Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granulomatous inflammation in many tissues and organs. We discuss it here because one presentation of sarcoidosis is as a restrictive lung disease. Other diseases, including mycobacterial or fungal infections and berylliosis, sometimes also produce noncaseating granulomas; therefore, the histologic diagnosis of sarcoidosis is one of exclusion. Although sarcoidosis can manifest in many different ways, bilateral hilar lymphadenopathy or lung involvement (or both), visible on chest radiographs, is the major finding at presentation in most cases. Eye and skin involvement each occurs in about 25% of cases, and either may occasionally be the presenting feature of the disease.
Sarcoidosis occurs throughout the world, affecting both genders and all races and age groups. There are, however, certain interesting epidemiologic trends:
A consistent predilection for adults younger than 40 years of age.
A high incidence in Danish and Swedish populations, and in the United States among African Americans (in whom the frequency is 10 times higher than in whites).
A higher prevalence among nonsmokers, an association that is virtually unique to sarcoidosis among pulmonary diseases.
Although the etiology of sarcoidosis remains unknown, several lines of evidence suggest that it is a disease of disordered immune regulation in genetically predisposed individuals exposed to certain environmental agents. The role of each of these contributory influences is summarized in the following discussion.
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Several immunologic abnormalities in sarcoidosis suggest the development of a cell-mediated response to an unidentified antigen. The process is driven by CD4+ helper T cells. These immunologic “clues” include the following:
Intraalveolar and interstitial accumulation of CD4+ TH1 cells, with peripheral T cell cytopenia
Oligoclonal expansion of CD4+ TH1 T cells within the lung as determined by analysis of T cell receptor rearrangements
Increases in TH1 cytokines such as IL-2 and IFN-γ, resulting in T cell proliferation and macrophage activation, respectively
Increases in several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein-1α) that favor recruitment of additional T cells and monocytes and contribute to the formation of granulomas
Anergy to common skin test antigens such as Candida or purified protein derivative (PPD)
Familial and racial clustering of cases, suggesting the involvement of genetic factors
After lung transplantation, sarcoidosis recurs in the new lungs in at least one-third of patients, but without any effect on survival. Finally, several putative “antigens” have been proposed as the inciting agent for sarcoidosis (e.g., viruses, mycobacteria, Borrelia, pollen), but there is no “smoking gun” linking sarcoidosis to any specific antigen or infectious agent.
MORPHOLOGYThecardinalhistopathologicfeatureofsarcoidosis,irrespectiveoftheorganinvolved,isthenonnecrotizing epithelioid granuloma (