Atypical Cellular Disorders

Some immunologic diseases are characterized by profound loss or primary dysfunction of a given population of cells. The atypical cellular disorders discussed here all bear some similari-ties in that abnormal proliferations of lympho-cytes and macrophages or dendritic cells result in lymphadenopathy, skin rashes, bone lesions and infiltrations of nearly any other organ system. What are the similarities and the differ-ences between Langerhans cell histiocytosis (LCH), sinus histiocytosis with massive lymphad-enopathy (SHML) or Rosai-Dorfman disease, and Castleman’s disease (CD)? Studies on LCH have some advantages since it was described before the others, and organized clinical trials have been done since the 1980s. The understanding of SHML benefited from a registry maintained by Drs. Rosai and Dorfman. CD was described fifty years ago and for one subtype has the most clearly defined etiology (HHV-8 infection) of the three atypical cellular disorders discussed here. In Section I, Dr. Kenneth McClain examines the unanswered question of whether LCH is a malignant clonal disorder or an inflammatory response triggered by aberrant cytokine expres-sion or a virus. Advocates of the malignant proliferation theory rest their case primarily on the following two points: Clonality of the CD1a+ Langerhans cells was demonstrated by analysis of the human androgen receptor in patients with single bone lesions (Low Risk) or multisystem disease including spleen, liver, bone marrow, or lung (High Risk). Although no consistent chro-mosomal abnormalities have been reported, loss of heterozygosity (LOH) has been defined by comparative genomic hybridization. Those in the “inflammatory response ” camp note that non-clonal proliferation of Langerhans cells in adult pulmonary LCH also have LOH by the same method. The pathologic cells have not been successfully grown in culture or immune-deficient mice and don’t have a “malignant” morphology. While the basic scientific arguments continue, important advances in the treatment of LCH have been made by international collabora-tions of the Histiocyte Society. Risk groups have been clearly defined and the response to therapy after the initial 6 weeks is known to be the strongest prognostic variable for outcome