LCH is a disorder with a broad spectrum of forms: it can be local, asymptomatic with an indolent course, limited to an isolated bone lesion, or systemic and aggressive involving multiple organs and producing significant symptoms. Thus, the clinical manifestations depend on the site of the lesions and the systems involved. Historically, LCH has been described under various names: Letterer–Siwe disease is the prototype of the acute, disseminated, multisystemic form that usually appears in infants or newborns. Its course, if the disease is untreated, is fatal; Hand–Schüller–Christian disease is the chronic, progressive, multifocal form, commonly beginning in childhood; eosinophilic granuloma is the localized, benign form; and Hashimoto–Pritzker disease represents the benign, self-healing variant of LCH, usually present at birth or during the first few days of life. In 1997, experts of the Reclassification Working Group of the Histiocyte Society advocated the disuse of the eponyms. They recommended the use of the term Langerhans cell histiocytosis only and the stratification of patients based on the extent of disease. The classification system for histiocytosis defined by the Histiocyte Society is shown in Table 147-1. At present, it seems realistic to describe LCH as a continuum as in Fig. 147-2, because every patient is unique with regard to the type, number, and location of lesions.
Table 147-1 Classification of Langerhans-Cell Histiocytosis (LCH) ||Download (.pdf)
Table 147-1 Classification of Langerhans-Cell Histiocytosis (LCH)
|Localized (single site)||Monostotic bone involvementa|
|Isolated skin involvement|
|Solitary lymph node involvement|
|Multiple site||Polyostotic bone involvementa|
|Multifocal bone disease (two or more different bones)|
|Multiple lymph node involvement|
|Low-risk group||Disseminated disease with involvement of low-risk organs (skin, bone, lymph node, pituitary)|
|High-risk group||Disseminated disease with involvement of one or more of the high-risk organs (hematopoietic system, lungs, liver, and spleen)|
Clinical spectrum of LCH. Any single patient affected by LCH can be situated in a given point of the arrow.
Although the historical terminology can be maintained for didactic purposes, it is more important to distinguish the forms with systemic involvement that require systemic management (multisystemic LCH) from those with localized lesions and the best prognosis that can be treated with a topical medication or observational approach (single-system LCH) or that are “self-healing” (Fig. 147-3).
Approach to the patient with Langerhans cells histiocytosis.
The Writing Group of the Histiocyte Society proposed a guideline identifying confidence levels for the diagnosis of class I histiocytosis (LCH). These criteria were as follows: (1) presumptive diagnosis—light morphologic characteristics; (2) designated diagnosis—light morphologic features plus two or more supplemental positive results to stains for adenosine triphosphatase, S100 protein, α-d-mannosidase, and peanut lectin; (3) definitive diagnosis—light morphologic characteristics plus Birbeck granules in the lesional cell visible with electron microscopy and/or positive results on staining for CD1a antigen on the lesional cell.
Current immunostaining techniques allow the definitive diagnosis of LCH from just paraffin-embedded tissue, which avoids the need for sophisticated and expensive methods such as electron microscopy. Because the location and diffusion of the lesions have a significant influence on the course of the disease and its prognosis, various classification schemes assign scores for each organ and system involved. The former classification of LCH into three or four disease categories is no longer used. The present system attempts to evaluate the extent of involvement and its relationship to prognosis. The former classification of LCH into three or four disease categories is no longer used. The present system attempts to evaluate the extent of involvement and its relationship to prognosis.
Cutaneous manifestations are very common in LCH and may represent the earliest sign of the disease. The typical lesion is a small translucent papule, 1–2 mm in diameter, slightly raised, rose-yellow (Figs. 147-4A and 147-4B), and usually located on the trunk (see Figs. 147-4A and 147-4B) and scalp. The lesions frequently show scaling (see Fig. 147-4A) and may become crusted and ulcerated (see Figs. 147-4B and 147-4C). Vesicles and pustules may occur, simulating eczema, miliaria, scabies, and varicella. This is an especially common presentation during the neonatal period (first month of life). The presence of purpura is a poor prognostic sign. Hashimoto–Pritzker disease has traditionally been characterized by the eruption of multiple or solitary elevated, firm, red–brown nodules (Fig. 147-5A) or flesh-red lesions similar to infantile angiomas; late papulonodular lesions may show elevated borders and ulcerate easily. These lesions can grow in size and number in the first few weeks of life, and some may become quite large. They then form brown crusts, which are shed and occasionally leave whitish atrophic scars after spontaneous resolution. Since the original description of the papulonodular lesions, it is clear that small reddish-brown crusted papules that may resemble chickenpox are also a common manifestation of “self-healing Langerhans cell histocytosis,” with spontaneous clearance by 2–3 months of age (see Fig. 147-5B). Presentation with extensive, erosive, superficial lesions suggestive of congenital bullous epidermolysis has also been described.8
Extensive Langerhans cell histiocytosis. A. Abdominal area of infant with multiple yellowish erythematous papules covered by scale or crust. B. Infant with multiple ulcerated skin lesions on the trunk. C. Severe disease with confluent erosive and crusted lesions forming ulcers; distension of the abdomen reflects hepatosplenomegaly.
A. Congenital “self-healing” reticulohistiocytosis (also called self-regressive cutaneous LCH and formerly Hashimoto–Pritzker disease). Multiple disseminated, elevated, firm red–brown or dark red nodules (multiple form) present at birth. (From Bonifazi L et al: Congenital self-healing histiocytosis. Arch Dermatol 118:267, 1982, with permission.) B. Resolving crusted reddish brown papules of congenital self-healing Langerhans cell histiocytosis with chickenpox-like lesions.
Cutaneous lesions may appear rapidly in successive crops. The lesions tend to merge on the scalp, mimicking seborrheic dermatitis or folliculitis, and leading to alopecia, and on the folds (retroauricular, axillary, and genital), mimicking intertrigo. Occasionally, the lesions merge into plaques on the medial aspect of the chest (Fig. 147-6), the midback, and temporoparietal regions, and may become xanthomatous.
Extensive Langerhans cell histiocytosis. The papuloscaling and papulocrusted lesions show a typical distribution on the trunk and the scalp. The involvement of the face in this patient is unusual.
Mucous membrane lesions are commonly noduloulcerative and mainly involve the perioral area and gingiva (Fig. 147-7) and the perigenital or perianal regions (Fig. 147-8). Oral manifestations may be the first sign of LCH: nonspecific pain, aphthae, gingival bleeding, candidiasis, ulceration with loosening of the teeth, and premature eruption of the teeth can be observed.
Extensive Langerhans cell histiocytosis. Infiltrating lesions of the gingival tissue which frequently leads to loss of teeth.
Restricted Langerhans cell histiocytosis. Noduloulcerative lesions in the vulva and on the perianal area. These lesions, although rare, are as unique as the bone lesions.
Nail changes include fragile lamina, paronychia, subungual pustules, nail fold destruction, onycholysis, subungual hyperkeratosis, longitudinal grooving, and pigmented and purpuric striae of the nail bed (Fig. 147-9). These features are considered to be unfavorable prognostic signs. Cutaneous manifestations in elderly patients (Fig. 147-10) are similar to those seen in children.
Extensive Langerhans cell histiocytosis. All nails, save one, show purpuric linear lesions of the nail bed. Nail changes are considered an unfavorable prognostic sign.
Extensive Langerhans cell histiocytosis in an 81-year-old woman. The diffuse papuloscaling and papulocrusted lesions on the trunk are similar to those seen in early childhood. Systemic involvement consists of hepatosplenomegaly and pulmonary lesions. (From Caputo R et al: Mucocutaneous expressions of Langerhans cell histiocytosis in adults. Eur J Dermatol 13:481, 1994, with permission.)
Related Physical Findings
Malaise, weight loss, failure to thrive, nausea, myalgia, arthralgia, and fever are frequently present in aggressive forms. Bone lesions are the most frequent manifestations of LCH (80% of cases), and bone involvement alone is seen in 50% to 60% of cases. The bones that are most commonly involved by LCH are the skull, femur, mandible, pelvis, and spine. Cervical LCH lesions often extend to paravertebral soft tissue, epidural space, pedicles, and even to the endplate and lamina.9 The lesions of the skull most often involve the temporoparietal region, in which infiltrates lead to limited osteolytic foci that merge to form typical “map” lesions (Fig. 147-11). Because osteolysis of the lower maxillary bones is also frequent, the teeth appear to be floating in the mouth in X-rays. Mastoid involvement is common and often symptomatic. Bone involvement can be shown by computed tomography (CT) or gadolinium-enhanced magnetic resonance imaging (MRI) and can lead to organ dysfunction such as diabetes insipidus and growth retardation. Retro-ocular bone involvement is responsible for exophthalmos. In addition, flat bones, vertebral bones, and long bones can be involved. Osteolytic lesions, either asymptomatic or accompanied by pain and functional impairment, are generally multiple and appear gradually. At times, lesions may cause a significant periosteal reaction. Extension to the adjacent tissues (e.g., muscles) can produce symptoms, which may be unrelated to the bone involvement. The onset can be insidious, and the osseous lesion can be single and may go undetected until spontaneous fracture or destruction of an organ occurs. When the lesions become symptomatic, there is localized pain, tenderness, soft tissue swelling, deformation, fracture or medullar compression (vertebra plana), or premature teeth loss.
Extensive Langerhans cell histiocytosis. Radiograph of the skull shows well-circumscribed osteolytic areas with a typical “map” appearance.
Bone marrow involvement, which is rare and generally occurs late in aggressive forms of LCH, is characterized by the presence of numerous histiocytic cells. When thrombocytopenia, leukopenia, and anemia occur, death is almost certain.
Conventional radiography and MRI can both be used in the diagnosis of bone LCH lesions, but MRI has an advantage in the detection of muscle involvement. In addition, isotopic bone scanning can be used for multiple lesions, and scintigraphy and fluorodeoxyglucose positron emission tomography can identify active osseous lesions. Isolated bone lesions, typically with bevelled margins and without sclerosis, have the best prognosis, whereas bone lesions with multisystem involvement predict a more problematic course.
Pulmonary involvement may be asymptomatic but can also cause death. Pulmonary lesions are more often problematic in elderly patients and are quite frequent (12% to 23% of patients). Functional signs consist of dyspnea, tachypnea with rib retraction, cough, cyanosis, and thoracic pain. Other signs include mediastinal compression and pneumothorax caused by bulla formation. In chest radiographs, the lungs may show a classic “honeycomb” appearance (Fig. 147-12) or a micronodular pattern. Pulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume. The diagnosis of LCH can be made if more than 5% of the cells in specimens obtained by bronchoalveolar lavage are Langerhans cells as indicated by immunostaining or electron microscopic examination. Involvement of the liver and spleen is quite frequent (15% to 50% of patients). Hepatic lesions may evolve to severe fibrosis, biliary cirrhosis, and liver failure. Hepatosplenomegaly, often due to portal infiltration by Langerhans cells or Kupffer cell hyperplasia, is never the initial sign of the disease but is a frequent complication and is a prognostically unfavorable sign, particularly when accompanied by jaundice and ascites. Splenomegaly may increase the severity of thrombocytopenia.
Extensive Langerhans cell histiocytosis. Bilateral involvement of the lungs characterized by multiple cystic cavities (honeycomb appearance). (Used with permission from E. De Juli, MD.)
LCH may manifest orally with single or multiple lesions of the alveolar or basal bone, ulcerated mucosal lesions accompanied by adenopathy and/or periodontal lesions. The latter show gingival inflammation, bleeding, recession, necrosis, odontalgia, dental hypermobility, and premature loss of teeth. The principal differential diagnoses include advanced periodontal disease or a periapical process of dental or periodontal origin.10 Gastrointestinal tract involvement in LCH is rare (∼1%–2% of the patients) but, when present, tends to manifest at a very young age. Symptoms are nonspecific and are due to mucosal infiltration.11 LCH may manifest as hematochezia, constipation, or diarrhea leading to protein-losing enteropathy and can range in severity from mild to life threatening.12 The gastrointestinal symptoms can be preceded by or associated with the characteristic cutaneous lesions in the majority of the patients. Although conventional radiographs may show either dilated or stenotic segments, the specific diagnosis can be made by only endoscopic biopsy. Since most of gut biopsies demonstrated histologic evidence of LCH, even in patients who were not experiencing gastrointestinal symptoms, endoscopic assessment of both the upper (gastroduodenal) and lower (distal colon) gastrointestinal tract should be considered with multiple mucosal biopsies in the initial LCH-staging studies in patients with no other evidence of systemic disease. Since patients with gastrointestinal tract involvement of LCH have poor outcome, they should be treated as a multisystemic disease irrespective of the patient's clinical status.
Lymphadenopathy is rarely prominent but has been noted in 25% to 75% of fatal cases. Cervical lymph nodes are the most often affected. The nodes are only rarely symptomatic, but if massive, they may damage the surrounding structures. For example, enlargement of the nodes surrounding the respiratory tract may provoke cough, dyspnea, or cyanosis. Suppuration and chronic drainage can also occur.
Diabetes insipidus is present in more than 50% of cases and occurs more often in patients with involvement of the skull and the orbits. It should be evaluated by water deprivation testing and measurement of urinary levels of arginine vasopressin. Diabetes insipidus is easily controlled by vasopressin therapy. Although diabetes insipidus is an obvious marker of skull invasion, it is not considered a prognostically unfavorable symptom. Growth retardation in children can be due to anterior pituitary involvement leading to growth hormone deficiency; however, it is more commonly caused by chemotherapy, systemic steroids, malabsorption, and general malaise. Other endocrine organs, such as the pancreas, thymus, and gonads can also be affected.
Exophthalmos is present in only 10% to 30% of cases. It may be unilateral or bilateral and is due to retroocular bone infiltration by Langerhans cells. Mastoid involvement mimics an infectious mastoiditis and leads to chronic otitis media, otorrhea, and also deafness caused by the extension of the disease to the middle ear.
CNS involvement by LCH is probably not as uncommon as believed in the past. Moreover, the clinical picture is very heterogeneous and may develop years after the initial diagnosis of LCH with mild symptoms as subtle behavioral disturbances or learning difficulties.13 Besides growth retardation (in children), signs may include cranial nerve deficit, blurred vision, tremors, dysarthria, ataxia, reflex abnormalities, spastic paraplegia or tetraplegia, progressive intellectual deficit, headaches, psychosis, and hydrocephalus. Other signs, such as seizures and those related to increased intracranial pressure, are rare and depend on the site and size of the lesion. Cerebellar manifestations may appear as a first sign, followed by signs of involvement of the paraventricular cerebral white matter. CT or MRI may reveal tumor lesions as a sign of primary invasion or secondary atrophic or demyelinating lesions. Yet other patients are free of neurologic symptoms despite typical MRI changes.
Hypogonadotropic hypogonadism,14 chronic erosive oligoarthritis of large joints,15 and a high incidence of hearing loss16 have also been reported. An association between LCH and acute myeloid leukemia has been recorded in a few series.17