sábado, 29 de junio de 2019

Langerhans Cell Histiocytosis Treatment (PDQ®) 2/7 —Health Professional Version - National Cancer Institute

Langerhans Cell Histiocytosis Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Langerhans Cell Histiocytosis Treatment (PDQ®)–Health Professional Version



Childhood LCH

Incidence

The annual incidence of Langerhans cell histiocytosis (LCH) has been estimated to be between two and ten cases per 1 million children aged 15 years or younger.[1-3] The male-to-female ratio (M:F) is close to one, and the median age of presentation is 30 months.[4] A 4-year survey of 251 new LCH cases in France found an annual incidence of 4.6 cases per 1 million children younger than 15 years (M:F = 1.2).[5] A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per 1 million child-years.[6]
Surveillance, Epidemiology, and End Results registry data from 2000 to 2009 were reviewed to identify high-risk LCH cases and assess demographic variables.[7] On the basis of 145 cases, the age-standardized incidence was 0.7 per 1 million children per year, with lower incidence in black patients (0.41 per 1 million) and higher incidence in Hispanic patients (1.63 per 1 million) younger than 5 years. Crowded living conditions and lower socioeconomic circumstances were associated with a higher risk of LCH, possibly because of the correlation with maternal and neonatal infections.[8]
Identical twins and non-twin siblings with LCH, as well as LCH in multiple generations in one family, have been reported.[9]

Etiology

The etiology of LCH is unknown.

Risk Factors

Although the following risk factors have been identified for LCH, strong and consistent associations have not been confirmed:
  • Parental exposure to solvents.[8]
  • Family history of cancer.[10]
  • Personal or family history of thyroid disease.[8,11]
  • Perinatal infections.[8,10]
  • Parental occupational exposure to metal, granite, or wood dust.[10]
  • Ethnicity and race.[7]
  • Low socioeconomic status.[7]
  • Lack of childhood vaccinations.[10]
Efforts to define a viral cause have not been successful.[12,13] One study has shown that 1% of patients have a positive family history for LCH.[9]

Clinical Presentation

LCH most commonly presents with a painful bone lesion, with skin being the second most commonly involved organ. 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 in high-risk patients. Chronic recurrent involvement of low-risk organs, while usually not life-threatening, can result in potentially devastating long-term consequences.
  • High-risk organs include the liver, spleen, and hematopoietic system (defined by the presence of pathologic CD1a-positive or CD207-positive cells in the bone marrow, although newer technologies [BRAF V600E detection by polymerase chain reaction or immunostaining] are resulting in more-reliable detection of LCH cells in the bone marrow). High-risk patients are typically younger than 2 years.
  • Low-risk organs include the skin, bone, lung, lymph nodes, gastrointestinal tract, pituitary gland, thyroid, thymus, and central nervous system (CNS). Involvement of every organ except kidney and gonads has been described.
Patients may present with single-organ involvement (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. Patients can have LCH of the skin, bone, lymph nodes, and pituitary gland in any combination and still be considered at low risk of death, although there may be relatively high risk of developing long-term consequences of the disease.
Treatment decisions for patients are based on whether high-risk or low-risk organs are involved and whether LCH presents as unifocal, multifocal, or multisystem disease.

Single-system low-risk disease presentation

In single-system low-risk 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 gland.
Skin and nails
  • Infants: Seborrheic involvement of the scalp may be mistaken for prolonged cradle cap in infants, unless the classic purpuric component is present. The second most common site involves the body creases, such as the antecubital fossa and perineum. Infants with LCH may also present with a generalized skin rash, which may mimic many other skin disorders and may or may not be pruritic. Vesicular LCH skin lesions need to be differentiated from congenital infections.
    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% (36 of 61 patients) had multisystem disease, and 72% of the patients with multisystem disease had risk-organ involvement.[14] A retrospective analysis of 71 infants and children with apparent skin-only LCH found that those older than 18 months were more likely to have multisystem involvement and often relapsed after treatment with vinblastine and prednisone.[15] Eight of 11 patients in this category had circulating cells with the BRAF V600E mutation, compared with only 1 of 13 patients in the skin-only group. Patients younger than 1 year with skin-only disease who were completely evaluated to exclude any other site of disease had an 89% 3-year progression-free survival with initial therapy.
    Skin-only LCH may be self-limited because the lesions may disappear without therapy during the first year of life. Therapy is used only for very extensive rashes, pain, ulceration, or bleeding. These patients must be watched closely because skin-only LCH in neonates and very young infants may progress within weeks or months to high-risk multisystem disease, which may be life-threatening.[16-18]
    Hashimoto-Pritzker disease or congenital spontaneous regressing skin histiocytosis is a self-limited disease that has the same immunohistochemical staining as LCH but, on electron microscopy, shows dense bodies thought to be senescent mitochondria.[19] Careful review of the original cases revealed that some patients progressed to multisystem LCH; the distinction between skin-only LCH and Hashimoto-Pritzker disease is felt to be without clinical value because all of these infants should be carefully observed after diagnosis.
    A review of patients presenting in the first 3 months of life with skin-only LCH compared the clinical and histopathologic findings of 21 children whose skin LCH regressed with those of 10 children who did not regress.[17] 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, on the genitalia, or in the 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.[20]
Oral cavity
In the mouth, presenting symptoms include gingival hypertrophy and ulcers on the soft or hard palate, buccal mucosa, or tongue and lips. Hypermobile teeth (floating teeth) and tooth loss usually indicate involvement of underlying bone.[21,22] Lesions of the oral cavity may precede evidence of LCH elsewhere.
Bone
Bone is the most commonly affected system, estimated to be affected in 80% of patients with LCH. LCH can occur in any bone of the body, although the hands and feet are often spared.[23]
Sites of LCH bone lesions 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,[24] 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, pelvis, and vertebra: Other frequently involved skeletal sites are femur, ribs, humerus, pelvis, 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,[25] an indication of an urgent need for magnetic resonance imaging (MRI) scan.
  • CNS-risk bones: Proptosis from an LCH mass in the orbit mimics rhabdomyosarcoma, neuroblastoma, and benign fatty tumors of the eye.[26]
    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-riskgroup. These patients have a threefold increased risk of developing diabetes insipidus and other CNS disease. Because of the increased risk of diabetes insipidus, systemic treatment is recommended for these patients.
Lymph nodes and thymus
The cervical nodes are most frequently involved and may be soft-matted 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.[27]
Pituitary gland
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 system 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 gland
Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.[28]

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; these are divided into high-risk sites (liver, spleen, bone marrow) and low-risk sites (all other sites).
Multisystem low-risk disease
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).[29] These patients also had a higher incidence of diabetes insipidus, correlating with the higher frequency of risk-bone lesions. By contrast, a study from members of the Histiocyte Society found decreased mortality in high-risk multisystem LCH patients who had bone involvement, suggesting that those with bone LCH may have more indolent disease.[30]
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 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.[31]
Patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[32,33] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination that includes multiple biopsies is usually needed.
Lung
In LCH, the lung is less frequently involved in children than in adults because smoking in adults is a key etiologic factor.[34] 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.[35] 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.[36] Widespread fibrosis and declining diffusion capacity are much less common in children. In young children with diffuse disease, therapy can halt the 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.[37] However, a multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor, with 5-year overall survival rates of 94% for those with pulmonary involvement and 96% for those without pulmonary involvement.[38] Isolated pulmonary involvement is rarely seen in children.
Endocrine system
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.[39] 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. A biopsy of the pituitary gland may be indicated when the pituitary gland is the only site of disease and the stalk is greater than 6.5 mm or there is a hypothalamic mass.[40] If the pituitary disease is associated with other sites of involvement, these sites can be biopsied to establish the diagnosis.
Approximately 4% of LCH patients present with an apparently idiopathic form 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, while 18% were diagnosed with craniopharyngioma and 10% with germinoma.[41] A prospective study of the etiology of central diabetes insipidus in children and young adults found that 15% had LCH, 11% had a germinoma, and 7% had a craniopharyngioma.[42] The other diagnoses were related to trauma, familial association, or midline defects, and 50% remained idiopathic. When the pituitary stalk is thickened or is very large, there is a 50% chance the patient will have a germinoma, LCH, or lymphoma.[43] Decisions about when to treat or whether to treat a patient with apparent isolated central diabetes insipidus as LCH without a biopsy remain controversial. These patients should be monitored closely for signs of any of the possible diagnoses.
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.[44,45] Anterior pituitary deficits include secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins. This incidence appears to be higher in LCH patients than in those with true idiopathic central diabetes insipidus.
Patients with diabetes insipidus caused by LCH have a 50% to 80% chance of developing other lesions that are diagnostic of LCH within 1 year of diabetes insipidus onset, including bone, lung, and skin lesions.[40,44] More commonly, LCH patients present with diabetes insipidus later in the course of the disease, as noted in the following studies:
  • One study compared the incidence of diabetes insipidus in patients who received no systemic therapy with that in patients who received 6 months of vinblastine/prednisone therapy. Patients who received no systemic therapy had a 40% incidence of diabetes insipidus; patients who were treated with chemotherapy had a 20% incidence of diabetes insipidus. This finding strongly supports treatment of CNS-risk bones, even when the disease occurs in a single site.[46]
  • A study of 589 patients with LCH revealed a 24% 10-year risk of pituitary involvement.[39] Diabetes insipidus was seen at a mean of 1 year after LCH diagnosis. Fifty-six percent of LCH patients who developed diabetes insipidus developed anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of diabetes insipidus. No decrease in the 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.[39]
Using longer therapy and more drugs, the German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukaemieforschung und -therapie im Kindesalter [DAL]) group found a 12% cumulative incidence of diabetes insipidus.[46] The incidence of diabetes insipidus was also lower in patients treated with more-intensive chemotherapy regimens on the HISTSOC-LCH-III (NCT00276757) and JLSG-96 and JLSG-02 studies in Japan (8.9% for multisystem patients) compared with the HISTSOC-LCH-I and HISTSOC-LCH-II studies (14.2%).[47-51] Overall, diabetes insipidus occurred in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[45,52]
Patients with multisystem disease and craniofacial involvement (particularly of the orbit, mastoid, and temporal bones) at the time of diagnosis carried a significantly increased risk of developing diabetes insipidus during the disease course (relative risk, 4.6), with 75% of patients with diabetes insipidus having these CNS-risk bone lesions.[46] 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.
Ocular
Although rare, ocular LCH, sometimes leading to blindness, has been reported. Other organ systems may be involved, and the ocular LCH may not respond well to conventional chemotherapy.[26]
CNS
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.[53] These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes and are, therefore, active LCH lesions.[54]
Patients with large pituitary tumors (>6.5 mm) have a higher risk of anterior pituitary dysfunction and neurodegenerative CNS LCH.[55] 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; it worsened in 19 patients. Five patients 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 10 patients; and thyroid hormone deficiency occurred in 10 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.
Brain MRI scans 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.[56] 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.[57] 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.[58] Seven of these patients had diabetes insipidus, and five patients had radiographic evidence of LCH CNS neurodegenerative changes.[58] Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than did those with other LCH lesions.
The first histological evaluation of neurodegenerative lesions reported prominent T-cell infiltration, usually in the absence of the CD1a-positive dendritic cells along with microglial activation and gliosis.[54] However, in a report from 2018, analysis of brain tissue from patients with neurodegenerative-disease LCH showed perivascular infiltration of CD207-negative cells staining with the BRAF V600E mutant protein in the pons, cerebellum, and basal ganglia. These are areas identified by the characteristic abnormal MRI findings on T2 fluid-attenuated inversion recovery (FLAIR) images. Quantitative polymerase chain reaction analysis of these areas showed increased numbers of BRAF-mutated cells and elevated expression of osteopontin. Brain tissue in these areas showed active demyelination, correlating with the radiologic findings and clinical deficits.[59]
Multisystem high-risk disease
Liver (sclerosing cholangitis)
One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis.[60] 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 the only definitive way to determine whether active LCH or residual 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, lead to fibrosis and sclerosis around the bile ducts.[61]
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 result in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported.[62] Splenectomy is performed only as a life-saving measure.
Bone marrow
Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, and skin and who present with significant thrombocytopenia and anemia with or without neutropenia.[63] 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.[64] A high content of bone marrow macrophages can obscure LCH cells.[65] Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis involving the bone marrow.[66] The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation which, in the most severe cases, presents with typical manifestations of hemophagocytic lymphohistiocytosis such as cytopenias and hyperferritinemia.

Diagnostic Evaluation

The complete evaluation of any patient, presenting with either single-system or multisystem disease, should include the following:[67]
  • History and physical exam: A complete history and physical exam with special attention to the skin, lymph nodes, ears, oral pharynx, gingiva, tongue, teeth, bones, lungs, thyroid, liver and spleen size, bone abnormalities, growth velocity, and history of excessive thirst and urination.
Other tests and procedures include the following:
  • Blood tests: Blood tests include complete blood count with leukocyte differential and platelet count, liver function tests (e.g., bilirubin, albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and prothrombin time/partial thromboplastin time in patients with hepatomegaly, jaundice, elevations of liver enzymes, or low albumin), and serum electrolytes.
    In severe multisystem LCH, additional tests for secondary hemophagocytic lymphohistiocytosis such as ferritin, triglycerides, fibrinogen, d-dimers, and lactate dehydrogenase may be indicated.
  • BRAF V600E assessment: Although BRAF mutation assessment is not a required part of the workup for LCH, the BRAF mutation can be detected by either immunohistochemistry or molecular diagnostic methods in fresh and formalin-fixed tissue.
  • Urine tests: Urine tests include urinalysis and a water-deprivation test if diabetes insipidus is suspected. Water deprivation tests in very young children, especially infants, is performed under medical monitoring.
  • Bone marrow aspirate and biopsy: The bone marrow aspirate and biopsy is indicated for patients with multisystem disease who have unexplained anemia or thrombocytopenia. The biopsy should be stained with anti-CD1a and/or anti-CD207 (langerin) and anti-CD163 immunostains to facilitate the detection of LCH cells.
  • Radiologic and imaging tests: Radiologic tests for the first level of screening include skeletal survey, skull series, bone scans, and chest X-ray. Newer diagnostic imaging modalities, including whole-body MRI scan or somatostatin analog scintigraphy, augment but do not replace the standard tests. Positron emission tomography (PET) scans are becoming more widely used because of superior diagnostic index and evaluation of response to therapy compared with bone scans.[68-72]
    • CT scan: CT scan of the head may be indicated if orbital, mastoid, or other maxillofacial involvement is suspected. Imaging tests may include MRI scan with gadolinium contrast of the brain for patients with diabetes insipidus or suspected brain or vertebral involvement.[73]
      CT scan of the lungs may be indicated for patients with abnormal chest X-rays or pulmonary symptoms. High-resolution CT scans may show evidence of pulmonary LCH when the chest X-ray is normal; thus, in infants and toddlers with normal chest X-rays, a CT scan may be considered. Patients with pulmonary LCH may also have normal chest X-rays and abnormal pulmonary function tests.[74]
      LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scan, if indicated.[75]
    • Fluorine F 18-fludeoxyglucose (18F-FDG) PET scan: 18F-FDG PET scan abnormalities were reported in the brains of seven patients with LCH who exhibited neurologic and radiographic signs of neurodegenerative disease.[72] There was good correlation with MRI findings in the cerebellar white matter, but less so in the caudate nuclei and frontal cortex. It was suggested that PET scans of patients at high risk of developing neurodegenerative LCH could show abnormalities earlier than MRI.[72] PET scans often demonstrate lesions not found by other modalities and show a decrease of activity after 6 weeks of therapy, thus providing a better assessment of response to therapy than bone scans or plain X-rays.[71]
    • MRI: MRI findings of patients with diabetes insipidus include thickening and nodularity of the pituitary stalk with loss of the posterior pituitary bright spot, reflecting absence of antidiuretic hormone. Later in the course, the stalk generally atrophies, but this should not be used as evidence of response to therapy.
      All patients with vertebral body involvement need careful assessment of associated soft tissue, which may impinge on the spinal cord.
      MRI findings of CNS LCH include T2 FLAIR enhancement in the pons, basal ganglia, white matter of the cerebellum, and mass lesions or meningeal enhancement. In a report of 163 patients,[56] meningeal lesions were found in 29% and choroid plexus involvement in 6%. Paranasal sinus or mastoid lesions were found in 55% of patients versus 20% of controls, and accentuated Virchow-Robin spaces were found in 70% of patients versus 27% of controls.
  • Biopsy: Lytic bone lesions, skin, and lymph nodes are the sites most frequently biopsied for diagnosis of LCH. A liver biopsy is indicated when a child with LCH presents with hypoalbuminemia not caused by gastrointestinal LCH or other etiology. These patients usually have elevated levels of bilirubin or liver enzymes. An open lung biopsy may be necessary for obtaining tissue for diagnosis of pulmonary LCH when bronchoalveolar lavage is nondiagnostic.
    A pathologic diagnosis is always required to make a definitive diagnosis. However, this may sometimes be difficult or contraindicated, such as in isolated pituitary stalk disease or vertebra plana without a soft tissue mass, when the risk outweighs the benefit of a firm diagnosis.

Prognosis

Survival is closely linked to the extent of disease at presentation when high-risk organs (liver, spleen, and/or bone marrow) are involved, as well as the response to initial treatment. Many studies have confirmed the high mortality rate (35%) in high-risk multisystem patients who do not respond well to therapy in the first 6 weeks. For many years, lung was thought to be a high-risk organ, but isolated lung involvement in pediatric LCH is no longer considered to pose a significant risk of death.[38] Because of treatment advances, including early implementation of additional therapy for poor responders, the outcome for children with LCH involving high-risk organs has improved.[48,49] Data from HISTSOC-LCH-III (NCT00276757) showed an 84% overall survival (OS) rate for patients treated for 12 months with systemic chemotherapy.[50]
Patients with single-system disease and low-risk multisystem disease do not usually die from LCH, but recurrent disease may result in considerable morbidity and significant late effects.[76] Overall, recurrences have been found in 10% of patients with single-system unifocal disease, 25% of patients with single-system multifocal bone LCH, and 50% of both low-risk multisystem patients and high-risk multisystem patients who achieve nonactive disease status with chemotherapy. HISTSOC-LCH-III data showed a significant difference in reactivation rate for low-risk organ patients randomly assigned to receive 6 months of treatment (54%) versus 12 months of treatment (37%).[50] Similarly, the nonrandomized high-risk group who were all treated for 12 months had a reactivation rate of 30% compared with more than 50% in previous studies with 6 months of the same therapy.[50]
Most good-responder, high-risk patients who have a reactivation (30%) do so in low-risk organs such as bone and then have the same risk of late effects as the low-risk multisystem patients.[50] The major current treatment challenge is to reduce this overall 20% to 30% incidence of reactivations and the significant incidence of serious permanent consequences in this group of patients.
Apart from disease extent, prognostic factors for children with LCH include the following:
  • Age at diagnosis: Although age younger than 2 years was once thought to portend a worse prognosis, data from the HISTSOC-LCH-II study showed that patients aged 2 years or younger without high-risk organ involvement had the same response to therapy as did older patients.[49] By contrast, the OS was poorer in neonates with risk-organ involvement compared with infants and children with the same extent of disease when patients were treated for only 6 months.[49]
  • Response to treatment: Response to therapy at 6 to 12 weeks has been shown to be a more important prognostic factor than age.[14] The overall response to therapy is influenced by the duration and intensity of treatment.[48,49]
  • Site of involvement: Involvement of craniofacial bones including orbital, mastoid, and temporal bones is associated with an increased risk of diabetes insipidus and an increased frequency of anterior pituitary hormone deficiencies and neurologic problems, although the strength of this correlation is controversial. (Refer to the Endocrine system subsection in the Multisystem disease presentation section of this summary for more information about diabetes insipidus.) Because of the permanent nature of established diabetes insipidus and the risk of progression to even more serious endocrine and CNS consequences, the Histiocyte Society trials suggest chemotherapy for patients with unifocal risk-bone disease until this problem can be clarified in a well-designed prospective study.
  • BRAF mutation: A study of 173 patients with the BRAF V600E mutation and 142 without the mutation revealed that the mutation occurred in 88% of patients with high-risk disease, 69% of patients with multisystem low-risk LCH, and 44% of patients with single-system low-risk LCH.[77] The mutation was also found in 75% of patients with neurodegenerative syndrome and 73% of patients with pituitary involvement. Resistance to initial treatment and relapse were higher in patients with the mutation.[77]
    An earlier study of 100 patients did not find these clinical correlations with the BRAFV600E mutation.[78]

Follow-up Considerations in Childhood LCH

Because of the risk of reactivation (which ranges from 10% in single-system unifocal bone lesions to close to 50% in low-risk and high-risk multisystem LCH) and the risk of permanent long-term effects, LCH patients need to be monitored for many years.
Patients with diabetes insipidus and/or skull lesions in the orbit, mastoid, or temporal bones appear to be at higher risk of LCH CNS involvement and LCH CNS neurodegenerative syndrome. These patients should have MRI scans with gadolinium contrast at the time of LCH diagnosis and every 1 to 2 years thereafter for 10 years to detect evidence of CNS disease.[57] The Histiocyte Society CNS LCH Committee does not recommend any treatment for radiologic CNS LCH of the neurodegenerative type if there is no associated clinical neurodegeneration. However, careful neurologic examinations and appropriate imaging with MRI are suggested at regular intervals. Brain stem auditory evoked responses should also be done at regular intervals to define the onset of clinical CNS LCH as early as possible, as this may affect response to therapy.[79] When clinical signs are present, intervention may be indicated. Available studies of different forms of therapy for CNS neurodegeneration suggest that the neurodegenerative changes may be stabilized or improved, but only if therapy is started early.[79] (Refer to the LCH CNS neurodegenerative syndrome section of this summary for more information.) Careful follow-up of patients at risk is critical.
For children with LCH in the lung, pulmonary function testing and chest CT scans are sensitive methods for detecting disease progression.[36]
A 16-year follow-up study of patients from one institution suggested that children with LCH have an increased risk of developing adult smoker's lung LCH compared with the normal young adult who smokes. Ongoing re-education regarding this risk should be part of the routine follow-up of children with LCH at any site.[36]
In summary, many patients with multisystem disease will experience long-term sequelae caused by their underlying disease and/or treatment. Endocrine and CNS sequelae are the most common. These long-term sequelae significantly affect health quality of life in many of these patients.[80][Level of evidence: 3iiiC] Specific long-term follow-up guidelines after treatment of childhood cancer or in those who have received chemotherapy have been published by the Children's Oncology Group and are available on their website.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[81] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Pathologists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[82] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
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