 630-6, 2001. [PUBMED Abstract]
- Roden AC, Hu X, Kip S, et al.: BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 38 (4): 548-51, 2014. [PUBMED Abstract]
- Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000. [PUBMED Abstract]
- Delobbe A, Durieu J, Duhamel A, et al.: Determinants of survival in pulmonary Langerhans' cell granulomatosis (histiocytosis X). Groupe d'Etude en Pathologie Interstitielle de la Société de Pathologie Thoracique du Nord. Eur Respir J 9 (10): 2002-6, 1996. [PUBMED Abstract]
- Chaulagain CP: Pulmonary langerhans' cell histiocytosis. Am J Med 122 (11): e5-6, 2009. [PUBMED Abstract]
- Lin MW, Chang YL, Lee YC, et al.: Pulmonary Langerhans cell histiocytosis. Lung 187 (4): 261-2, 2009. [PUBMED Abstract]
- Tazi A, Hiltermann J, Vassallo R: Adult lung histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 187-207.
- Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006. [PUBMED Abstract]
- Crausman RS, Jennings CA, Tuder RM, et al.: Pulmonary histiocytosis X: pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 153 (1): 426-35, 1996. [PUBMED Abstract]
- Diette GB, Scatarige JC, Haponik EF, et al.: Do high-resolution CT findings of usual interstitial pneumonitis obviate lung biopsy? Views of pulmonologists. Respiration 72 (2): 134-41, 2005 Mar-Apr. [PUBMED Abstract]
- Soler P, Bergeron A, Kambouchner M, et al.: Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis? Am J Respir Crit Care Med 162 (1): 264-70, 2000. [PUBMED Abstract]
- Kim HJ, Lee KS, Johkoh T, et al.: Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol 21 (7): 1406-15, 2011. [PUBMED Abstract]
- Abdallah M, Généreau T, Donadieu J, et al.: Langerhans' cell histiocytosis of the liver in adults. Clin Res Hepatol Gastroenterol 35 (6-7): 475-81, 2011. [PUBMED Abstract]
- Howarth DM, Gilchrist GS, Mullan BP, et al.: Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 85 (10): 2278-90, 1999. [PUBMED Abstract]