Chapter 147. Cutaneous Langerhans Cell Histiocytosis

The term “histiocytoses” identifies a group of diseases that have in common the proliferation of cells of the mononuclear phagocyte system, including dendritic cells.

Histiocytes, formally connective tissue macrophages, and dendritic cells constitute two of the major types of nonlymphoid mononuclear cells and are involved in immune and nonimmune inflammatory responses. Both cells arise in the bone marrow from pluripotential stem cells, but follow different paths of differentiation (Fig. 147-1). The macrophage, detectable by CD68, is a monocyte in the peripheral blood and a macrophage in tissue. It may differentiate into a number of different giant cells, including foreign body, epithelioid, Touton, and Langhans types.

Dendritic cells are antigen-presenting cells that interact with T cells. The prototype of dendritic cell in the skin is the Langerhans cell (LC). First described by Paul Langerhans in 1868 as a neuronal cell, the LC was first linked to antigen presentation during the 1940s. Precursor cells to the LCs migrate from the dermis into the epidermis where they complete differentiation. LCs have long cytoplasmic projections and a large almost kidney-shaped nucleus. Electron microscopy reveals the characteristic cytoplasmic organelle, the Langerhans or Birbeck granule, a tennis racket-shaped structure that is involved in pinocytosis and receptor-mediated endocytosis. Langerin (CD207), a receptor that permits internalization of antigen into Birbeck granules and presentation of antigen at the cell surface, is the most specific marker for LCs. LCs are also S100- and CD1a-positive. Once LCs have contacted antigen, they move via the lymphatics to the T-cell zones of the regional lymph nodes where they are designated interdigitating reticulum cells. There LCs present antigen to naive T-cells, activating them to proliferate if the antigen is recognized. Indeterminate cells are most likely immature Langerhans cells that lack Birbeck granules. Dermal dendritic cells are perivascular cells that are also capable of antigen uptake and presentation. Dermal macrophages can be identified in the normal dermis but their number increases during inflammation. Dermal macrophages, dermal dendritic cells, and Langerhans cells have a common bone marrow precursor, explaining why there are so many overlapping functions and markers.1

Langerhans cell histiocytosis (LCH) is characterized by aberrant proliferation of the LCs. Lichtenstein grouped Letterer–Siwe disease, Hand–Schüller–Christian disease, and eosinophilic granuloma of bone as “histiocytosis X” in 1953, based on finding abnormal histiocytes in these three related disorders. During the ensuing decade, Basset and Nezelof investigated novel intracellular granules in the lesional histiocytes and recognized them to be identical to those described in normal LCs. The term Langerhans cell histiocytosis (LCH) is now preferred to “histiocytosis X”.2

The prevalence of LCH is internationally estimated to be from 4.0 to 5.4 per million population, but these numbers may be low because of failure to recognize the organ and skin involvement in many patients. In children, the annual incidence is estimated at 0.5 per 100,000 children in the United States and at 4 per million worldwide.3 The male–female ratio is 2:1. The disease can occur in individuals of any age and can also be congenital, but is most common in children aged 1–3 years.

Histiocytoses are caused by a dysregulated proliferation or activation of dendritic cells or macrophages, both belonging to the mononuclear phagocyte system. Despite the improved knowledge of the classification of histiocytic disorders and the establishment of guidelines for diagnosis, treatment, and follow-up provided by the Histiocyte Society, the etiology and pathogenesis of most of these diseases are poorly understood, partially because of the lack of reliable animal models.4

The pathogenesis of LCH remains a mystery despite numerous investigative efforts. In addition to genetic factors, infectious agents (especially viruses), and cellular and immune system dysfunction, including abnormalities of lymphocytes and cytokines (interleukin 1α, interleukin 10), cellular adhesion molecules, and a combination of these, have been implicated. The role of genetics is not well defined. Although LCH has been reported in both monozygotic and dizygotic twins, the relative rarity of the familial occurrence does not favor a significant hereditary influence.

The reactive versus neoplastic nature of LCH cells is also debated. Although clonality has been demonstrated in all forms of LCH, this does not mean that the process is histologically and biologically malignant. The following features substantiate the reactive hypothesis: (1) LCH cells are highly differentiated, (2) histologically the granulomatous lesions resemble those seen in infections or foreign-body reactions, and (3) lesions may spontaneously regress. These pathogenic steps have been suggested: (1) viruses induce activation of histiocytes, (2) immunologic mechanisms produce the pathologic Langerhans cell phenotype, and (3) a cytokine-mediated storm results in LCH lesions. Many viruses (human herpesvirus 6, cytomegalovirus, adenovirus, and parvovirus) are suspected to play an etiologic role, but none has been proven to be responsible for the disease.

In contrast, the following observations support a clonal neoplastic origin of LCH: (1) bone marrow derivation and clonality of LCH cells, (2) the existence of familial cases of LCH, (3) findings of chromosomal instability with an abnormality on chromosome 7 and of p53 protein in LCH, and (4) cooccurrence of LCH and a myelodysplastic marrow. Two possible explanations have been proposed for the association between LCH and myelodysplasia. The first is that the marrow dysplastic features are secondary to the infiltration of the marrow by LCH cells induced by cytokines and do not represent elements of a true myelodysplastic syndrome. A second possibility is that the abnormal marrow cells are related to the clonal LCH cells and are part of the disease process, for example, myelodysplastic cells could be arising from the same clonal cell, an anomalous pluripotent dendritic (stem) cell line. This possibility raises the issue of whether LCH could be considered a “myeloid dendritic stem cell disorder.” These findings also suggest a genetic predisposition in LCH and stimulate the search for potential candidate genes in LCH. Figure 147-1 illustrates the histiocyte developmental pathway according to Jaffe et al.5

Classification

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.

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).

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 Lesions

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

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.

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.

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.

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.

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.

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

The recommended laboratory evaluations for a patient with LCH are shown in Table 147-2. Other investigations that should be carried out in LCH are listed in Table 147-3.

Imaging Studies

Diagnostic imaging, from plain films to axial high-resolution CT and gadolinium-enhanced MRI, plays a major role in the diagnosis and management of LCH. The most common intracranial manifestation in LCH is hypothalamic pituitary region infiltration in 10% to 15% of patients with LCH and is associated with diabetes insipidus or anterior pituitary hormone deficiency. The second-most common CNS finding is neurodegenerative LCH, characterized by bilateral symmetric lesions in the dentate nucleus of the cerebellum or basal ganglia of variable signal intensity on MRI. By conventional MRI, using T1- and T2-weighted sequences, the classical pattern of neurodegeneration in LCH is represented by bilateral T2-hyperintense and T1-hypointense, noncontrast-enhancing signal alterations and discrete T1-hyperintense calcifications.18 Susceptibility-weighted imaging (SWI), a newly developed MRI sequence, is more sensitive for intraparenchymal calcifications and hemorrhages. SWI may reveal areas of tissue injury, for example, certain gray matter structures, like the substantia nigra, that go undetected on conventional MRI.19

As already noted, bone involvement can be investigated using isotopic bone scans to reveal multiple lesions and fluorodeoxyglucose positron emission tomography to identify active osseous lesions. These techniques may allow the precise visualization of lesions in potentially dangerous bony locations such as the skull and the spine. In the thorax, reticulonodular shadowing and honeycombing of the lung with preserved lung volume is typically revealed.

Histopathologic, Immunohistochemical, and Ultrastructural Evaluation

The pathologic features of LCH provide the unifying aspect for the entire continuum of LCH disorders. The common histologic element of the different lesions is the typical “LCH cell,” a cell easily identified and differentiated from the nonspecific elements of the infiltrate by its size and configuration. This cell is approximately four to five times larger than small lymphocytes, has an irregular and vesiculated nucleus, is often reniform (kidney shaped), and has abundant, slightly eosinophilic cytoplasm (Figs. 147-13, 147-14, and 147-15). The histologic patterns observed in LCH are of three types: (1) proliferative, (2) granulomatous, and (3) xanthomatous. A proliferative reaction is seen in early papules. It consists of an extensive epidermotropic, lichenoid infiltration of LCH cells in the upper dermis. The epidermis soon becomes compressed, thinned, invaded, and even destroyed (see Fig. 147-13). In the upper dermis, LCH cells are typically separated by edema, whereas in the lower dermis their cell membranes coalesce. In the deep dermis, the infiltrate is often localized around vessels and may invade the hypodermis. A few mitotic figures are occasionally found. Cytologic examination of LCH cells is easily accomplished by scraping early papules. The granulomatous reaction (see Fig. 147-14) consists of an aggregation of LCH cells with some multinucleated histiocytes and a varying number of eosinophils, generally in clusters. Neutrophils, lymphocytes, and plasma cells may also be present in the infiltrate. This type of reaction is seen in the chronic stages of the disease. The xanthomatous reaction is encountered mainly in what was formerly called HSC and consists of numerous foam cells intermingled with LCH cells and eosinophils (see Fig. 147-15). Multinucleated giant cells are frequently seen. They are mainly of the foreign-body type but occasionally may have the appearance of Touton giant cells. Lipid accumulation is considered to be a late secondary phenomenon. These different types of histologic reactions may be found simultaneously in the same patient, and the visceral lesions present in LCH show the same three types of reactions observed in the skin.

In historical, nodular Hashimoto–Pritzker disease, the infiltrate appears to consist mostly of large multinucleated giant cells intermingled with typical LCH cells. The cytoplasm of the giant cells is either acidophilic or has a “ground glass” appearance. It is usually localized in the middermis and deep dermis; occasionally, the epidermis may be infiltrated and ulcerated. The LCH cells show the immunophenotype of normal Langerhans cells, expressing high levels of major histocompatibility complex class II molecules, CD1a complex, CD4, CD207 molecules, and S100 protein. Electron microscopic studies show that approximately 50% of the histiocytes of LCH contain Langerhans granules (see eFig. 147-15.1).

E-cadherin expression on LCs in lesional skin may be an indicator of a good prognosis and limited disease. Some authors suggest testing E-cadherin expression on frozen tissue samples because of a lack of sensitivity in the use of paraffin-embedded tissue. Regulator T (Treg) cells have been shown to be numerous in skin lesions of LCH and may be involved in its pathogenesis, but their density does not predict disease evolution.20

The differential diagnosis for LCH is summarized in Boxes 147-1 and 147-2.

Intercurrent infections, mainly candidiasis and sometimes dermatophytosis, are frequently observed in LCH, especially in LSD. The development of severe pyogenic abscesses has been reported in elderly patients. The results of the progressive destruction of the surrounding tissue by invading histiocytes can therefore be highly variable and multifocal. The association of LCH with malignant neoplasms, particularly solid tumors (lung tumors, celiomesenteric neuroblastoma), malignant lymphomas, or acute leukemia is not unusual. In some of these cases, LCH may be considered as a reactive process associated with malignancy. Neoplasms may also be related to chemotherapy or radiotherapy for LCH. The synchronous occurrence of LCH with leukemia may be interpreted as additional clinical evidence in favor of a common origin of monocytes and Langerhans cells.

Although the presence of numerous lesions, either in the skin or in other tissues, generally indicates an unfavorable course, the evolution of LCH is unpredictable. The prognosis is based on clinical features and is related to the age at onset, the rate of disease progression, and the number of organ systems involved. It is not related to the histopathologic features. In short, an early-onset (under the age of 2 years), extensive disease, and the presence of organ failure are the three main negative prognostic indicators.

Single-system LCH is usually associated with a good prognosis, whereas multisystem LCH may be fatal. However, some patients with multiple lesions have been reported to recover spontaneously. The appearance of xanthomatous lesions in the course of LCH is considered by some authors to be an expression of a shift from a disseminated aggressive form into a progressive chronic form; others believe that these lesions may represent a distinct clinical entity independent of the primary disease. Organ dysfunction (liver, bone marrow, and lung), which occurs in approximately 15% of patients with LCH, is the most important predictor of poor outcome; however, diabetes insipidus is not a poor prognostic indicator. In infants with organ dysfunction, the mortality rate may be as high as 50% to 65%. The most frequent causes of death are pulmonary and bone marrow dysfunction and intercurrent infections.

It is impossible to attribute significance to any single sign, but jaundice, thrombocytopenia, anemia, hepatic failure, and nail involvement are considered unfavorable prognostic indicators. A favorable prognosis is associated with a small number of lesions, nodular lesions, prompt resolution of lesions, and the involvement of only one organ system (skin or bones). Multisystem LCH carries a better prognosis in adults than in children.

Liver dysfunction is considered present if there is hypoproteinemia not due to protein-losing enteropathy (less than 5.5 mg/dL total protein and/or less than 2.5 g/dL of albumin), edema, ascites, and/or hyperbilirubinemia (total serum bilirubin of more than 1.5 mg/dL). Lung dysfunction is considered present if there is cough, dyspnea or tachypnea, cyanosis, radiologically evident interstitial disease, restrictive lung disease, pneumothorax, or pleural effusion attributable to the disease rather than to infection.22 The presence of dense areas on radiography alone is not interpreted as evidence of dysfunction. Hematopoietic dysfunction is considered present if there is anemia (less than 10 g/dL hemoglobin) not due to infection or iron deficiency, leukopenia (white blood count of fewer than 4,000/μL), or thrombocytopenia (fewer than 100,000 platelets/μL). The presence of excessive numbers of histiocytes in the marrow aspirate per se is not considered as evidence of dysfunction. Hypercalcemia is also associated with a poor prognosis and is sometimes caused by bone resorption or excess prostaglandin production. Finally, the rapidity and intensity of the clinical response to initial treatment is a good indicator of prognosis.

Hashimoto–Pritzker disease is classically characterized by congenital or neonatal isolated cutaneous involvement (nodules in the historical cases, papules and vesicopustules in other cases) without systemic involvement. Lesions regress spontaneously in weeks to months, with an excellent prognosis. As such, Hashimoto–Pritzker disease is the prototype of self-regressive cutaneous LCH (SR-LCH; also called “self-healing” LCH). However, in the same age group, cutaneous involvement is also the most common presentation of nonself-regressive cutaneous LCH (NSR-LCH). Unfortunately, there are no absolute criteria that can reliably distinguish SR-LCH from NSR-LCH in the neonatal and early infancy periods other than continued follow-up for signs of resolution.

In the recent past, it has been postulated that a higher degree of necrosis and ulceration on physical examination and a denser infiltrate of eosinophils on histopathology would suggest a self-healing process as opposed to a multisystem disease. Despite these differences, patients who were initially diagnosed with single-system LCH (cutaneous involvement only) eventually developed progression of the disease and required systemic treatment.21

A recent retrospective survey has reviewed a cohort of 31 patients with a diagnosis of cutaneous LCH in the first 3 months of life and no previous visceral LCH in an attempt to define predictors of disease evolution. While no single item can be a reliable indicator of a good prognosis, a solitary lesion or the tendency to involve the extremities were more common in SR-LCH. Given the marked overlapping features of SR-LCH and NSR-LCH, the term Hashimoto–Pritzker disease should be avoided. Spontaneous regression of the lesions, the lack of multiorgan involvement, and close long-term follow-up to monitor for progression of the disease are the only ways to definitively diagnose SR-LCH.22

Treatment strategies for LCH are chosen on the basis of the age of the patient, the extent of disease, and the location of lesions (see Fig. 147-3 and the treatment algorithm in eFig. 147-15.2).

In single-system disease involving skin or bone, management is nonaggressive. In children with skin involvement only, observation is the best option. Topical drugs, including corticosteroids (also intralesional injections),23 tacrolimus, and imiquimod,24 can be used for localized lesions. In adults with skin involvement only, topical treatment with nitrogen mustard may be effective. In one patient with localized LCH, complete clearance was achieved after 12 sessions of narrowband UVB with a cumulative dose 970 mJ/cm2.25 Significant improvement has been obtained with conventional psoralen plus UVA light treatment in a considerable number of cases. CO2 laser therapy has been suggested to treat periorificial eosinophilic granuloma. Systemic glucocorticoids or antimitotic drugs are indicated for limited disease only in resistant cases. The use of thalidomide at a dosage of 100 mg/day for 1 month and then 50 mg/day for 1 or 2 months may induce a remission of skin lesions. Usually, the disease recurs after treatment is stopped. The effect of thalidomide seems to be a result of its immunomodulatory and anti-inflammatory properties. In one case, a complete remission of skin lesions was obtained after oral isotretinoin therapy. The patient was treated with 1.5 mg/kg daily for 8 months and remained free of recurrence and visceral involvement for 5 years. For patients with bone involvement only, surgery (excision or curettage) is the treatment of choice if the lesions are accessible (see eFig. 147-15.3). In children, glucocorticoid injections into selected sites may prevent surgical trauma to developing teeth or the growth plate of long bones. In adults, radiotherapy is indicated for involvement of vertebrae, the sella turcica, and weight-bearing bones with risk of spontaneous fracture. In children, radiotherapy must be reserved for cases that fail to respond to other measures to avoid the risk of long-term effects. Recent data indicate that indomethacin at a daily dose of 1–2.5 mg/kg administered for an average of 7.7 months (range, 5–12 months) may effectively treat isolated LCH of bone in children.26 In the case of multiple bone lesions, monochemotherapy is suggested as with multiorgan involvement.

The management of patients with multisystem disease has several options. Currently, monochemotherapy with vinblastine with or without glucocorticoids is probably the most suitable treatment.27 Vinblastine is given intravenously at doses of 0.1–0.2 mg/kg (6.5 mg/m2) once weekly for 1–3 months. Readministration of the alkaloid should be instituted only when new lesions appear. In the event of relapse, retreatment with the same type of monochemotherapy results in complete clearing in 60% of cases. Finally, methylprednisolone (30 mg/kg intravenously on 3 consecutive days) may be the initial therapeutic choice.

Multiagent regimens including vincristine, cyclophosphamide, doxorubicin, and chlorambucil may be considered for patients for whom monochemotherapy is not effective. In refractory and advanced cases of LCH, cyclosporine and interferon-α2, and 2-chlorodeoxyadenosine (2-CdA, cladribine) have been used. cladribine has excellent activity in patients with LCH, even though response is not uniform across all risk groups. Recent literature have shown cladribine as monotherapy has significant activity in patients with disease in nonrisk organs such as bone, but limited activity in refractory risk organ disease. In a large prospective study, the only other factors predictive of response to cladribine were age at cladribine therapy and the time from diagnosis to cladribine therapy. The response to the drug and survival were significantly better in patients greater than 2 years of age, while the time from diagnosis to cladribine therapy was also significantly different in the responding patients compared to those who failed to respond. The potential serious side effects of cladribine (transient neutropenia, absolute monocytopenia, T-cell suppression, autoimmune hemolytic anemia, and severe skin rashes) call for a careful risk-benefit evaluation in each case. High-risk patients who fail to respond to cladribine have a high-risk of mortality.27

A current open pilot study of the Histiocyte Society for patients with refractory LCH is investigating whether the response rate can be improved by the addition of cytosine arabinoside (Ara-C) to cladribine. Allogenic bone marrow transplantation or autotransplantation with CD1a-depleted bone marrow has been successful in some patients. Other approaches, including stem cell transplantation with myeloablative and nonmyeloablative preparative regimes, are also being tested (eFig. 147-15.2).