Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis

Suman Malempati

H. Stacy Nicholson

Langerhans cell histiocytosis (LCH) is a disorder characterized by clonal proliferation of cells in the mononuclear phagocyte system. Since the first case was described more than a century ago,1 LCH has often been a source of confusion, perhaps best demonstrated by the several labels given to the disorder during the past 100 years. Since 1985, Langerhans cell histiocytosis has been the preferred term,2, 3 replacing histiocytosis X, coined in 1953.4 The X demonstrated the lack of knowledge about the etiology and pathophysiology of LCH, and about how the different clinical syndromes were related. The term histiocytosis X did serve to bind the syndromes, which included Hand-Schuller-Christian syndrome, Letterer-Siwe disease, eosinophilic granuloma, Hashimoto-Pritzker syndrome,5 self-healing histiocytosis,6 and pure cutaneous histiocytosis,7 into one clinical entity. The term Langerhans cell histiocytosis reflects the central role of the Langerhans cell in these diseases. LCH also distinguishes these disorders from other histiocytic syndromes, which include primary and secondary hemophagocytic lymphohistiocytosis, Rosai-Dorfman disease, and neoplastic disorders such as acute monocytic leukemia, malignant histiocytosis, and true histiocytic lymphoma.3 This chapter focuses on LCH.


Although estimates vary by region and time period, the annual childhood incidence of LCH has been estimated to be approximately 4 to 9 cases per million.18, 19, 25 The discrepancy between epidemiologic studies is likely due to variation in reporting and data collection. Across studies, there is consistently a slight
predominance of cases in males.18, 19, 20 LCH occurs less frequently in adults with an incidence of 1 to 2 cases per million per year.21 The disease is more common and tends to be more severe in younger children. For children under 1 year of age, the annual incidence is 9.9 cases per million.22 Almost all cases of multisystem LCH occur before 5 years of age.23, 24, 25 In an exploratory case-control study comparing 177 children with LCH to children with cancer and community controls,20 LCH was associated with a family history of benign tumors and less strongly with feeding problems during infancy. Other factors associated with LCH in this study were maternal urinary tract infections during pregnancy and blood transfusions during infancy. Factors not associated with LCH were the typical childhood viral infections and medication use. In a case-control study of 459 children with LCH, which compared risk factors in children with LCH to those in both community and cancer controls,26 LCH was associated with neonatal infections, solvent exposure, and thyroid disease in the proband or the family. Childhood immunizations appeared to be protective. Reports of seasonal variation in incidence are conflicting18, 25 Familial clustering of LCH has been observed, suggesting that a genetic predisposition may exist.27 The concordance rates between dizygotic and monozygotic twins are 33% and 80%, respectively. In addition, patients with LCH may have a predisposition to cancer and vice versa. Links with both solid tumors and leukemia have been documented.28 Several cases of LCH developing in patients with acute lymphoblastic and acute myelogenous leukemia have been reported.29, 30, 31, 32 Patients with LCH have genetic instability and increased chromosomal breakage, which also suggests a genetic predisposition to malignancy.33, 34, 35


LCH can present along a continuum of illness, ranging from indolent to explosive disease. In some patients, pathologic lesions are solitary, whereas in others they are widely disseminated. Moreover, the distribution of lesions in a given patient may vary considerably over time. Although LCH can occur at any age, it occurs with greatest frequency in infants and children. The median age at diagnosis for all disease variants is 3 to 6 years.18, 19 The acute disseminated form of the disease characteristically occurs in younger children and almost all cases occur before the age of 5 years.25 Children younger than 1 year old, in particular, often present with multiple organ involvement.22, 74 The more indolent forms of LCH occur primarily in older children and young adults.75 Approximately 70% of cases of LCH in children involve a single organ system, with bone being the most common site.18, 19, 22, 25 Table 60.1 shows the distribution of involved sites
by age at diagnosis of LCH. The most commonly involved organ in adults is bone, often accompanied by an adjacent soft tissue mass.76, 77 Other organs that are involved less often in adults include the lungs and pituitary gland.76 In adults, multisystem disease, including liver, lymph node, and bone marrow involvement, is extremely rare.

The traditional classification of clinical variants was based on patterns of organ involvement.8 Eosinophilic granuloma was used to describe a syndrome characterized by single or multiple bone lesions in the absence of visceral involvement.13 When granulomas involved the liver, spleen, lymph nodes, skin, central nervous system (CNS), or bone marrow as well as bones, the disorder was called Letterer-Siwe disease.11, 12 The triad of multiple bone lesions, exophthalmos (resulting from retro-orbital granulomas), and diabetes insipidus (DI; the result of hypothalamic or pituitary involvement) constituted Hand-Schuller-Christian disease (Figs. 60.3 and 60.4).9 The separation of eosinophilic granuloma of bone from syndromes characterized by visceral dissemination proved to be useful prognostically. However, the distinction between Letterer-Siwe disease and Hand-Schuller-Christian disease was often subtle and clinically irrelevant. The current classification is based on the number of organ systems involved and the number of sites involved within an organ system.23, 78 The main classifications of disease are unifocal eosinophilic granuloma (i.e., single-system, single-site disease, usually in bone), multifocal eosinophilic granuloma (i.e., single-system, multiplesite disease, usually in bone), and acute disseminated histiocytosis (i.e., multisystem disease). The presence and degree of organ dysfunction are important distinctions in those with multisystem disease.78

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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Langerhans Cell Histiocytosis
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