Clinical Manifestations

LCH has an extremely variable presentation. The skeleton is involved in 80% of patients and may be the only affected site, especially in children >5 yr of age. Bone lesions may be single or multiple and are seen most commonly in the skull (Fig. 501-1). Other sites include the pelvis, femur, vertebra, maxilla, and mandible. They may be asymptomatic or associated with pain and local swelling. Involvement of the spine may result in collapse of the vertebral body, which can be seen radiographically, and may cause secondary compression of the spinal cord. In flat and long bones, osteolytic lesions with sharp borders occur and no evidence exists of reactive new bone formation until the lesions begin to heal. Lesions that involve weight-bearing long bones may result in pathologic fractures. Chronically draining, infected ears are commonly associated with destruction in the mastoid area. Bone destruction in the mandible and maxilla may result in teeth that, on radiographs, appear to be free floating. With response to therapy, healing may be complete.

Figure 501-1 Two skull radiographs from patients with Langerhans cell histiocytosis (LCH). Left, The patient was >2 yr of age and had involvement limited to isolated bone lesions (arrows). She had a good recovery. Right, The patient was <2 yr of age and had extensive bone disease (arrows), a febrile course, anemia, severe skin eruption, generalized lymphadenopathy, hepatosplenomegaly, pulmonary infiltrates, and a fatal outcome despite antitumor chemotherapy. These patients represent opposite ends of the clinical spectrum of LCH.

About 50% of patients experience skin involvement at some time during the course of disease, usually as a hard-to-treat scaly, papular, seborrheic dermatitis of the scalp, diaper, axillary, or posterior auricular regions. The lesions may spread to involve the back, palms, and soles. The exanthem may be petechial or hemorrhagic, even in the absence of thrombocytopenia. Localized or disseminated lymphadenopathy is present in approximately 33% of patients. Hepatosplenomegaly occurs in approximately 20% of patients. Various degrees of hepatic malfunction may occur, including jaundice and ascites.

Exophthalmos, when present, often is bilateral and is caused by retro-orbital accumulation of granulomatous tissue. Gingival mucous membranes may be involved with infiltrative lesions that appear superficially like candidiasis. Otitis media is present in 30-40% of patients; deafness may follow destructive lesions of the middle ear. In 10-15% of patients, pulmonary infiltrates are found on radiography. The lesions may range from diffuse fibrosis and disseminated nodular infiltrates to diffuse cystic changes. Rarely, pneumothorax may be a complication. If the lungs are severely involved, tachypnea and progressive respiratory failure may result.

Pituitary dysfunction or hypothalamic involvement may result in growth retardation. In addition, patients may have diabetes insipidus; patients suspected of having LCH should demonstrate the ability to concentrate their urine before going to the operating room for a biopsy. Rarely, panhypopituitarism may occur. Primary hypothyroidism due to thyroid gland infiltration also may occur.

Patients with multisystem disease who are affected more severely may have systemic manifestations, including fever, weight loss, malaise, irritability, and failure to thrive. Bone marrow involvement may cause anemia and thrombocytopenia. Two uncommon but serious and unusual manifestations of LCH are hepatic involvement (leading to fibrosis and cirrhosis) and a peculiar central nervous system (CNS) involvement characterized by ataxia, dysarthria, and other neurologic symptoms. Hepatic involvement is associated with multisystem disease that is often already present at the time of diagnosis. In contrast, the CNS involvement, which is progressive and histopathologically characterized by gliosis, and for which no treatment is known, may be observed only many years after the initial diagnosis of LCH, which may have consisted only of mild bone disease. Neither of these manifestations evidences Langerhans cells or Birbeck granules, and both are suspected to be driven initially by cytokine abnormalities.

After tissue biopsy, which is diagnostic and is easiest to perform on skin or bone lesions, a thorough clinical and laboratory evaluation should be undertaken. This should include a series of studies in all patients (complete blood cell count, liver function tests, coagulation studies, skeletal survey, chest radiograph, and measurement of urine osmolality). In addition, detailed evaluation of any organ system that has been shown to be involved by physical examination or by these studies should be performed to establish the extent of disease before initiation of treatment.

Treatment and Prognosis

The clinical course of single-system disease (usually bone, lymph node, or skin) generally is benign, with a high chance of spontaneous remission. Therefore, treatment should be minimal and should be directed at arresting the progression of a bone lesion that could result in permanent damage before it resolves spontaneously. Curettage or, less often, low-dose local radiation therapy (5-6 Gy) may accomplish this goal. Multisystem disease, in contrast, should be treated with systemic multiagent chemotherapy. Several different regimens have been proposed, but a central element is the inclusion of either vinblastine or etoposide, both of which have been found to be very effective in treating LCH. Treatment of multisystem LCH includes therapy with multiple agents, designed to reduce reactivation of disease and long-term consequences. The response rate to therapy, contrary to previous belief, is high, and mortality in severe LCH has been substantially reduced by multiagent chemotherapy, especially if the diagnosis is made accurately and expeditiously. Experimental therapies, suggested only for unresponsive disease (often in very young children with multisystem disease and organ dysfunction who have not responded to multiagent initial treatment), include immunosuppressive therapy with cyclosporine/antithymocyte globulin and possibly certain new agents and modalities, such as imatinib, 2-chlorodeoxyadenosine, and stem cell transplantation. Late (fibrotic) complications, whether hepatic or pulmonary, are irreversible and require organ transplantation to be definitively treated. Current treatment approaches and experimental protocols for both class I and class II histiocytoses can be obtained at the website for the Histiocyte Society: www.histiocytesociety.org.

Clinical Manifestations

The major forms of HLH, familial hemophagocytic lymphohistiocytosis (FHLF) and secondary HLH, have a remarkably similar presentation consisting of a generalized disease process, most often with fever, maculopapular and/or petechial rash, weight loss, and irritability (Tables 501-4 and 501-5). FHLH also is characterized by severe immunodeficiency. Children with FHLH frequently are <4 yr of age, and children with secondary HLH may present at an older age, but both forms are now recognized as presenting at any age. Physical examination often reveals hepatosplenomegaly, lymphadenopathy, respiratory distress, and symptoms of CNS involvement that are not unlike those of aseptic meningitis. The cerebrospinal fluid (CSF) in CNS involvement of FHLH is characterized by CSF cells that are the same phagocytic macrophages found in the peripheral blood or bone marrow. The definitive diagnosis is based on a set of criteria recently formulated by the Histiocyte Society: It can be made either on the basis of a molecular (genetic) defect (see later) or on the pathologic findings of hemophagocytosis in bone marrow biopsy and/or clinical findings of fever, splenomegaly, and associated laboratory findings (in both forms of HLH), including hyperlipidemia, hypofibrinogenemia, elevated levels of hepatic enzymes, extremely elevated levels of circulating soluble interleukin-2 receptors released by the activated lymphocytes, very high levels of serum ferritin (often >10,000), and cytopenias (especially pancytopenia from hemophagocytosis in the marrow). No absolute clinical or laboratory distinction can be made between FHLH and secondary HLH, although genetic markers for FHLH can complement a positive family history for other affected children. HLH may be present in the absence of genetic mutations of the perforin or Munc 13-4 genes, and can be diagnosed by the presence of 5 of the following: fever, splenomegaly, cytopenia of 2 cell lines, hypertriglyceridemia or hypofibrinogenemia, hyperferritinemia, elevated soluble CD25 (interleukin-2 receptor), reduced or absent NK cells, and bone marrow, CSF, or lymph node evidence of hemophagocytosis.

Treatment and Prognosis

The diagnostic distinction between FHLH and secondary HLH sometimes can be based on the acute onset of secondary HLH in the presence of a documented infection. In this case, treatment of the underlying infection, coupled with supportive care, is critical. If the diagnosis is made in a setting of iatrogenic immunodeficiency, immunosuppressive treatment should be withdrawn and supportive care should be instituted along with specific therapy for underlying infection. When FHLH (gene mutations in perforin or Munc 13-4 proteins) is diagnosed or suspected and when an infection cannot be documented, therapy currently includes etoposide, corticosteroids, and intrathecal methotrexate. It should be stressed that pancytopenia is not a contraindication to cytotoxic therapy in FHLH. Some recommend antithymocyte globulin and cyclosporine for maintenance therapy. Nevertheless, even with chemotherapy, FHLH remains ultimately fatal, often after a relapse of the disease. Allogeneic stem cell transplantation is effective in curing approximately 60% of patients with FHLH.

In contrast, in secondary HLH, when an infection can be documented and effectively treated, the prognosis may be excellent without any other specific treatment. However, when a treatable infection cannot be documented, which is the case in most patients presumed to have secondary HLH, the prognosis may be as poor as that of FHLH, and an identical chemotherapeutic approach, including etoposide, is recommended, even in the face of cytopenias. It is theorized that in both cases, by its cytotoxic effect on macrophages, etoposide interrupts cytokine production, the hemophagocytic process, and the accumulation of macrophages, all of which may contribute to the pathogenesis of IAHS. A broad spectrum of infectious agents, viruses (e.g., cytomegalovirus, Epstein-Barr virus, human herpesvirus 6), fungi, protozoa, and bacteria may trigger secondary HLH, usually in the setting of immunodeficiency (see Table 501-2). A thorough evaluation for infection should be undertaken in immunodeficient patients with hemophagocytosis. Rarely, the same syndrome may be identified in conjunction with a rheumatologic disorder (e.g., systemic lupus erythematosus, Kawasaki disease) or a neoplasm (leukemia); in this case, treatment of the underlying disease may cause resolution of the hemophagocytosis. In some patients, interferon and intravenous immunoglobulin have been effective.