Contributed by Peter W. Schutz, MD, PhD; Christopher R. Honey, MD, DPhil, FRCS; Stephen Yip, MD, PhD, FRCPC
DIAGNOSIS
Langerhans Cell Histiocytosis (LCH)
DISCUSSION
Langerhans cell histiocytosis is a proliferative disorder of myeloid dendritic cells in association with eosinophils, lymphocytes, macrophages, and neutrophils. It may affect one or multiple organ systems. Case reports exist for involvement of almost all sites in the body. Whereas bone lesions are the most frequent presentation in children, they are less frequent in adults, who more often present with lung involvement. The overall incidence in children is estimated around 1 in 200 000 and in adults somewhat less - but precise numbers are not known owing to the rarity of the diseases and a high rate of suspected underdiagnosis. By the same token, natural history and best treatment in adults are little understood.
In a retrospective review of the International LCH Registry the majority of adults with Langerhans cell histiocytosis presented between the ages of 20-40 years (1). Single system disease was present in about 30 %, with lungs most often affected (50%) followed by bone (40%), and skin (7%). Multiple systems were involved in 70 % of patients at presentation with lung (66 %) and bone (60%) most frequently, and skin, hepatosplenic system, and thyroid less often affected. These numbers may vary somewhat in different retrospective series. However, they illustrate the importance of a systemic work-up after diagnosis of LCH in a single site. Extensive investigations in the present case including PET scan showed no other lesions in the patient at the time of presentation.
Bone involvement in adults most often presents in the skull and mandible, followed by ribs and pelvis, with spinal involvement only rarely seen (7). Clinically, skull lesions often cause swelling and local pain or headache (3, 5, 9, 10, 13, 14). On imaging, lesions are osteolytic with the differential including plasmacytoma, metastatic lesion, fibrous dysplasia, hemangioma, and osteomyelitis. One bone (unifocal) or multiple bones (multifocal) may be involved. Multifocal lesions warrant consideration of systemic therapy (11). Although the present case shows two spatially separated lesions, they both arose in right frontal bone and thus belong to one disease focus.
Histologically, Langerhans cells are characterized by elongated, grooved and folded nuclei, fine chromatin with delicate nuclear membrane, inconspicuous nucleoli, and moderate amounts of cytoplasm. In contrast to dendritic cells, no processes are present on the surface of lesional Langerhans cells. There is a mixed and variable inflammatory background composed of eosinophils, macrophages which may form giant cells, neutrophils, and lymphocytes. Eosinophils may form abscesses with abundant Charcot Leyden crystals. Early lesions show a predominance of Langerhans cells and eosinophils, whereas late lesions show increasing fibrosis and foamy macrophages (8), suggestive of a lesional dynamic that is poorly understood. Histologic diagnosis is confirmed by immunopositivity for CD1a and/or langerin. Diagnosis may also be confirmed by the presence of Birbeck granules upon electron microscopy. These ancillaries allow differentiation from inflammatory processes.
Proliferation of Langerhans cells is thought to represent a clonal expansion. Recently, contributions to the molecular pathogenesis of this expansion suggest that the BRAF V600E mutation may be present in about half of cases (2), and that constitutional Notch activation through Jagged2 may be distinctive of LCH (6). Both insights may create a basis for targeted systemic therapies in the future.
At present, there are no generally accepted treatment standards for LCH bone lesions in adults, and our knowledge of treatment response, relapse rates, and prognosis is limited. Whereas unifocal lesions are often treated surgically, many elect to add prednisone and/or chemotherapy for multifocal and multisystem lesions (11). A recent pilot study suggested that ARA-C may be the chemotherapeutic agent with best effectiveness and risk profile for LCH bone lesions in adults (4). Nevertheless, relapse rates are reported in the range of 30%, regardless of treatment regimen. Prognosis of single system bone disease is generally good with estimated 5-year event-free survival of 100%, as compared to multi-system disease with 92 % and isolated lung disease with 87 % (1).
An incompletely understood phenomenon is the long term development of permanent neuroendocrine or CNS changes in patients with Langerhans cell histiocytosis of craniofacial bones (orbit, temporal, sphenoid, maxillary bones) - but not of bones of the vault. It is estimated that up to 30 % of these CNS-risk patients develop Diabetes insipidus. A recent study of a pediatric case series suggested that there may also be a risk for other intracranial pathologies including neurodegenerative changes on MRI and neurocognitive changes (4, 12). The Histiocyte Society recommends systemic therapy and follow-up with biannual MRI for patients with CNS risk lesions (11). The present patient, however, does not have CNS risk lesions.
Langerhans cell histiocytosis of bone may come to the attention of neuropathologists in the form of cranial vault, craniofacial or spinal lesions in an adult or pediatric patient - the diagnosis has implications for future management and follow up of the patient. Moreover, enrolment of patients in multicenter studies may enhance our understanding of this rare disease.
REFERENCES
Contributed by Peter W. Schutz, MD, PhD; Christopher R. Honey, MD, DPhil, FRCS; Stephen Yip, MD, PhD, FRCPC
International Society of Neuropathology