A Clinicopathological Classification of Granulomatous Disorders

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 techniques 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 Meninges organisms are usually found at the periphery, Swimming pool and fish tank Skin M marinum or M balneum where granulation tissue is most extensive. granuloma Soft tissues While it is relatively easy to diagnose Buruli Draining lymph nodes skin ulcers on the basis of clinical features and Buruli ulcer Skin M ulcerans Soft tissues histological findings, microbiological identification of the causal mycobacteria may some- times be quite diYcult, requiring long periods skin infection may be inconspicuous, the of culture. Newer techniques such as gas phase draining lymph nodes are extensively involved chromatography are becoming useful for iden- and caseous. A similar microscopic picture, tification of the acid-fast bacilli in low count with conspicuous plasma cell infiltration, is subcultures. associated with granulomas due to other opportunistic mycobacteria. Fish tank granulo- Granulomatous mycoses mas develop in persons with minor abrasions Granulomatous fungal infections mimic sar- who dip their hands in tropical fish tanks. Usu- coidosis worldwide. It is important to recognise ally a solitary granuloma, nodule, or pustule or exclude fungi localised to one system or dis- forms, which may ulcerate or suppurate; but, seminated; in particular, granulomatous fungal multiple lesions may extend along the line of meningitis needs to be distinguished from sar- lymphatic vessels. coidosis by all available techniques (table 4). Biopsy specimens that are cultured on Löwenstein-Jensen medium at room tempera- Whipple’s disease ture yield pigmented mycobacterial colonies in George Hoyt Whipple’s single case report 2–4 weeks. The response to treatment is described a 37 year old medical missionary variable and not dramatic. Antituberculous who presented with fever, polyarthritis, and drugs, cotrimoxazole, and high doses of mino- steatorrhoea.7 It is a chronic multisystem cycline have been advocated. granulomatous disorder aVecting middle aged The development and application of mo- white males, presenting with fever, polyarthri- http://pmj.bmj.com/ lecular techniques such as PCR may in the tis, weight loss, and diarrhoea progressing to future allow more accurate diagnosis. malabsorption. There may be hepatospleno-

Table 4 Granulomatous mycoses

Fungus Clinical diagnosis Immunopathology Method of diagnosis Treatment Nocardia sp Actinomycosis Pneumonia Microscopy Penicillin

Actinomyces sp Granuloma Culture Minocycline on September 26, 2021 by guest. Protected copyright. Fibrosis Coccidioides immitis Coccidioidomycosis Bronchopneumonia Culture Amphotericin B Cavitation CFT Flucytosine Chronic granuloma ELISA Fluconazole Tube precipitin Cryptococcus neoformans Cryptococcosis Pneumonia Microscopy Fluconazole Infarction Culture Amphotericin B Abscess Flucytosine Granuloma ﬁbrosis Candida sp Candidiasis Abscess Microscopy Nystatin Monoliasis Necrosis Culture Amphotericin B Granuloma Sporothrix schenkii Sporotrichosis Granuloma Microscopy, culture Amphotericin B Histoplasma capsulatum Histoplasmosis Pneumonia CFT Amphotericin B Cavitation Microscopy Ketoconazole Granuloma Radioimmunoassay Rifampicin Culture Aspergillus fumigatus Aspergillosis Necrotising granuloma Microscopy Amphotericin B Culture Itraconazole Precipitins Paracoccidioides brasilliense South American blastomycosis Bronchopneumonia Culture Amphotericin B Pulmonary cavities Sputum Flucytosine Exudate → granuloma CFT Sulfadiazine Blastomyces dermatitidis Blastomycosis Microabscess Culture Amphotericin Pneumonia Itraconazole Phialophora sp Chromoblastomycosis Cutaneous granuloma Culture Flucytosine Madurella sp Mycetoma Subcutaneous granuloma Grains in pus Ketoconazole Itraconazole Dapsone

CFT = complement ﬁxation test. ELISA = enzyme linked immunosorbent assay.

www.postgradmedj.com 460 James Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from megaly and generalised lymphadenopathy. Bi- sis, infectious mononucleosis, and non- opsy of lymph node, liver, or small intestine Hodgkin’s lymphoma. A viral aetiology is reveals foci of PAS staining foamy macro- strongly suspected on the basis of clinical phages in all sites. The PAS positive material features, although serological and ultrastruc- within these histiocytes corresponds with lyso- tural studies have not yet identified an somes containing bacilliform bodies. Electron infectious agent.10 microscopy reveals rod shaped bacilli, termed Whipple bacilli or T whippelii or Whipple asso- (2) VASCULITIS ciated bacterial organism.8 The nucleic acids The family of vasculitic granulomatoses com- extracted from an endoscopic biopsy specimen prise Wegener’s granulomatosis, necrotising of the proximal small bowel of a patient with sarcoidal granulomatosis, Churg-Strauss syn- Whipple’s disease has been subjected to nucle- drome, lymphomatoid granulomatosis, polyar- otide sequencing and amplification by the teritis nodosa, bronchocentric granulomatosis, PCR. The resulting PCR product from the giant cell arteritis, and systemic lupus ery- bacterial 16S ribosomal DNA was then the thematosus. They may occasionally be con- subject of a computer database search for the fused with sarcoidosis and hypersensitivity rRNA sequences most similar to it. It showed pneumonitis (extrinsic allergic alveolitis), so a that Whipple bacilli were most likely to belong careful clinicopathological synthesis is essential to the family of Gram positive bacteria of the (table 5). rhodococcus, streptomyces and arthrobacter Granulomatous vasculitis is a small group of genera, and more weakly related to mycobacte- systemic disorders of unknown cause and ria. PCR primers for T whippeli now provide a obscure pathogenesis. It has long been consid- helpful diagnostic technique.9 ered that both humoral and cellular immune mechanisms are involved, and a cascade of Cat scratch disease cytokines may influence their course. The Cat scratch disease or fever is also known as future management may indeed depend upon benign lymphoreticulosis or regional granulo- manipulation of this cytokine network. matous lymphadenitis. It only occurs in humans, especially those who are scratched or (3) IMMUNOLOGICAL ABERRATIONS bitten by kittens and then develop regional The causal agent or antigenic insult remains lymphadenitis proximal to the site of injury. unrecognised in many granulomatous disor- Primary involvement is that of the lymph ders so they are clumsily lumped together as a nodes, which first show lymphoid hyperplasia. group in which an immunological upset plays a Later, scattered granulomas with central areas major part. They are waiting for the cause to be of necrosis coalesce to form abscesses. B hense- found or the immune process better under- lae is the responsible Gram negative bacillus. It stood. Within this category are sarcoidosis, pri- is identified by PCR hybridisation and indirect mary biliary cirrhosis, hepatic granulomatous fluorescent antibody assay. disease, Langerhans’ granulomatosis, orofacial The histopathological features of cat scratch granulomatosis, Peyronie’s disease, Blau’s syn- disease are not diagnostic and may be mistaken drome, hypogammaglobulinaemia, and im- http://pmj.bmj.com/ for tularaemia, lymphogranuloma venereum, mune complex disease. syphilis, brucellosis, atypical mycobacterial infections, fungal infections, and toxoplasmo- Sarcoidosis sis. Warthin-Starry silver staining is used to Sarcoidosis is a multisystem disorder of detect B henselae, which may be present in the unknown cause(s) most commonly aVecting early phase of the disease. A skin test antigen young adults, and frequently presenting with

has been made from lymph node pus. It is hilar lymphadenopathy, pulmonary infiltration, on September 26, 2021 by guest. Protected copyright. inoculated intradermally, and the degree of ocular and skin lesions. The diagnosis is estab- induration and erythema is measured at 48 lished most securely when well recognised hours. clinicoradiographic findings are supported by The cat scratch antigen skin test is positive in histological evidence of widespread epithelioid about 90% of patients who are clinically granuomas in more than one system. Multisys- suspected of having the disease. This test will tem sarcoidosis must be diVerentiated from become redundant when techniques for ampli- local sarcoid tissue reactions. There is imbal- fying specific nucleotide sequences with PCR ance of CDT4:T8 subsets, an influx of Th1 come into general use. There is no well recog- helper cells to sites of activity, hyperactivity of nised response to antibiotics, and recovery B cells, and circulation of immune complexes. usually occurs without treatment. Markers of activity include raised levels of serum angiotensin converting enzyme and Kikuchi’s disease monocyte chemoattractant protein-1; abnor- This disorder was described in 1972 by a Japa- mal calcium metabolism; a positive Kveim- nese pathologist and is characterised by Siltzbach skin test; intrathoracic uptake of lymphadenitis showing focal reticulum cell radioactive gallium; and abnormal fluorescein hyperplasia, nuclear debris, and phagocytosis.9 angiography. Clinically there is localised tender cervical The course and prognosis correlate with the lymphadenopathy with an upper respiratory mode of onset. An acute onset usually heralds prodrome. Most cases occur in women under a self limited course of spontaneous resolution the age of 30 years. Kikuchi’s disease occurs whereas an insidious onset may be followed by world wide and has been often confused with relentless progressive fibrosis. Corticosteroids toxoplasmosis, cat scratch disease, tuberculo- relieve symptoms, suppress the formation of

www.postgradmedj.com Granulomatous disorders 461 Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from granulomas (including Kveim-Siltlzbach granulomas), and normalise both levels of serum angiotensin converting enzyme and the uptake of gallium. A synthesis of clinical features, radiology, histology, biochemical changes, and immunological abnormalities helps to distinguish it from non-speciﬁc local

lupus pernio and SURT sarcoid tissue reactions. Sarcoidosis Inconspicuous Tumour necrosis factor alpha (TNF-á)isa proinﬂammatory cytokine widely recognised and implicated in inﬂammatory disorders including sarcoidosis. It is inhibited by tumour necrosis factor receptor (TNF-R) which is recognised in two forms p55 (CD120a) and p75 (CD1206) receptors. This TNF-TNF-R bal- ance in favour of inhibition may represent a homoeostatic mechanism which protects the patient from excessive TNF production in sarcoidosis. TNF-R p55 is increased in stage I more than stage II/III sarcoidosis, suggesting that homoeostasis is responsible for a more Bronchocentric granulomatosis Asthma No asthma Bronchial obstruction Eosinophilia Eosinophilia ±± benign outcome at this early stage of sarcoidosis.11

Crohn’s disease The commonest cause of granulomatous inflammation in the gastrointestinal tract is Crohn’s disease. This reaction seems to centre Necrotising sarcoid granulomato sis on the blood vessels of the intestinal wall causing multifocal gastrointestinal infarction. There may be associated lung changes, including pulmonary vasculitis, granulomatous interstitial lymphocytic infiltration, alveolitis, and interstitial fibrosis. Alveolar macrophages may

Churg-Strauss syndrome show an increased spontaneous superoxide anion production. An increase in CD4 cells is found in bronchoalveolar ﬂuid and even in sputum. Serum antibody increases include antireticulin antibody, antisaccharomyces cer- evisiae antibody (ASCA), and p-antineutrophil http://pmj.bmj.com/ cytoplasmic antibody (ANCA). There is con- cordance between ASCA and p-ANCA. ASCA occurs in up to 60% of patients, particularly with familial Crohn’s disease; and ASCA is Lymphomatoid granulomatosis Arthralgia− −−+ +− Very rare Malaise Infrequent Always + + Always evident in 20% of ﬁrst degree relatives.51213

Primary biliary cirrhosis (PBC) on September 26, 2021 by guest. Protected copyright. PBC is a chronic non-suppurative destructive cholangitis14 in which epithelioid granulomas are in close association with bile ducts. It predominates in women of the reproductive years of age and it is distinguished by the presence of serum mitochondrial antibodies. It is classiﬁed as an autoimmune disorder and over- laps with other autoimmune disorders including Sjogren’s syndrome, rheumatoid arthritis, the calcinosis Raynaud oesophagus sclero- derma telangiectasia (CREST) syndrome, scle- Wegener’s granulomatosis Classic Limited RhinorrhoeaEpistaxis±± DyspnoeaANCA Haemoptysis±± Steroids Asthma Pneumonia Pleurisy Cough Asathioprine Dyspnoea Azathioprine Pleurisy Azathioprine Azathioprine

inconspicuous. roderma, and systemic lupus erythematosus. ± Cholangiocyte apoptosis is responsible for bile duct destruction due to aberrant expression of the major autoantigen, the E2 subunit of the pyruvate dehydrogenase complex. There is some evidence that PBC with high titres of antinuclear antibodies progress slower and result in a better prognosis than those with low V erential diagnosis of pulmonary granulomatous vasculitis titre or negative antinuclear antibodies. PBC histology may be granulomatous or alternatively eosinophilic. Could this be due to OpacitiesCavitation + ++ + + + + Infiltration + + + Pulmonary fibrosis Particularly is upper lobes Infiltration + Features F:MDecade of incidencePresentationUlcerated nose and nasal septumSaddle nose 50Chest + radiography Hilar Sinusitis adenopathyKidneys M > FOcularAllergy Skin lesionsCentral nervous systemCardiacCharacteristics 50 −Granulomas + +VasculitisNecrosis + EqualTreatment Glomerulonephritis in 85%Prognosis + 30–50 + − − ESR Cough M slightly more frequent + Same − ++ Renal vasculitis Prominent Cyclophosphamide and resemble infarcts − 50 Guarded Bronchitis − − − Same − − − − + Prominent Fever 30 ++ and − 40 + − Same Cyclophosphamide − − − Asthma 30 Prominent Always − Steroids Poor Rare Same Prominent − Bronchiectasis + Cough Eosinophilia − Steroids − Same 60 Always − + Rare − − Insignificant symptoms Corticosteroids Poor − − 30 and 40 ++ − − Only when − associated with − Hypersensitivity + to aspergillus Good − Nephrocalcinosis − Steroids Raised SACE Inconspicuous − − − Good − − + + − + + Good + Table 5 Di ANCA: antineutrophil cytoplasm autoantibody; ESR = erythrocyte sedimentation rate; SACE = serum angiotensin converting enzyme; SURT = sarcoidosis upper respiratory tract. + Present, ++ prominent, − absent, the predominant influence of either the Th1

www.postgradmedj.com 462 James Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from cytokine cascade producing granulomas or the X bodies (Birbeck granules) in macrophages. Th2 cascade causing an eosinophilic response? Langerhans’ or X bodies are an ultrastructural The aetiology of PBC remains unknown. feature in 90% of patients. They are identical to There are similarities between Escherichia coli the granules in Langerhans’ epidermal cells and mitochondrial components; cross reactiv- and consist of intracytoplasmic rod, plate, or ity between bile duct mitochondria and bacte- cup-like pentalaminar structures. The presence ria is a possibility. An increased incidence of of these tennis racket shaped ultrastructural Gram negative urinary tract infections is Birbeck granules is diagnostic of the disorder. recognised in PBC. It has been likened to the They have surface adenosine triphosphate chronic graft-versus-host rejection with similar activity identifiable by gold fluorescence. These structural change in the bile ducts, lacrimal and diagnostic cells are readily found by broncho- pancreatic ducts, which have a high concentra- alveolar lavage, and this technique may make tion of HLA class II antigens on the epithelial lung biopsy unnecessary. It may also be a likely surface. means of detecting a possible causal agent in AdiVerential diagnosis of some hepatic the future. granulomatous disorders is appended (table 6). Orofacial granulomatosis (Melkersson-Rosenthal Langerhans’ cell granulomatosis syndrome) The term Langerhans’ cell granulomatosis This is a rare granulomatous disorder of the refers to proliferative disorders of histiocytes, mouth and adjacent tissues, involving the oral previously referred to as histiocytosis X. It mucosa, gum, lips, tongue, pharynx, eyelids, encompasses a group of disorders of unknown and skin of the face. aetiology characterised by granulomatous infil- Melkersson described an association be- tration of the lungs, bone, skin, lymph nodes, tween facial oedema and facial paralysis.16 and brain.515The clinical conditions have been Rosenthal added the features of lingua plicata known by several names, based on the type of or scrotal tongue.17 Other clinical features presentation, sites of involvement, rate of include granulomatous cheilitis, oedema of the progression, and degree of associated immune gums and scalp, salivary gland dysfunction, dysfunction. They include eosinophilic granu- granulomatous blepharitis, trigeminal neural- loma, Letterer-Siwe disease, and Hand- gia, Raynaud’s phenomenon, and even chronic Schüller-Christian disease. They are diVerent hypertrophic granulomatous vulvitis.18 19 Pa- expressions of the same basic disorder, in tients with this disorder do not have chest which the proliferation of Langerhans’ cells radiography changes, nor uveitis; and the results from disturbances in immunoregula- Kveim-Siltzbach skin test is negative. This rare tion. disorder may be immunologically mediated for Langerhans’ histiocytes are bone marrow the T cell receptor B (TCRVB) repertoire is derived monocyte macrophage cells; they restricted.20 This is evident in oral mucosal include Langerhans’ epidermal cells, KupVer’s lymphocytes, and it is associated with a local T cells in the liver, osteoclasts, and alveolar mac- cell clonal expansion. These features suggest a rophages. They are human leucocyte antigen delayed type reaction in response to an http://pmj.bmj.com/ DR positive functioning macrophages that unknown antigen. Local cytokine release may present antigen to T cells and play a part in cell be responsible for the granulomatous reaction. mediated immunity. Unlike histiocytes, Lang- erhans’ cells can be stained immunohisto- Blau’s syndrome chemically for S-100 protein and OKT-6. Edward Blau is a Wisconsin paediatrician who Lung biopsy reveals a mixed cellular exu- described a multisystem granulomatous dis-

date, foam cells, eosinophils, and characteristic ease of the skin, eyes and joints, resembling on September 26, 2021 by guest. Protected copyright. childhood sarcoidosis.21 The histology may be Table 6 DiVerential diagnosis of some diseases with hepatic granulomas indistinguishable so paediatricians should be aware of significant diVerences between the Disease Diagnostic aids two disorders. The most frequent manifesta- Sarcoidosis Chest radiograph; Kveim; SACE tion is swelling of the wrists, fingers, ankles, and Bronchoalveolar lavage elbows in the first decade of life. Because of the Tuberculosis Tuberculin skin test granulomatous histology of synovial tissue, it Bronchoalveolarlavage Acid-fast staining may be misdiagnosed as tuberculosis of bone. Isolation organism There may be progression of flexion contrac- Brucellosis Blood culture tures of joints (campodactyly) due to post- Agglutinin titre Berylliosis Industrial exposure inflammatory fibrotic scarring at insertion Chest radiograph points of finger and toe flexor tendons. There is Syphilis Treponema test a granulomatous red papular eruption of the Leprosy Race; lepromin skin test Histoplasmosis Complement fixation test skin with a butterfly distribution on the face. It Chest radiograph coincides with exacerbations of the granuloma- Infectious Blood film, monospot, IgM mononucleosis Epstein-Barr antibodies tous iritis. AIDS Poorly formed granulomas Blau’s syndrome is a multisystem disorder in Acid-fast and fungal stains which there is no lung involvement; this may be HIV test Primary biliary Mitochondrial antibody an important diVerence from other granuloma- cirrhosis tous disorders. Lymphomas Chest radiograph; lymph node biopsy The granulomas of Blau’s syndrome are Computed tomography indistinguishable from those of sarcoidosis by SACE = serum angiotensin converting enzyme. light microscopy or by immunocytochemistry.

www.postgradmedj.com Granulomatous disorders 463 Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from However asteroid, Schaumann and conchoid Thrasher et al used an adenovirus vector bodies, organisms, calcification and crystalline expressing p47-phox to transduce patients’ inclusions, necrosis and fibrin deposition are defective monocytes.23 Nitroblue tetrazolium absent. staining indicated that NADPH oxidase activity was restored to those cells. This technique Granulomatous hypogammaglobulinaemia oVers a rapid means for molecular diagnosis On rare occasions, one wonders whether the and points to a therapeutic future of gene patient has hypogammaglobulinaemia or sar- transduction. coidosis or both. Confusion arises since both conditions may present with multisystem Chronic granulomatous disease in adults (CGD) granulomas, hypersplenism, and poor cellular Chronic granulomatous disease is being recog- immunity. The hypogammaglobulinaemia may nised more commonly in adults. Although it is be selective IgA deficiency or a more wide- still rare it should be excluded in adults with spread deficiency of IgA, IgG, and IgM. There unexplained granulomas or infections.24 Anti- is bedside clinical evidence of loss of both B biotic prophylaxis and the use of IFN-ã has and T lymphocyte function, which is also allowed children, mostly with reduced gp91- evident by in vitro lymphoproliferative assays. phox (X91-CGD), to present for the first time in young adult life. The NBT is insuYcient as (4) LEUCOCYTE OXIDASE DEFECTS a screening test for it may give values close to Killing of bacteria depends on a burst of respira- normal in adults. It should be complemented tory enzyme activity which leads to the produc- by chemoluminescence or cytochrome b re- tion of hydrogen peroxide and superoxide in duction. This is important because of the ben- phagocytes. Neutrophils in chronic granuloma- efits of earlier diagnosis and treatment, infec- tous disease of childhood (CGDC) are unable to tion prophylaxis, and genetic counselling. kill some ingested bacteria because they are deficient in enzymes needed for this superoxide (5) HYPERSENSITIVITY PNEUMONITIS (EXTRINSIC respiratory burst. These defective enzymes may ALLERGIC ALVEOLITIS) be nicotinamide adenine dinucleotide phos- Repeated inhalation of various antigens may phate (NADPH) oxidase, myeloperoxidase, provoke a granulomatous inflammatory re- cytochrome B, pyruvate kinase, glucose-6- sponse in the bronchoalveolar spaces and phosphate dehydrogenase, or the lack of lys- interstitium giving rise to a family of pulmo- ozyme or lactoferrin, each perhaps contributing nary disorders termed hypersensitivity pneu- adiVerent clinical profile. The classical X linked monitis or extrinsic allergic alveolitis. The best disorder occurs in boys aged about 5 years, pre- recognised members of the family are farmers’ senting with hepatosplenomegaly, generalised lung, pigeon breeders’ lung, and humidifier lymphadenopathy, weeping granulomatous skin fever. The clinical picture may be acute and lesions, and diVuse miliary lung infiltration. The explosive, subacute and insidious, or chronic history is of multisystem sarcoid granulomas. and protracted; cough and dyspnoea on There is more than one X linked form and also exertion, fatigue, and weight loss are common. more than one autosomal recessive variety, for The end stage is characterised by irreversible http://pmj.bmj.com/ there is more than one mechanism for initiating restrictive lung function and cardiac failure. oxidative metabolism.22 Patients with CGDC Pathogenesis involves a complex interplay of suVer from infections with catalase-producing circulating immune complexes, immediate staphylococci and enterobacteria. Organisms hypersensitivity, and exuberant cell mediated that lack catalase supply the neutrophil with the immunity. The diagnosis is established by a hydrogen peroxide for their own destruction. history of occupational exposure; suggestive

Thus catalase negative organisms, such as pneu- clinical and radiological changes; and demon- on September 26, 2021 by guest. Protected copyright. mococci or streptococci, present no problem to stration of precipitating serum antibodies. Mid these patients. Neutrophil leucocytes of normal to late inspiratory crackles and the absence of patients with bacterial infections reduce nitro- finger clubbing are notable features. An blue tetrazolium from colourless to form blue- increase in CD8+ T cells in bronchoalveolar black formazan granules in the cytoplasm. This fluid is also noteworthy. fails to occur in the leucocytes of CGDC children or in the mothers of the X linked vari- (6) CHEMICALS ety. The X linked variety is due to mutations in There are four granuloma forming chemicals: the gene for the gp 120-phox subunit of the beryllium, zirconium, silica, and talc.513 phagocyte cytochrome b, an essential compo- Beryllium disease mainly aVects the lungs nent of superoxide-generating NADPH oxidase. following inhalation of soluble, finely particu- Most patients have undetectable levels of late beryllium and its salts. Direct implantation cytochrome b and no phagocyte NADPH may also give rise to skin ulcers and nodules. oxidase activity. This gives rise to life threatening Pulmonary disease may be acute or chronic bacterial and fungal infections in infancy. Some (CBD); the former is a chemical pneumonitis patients have a milder course because they retain after massive exposure to fumes whereas CBD some cytochrome NADPH oxidase activity. is a chronic granulomatous disorder. It is due IFN-ã has proved helpful in enhancing host to occupational exposure in a variety of indus- defences and thereby reducing the incidence of trial processes, alloy workers, ceramic workers, life threatening infections, particularly those and in space and atomic engineers. The respi- infections characterised by persistence in mac- ratory symptoms are in keeping with diVuse rophages (toxoplasmosis, leishmaniasis, and and nodular fibrosis of the lungs, with pleural mycobacteriosis).9 thickening and late cystic changes. The granu-

www.postgradmedj.com 464 James Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from loma contains a variety of inclusion bodies, (8) MISCELLANEOUS Schaumann and asteroid; they are end prod- Granulomatous angiitis ucts of the actively secreting epithelioid cells. Granulomatous angiitis is a multifocal chronic Diagnostic criteria include history of exposure; inflammatory disorder in which magnetic reso- consistent clinicoradiological features, granulo- nance imaging may show multiple discrete matous histology, and tissue analysis for beryl- granulomas. The initial diagnosis may suggest lium. an infection, such as tuberculosis or toxoplasmosis, or alternatively intravascular lympho- Zirconium matosis. This chemical was recognised as a cause of deodorant axillary granulomas in sensitised Granuloma annulare individuals. A 1:10 000 solution of zirconium These skin lesions may be single, multiple, or chloride or nitrate inoculated intradermally disseminated with flat centre and a well deline- produced a palpable nodule, which, on biopsy, ated edge. The histology is of a necrobiotic area revealed sarcoid tissue. This was specific for with palisading granulomas in giant cells. A zirconium hypersensitivity. This skin test is similar histological reaction may be seen in very similar to the Kveim-Siltzbach skin test for rheumatoid disease and with a ruptured sarcoidosis. Zirconium is no longer in deodor- sebaceous cyst. ants so these axillary granulomas are no longer Actinic granuloma seen. However it is of some academic interest This disfiguring condition is a granulomatous that there are four granulomatous disorders in reaction to excessive sun exposure. There is which skin tests behave in this peculiar fashion, debate whether it is a distinct clinicopathologi- mimicking the Kveim-Siltzbach test. The other cal entity or a variant of granuloma annulare or two were the beryllium patch test and the Mit- multiforme and necrobiosis lipoidica. Treat- suda skin test in lepromatous leprosy. ment with isotretinoin has prevented development of new granulomas and produced almost Silicosis complete resolution of established lesions. Inhalation of pure silica may be followed by dense nodular and rarely diVuse pulmonary Granulomatous rosacea fibrosis. The silica granuloma is readily identi- Rosacea has been described as the curse of the fied by the presence of crystalline birefringent Celts.25 It is commoner in women, aged 30 to crystals in macrophages with foreign body 50 years. There is a background diathesis of rather than Langhans-type giant cells. flushing and blushing, upon which develops erythema, papules, pustules, telangiectasia, Pulmonary talc granulomatosis furuncles on the face, neck and v-shaped area This is due to the inhalation of talc in the form of the chest. Granulomatous or lupoid rosacea of talcum powder or by prolonged repeated nodules may also involve the lower eyelids. intravenous administration of pentazocine Histology reveals perifollicular and perivascu- (75% talc). lar granulomas; it needs to be distinguished http://pmj.bmj.com/ from micronodular sarcoidosis, particularly since both conditions may be associated with (7) NEOPLASIA iritis and conjunctivitis. Minidose isotretinoin, There is often a granulomatous component in 2.5 mg to 5 mg daily, oral tetracycline, or met- malignant disease. Sarcoid granulomas may be ronidazole may be helpful for lupoid rosacea. found in various tumours and in their draining lymph nodes, particularly those draining carci- Other

noma of the lung, stomach, and uterus. They Do not be surprised if the histological report of on September 26, 2021 by guest. Protected copyright. may also be found in tumours that have been a removed sebaceous cyst indicates a granu- treated by radiotherapy or chemotherapy, since loma. The same granulomatous reaction oc- treatment may produce a granulomagenic sub- curs in chalazion, dermoid, panniculitis, sea stance which spreads to draining lymph nodes. urchin spine injury, tattoos, or malakoplakia. It There is diagnostic confusion between sar- indicates a vigorous macrophage Th1 reaction coidosis and Hodgkin’s disease, in which multi- to the antigenic insult, involving cytokines and system granulomas are also observed. The dif- other biological mediators (fig 1). It indicates a ficulty usually arises in the interpretation of good defence and a satisfactory outcome small specimens of aspiration liver biopsies, or against the antigenic aggression. the occasional patient in whom the spleen is replaced by sarcoid tissue obliterating tumour 1 James DG. What makes granulomas tick? Thorax 1991;46:734–6. tissue. Intrathoracic Hodgkin’s disease most 2 James DG.Granuloma formation signifies a Th1 cell profile. frequently aVects the upper mediastinum Sarcoidosis 1995;12:1–3. 3 Roman J, Leon YJ, Gal A, et al. Distribution of extracellular rather than hilar lymph nodes, and it is matrices, matrix receptors, and transforming growth predominantly unilateral. The hilar nodes tend factor-1 in human and experimental living granulomatous inflammation. Am J Med Sci 1995;309:124–33. to fuse with the right cardiac border whereas in 4 Reiser H, Stadecker MJ. Costimulatory B7 molecules in the sarcoidosis they stand away from the cardiac pathogenesis of infectious and autoimmune diseases. N Engl border. Both disorders show depression of cell JMed1996;335:1369–77. 5 James DG, Zumla A. The granulomatous disorders. mediated immunity. In Hodgkin’s disease, the Cambridge: Cambridge University Press, 1999. Kveim-Siltzbach test is negative and serum 6 Zumla A, James DG. Granulomatous infections: etiology and classification. Clin Infect Dis 1996;23:146–58. angiotensin converting enzyme levels are raised 7 Whipple GH. A hitherto undescribed disease characterised in only about 10% of patients, compared with anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Johns Hopkins Hospital 60% in sarcoidosis. Bulletin 1907;18:382–91.

www.postgradmedj.com Granulomatous disorders 465 Postgrad Med J: first published as 10.1136/pmj.76.898.457 on 1 August 2000. Downloaded from 8 Spapen HDM, Segers O, DeWit N. Electron microscopic 17 Rosenthal C. Facialislahmung und lingua plicata. Z Neurol detection of Whipple’s bacillus in sarcoidlike periodic acid- Psychol 1930;131:475–501. SchiV-negative granulomas. Dig Dis Sci 1989;34:640–3. 18 Wiesenfeld D, Ferguson MM, Mitchell DN, et al. Oro-facial 9 Kikuchi M. Lymphadenitis showing focal reticulum cell granulomatoses. A clinical and pathological analysis. QJ hyperplasia with nuclear debris and phagocytosis. Nippon Med 1985;54:101–13. Ketsueki Gakkai Zassi 1972;35:378–80. 19 Larsson E, Westmark P. Chronic hypertrophic vulvitis—a 10 Kuo TT. Kikuchi’s disease (histiocytic necrotising lymphadenitis). A clinicopathological study of 79 cases with an condition with similarities to cheilitis granulomatosa. analysis of histologic subtypes, immunohistology, and DNA (Melkersson-Rosenthal syndrome). Acta Derm Venerol ploidy. Am J Surg Pathol 1995;7:798–809. (Stockh) 1978;58:92–3. 11 Armstrong L, Foley NM, Millar AB.Inter-relationship 20 Lim SH, Stephens P, Cao QK, et al. Molecular analysis of T between tumour necrosis factor-alpha (TNF-á) and soluble cell receptor variability in a patient with orofacial granulo- receptors in pulmonary sarcoidosis. Thorax 1999;54:524– matosis. Gut 1997;40:683–6. 30. 21 Blau EB. Familial granulomatous arthritis, iritis and rash. J 12 Vermeire S, Peeters M, Joossens S, et al. The value of Pediatr 1985;5:689–93. anti-saccharomyces cerevisial antibodies (ASCA) as clinical 22 Curnette JT. Chronic granulomatous disease: the solving of marker in Crohn’s disease (CD). Gastroenterology 1999;116: a clinical riddle at the molecular level. Clin Immunol Immun- abstr 3647. opathol 1993;67:S2–15. 13 James DG, Jones Williams W. Sarcoidosis and other 23 Thrasher AJ, Casimir CM, Kinnon C, . Gene transfer to Philadelphia: WB Saunders, 1985. et al granulomatous disorders. primary chronic granulomatous disease monocytes. 14 Sherlock S, Dooley J. Diseases of the liver and biliary system. Lancet 10th Ed. Oxford: Blackwell, 1997: 461. 1995;346:92–3. 15 Hance AJ, Candranel J, Soler P, et al. Pulmonary and extra- 24 Schapiro BL, Newburger PE, Klempner MS, et al. Chronic pulmonary Langerhans’ cell granulomatosis (histiocytosis granulomatous disease presenting in a 69 year old man. N X). Semin Respir Med 1988;9:349–68. Engl J Med 1991;325:1786–90. 16 Melkersson E. U fall au recidiverande facialispares. Hygiea 25 Jansen T, Plewig G. Rosacea: classiﬁcation and treatment. J 1928;90:737–41. R Soc Med 1997;90:144–50. http://pmj.bmj.com/ on September 26, 2021 by guest. Protected copyright.