The group of diseases now collectively known as Langerhans cell histiocytosis (LCH) include entities formerly referred to as histiocytosis X, eosinophilic granuloma, Letterer-Siwe disease, Hand-Schüller-Christian disease, Hashimoto-Pritzker syndrome, self-healing histiocytosis, pure cutaneous histiocytosis, Langerhans cell granulomatosis, type II histiocytosis, and the generic term nonlipid reticuloendotheliosis. LCH is a rare disease that affects five children per million population and about one to two adults per million population. It is predominantly a childhood disease, with more than 50% of affected individuals younger than 15 years of age. The peak incidence is between 1 and 4 years old. The first case of LCH was described by Dr. Thomas Smith in 1865 in a 4-year-old with punched-out lesions of the calvarium. The skull defects were originally thought to be congenital based on drawings because x-rays were not developed until 1895. The child died 1 month later of respiratory complications related to whooping cough. Hand-Schüller-Christian disease was independently described by Hand in 1893, Schuller in 1915, and Christian in 1920 in patients with exophthalmos, polyuria, and skull defects. The disease was initially attributed to tuberculosis infection. Letterer-Siwe disease was described by Letterer in 1924 and by Siwe in 1933 as an acute disorder of the reticuloendothelial system in two young children. This disease was characterized by marked hepatosplenomegaly, lymphadenopathy, bone tumors, anemia, and hyperplasia of nonlipidized histiocytes. Eosinophilic granuloma of bone was first described by Mignon in 1930 as a granulomatous bone lesion in an adolescent male.

In 1940 Lichtenstein and Jaffe described a case of a solitary bone lesion of the femur in a 4-year-old girl that did not suggest any classified disease of bone, either inflammatory or neoplastic. This case also notably consisted of sheetlike collections of histiocytes. Earlier reports suggested the possibility of myeloma with prevalence of eosinophilic cells or osteomyelitis with eosinophil reaction. The authors believe that the lesion represented neither a myeloma nor an osteomyelitis as had been suggested by others, but rather some type of granuloma. However, it did not fit into any of the recognized granuloma categories. Moreover, they proposed that the granuloma existed in response to a virus. The name eosinophilic granuloma of bone was applied because of the preponderance of eosinophils, although the authors fully recognized that the basic cells were histiocytes. The authors pointed out those specific clinical features that might lead one to suspect the presence of eosinophilic granuloma of bone even before surgical intervention is attempted. Among these were the occurrence of the lesion in a child or a very young adult; a short history of painful localized swelling of only several weeks duration; radiographic evidence of a rarefied and destructive bone lesion, especially in the calvarium, but also in the ribs or in a long bone and with perforation of the cortex; and perhaps a palpable soft tissue mass overlying the affected bone. Jaffe and Lichtenstein were quick to point out that these features may lead the clinician to suspect malignant disease, specifically a Ewing’s sarcoma.

Jaffe and Lichtenstein also reported the realization that multiple bone lesions may be encountered and of the same kind as the solitary lesions. They recommended that even in cases in which there was supposedly only a solitary lesion in bone, additional lesions may be present and should be searched for radiographically. This radiographic investigation is referred to as a skeletal survey. Aside from the known focus of LCH, a negative skeletal survey in combination with no suspicion for visceral involvement will proclaim a patient has monostotic eosinophilic granuloma.

The clinical varieties of LCH range from a curable, solitary, destructive lesion of bone to a lethal leukemia-like disorder that primarily affects infants. The clinically evident pathologic condition in LCH is broadly divided into two categories: direct involvement with the disease (i.e., bone or organ lesions) and secondary consequences resulting from permanent damage by the primary disease (i.e., exophthalmos, diabetes insipidus, fractures, and loss of teeth). This pathologic process is well recognized to be a neoplastic process. LCH affects the head and neck region quite commonly, particularly the skull and jaws. With jaw involvement, 90% of patients are younger than 40 years of age, with a mean of 19 years. Unifocal involvement of the jaws represents about 50% of maxillofacial LCH, with multifocal single system disease and multifocal multisystem disease equally accounting for the other 50%. The mandible is involved approximately three times more commonly than the maxilla. The posterior region of the jaws is more commonly involved than the anterior region. Early disease in the oral and maxillofacial region is manifested by lytic lesions of the jaws, often seen as localized, punched-out radiolucencies with no calcification and no sign of sclerosis or reaction at the borders ( Figure 28-1 ). The most common symptom is pain, although a mass may also be a presenting symptom. With advanced disease, there may be severe alveolar bone resorption producing the appearance of “teeth floating in air” ( Figure 28-2 ). As will be discussed in detail in this chapter, the extent of the disease process often dictates surgical therapy for a unifocal eosinophilic granuloma of the jaws. Prompt diagnosis of disease is paramount to providing curative surgical therapy with little or no deformity. The surgeon should consider LCH on a differential diagnosis of lucent lesions of the jaws, especially in patients younger than 40 years of age.

This panoramic radiograph demonstrates a unifocal LCH of the left mandible.

An advanced case of LCH of the bilateral mandible manifested by appearance of “teeth floating in air.” This patient proved to have multifocal single system disease. The second deposit of eosinophilic granuloma was found in the fibula.

THE LANGERHANS CELL

The term histiocyte refers to two groups of immune cells: macrophages and dendritic cells. The Langerhans cell is a mononuclear cell of bone marrow origin that belongs to the dendritic cell family. It can be generated from peripheral blood monocytes by the action of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor ∝. The normal Langerhans cell is recognized to be an important antigen-presenting cell in the skin that represents the most peripheral extension of the immune system. They are normally found in mucosa, lymph nodes, and bone marrow. With the uptake of antigen, Langerhans cells migrate to afferent lymphatic channels and make their way to paracortical zones in regional lymph nodes. Once there, the endocytosed antigens are presented to naive helper T cells. Langerhans cells have not proven to be clonal. In 1868 Paul Langerhans, a 21-year-old medical student at the University of Berlin under the mentorship of Professor Virchow, described the cell that bears his name. His initial impression was that the cell was a nerve receptor cell because of its stellate, dendritic appearance. Only in later years did Langerhans realize that his original supposition was incorrect. In 1961 Birbeck et al described the organelle that has become the unique label of the cell. Interestingly, there are stages of the cell’s development when the Birbeck granule is not identified. Typically, two characteristics are observed in Langerhans cells. The first is the presence of Birbeck granules. These intracellular structures are rod shaped with a ballooning at one end that resembles a tennis racket. Under electron microscopy, the Birbeck granule ( Figure 28-3 ) consists of a bilayered membrane. They can also be observed to develop as invaginations of the cell membrane. These findings resulted in a hypothesis that the granules represented the cellular response to an antigen presented on this cell and therefore reflect the normal function of Langerhans cells. One theory with respect to the pathogenesis of LCH therefore is that immunologic stimulation of this normal antigen-presenting cell may continue in an uncontrolled manner, and this results in proliferation and accumulation of these cells. The second characteristic of Langerhans cells, which is diagnostic of the pathologic condition, is that they stain strongly positive for the presence of CD1a on their surfaces. This property is highly characteristic of Langerhans cells, but not of other cells of histiocytic origin.

An electron micrograph demonstrating a characteristic Birbeck granule (BG) found in LCH. Original magnification × 50,000. Inset = original magnification × 100,000.