Presentation of LCH in Children
Single-System Disease Presentation
Skin and nails
Lymph nodes and thymus
Multisystem Disease Presentation
Bone and other organ systems
Central nervous system
Langerhans cell histiocytosis (LCH) usually presents with a skin rash or painful bone lesion. Systemic symptoms of fever, weight loss, diarrhea, edema, dyspnea, polydipsia, and polyuria, relate to specific organ involvement and single-system or multisystem disease presentation as noted below.
Specific organs are considered high-risk or low-risk organs when involved with disease presentation. Risk refers to the risk of mortality.
- High-risk organs include liver, spleen, and bone marrow.
- Low-risk organs include skin, bone, lymph nodes, gastrointestinal tract, pituitary gland, and central nervous system (CNS).
Additionally, patients may present with a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal); or LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or it may be disseminated. Treatment decisions for patients are based upon whether high-risk or low-risk organs are involved and whether LCH presents as a single-system or multisystem disease. Patients can have LCH of the skin, bone, lymph nodes, and pituitary in any combination and still be considered at low-risk of death, although there may be relatively high-risk for long-term consequences of the disease.Single-System Disease Presentation
In single-system LCH, as the name implies, the disease presents with involvement of a single site or organ, including skin and nails, oral cavity, bone, lymph nodes and thymus, pituitary gland, and thyroid.Skin and nails
- Infants: Seborrheic involvement of the scalp may be mistaken for prolonged cradle cap in infants. Infants may also present with brown to purplish papules over any part of their body (Hashimoto-Pritzker disease). Similar to that of stage 4S neuroblastoma, this manifestation may be self-limited as the lesions often disappear with no therapy during the first year of life. However, these patients must be watched very closely for systemic disease which may present after the initial skin lesions.[2,3] In a report of 61 neonatal cases from 1,069 patients in the Histiocyte Society database, nearly 60% had multisystem disease and 72% had risk organ involvement.
A review of patients presenting in the first 3 months of life with skin-only LCH, compared the clinical and histopathologic findings in 21 children whose skin LCH regressed with 10 children who did not regress. Patients with regressing disease had distal lesions that appeared in the first 3 months of life and were necrotic papules or hypopigmented macules. Nonregressing patients who required systemic therapy were more often intertriginous. Immunohistochemical studies showed no difference in IL-10, Ki-67, or E-cadherin expression and T-reg number between the two clinical groups.
- Children and adults: Children and adults may develop a red papular rash in the groin, abdomen, back, or chest that resembles a diffuse candidal rash. Seborrheic involvement of the scalp may be mistaken for a severe case of dandruff in older individuals. Ulcerative lesions behind the ears, involving the scalp, under the breasts, or genitalia or perianal region are often misdiagnosed as bacterial or fungal infections.
Fingernail involvement is an unusual finding that may present as a single site or with other sites of LCH involvement. There are longitudinal, discolored grooves and loss of nail tissue. This condition usually responds to the common LCH therapies.
In the mouth, presenting symptoms include gingival hypertrophy, and ulcers of the soft or hard palate, buccal mucosa, or on the tongue and lips. Hypermobile teeth (floating teeth) and tooth loss may occur.[7,8] Lesions of the oral cavity may precede evidence of LCH elsewhere.Bone
LCH can occur in any bone of the body, although the hands and feet are often spared. Sites of LCH in children include the following:
- Lytic lesion of the skull: The most frequent site of LCH in children is a lytic lesion of the skull, which may be asymptomatic or painful. It is often surrounded by a soft tissue mass which may impinge on the dura.
- Femur, ribs, humerus, and vertebra: The second most frequently involved skeletal sites are femur, ribs, humerus, and vertebra. Spine lesions may involve any vertebra, although involvement of the cervical vertebrae is most common and spine lesions are frequently associated with other bone lesions. Spine lesions may result in collapse of the vertebral body (vertebra plana). Vertebral lesions with soft tissue extension often present with pain and may present with significant neurologic deficits, an indication for an urgent magnetic resonance imaging (MRI) scan.
- Orbit: Proptosis from an LCH mass in the orbit mimics rhabdomyosarcomas, neuroblastoma, and benign fatty tumors of the eye.
- Facial bones and anterior or middle cranial fossae: Lesions of the facial bones or anterior or middle cranial fossae (e.g., temporal, sphenoid, ethmoid, zygomatic) with intracranial tumor extension comprise part of a CNS-risk group. These patients have a threefold increased risk of developing diabetes insipidus and an increased risk of other CNS disease.
The cervical nodes are most frequently involved and may be soft- or hard-matted groups with accompanying lymphedema. An enlarged thymus or mediastinal node involvement can mimic lymphoma or an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture and histologic examination is mandatory for these presentations.Pituitary gland
The posterior part of the pituitary gland can be affected in patients with LCH causing central diabetes insipidus. (Refer to the Endocrine subsection in the Multisystem Disease Presentation section of this summary for more information.) Anterior pituitary involvement often results in growth failure and delayed or precocious puberty.Thyroid
Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.Multisystem Disease Presentation
In multisystem LCH, the disease presents in multiple organs or body systems including bone, abdominal/gastrointestinal system (liver and spleen), lung, bone marrow, endocrine system, eye, CNS, skin, and lymph nodes.Bone and other organ systems
LCH patients may present with multiple bone lesions as a single site (single-system multifocal bone) or bone lesions with other organ systems involved (multisystem including bone). A review of single-system multifocal bone and multisystem including bone patients treated on the Japanese LCH study (JLSG-02) found patients in the multisystem including bone group were more likely to have lesions in the temporal bone, mastoid/petrous bone, orbit, and zygomatic bone (CNS-risk). Patients with multisystem including bone had a higher incidence of diabetes insipidus, correlating with the higher frequency of lesions in the noted facial bones. There was no difference in the outcome to treatment, which is more intense in the JLSG-02 study compared with the LCH-II study.Abdominal/gastrointestinal system
In LCH, the liver and spleen are considered high-risk organs, and involvement of these organs affects prognosis. Involvement in this context means the liver and spleen are enlarged from direct infiltration of LCH cells or as a secondary phenomenon of excess cytokines, which cause macrophage activation or infiltration of lymphocytes around bile ducts. LCH has a portal (bile duct) trophism that leads to biliary damage and ductal sclerosis. A percutaneous (peripheral) liver biopsy may not be diagnostic of the infiltrate that tends to be more central in the liver, but will show the upstream obstructive effects of distal biliary occlusion. Hepatic enlargement can be accompanied by dysfunction, leading to hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies. Sonography, computed tomography (CT), or MRI of the liver will show hypoechoic or low-signal intensity along the portal veins or biliary tracts when the liver is involved with LCH.Liver (sclerosing cholangitis)
One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis. This usually occurs months after initial presentation, but on occasion may be present at diagnosis. The median age of children with this form of hepatic LCH is 23 months.
Patients with hepatic LCH present with hepatomegaly or hepatosplenomegaly, and elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase levels. Biopsies show no LCH cells but infiltrating lymphocytes surrounding the bile ducts may be present. It is thought that cytokines, such as TGF-beta, elaborated by lymphocytes during the active phase of the disease, leads to fibrosis and sclerosis around the bile ducts.
Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy because the LCH is no longer active, but the fibrosis and sclerosis remain. Liver transplantation is the only alternate treatment when hepatic function worsens. In one series of 28 children undergoing liver transplantation, 78% survived and 29% had recurrence of LCH but only two cases of recurrent LCH occurred in the transplanted liver. The patients who undergo liver transplant for LCH may have a higher incidence of posttransplant lymphoproliferative disease.Spleen
Massive splenomegaly may lead to cytopenias because of hypersplenism and may cause respiratory compromise. Splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation results in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported. Splenectomy is only performed as a life-saving measure.Other gastrointestinal manifestations
A few patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[19,20] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination including multiple biopsies is usually needed.Lung
In LCH, the lung is less frequently involved in children than in adults, in whom smoking is a key etiologic factor. The cystic/nodular pattern of disease reflects the cytokine-induced destruction of lung tissue. Classically, the disease is symmetrical and predominates in the upper and middle lung fields, sparing the costophrenic angle and giving a very characteristic picture on high-resolution CT scan. Confluence of cysts may lead to bullous formation and spontaneous pneumothorax can be the first sign of LCH in the lung, although patients may present with tachypnea or dyspnea. Ultimately, widespread fibrosis and destruction of lung tissue leads to severe pulmonary insufficiency. Declining diffusion capacity may also herald the onset of pulmonary hypertension. In young children with diffuse disease, therapy can halt progress of the tissue destruction and normal repair mechanisms may restore some function.
Pulmonary involvement is present in approximately 25% of children with multisystem low-risk and high-risk LCH. However, a multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor, with a 5-year overall survival rate of 94% versus 96% for those with or without pulmonary involvement.Bone marrow
Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, and skin who present with significant thrombocytopenia and anemia with or without neutropenia. Others have only mild cytopenias and are found to have bone marrow involvement with LCH by sensitive immunohistochemical or flow cytometric analysis of the bone marrow. All of the bone marrow biopsy specimens (22 of 22 specimens) in one study had increased numbers of dysplasia of megakaryocytes, often with emperipolesis (active penetration by one cell into and through a larger cell). Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow. The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation.Endocrine system
Diabetes insipidus, caused by LCH-induced damage to the anti-diuretic hormone (ADH)–secreting cells of the posterior pituitary, is the most frequent endocrine manifestation in LCH. MRI scans usually show nodularity and/or thickening of the pituitary stalk and loss of the pituitary bright spot on T2-weighted images. Pituitary biopsies are rarely done and usually only when the stalk is greater than 6.5 mm or there is a hypothalamic mass. Most often the diagnosis is established by biopsying the skin, bone, or lymph node of a patient who also has pituitary abnormalities.
Approximately 4% of patients present with an apparently idiopathic presentation of diabetes insipidus before other lesions of LCH are identified, 7% concomitantly with another location and 14% after extrapituitary diagnosis of LCH. A report of 26 patients who presented with isolated diabetes insipidus as the initial manifestation of LCH described their natural history. Eleven of the patients presenting with isolated central diabetes insipidus also had anterior pituitary deficits. These included secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins. Twenty-two of the 26 patients ultimately developed extrapituitary lesions of LCH, including bone (n = 15), lung (n = 9), and skin (n = 9), in a median time of 1 year (range, 1 month to 14.2 years).
Patients with diabetes insipidus have a 50% to 80% chance of developing other lesions diagnostic of LCH within 1 year of identifying diabetes insipidus. A study of 589 patients with LCH revealed the 10-year risk of pituitary involvement was 24%. These investigators did not see a decreased incidence of diabetes insipidus in chemotherapy-treated patients, but this may reflect the length of the therapy and/or the number of drugs used. Using longer therapy and more drugs, the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) Group and the Japanese Langerhans Cell Group found the cumulative incidence to be 12%.[33,34] Diabetes insipidus followed initial LCH diagnosis by a mean of 1 year and growth hormone deficiency occurred 5 years later.
Patients with multisystem disease and craniofacial involvement at the time of diagnosis, particularly of the orbit, mastoid, and temporal bones, carried a significantly increased risk of developing diabetes insipidus during their course (relative risk, 4.6), with 75% of patients with diabetes insipidus having these CNS-risk bone lesions. This risk increased when the disease remained active for a longer period of time or reactivated. The risk for development of diabetes insipidus in this population was 20% at 15 years after diagnosis. The incidence of diabetes insipidus was lower in patients treated with more intensive chemotherapy regimens on the JLSG-96 and JLSG-02 studies in Japan (8.9% for multisystem patients) than on the LCH-I and LCH-II studies (14.2%).[34-36] Fifty-six percent of diabetes insipidus patients will develop anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of diabetes insipidus. Diabetes insipidus occurs in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[37,38]Ocular
Although very rare, there have been several cases of ocular involvement by LCH, sometimes leading to blindness. Patients may have other organ systems involved, and the ocular LCH may not respond well to conventional chemotherapy.Central nervous system
CNS disease manifestations
LCH patients may develop mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter. These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes, and are, therefore, active LCH lesions.
Patients with large pituitary tumors (>6.5 mm) have a high risk of anterior pituitary dysfunction and neurodegenerative CNS LCH. A retrospective study of 22 patients found that all had radiologic signs of neurodegenerative CNS LCH detected at a median time of 3 years and 4 months after LCH diagnosis and that it worsened in 19 patients. Five had neurologic dysfunction. Eighteen of 22 patients had anterior pituitary dysfunction and 20 had diabetes insipidus. Growth hormone deficiency occurred in 21 patients; luteinizing hormone/follicle-stimulating hormone deficiency occurred in ten patients; and thyroid hormone deficiency occurred in ten patients.LCH CNS neurodegenerative syndrome
A chronic neurodegenerative syndrome that is manifested by dysarthria, ataxia, dysmetria, and sometimes behavior changes develops in 1% to 4% of LCH patients. These patients may develop severe neuropsychologic dysfunction. MRI scan results from these patients show hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted images or hyperintense lesions of the basal ganglia on T1-weighted images and/or atrophy of the cerebellum. The radiologic findings may precede the onset of symptoms by many years or be found coincidently. A study of 83 LCH patients who had at least two MRI studies of the brain for evaluation of craniofacial lesions, diabetes insipidus, and/or other endocrine deficiencies of neuropsychological symptoms has been published. Forty-seven of 83 patients (57%) had radiological neurodegenerative changes at a median time of 34 months from diagnosis. Of the 47 patients, 12 (25%) had clinical neurological deficits that presented 3 to 15 years after the LCH diagnosis. Fourteen of the 47 patients had subtle deficits in short-term auditory memory.
A study of CNS-related permanent consequences (neuropsychologic deficits) in 14 of 25 LCH patients followed for a median of 10 years has been published. Seven of these patients had diabetes insipidus and five patients had radiographic evidence of LCH CNS neurodegenerative changes. Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than those with other LCH lesions.
Histological evaluation of these neurodegenerative lesions shows a prominent T-cell infiltration, usually in the absence of the CD1a-positive dendritic cells along with microglial activation and gliosis. The neurodegenerative form of the disease has been compared to a paraneoplastic inflammatory response.References
- Munn S, Chu AC: Langerhans cell histiocytosis of the skin. Hematol Oncol Clin North Am 12 (2): 269-86, 1998. [PUBMED Abstract]
- Stein SL, Paller AS, Haut PR, et al.: Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. Arch Pediatr Adolesc Med 155 (7): 778-83, 2001. [PUBMED Abstract]
- Lau L, Krafchik B, Trebo MM, et al.: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 46 (1): 66-71, 2006. [PUBMED Abstract]
- Minkov M, Prosch H, Steiner M, et al.: Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer 45 (6): 802-7, 2005. [PUBMED Abstract]
- Battistella M, Fraitag S, Teillac DH, et al.: Neonatal and early infantile cutaneous langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms. Arch Dermatol 146 (2): 149-56, 2010. [PUBMED Abstract]
- Ashena Z, Alavi S, Arzanian MT, et al.: Nail involvement in langerhans cell histiocytosis. Pediatr Hematol Oncol 24 (1): 45-51, 2007 Jan-Feb. [PUBMED Abstract]
- Madrigal-Martínez-Pereda C, Guerrero-Rodríguez V, Guisado-Moya B, et al.: Langerhans cell histiocytosis: literature review and descriptive analysis of oral manifestations. Med Oral Patol Oral Cir Bucal 14 (5): E222-8, 2009. [PUBMED Abstract]
- Hicks J, Flaitz CM: Langerhans cell histiocytosis: current insights in a molecular age with emphasis on clinical oral and maxillofacial pathology practice. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100 (2 Suppl): S42-66, 2005. [PUBMED Abstract]
- Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980. [PUBMED Abstract]
- Peng XS, Pan T, Chen LY, et al.: Langerhans' cell histiocytosis of the spine in children with soft tissue extension and chemotherapy. Int Orthop 33 (3): 731-6, 2009. [PUBMED Abstract]
- Burnett A, Carney D, Mukhopadhyay S, et al.: Thyroid involvement with Langerhans cell histiocytosis in a 3-year-old male. Pediatr Blood Cancer 50 (3): 726-7, 2008. [PUBMED Abstract]
- Imashuku S, Kinugawa N, Matsuzaki A, et al.: Langerhans cell histiocytosis with multifocal bone lesions: comparative clinical features between single and multi-systems. Int J Hematol 90 (4): 506-12, 2009. [PUBMED Abstract]
- Wong A, Ortiz-Neira CL, Reslan WA, et al.: Liver involvement in Langerhans cell histiocytosis. Pediatr Radiol 36 (10): 1105-7, 2006. [PUBMED Abstract]
- Braier J, Ciocca M, Latella A, et al.: Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis. Med Pediatr Oncol 38 (3): 178-82, 2002. [PUBMED Abstract]
- Kelly M, Kolb M, Bonniaud P, et al.: Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des 9 (1): 39-49, 2003. [PUBMED Abstract]
- Hadzic N, Pritchard J, Webb D, et al.: Recurrence of Langerhans cell histiocytosis in the graft after pediatric liver transplantation. Transplantation 70 (5): 815-9, 2000. [PUBMED Abstract]
- Newell KA, Alonso EM, Kelly SM, et al.: Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children. J Pediatr 131 (1 Pt 1): 98-104, 1997. [PUBMED Abstract]
- Goyal R, Das A, Nijhawan R, et al.: Langerhans cell histiocytosis infiltration into pancreas and kidney. Pediatr Blood Cancer 49 (5): 748-50, 2007. [PUBMED Abstract]
- Hait E, Liang M, Degar B, et al.: Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review. Pediatrics 118 (5): e1593-9, 2006. [PUBMED Abstract]
- Geissmann F, Thomas C, Emile JF, et al.: Digestive tract involvement in Langerhans cell histiocytosis. The French Langerhans Cell Histiocytosis Study Group. J Pediatr 129 (6): 836-45, 1996. [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]
- Abbritti M, Mazzei MA, Bargagli E, et al.: Utility of spiral CAT scan in the follow-up of patients with pulmonary Langerhans cell histiocytosis. Eur J Radiol 81 (8): 1907-12, 2012. [PUBMED Abstract]
- Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007. [PUBMED Abstract]
- Odame I, Li P, Lau L, et al.: Pulmonary Langerhans cell histiocytosis: a variable disease in childhood. Pediatr Blood Cancer 47 (7): 889-93, 2006. [PUBMED Abstract]
- Ronceray L, Pötschger U, Janka G, et al.: Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr 161 (1): 129-33.e1-3, 2012. [PUBMED Abstract]
- McClain K, Ramsay NK, Robison L, et al.: Bone marrow involvement in histiocytosis X. Med Pediatr Oncol 11 (3): 167-71, 1983. [PUBMED Abstract]
- Minkov M, Pötschger U, Grois N, et al.: Bone marrow assessment in Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (5): 694-8, 2007. [PUBMED Abstract]
- Galluzzo ML, Braier J, Rosenzweig SD, et al.: Bone marrow findings at diagnosis in patients with multisystem langerhans cell histiocytosis. Pediatr Dev Pathol 13 (2): 101-6, 2010 Mar-Apr. [PUBMED Abstract]
- Favara BE, Jaffe R, Egeler RM: Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 5 (2): 130-40, 2002 Mar-Apr. [PUBMED Abstract]
- Prosch H, Grois N, Prayer D, et al.: Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (5): 594-9, 2004. [PUBMED Abstract]
- Marchand I, Barkaoui MA, Garel C, et al.: Central diabetes insipidus as the inaugural manifestation of Langerhans cell histiocytosis: natural history and medical evaluation of 26 children and adolescents. J Clin Endocrinol Metab 96 (9): E1352-60, 2011. [PUBMED Abstract]
- Donadieu J, Rolon MA, Thomas C, et al.: Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study. J Pediatr 144 (3): 344-50, 2004. [PUBMED Abstract]
- Grois N, Pötschger U, Prosch H, et al.: Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 46 (2): 228-33, 2006. [PUBMED Abstract]
- Shioda Y, Adachi S, Imashuku S, et al.: Analysis of 43 cases of Langerhans cell histiocytosis (LCH)-induced central diabetes insipidus registered in the JLSG-96 and JLSG-02 studies in Japan. Int J Hematol 94 (6): 545-51, 2011. [PUBMED Abstract]
- Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001. [PUBMED Abstract]
- Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008. [PUBMED Abstract]
- Gadner H, Heitger A, Grois N, et al.: Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol 23 (2): 72-80, 1994. [PUBMED Abstract]
- Dunger DB, Broadbent V, Yeoman E, et al.: The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med 321 (17): 1157-62, 1989. [PUBMED Abstract]
- Boztug K, Frimpong-Ansah K, Nanduri VR, et al.: Intraocular Langerhans cell histiocytosis in a neonate resulting in bilateral loss of vision. Pediatr Blood Cancer 47 (5): 633-5, 2006. [PUBMED Abstract]
- Grois NG, Favara BE, Mostbeck GH, et al.: Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 12 (2): 287-305, 1998. [PUBMED Abstract]
- Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005. [PUBMED Abstract]
- Fahrner B, Prosch H, Minkov M, et al.: Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis. Pediatr Blood Cancer 58 (4): 606-10, 2012. [PUBMED Abstract]
- Prayer D, Grois N, Prosch H, et al.: MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 25 (5): 880-91, 2004. [PUBMED Abstract]
- Wnorowski M, Prosch H, Prayer D, et al.: Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153 (1): 127-32, 2008. [PUBMED Abstract]
- Mittheisz E, Seidl R, Prayer D, et al.: Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 50-6, 2007. [PUBMED Abstract]