The hallmark of Langerhans cell histiocytosis (LCH) in most patients is an osseous lesion. When the bone is the only organ involved, the disease is referred to as eosinophilic granuloma. EG is the benign form of the 3 clinical variants of Langerhans cell histiocytosis, which include Litterer-Siwe disease, Hand Schuller-Christian disease, and EG (formerly termed histiocytosis X). When more organs are affected, causing cranial lesions, diabetes insipidus, and exophthalmos, it is refered to a Hand-Schuller-Christian disease. The disseminated form of LCH, called Litterer-Siwe disease, is more often seen in infants and children who are less than 3 years old and is characterized by wasting, hepatosplenomegally, generalized lymphadenopathy, skin rash, generalized multiple lesions, and sometimes pancytopenia.
EG is characterized by a single or multiple skeletal lesions, and it predominantly affects children, adolescents, or young adults. Solitary lesions are more common that multiple lesions. When multiple lesions occur, the new osseous lesions appear within 1-2 years. Any bone and be involved, but the most common sites include the skull, mandible, spine, ribs, and long bones.
-Etiology and Pathogenesis:
EG is a benign disorder that affects children and young adults, particularly males. The solitary bone lesion may be asymptomatic, or it may cause bone pain because of expansion of the medullary bone. Pathologic fractures may ensue. The pathogenesis of LCH is unknown. An ongoing debate exists over whether this is a reactive or neoplastic process. Arguments supporting the reactive nature of this disorder include the occurrence of spontaneous remissions, the failure to detect aneuploidy, metaphase or karyotypic abnormalities, and the good survival rate in patients without organ dysfunction. On the other hand, the infiltration of organs by aberrant cells, a possible lethal evolution, and the cancer-based modalities of successful treatment are all consistent with a neoplastic process. In addition, the demonstration of LCH as a monoclonal proliferation by X chromosome-linked DNA probes supports a neoplastic origin for this proliferation; however, the presence of this finding in distinct subtypes with different evolutions demands further investigations to evaluate its significance.
There is evidence for a role of immune dysfunction in the pathogenesis of LCH by the creation of a permissive immunosurveillance system. Abnormalities of suppressor cell number and function have been documented in several reports. Increased levels of messenger RNA for macrophage colony stimulating factor and platelet derived growth factor have been detected in cells from a pulmonary LCH lesion.
LCH is a rare disease. Estimated annual incidence ranges from 0.5-5.4 per million persons per year. Approximately 1200 new cases per year are reported in the United States. More than half of the patients younger than 2 years, with disseminated LCH and organ dysfunction die of the disease; whereas, unifocal LCH and the majority of cases of congenital self-healing histiocytosis, are self-limited. Multifocal chronic LCH is self-limited in most cases, though increased mortality has been observed among infants with pulmonary involvement. Prevalence of LCH seems to be higher among whites. Incidence of LCH is greater in males than in females (male-to-female ratio 2:1). LCH affects patients from neonates to adults. Age of onset varies according to the variety of LCH. Letterer-Siwe disease occurs predominantly in children younger than 2 years. The chronic multifocal form, including the Hand-Schuller-Christian syndrome, has a peak of onset between 2-10 years of age. Localized eosinophilic granuloma occurs mostly frequently in those aged 5-15 years.
Most patients have no symptoms, and the diagnosis is usually based on radiographic demonstration of a destructive bone lesion arising from the marrow cavity and on characteristic morphologic findings. Localized bone pain and focal tenderness may occur as a result of bone erosion and, rarely, a pathologic fracture. A swelling or mass may be palpable at the site of osseous involvement. Rarely, children may present with fever and leukocytosis. Involvement of the mastoid process involvement may appear with intractable otitis media with a chronic discharge. Mandibular involvement may present with gingival and continuous soft-tissue swelling.
Definite diagnosis is based on biopsy. Because of the absence of distinctive morphologic characteristics of the LCH cell, special studies are used to identify the cell. The Birbeck granule is the distinctive ultrastructural hallmark of the LC. It consists of an intracytoplasmic membranous body, 33 nm wide and 190-360 nm long, possessing a short, rodlike shape with a dotted line down the midline of the space between the membranes (resembling a zipper) and a terminal expansion in the form of a vesicle giving a "racquet" appearance. Although these granules are resistant to destruction by formalin fixation and paraffin embedding, the sensitivity of detection in such specimens is slightly decreased. Birbeck granules are rarely detected in lesions of the liver, gastrointestinal tract, and spleen. Langerhans cells also contain laminated substructures of lysosomes, tuboreticular structures, and trilaminar membranous loops.
The Writing Group of the Histiocyte Society (1987) has proposed 3 levels of certainty in the diagnosis of LCH based on the clinical features, histopathology, and special immunohistochemical techniques. A presumptive diagnosis is based on a typical clinical presentation and light microscopic findings. A designated diagnosis includes light microscopy in combination with positive S-100 and PNA staining studies. To make a definitive diagnosis, identification of Birbeck granules and CD1a antigens is required.
Solitary bone lesions are treated locally with curettage or excision. Painful bone lesions may require intralesional steroid injection (triamcinolone acetonide). Polyostotic bone lesions are best treated with indomethacin or a short course of systemic steroids. Rarely, lesions that are unusually large and painful occur in inaccessible sites or involve vital structures. They require radiation (3-6 Gy [300-600 rads]).
DDX for a lytic skull lesion includes multiple pathologic entities such as cranial fasciitis, eosinophilic granuloma, juvenile fibromatosis, juvenile fibrosarcoma, primary bone neoplasms, hemangioma, epidermoid cyst, metastasis, syphilis, sarcoidosis, tuberculosis, and leptomeningeal cysts.