Late Disease and Treatment Effects of Childhood LCH
The reported overall frequency of long-term consequences of Langerhans cell histiocytosis (LCH) has ranged from 20% to 70%. The reason for this wide variation is due to case definition, sample size, therapy used, method of data collection, and follow-up duration. Of note, in one study of the quality of life of long-term survivors of skeletal LCH, the quality-of-life scores were not significantly different from healthy control children and adults. In addition, the quality-of-life scores were very similar between those with and without permanent sequelae. In another study of 40 patients who were carefully screened for late effects, adverse quality-of-life scores were found in more than 50% of patients. Seventy-five percent of patients had detectable long-term sequelae—hypothalamic/pituitary dysfunction (50%), cognitive dysfunction (20%), and cerebellar involvement (17.5%) being the most common.
Children with low-risk organ involvement (skin, bones, lymph nodes, or pituitary gland) have an approximately 20% chance of developing long-term sequelae. Patients with diabetes insipidus are at risk for panhypopituitarism and should be monitored carefully for adequacy of growth and development. In a retrospective review of 141 patients with LCH and diabetes insipidus, 43% developed growth hormone (GH) deficiency. [4-6] The 5-year and 10-year risks of GH deficiency among children with LCH and diabetes insipidus were 35% and 54%, respectively. There was no increased reactivation of LCH in patients who received GH compared with those who did not.
Growth and development problems are more frequent because of the young age at presentation and the more toxic effects of long-term prednisone therapy in the very young child. Patients with multisystem involvement have a 71% incidence of long-term problems.[3-6]
Hearing loss has been found in 38% of children who were treated for LCH. Seventy percent of patients with LCH in this study had ear involvement which included aural discharge, mastoid swelling, and hearing loss. Of those with computed tomography or magnetic resonance imaging (MRI) abnormalities in the mastoid, 59% had hearing loss.[Level of evidence: 3iiiC]
Neurologic symptoms secondary to vertebral compression of cervical lesions have been reported in 3 of 26 patients with LCH and spinal lesions. Central nervous system (CNS) LCH occurs most often in children with LCH of the pituitary or CNS-risk skull bones (mastoid, orbit, or temporal bone). Significant cognitive defects and MRI abnormalities may develop in some long-term survivors with CNS-risk skull lesions. Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem–evoked potentials.
Orthopedic problems from lesions of the spine, femur, tibia, or humerus may be seen in 20% of patients. These problems include vertebral collapse or instability of the spine that may lead to scoliosis and facial or limb asymmetry.
Diffuse pulmonary disease may result in poor lung function with higher risk for infections and decreased exercise tolerance. These patients should be monitored with pulmonary function testing, including the diffusing capacity of carbon monoxide and ratio of residual volume to total lung capacity.
Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplantation.
Dental problems characterized by loss of teeth have been significant for some patients, usually related to overly aggressive dental surgery.
Bone marrow failure secondary to LCH or from therapy is rare and is associated with a higher risk of malignancy. Patients with LCH have a higher-than-normal risk of developing secondary cancers.[13,14] Leukemia (usually acute myeloid) occurs after treatment, as does lymphoblastic lymphoma. Concurrent LCH/malignancy has been reported in a few patients, and some patients have had their malignancy first, followed by development of LCH. Three patients with T-cell acute lymphoblastic leukemia (T-ALL) and aggressive LCH were reported and, as with all histiocytic disorders associated with or following lymphoblastic malignancies, the same genetic changes were found in both diseases, suggesting a shared clonal origin.[15-17] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found. The authors of this study emphasized the plasticity of lymphocytes developing into Langerhans cells. In the second study, one patient with LCH after T-ALL who had the same T-cell receptor gene rearrangements and activating mutations of the NOTCH1 gene was described.
An association between solid tumors and LCH has also been reported. Solid tumors associated with LCH include retinoblastoma, brain tumors, hepatocellular carcinoma, and Ewing sarcoma.References
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