Postgrad Med J 2000;76:457–465 457 Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from REVIEWS A clinicopathological classification of granulomatous disorders D Geraint James Abstract Granulomatous disorders comprise a large Granulomatous disorders comprise a family sharing the common histological de- large family sharing the histological de- nominator of granuloma formation. Granulo- nominator of granuloma formation. A mas may be confluent or discrete; the degree of granuloma is a focal compact collection of necrosis is variable; the cell components diVer; inflammatory cells, mononuclear cells and the presence or absence of Schaumann predominating, usually as a result of the bodies and of calcification are distinctive. A persistence of a non-degradable product clinicopathological synthesis provides the most and of active cell mediated hypersensitiv- secure foundation. ity. There is a complex interplay between invading organism or prolonged antige- Granuloma formation naemia, macrophage activity, a Th1 cell A granuloma is a focal, compact collection of response, B cell overactivity and a vast inflammatory cells, mononuclear cells pre- array of biological mediators. DiVerential dominating; it is usually formed as a result of the persistence of a non-degradable product of diagnosis and management demand a active hypersensitivity. The granuloma is the Royal Free Hospital skilful interpretation of clinical findings end result of a complex interplay between School of Medicine, and pathological evidence. They are clas- University of London, invading organism or antigen, chemical, drug sified into infections, vasculitis, immuno- Rowland Hill Street, or other irritant, prolonged antigenaemia, London NW3 2PF, UK logical aberration, leucocyte oxidase macrophage activity, a Th1 cell response, B cell deficiency, hypersensitivity, chemicals, Correspondence to: overactivity, circulating immune complexes, Professor James and neoplasia. and a vast array of biological mediators (fig 1). (Postgrad Med J 2000;76:457–465) Areas of inflammation or immunological reac- Submitted 7 July 1999 Accepted 22 November 1999 Keywords: granuloma; Th1 cell; cytokines; neoplasia tivity attract monocyte macrophages which may fuse to form multinucleated giant cells, and a transformation of macrophages to http://pmj.bmj.com/ Antigens epithelioid cells. The granuloma is an active site of numerous enzymes and cytokines, and, with aging, fibronectin and numerous progres- Macrophage CD4 sion factors. There is a close relationship MHC class II ThO between activated macrophages bearing in- Molecules Lymphocyte creased expression of major histocompatibility complex (MHC) class II molecules and CD4+ Th1 lymphocytes. These T helper cells recog- on September 26, 2021 by guest. Protected copyright. IL-6 Costimulator nise protein peptides presented to them by IL-12 IL-4 CD28 antigen presenting cells bearing MHC class II molecules. The T cell induces interleukin-1 on the macrophage and thereafter a cavalcade of Th1 Th2 chemotactic factors promote granulomagen- esis. Interferon gamma (IFN-ã) increases the expression of MHC class II molecules on mac- Activated IL-2 IL-4 rophages, and activated macrophage receptors B cells IFN-γ IL-5 TNF IL-10 carry an Fc fraction of IgG to potentiate their ability to phagocytose. The end result is the Plasma epithelioid granuloma which progresses under cells Exuberant Anergy hypersensitivity, the impact of transforming—and platelet— cell mediated IL-4 derived growth factor towards fibrosis.1–3 Fibrosis immunity Fibroblast T cell activation also requires the B7:CD28/ CTLA:4 costimulatory pathway. With CD28 Macrophage Primed Th1 cells mediated costimulator, there is active T cell Fibrosis proliferation; without it, there is ignorance, Chemokines anergy, and apoptosis.4 Overstimulation of Th1 relative to Th2 cells leads to pronounced cell Granuloma mediated hyperactivity, tissue destruction, and Figure 1 The cytokine network (IFN-ã = interferon gamma; IL = interleukin; MHC = granuloma formation. This is slowed down by major histocompatibility complex; TNF = tumour necrosis factor). B7–1 or B7–2 antagonists. The opposite occurs www.postgradmedj.com 458 James Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from Table 1 Classification of granulomatous disorders (1) Infections (2) Vasculitis (5) Hypersensitivity Pneumonitis Fungi Wegener’s Farmers’ lung Histoplasma Necrotising sarcoidal Bird fanciers’ Coccidioides Churg-Strauss Mushroom workers’ Blastomyces Lymphomatoid Suberosis (cork dust) Sporothrix Polyarteritis nodosa Bagassosis Aspergillus Bronchocentric Maple bark strippers’ Cryptococcus Giant cell arteritis Paprika splitters’ Protozoa Systemic lupus erythematosus CoVee bean Toxoplasma Spatlese lung Leishmania (3) Immunological aberrations Metazoa Sarcoidosis (6) Chemicals Toxoplasma Crohn’s disease Beryllium Schistosoma Primary biliary cirrhosis Zirconium Spirochaetes Hepatic granulomatous disease Silica T pallidum Langerhan’s granulomatosis Starch T carateum Orofacial granulomatosis Talc T pertenue Peyronie’s disease Mycobacteria Blau’s syndrome (7) Neoplasia M tuberculosis Hypogammaglobulinaemia Carcinoma M leprae Histiocytosis X Reticulosis M kansasii Immune complex disease Pinealoma M marinum Dysgerminoma M avian (4) Leucocyte oxidase defects Seminoma BCG vaccine Chronic granulomatous disease of childhood and adults Reticulum cell sarcoma Bacteria Malignant nasal granuloma Brucella Yersinia (8) Miscellaneous infections Whipple’s disease Cat scratch Lymphogranuloma Kikuchi Buruli ulcer when Th2 seems to override Th1 influences. Tropheryma whippeli. Infective causes are sus- There is anergy and apoptosis, which may be pected but not yet established for sarcoidosis, reversed by CD28 agonists. Crohn’s disease, primary biliary cirrhosis, Immunohistochemistry has revealed a con- Kikuchi’s disease, Langerhans’ granulomato- tinuing role for fibronectin, collagen, integrin sis, and chronic granulomatous disease of receptors, and transforming growth factors in childhood. The aetiology, course, prognosis, that slippery road from a healthy granuloma- and treatment of granulomatous infections tous response to irreversible and unchangeable have been reviewed elsewhere.6 The present fibrosis. review draws attention to some which currently give rise to diagnostic confusion. Classification http://pmj.bmj.com/ This large family of granulomatous disorders Mycobacterial infections comprise infections, vasculitis, immunological This large family of mycobacteria is responsi- upsets, leucocyte oxidase defect, hypersensitiv- ble for granulomatous disorders of many ity, chemicals, and neoplasia (table 1). DiVer- diVerent systems (table 3). The invading ential diagnosis and management demand a organism is met by a vigorous cell mediated skilful interpretation of clinical findings and hypersensitivity reaction involving macro- histology5 (table 2). phages, Th1 lymphocytes, and their cytokines. The polymerase chain reaction (PCR) has on September 26, 2021 by guest. Protected copyright. (1) INFECTIONS uncovered mycobacterial DNA in sarcoid Infections are the commonest causes of dis- tissue and mycobacterial RNA has been seminated granulomatous disease (table 2). extracted from sarcoid spleen by liquid phase Some experts regard an infection as the root DNA/RNA hybridisation giving rise to false cause of all such disorders but that it still speculations concerning the aetiology of sar- remains undetected in some; over the past dec- coidosis. ade advances in molecular diagnostic tech- niques have allowed identification of causal Swimming pool (fish tank) mycobacterial organisms that were previously unrecognised. granuloma For instance, cat scratch disease is due to Bar- Mycobacterium marinum causes swimming pool tonella henselae and Whipple’s disease due to (fish tank) granuloma. Although the primary Table 2 Histological comparison of various granulomatous disorders Schaumann Interstitial cellular Mediastinal Features Sarcoid granuloma Necrosis bodies inflammation Cavities Vasculitis adenopathy Sarcoidosis + — +++ ±±—±+ Tuberculosis + ++ Caseation ± — ± + ± + (Primary) Extrinsic allergic alveolitis + (Acute stage) — ± ++ — ++ — Beryllium disease (chronic) + ± ++ ++ — — — Wegener’s granulomatosis ± ++ Infarction — ++ Giant cell ++ ++ Rare Lymphomatoid granulomatosis ± ++ — ++ Immature ±± Rare Bronchocentric granulomatosis + + — Eosinophil ±± Rare Necrotic sarcoidal granulomatosis + ++ — ++ Mature + ++ ± Churg-Strauss granulomatosis ++ ++ — ++ Mature — ++ Rare www.postgradmedj.com Granulomatous disorders 459 Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from Table 3 Granulomatous mycobacterial infections Beware also of sea urchin granuloma of the feet in bathers and fishermen stepping on sea Clinical disorder Common site Mycobacteria urchins. Tuberculosis Lung M tuberculosis Meninges Skin Buruli ulcer Intestine Mycobacterium ulcerans is the cause of Leprosy Skin M leprae chronic, relatively painless, cutaneous Buruli Tuberculoid Nervous system ulcers. The disease is most prevalent in Africa Lepromatous Soft tissues and Australia. The organism causes extensive Bronchopneumonia Lung M avium complex; M kansasii; undermined ulcers on the extensor surface of Lymphadenitis Lymph node M xenopi; M simiae; the extremities. The centres of the ulcers are Osteomyelitis Bone M scrofulaceum; M chelonee; AIDS Joints M malmoense; M fortuitum necrotic, and the edges are undermined; the