Presentation of LCH in Children
Langerhans cell histiocytosis (LCH) most commonly presents with a skin rash or a 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 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, lung, lymph nodes, gastrointestinal tract, pituitary gland, and central nervous system (CNS).
Patients may present with a single organ (single-system LCH), which may involve a single site (unifocal) or multiple sites (multifocal). Bone is the most common single organ site. Less commonly, 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 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 with LCH may also present with a generalized skin rash, which may mimic many other skin disorders. Skin LCH in infants may be limited to skin (skin-only disease) or may be part of multisystem LCH. 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.
Skin-only LCH, which had historically been known as Hashimoto-Pritzer, may be self-limited as the lesions may disappear with no therapy during the first year of life. Therapy is used only for very extensive rashes, pain, ulceration, or bleeding. Importantly, these patients must be watched closely as skin-only LCH may also progress within weeks or months to high-risk multisystem disease, which may be life-threatening.[2-4]
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 ten 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. Patients with nonregressing disease who required systemic therapy were more often intertriginous. Immunohistochemical studies showed no difference in interleukin (IL)-10, Ki-67, E-cadherin expression, or 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. Vesicular lesions may be seen and need to be differentiated from herpetic lesions.
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 often responds to the usual 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 usually indicate involvement of underlying bone.[6,7] Lesions of the oral cavity may precede evidence of LCH elsewhere.
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 vault, which may be asymptomatic or painful. It is often surrounded by a soft tissue mass that may extend internally to impinge on the dura.
- Femur, ribs, humerus, and vertebra: Other 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.
- CNS-risk bones: Proptosis from an LCH mass in the orbit mimics rhabdomyosarcomas, neuroblastoma, and benign fatty tumors of the eye.
Lesions of the facial bones or anterior or middle cranial fossae (e.g., temporal, orbit, sphenoid, ethmoid, zygomatic) with intracranial tumor extension comprise a CNS-risk group. These patients have a threefold increased risk of developing diabetes insipidus and other CNS disease. Because of the increased risk of diabetes insipidus, treatment is recommended for these patients.
Lymph nodes and thymus
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 an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture is indicated for these presentations. Mediastinal involvement is rare (<5%) and usually presents with respiratory distress, superior vena cava syndrome, or cough and tachypnea. The 5-year survival is 87%, with deaths mostly attributable to hematologic involvement.
The posterior part of the pituitary gland and pituitary stalk 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. Rarely, hypothalamic involvement may cause morbid obesity.
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
Patients with LCH 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 patients with single-system multifocal bone presentation and patients with multisystem including bone presentation who were treated on the Japanese LCH study (JLSG-02) found that 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 presentation 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 of treatment, which was more intense in the JLSG-02 study than in the LCH-II study.
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 cells have a portal (bile duct) tropism that may lead 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. While ultrasound and/or MRI-cholangiogram can be helpful in the diagnosis of this complication, liver biopsy is currently the only definitive way to determine whether active LCH or hepatic fibrosis is present. Biopsy results often show lymphocytes and biliary obstructive effects without LCH cells. Peribiliary LCH cells and, rarely, nodular masses of LCH, may also be present. It is thought that cytokines, such as transforming growth factor-beta (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. Despite the limitations, liver biopsy may be the only way to distinguish active LCH from end-stage fibrosis. 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, although other cases have been reported since the initial data was published. If at all possible, active LCH should be under control before transplant. The patients who undergo liver transplant for LCH may have a higher incidence of posttransplant lymphoproliferative disease.
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 result in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported. Splenectomy is performed only as a life-saving measure.
Other gastrointestinal manifestations
Patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[20,21] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination including multiple biopsies is usually needed.
In LCH, the lung is less frequently involved in children than in adults, because smoking in adults 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 may lead to severe pulmonary insufficiency. Declining diffusion capacity may also herald the onset of pulmonary hypertension. Widespread fibrosis and declining diffusion capacity are much less common in children. In young children with diffuse disease, therapy can halt progress of the tissue destruction and normal repair mechanisms may restore some function, although scarring or even residual nonactive cysts may continue to be visible on radiologic studies.
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.
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. A high content of bone marrow macrophages can obscure LCH cells. 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, which in the most severe cases, present with typical manifestations of hemophagocytic lymphohistiocytosis including cytopenias and hyperferritinemia.
Diabetes insipidus, caused by LCH-induced damage to the antidiuretic hormone-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. Pituitary disease is often associated with other sites of involvement; in order to avoid biopsy of the pituitary, these sites can be biopsied to establish the diagnosis.
Approximately 4% of LCH patients present with an apparently idiopathic presentation of diabetes insipidus before other lesions of LCH are identified. A review of pediatric patients presenting with idiopathic central diabetes insipidus showed that 19% eventually developed manifestations of LCH. Approximately 50% of patients who present with isolated diabetes insipidus as the initial manifestation of LCH either have anterior pituitary deficits at the time of diagnosis or develop them within 10 years of diabetes insipidus onset.[34,35] These included secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins.
Patients with diabetes insipidus due to LCH have a 50% to 80% chance of developing other lesions diagnostic of LCH within 1 year of diabetes insipidus onset, including bone, lung, and skin.[32,34] A study of 589 patients with LCH revealed the 10-year risk of pituitary involvement was 24%. No decrease in incidence of diabetes insipidus was seen 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 found the cumulative incidence to be 12%.[36,37] Diabetes insipidus followed initial LCH diagnosis at a mean of 1 year and growth hormone deficiency occurred 5 years later. The incidence of diabetes insipidus was lower in patients treated with more intensive chemotherapy regimens on the LCH-III and JLSG-96 and JLSG-02 studies in Japan (8.9% for multisystem patients) than on the LCH-I and LCH-II studies (14.2%).[37-40] 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.[35,41]
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. The risk increased when the disease remained active for a longer period of time or reactivated. The risk of diabetes insipidus development in this population was 20% at 15 years after diagnosis.
Although 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
Patients with LCH 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 higher 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 patients with LCH. These patients may develop severe neuropsychologic dysfunction with tremor, gait disturbances, ataxia, dysarthria, headaches, visual disturbances, cognitive and behavioral problems, and psychosis. 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 patients with LCH 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%) developed 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 patients with LCH who were monitored 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.
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