Brain Pathology Case of the Month - February 2002

FINAL DIAGNOSIS:    Langerhans' cell histiocytosis.


The histologic examination of this case shows typical features of Langerhans' cell histiocytosis. There is an atypical population of Langerhans' cells admixed with acute and chronic inflammatory cells. These large atypical cells often have deep grooved nuclei and are frequently nicknamed "coffee bean" nuclei. These atypical cells also share typical immunohistochemical features with Langerhans' cells and express CD1a and S100. The multinucleated giant cells, however, express features of macrophages and are positive for CD68 but negative for CD1a. The amount of eosinophils is not overwhelming but Langerhans' histiocytosis without eosinophils have been reported (1). The demonstration of Birbeck granules supported the presence of Langerhans' cells in this lesion. The minor trauma sustained by the patient probably produced a pathologic fracture of the lesion and this also explained the unusually high amount of osteoclast-like giant cells in this case.

Langerhans' cell histiocytosis (histiocytosis X) is a clonal proliferative disorder (2) of the antigen presenting Langerhans' cell (3). Local proliferation at the lesion sites has been shown by immunostaining for Ki-67 (4). Typically, the Langerhans' cells are admixed with a mixed population of acute and chronic inflammatory cells. The Langerhans' cells express CD1a and S100 (4,5,6). Demonstration of Birbeck granules that are characteristically 34 nm wide rod-shaped pentalaminar tubular structures with characteristic periodicity, a zipper-like central core, and a dilated end bulb, provides solid strong morphologic evidence on their Langerhans' cell origin (6). Birbeck granules, interestingly, are not real granules, but cytoplasmic invaginations of the cell surface membrane within the cytosol that are not associated with other organelles or the nuclear envelope (7).

Langerhans' histiocytosis is an all-encompassing term that covers the formerly known clinicopathologic entities of histiocytosis X that includes Lettere-Siwe disease, Hand-Schüller-Christan, disease, and eosinophilic granulomas. Based on the clonal proliferative properties of Langerhans' cell histiocytosis, it should be classified as a neoplastic disease. Langerhans' cell histiocytosis typically affects young patients and almost half of the cases occur under ten years of age. The skull and femur are most commonly involved. When the skull is involved, the orbit and the cranial base are frequently involved and produce the classic triad of bony defects, exophthalmos and diabetes insipidus. The cranial base involvement may extend into the brain and involve the hypothalamus. Involvement of other parts of the brain has also been reported.


  1. Papasozomenos SC . Hypothalamic Langerhans cell histiocytosis with no eosinophils. Clin Neuropathol 1999 Sep-Oct;18(5):260-4
  2. Willman CL, Busque L, Griffith BB, Favara BE, McClain KL, Duncan MH, Gilliland DG. Langerhans'-cell histiocytosis (histiocytosis X)- a clonal proliferative disease. N Engl J Med 1994 331:154-60
  3. Emile JF, Fraitag S, Leborgne M, de Prost Y, Brousse N . Langerhans' cell histiocytosis cells are activated Langerhans' cells. J Pathol 1994 174:71-6
  4. Hage C, Willman CL, Favara BE, Isaacson PG . Langerhans' cell histiocytosis (histiocytosis X): immunophenotype and growth fraction. Hum Pathol 1993 24:840-5
  5. Emile JF, Wechsler J, Brousse N, Boulland ML, Cologon R, Fraitag S, Voisin MC, Gaulard P, Boumsell L, Zafrani ES . Langerhans' cell histiocytosis. Definitive diagnosis with the use of monoclonal antibody O10 on routinely paraffin-embedded samples. Am J Surg Pathol 1995 19:636-41
  6. Mireau GW, Favara BE. S-100 protein immunohistocyemistry and electron microscopy in the diagnosis of Langerhans cell proliferative disorders: a comparative assessment. Ultrastruct Pathol 1986 10:303-309
  7. Hashimoto K. Lanthanum staining of Langerhans cell. Communication of Langerhans' cell granules with extracellular space. Arch Dermatol 1970 102:280-290.

Contributed by Kar-Ming Fung, MD, PhD, Jason M Schwalb, MD, Howard A Riina, MD, Jasvir S Kurana, MD, Justina M Mindaxy, MS, M. Sean Grady, MD, Ehud Lavi, MD

International Society of Neuropathology