editorial - thorax

Thorax 1982;37:81-87

EditorialVasculitis and granulomatosis of the respiratory tract

In 1973 Liebowl grouped together a number ofdiseases under the heading of pulmonary angiitisand granulomatosis. These conditions, of whichWegener's granulomatosis is the most familiar, arecharacterised by chronic inflammation, granulomaformation, vasculitis, and necrosis. The lungs areprimarily affected, but other organs may be involved.Because their clinical and radiological manifesta-tions are similar, they are frequently confused, notonly with each other but also with unrelated diseases.Furthermore, they are rare and experience in theirdiagnosis and management is limited: there has beenlittle opportunity for the type of multidisciplinaryapproach which has, for instance, solved so many ofthe problems of glomerular disease.

Since Liebow's paper was published there havebeen significant advances in the treatment of thesedisorders, and new facts about their aetiology andtheir relationship to other diseases have emerged.The purpose of this editorial is to discuss the conceptof pulmonary vasculitic and granulomatous diseasein the light of more recent knowledge, to outlinecurrent trends in management, and to indicate theareas in which further investigation is needed.

Classification

The diseases at present classified as pulmonaryvasculitis and granulomatosis are as follows :1-4classical Wegener's granulomatosis; limited Wegen-er's granulomatosis; lymphomatoid granulomatosis;Churg-Strauss syndrome; necrotising sarcoidgranulomatosis; bronchocentric granulomatosis.The aetiology of most of these conditions is

unknown or uncertain, and they must therefore begrouped according to their clinical and morphologi-cal features. The classification given here is con-venient, and forms a useful basis for diagnosis. Butit has no pathogenetic implications. The lung can6nly react to damage in a limited number of ways,and in fact each of these entities may have severaldifferent causes.

Address for reprint requests: Dr CW Edwards, Departmentof Histopathology, East Birmingham Hospital, BordesleyGreen East, Birmingham.

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Definitions, clinical features, and pathology

CLASSICAL WEGENER S GRANULOMATOSISSince Wegener's granulomatosis was first de-scribed in the nineteen thirties,5-7 numerous papersdealing with its clinical features, pathology, andtreatment have appeared.8-19 It is characterised by adiagnostic triad consisting of granulomatous vascu-litis of the upper and lower respiratory tract, ageneralised small vessel vasculitis, and focal glomeru-lonephritis.9 The sexes are affected equally, with apeak incidence in the fifth decade. Untreated patientsdie in about five months, usually of renal failure.8-10The initial lesions almost always occur in the

respiratory tract.16 20 Upper respiratory tract mani-festations start as a persistent "cold", with rhinor-rhoea, epistaxis, and sinusitis.19 Later there isobstruction and ulceration of the nose and naso-pharynx, perforation of the nasal septum, saddle nosedeformity, and eventually horrific destruction ofmid-facial structures.

In 95% of patients the lungs are involved.1620Radiological changes are impressive, but signs andsymptoms are often minimal. Main complaints areof chest pain, cough, and haemoptysis. Pneumo-thorax, hydropneumothorax, and bronchopleuralfistula have been described,2122 but clinical examina-tion of the chest is usually unrewarding. Radiographsreveal a constantly changing pattern of opacities,predominantly in the lower lung fields.21-26 Cavita-tion is frequent. Occasionally there is a reticulo-nodular pattern, or pleural thickening and effusion,22and endobronchial extension leads to segmentalcollapse in some cases.2126 Hilar and mediastinallymph node enlargement is rare. Respiratoryfunction tests indicate obstructive and restrictivedefects, and less commonly a reduction in diffusingcapacity.27

Focal glomerulonephritis occurs in 85 o ofpatients,20 often at a late stage. Hypertension israre,8 and clinical manifestations of renal involve-ment are uncommon in the early stages, althoughsome cases may present as Goodpasture's syn-drome.28

Classical Wegener's granulomatosis is a multi-system disease, and structures other than the

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respiratory tract and kidneys are frequently involved.Patients often complain of systemic symptoms suchas malaise, fever, and arthralgia. Ocular manifesta-tions include proptosis, keratoconjunctivitis andgranulomatous sclerouveitis ;20 there may be apapular, vesicular or bullous rash, skin ulcers orlesions in old operation scars;10 29 30 lesions of thenervous system may produce a variety of neuro-logical defects;16 31 32 and pericarditis and coronaryarteritis occur in 15 %.8 20 Testicular, epididymal,and breast lesions have also been reported.8 1032

Laboratory tests16 17 19 generally reveal a normo-chromic normocytic anaemia, a raised ESR, and apositive rheumatoid factor. Antinuclear factor andsmooth muscle antibodies may be present.17 33 IgAIs generally raised, whereas IgG is normal: changesin IgM are inconstant.'5-17 33-35 IgE may be raised,and circulating antibodies have been demon-strated.33-35On gross examination of the lungs there are one

or more necrotic, sometimes cavitated masses,surrounded by a rim of pale, consolidated lung.8-13The masses vary in size, and may sometimes involvean entire lobe. Histologically, in the lungs and otherorgans there is infiltration of the walls of veins andarteries by chronic inflammatory cells sometimeswith granuloma formation. Vessels are often occludedby thrombus or granulation tissue, elastic fibresare destroyed, and there may be fibrinoid necrosis.Eosinophils are rare. Tissue adjacent to the affectedvessels shows necrosis, chronic inflammation, andoccasional granulomata.The glomerulonephritis is focal and non-specific,

but there is chronic inflammation and occasionalgranulomata in the interstitium, often with phlebitisand arteritis.14 36 Immunofluorescent studies demon-strate IgG and complement, and at an ultrastruc-tural level there are subepithelial and subendothelialelectron dense deposits.

LIMITED WEGENER S GRANULOMATOSISThe concept of a variant of Wegener's granulo-matosis with absent or minimal lesions outside thelungs, no glomerulonephritis, and an indolentcourse was proposed by Carrington and Liebow in1966,37 and reaffirmed by Liebow in 1973.1 Since1966 further reports of this variant have appeared inthe literature.38-42

Systemic and pulmonary symptoms and signs aresimilar to those of classical Wegener's granulo-matosis, and the radiological and pathologicalchanges in the lungs are identical. Painful sub-cutaneous nodules and involvement of the gastro-intestinal tract or gall bladder may occur.37 Althoughfocal glomerulonephritis by definition, is neverpresent, granulomatous lesions are frequently found

in the kidneys as well as in other organs. Differentia-tion of the two variants on histological grounds isimpossible: the diagnosis can only be made byfollowing the course of the disease.

LYMPHOMATOID GRANULOMATOSISLymphomatoid granulomatosis is defined as anangiocentric and angiodestructive lymphoreticularand granulomatous disease affecting primarilythe lungs.1 43 44 Clinically and radiologically it issimilar to Wegener's granulomatosis, but thecellular infiltrate is atypical, and a proportion of casesdevelop a lymphoma. Most patients are between 30and 50 years of age, with a slight male prepon-derance. Onset is generally rapid, with cough,dyspnoea, haemoptysis, fever, malaise, and arth-ralgia. Skin manifestations, which may precedechanges in the lungs, include an erythematousmaculo-papular rash and subcutaneous, oftenulcerating nodules. Involvement of the central orperipheral nervous system is common, and patientscan present with a variety of neurological symptomsand signs. Radiographic abnormalities are similarto those of Wegener's granulomatosis.43 45 46 Labora-tory investigations reveal non-specific changes of nodiagnostic value. Most patients die within two yearsof massive pulmonary or cerebral infiltration, but insome there is spontaneous remission or excellentresponse to treatment.44 47The naked eye appearance of the lungs is essentially

the same as Wegener's granulomatosis, but thelesions tend to be more coalescent and destructive.Vascular and bronchial obstruction lead to infarctionand obstructive pneumonitis: the development ofthese secondary phenomena and their subsequentpartial resolution accounts for the constantlychanging radiological picture. Lesions are found inthe kidneys in about one-third of cases and in thebrain in about one-quarter.43 44 Glomerulonephritisdoes not occur. The adrenals, heart, pancreas, orprostate may also be affected, but lymph nodes arenot involved unless a lymphoma develops. Massivehepatic infiltration has been described, but isunusual.43 44 48

Histologically there is a proliferation of variouschronic inflammatory cells intermingled with largeatypical mononuclear elements. The proliferatingcells have a propensity to invade arterial and venousvessels, which are occluded and eventually destroyed:fibrinoid necrosis is only seen in fulminating cases.49The cellular infiltrate extends into bronchial wallsand lung. Similarchanges are seen in other organs, andin the skin there may be a lymphoma-like pictureand widespread fat necrosis.435051 The lymphomawhich sometimes develops is of an immunoblasticor plasmacytic and immunoblastic type.4452



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CHURG-STRAUSS SYNDROME

Churg-Strauss syndrome is a generalised necrotisingvasculitis similar to polyarteritis nodosa. Unlikepolyarteritis nodosa, however, there is lung involve-ment, a history of asthma, and a peripheral eosino-philia. It is more common in males and generallyoccurs in the fifth decade.54 Presenting featuresinclude bronchitis and asthma, transient or pro-

gressive pneumonic episodes, pleuritic pain andhaemoptysis. There may be a petechial or purpuricrash, or nodular ulcerating masses in the subcutis.55Signs and symptoms referable to the abdominalviscera and nervous system are similar to those ofpolyarteritis nodosa. Radiological findings in thechest vary between scattered areas of infiltration andmassive diffuse or nodular lesions.54 Cavitation israre. The chief laboratory abnormality is an eosino-philia which may rise to 81 %.The basic histological change is a necrotising

arteritis involving small veins and arteries down to a

capillary level.53 54 56 57 Vessel walls are infiltrated byneutrophil and eosinophil polymorphs, lymphocytesand plasma cells. Fibrinoid necrosis is common, andinflammatory cells extend into adjacent tissue. Thelungs and bronchi are infiltrated by eosinophils.Necrotising granulomatous nodules are also a

feature. These consist of a central area of alteredcollagen, surrounded by a palisade of radiallyarranged macrophages and giant cells.55 56

NECROTISING SARCOID GRANULOMATOSISThis condition is a granulomatous disorder of thepulmonary vessels and parenchyma which appears

to be intermediate between sarcoidosis and Wegener'sgranulomatosis. Since the original description byLiebow in 1973,1 a total of 62 cases have beenreported.58 It affects young or middle-aged adults,and is twice as common in females. Presentingfeatures are non-specific and include malaise, fever,cough, and pleuritic pain. Some patients are asympto-matic. Physical examination is generally un-

rewarding, but radiologically there are usually one

or more pulmonary opacities, or miliary mottlingwhich may become nodular later.1 58 59 Cavitationdoes not occui, and hilar lymph node enlargement isuncommon. The characteristic lymphadenopathy,uveitis, and skin lesions of sarcoidosis are absent.Extrathoracic manifestations have only been re-

corded once, in a child with neurological and retinalinvolvement.60The naked eye lesions consist of ill-defined areas of

necrosis and consolidation in the lung. They are

often more widespread than the radiographssuggest.59 Histologically the picture is one ofepithelioid cell and giant cell granulomata with

varying degrees of necrosis. Where the granulomatacoalesce there is widespread colliquitive or coagu-lative necrosis with effacement of normal lungstructures.' 5859 Pulmonary arteries and veins areinfiltrated by necrotising granulomata or a morediffuse proliferation of giant cells and epithelioidcells. Near necrotic foci, vessel walls are destroyedby lymphocytes, plasma cells, and histiocytes.Bronchial involvement and obstruction with distalpneumonitis is common. Hilar nodes show eithernon-specific reactive change or occasional minutegranulomata. The pleura may show fibrosis orgranulomatous thickening.

BRONCHOCENTRIC GRANULOMATOSISBronchocentric granulomatosisl 61 is, as the nameimplies, primarily a bronchial condition: vascularinvolvement is secondary. It is one of the disordersassociated with hypersensitivity to Aspergillus, and ischaracterised by bronchiectasis, bronchial obstruc-tion, and pulmonary fibrosis. Patients fall into twogroups depending upon whether or not there is ahistory of asthma.6' The asthmatic group tends to beyounger, with a mean age of 22 years: presentingsymptoms are cough, chest pain, and dyspnoea,often associated with eosinophilia and a raised ESR.The mean age of the non-asthmatic group is around50 years: symptoms in this group may be minimal, oragain there may be cough, chest pain, or dyspnoea.Eosinophilia is less common.

In neither group can precipitin reactions toAspergillus be relied upon for diagnosis, and fungiare rarely isolated from the sputum. Radiologicalchanges tend to occur mainly in the upper lobes andmay consist of rounded masses or areas of consolida-tion and atelectasis. In 75% of cases lesions areunilateral.On gross examination bronchi are dilated, filled

with yellow-white cheesy material, and surroundedby cuffs of grey-white tissue. At a microscopic levelin early lesions part of the epithelial lining is replacedby spindle-shaped epithelioid cells arranged radiallyto the lumen. Later, when the epithelium is com-pletely replaced, the lumen fills with necrotic cellulardebris, producing the characteristic granulomatousappearance. In older lesions the central necrotic areabecomes homogeneous, or it may contain masses ofeosinophil granules. Tissue around the affectedbronchi are infiltrated by chronic inflammatory cells,eosinophils being more prominent in the asthmaticgroup. Pulmonary arteries may be involved by directextension, with intimal thickening on the sideadjacent to the bronchus. The submucosa of largecentral bronchi is often infiltrated by chronic inflam-matory cells: occasionally there are granulomata in



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the subepithelial layer, and there may be a strikingchondritis and perichondritis. Fungal hyphae arefrequently seen in the bronchial lumens in asthmaticpatients.

Diagnosis

The most common diagnostic problem posed by thisgroup of conditions is that of a patient with radio-logical opacities in the lungs. Clearly the differentialdiagnosis embraces almost any pulmonary disease,but there are a number of useful pointers. A historyof asthma suggests Churg-Strauss syndrome orbronchocentric granulomatosis, and patients withclassical Wegener's granulomatosis and Churg-Strauss syndrome62 often complain of upper res-piratory tract symptoms. Physical examination isoften unrewarding, but particular attention shouldbe paid to the nose, nasopharynx and skin. Theradiological lesions of Wegener's granulomatosisand lymphomatoid granulomatosis are often con-fined to the lower parts of the lung, and characteris-tically wax and wane.'323 43 In Wegener's granulo-matosis there is usually anaemia, a high ESR, apositive rheumatoid factor, and derangement ofimmune globulins. Churg-Strauss syndrome andbronchocentric granulomatosis are associated withan eosinophilia.

In patients with upper respiratory tract manifesta-tions the differential diagnosis includes all theconditions which cause the "lethal midline granu-loma" syndrome.63 64 Again the history, clinicalexamination, and results of laboratory tests shouldsuggest the nature of the underlying disorder.The final diagnosis depends upon the correct

interpretation of biopsy material. An adequatesample must be submitted to the pathologist. Biopsiesof the bronchial mucosa, and transbronchial andneedle biopsies of the lung parenchyma are too smalland often unrepresentative: thoracotomy is essen-tial.18 25 65 Biopsies of the upper respiratory tractshould be as large as possible. The focal glomeru-lonephritis of classical Wegener's granulomatosis isof a non-specific type; renal biopsy has a place inmanagement, but will not in itself confirm the diag-nosis.

Treatment

It is now generally accepted that the treatment ofchoice in classical Wegener's granulomatosis iscyclophosphamide,20 66 67 which is curative in alarge percentage of cases. It is often possible totaper off therapy when a complete remission has beenobtained, although there may be problems withresidual bronchial stenosis or interstitial lung

disease.'8 27 Steroids have a place in the treatment ofskin lesions, ocular manifestations and serosalinvolvement,18 and also in fulminating cases.20 68Cyclophosphamide is advocated in the limited formof Wegener's granulomatosis by most authorities,but some suggest a period of observation when asolitary lesion has been excised.'7There is no established treatment for lymphoma-

toid granulomatosis. A variety of combinations ofsteroids and chemotherapy have been used, but nonehas been found particularly effective.'7 44 Fauci andhis colleagues20 have found cyclophosphamideeffective in the early stages of the disease, whereasothers advocate excision and radiotherapy44 orradiotherapy alone.69 70 The situation regarding thetreatment of the other members of this group ofdiseases is problematical. Steroids54 and cyclo-phosphamide20 have both been used in the Churg-Strauss syndrome. Resection is curative in somecases of necrotising sarcoidal granulomatosis andbronchocentric granulomatosis, but steroids andchemotherapy still appear to have a place.59 61

Comment

Classical Wegener's granulomatosis is a well-documented clinico-pathological entity, and the siteof the initial lesions, the immunoglobulin abnor-malities, and the focal glomerulonephritis all suggesthypersensitivity to an inhaled antigen.'3 1617 34 Thenature of the offending antigen remains obscure. Nomicro-organisms have been implicated, althoughsecondary infection with Staphylococcus aureus andPseudomonas aerogenosa is common.'6 18The status of limited Wegener's granulomatosis is

less certain at present. Many authorities feel that thetwo variants are part of the same disorder, and thatthe difference is only one of degree: the response totherapy is the same, and limited lesions may laterbecome generalised.15 16 The concept of an attenuatedform of Wegener's granulomatosis is attractive, andit is tempting to place all slowly progressive andlocalised lesions with a similar histology into thiscategory. But necrosis, angiitis, and granulomaformation are seen in many disease processes.Ulbright and Katzenstein,71 in a review of solitarynecrotising granulomas of the lung, found fungal oracid-fast organisms in 70%. They emphasise thatthere is a spectrum of histological changes betweenWegener's granulomatosis and infectious granu-lomas, and advocate a thorough search for aninfecting agent before a diagnosis is made.An interesting re-classification of Wegener's

granulomatosis and lymphomatoid granulomatosiswas proposed by Saldana and his co-workers in1977.47 They arranged pulmonary angiitis and



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granulomatosis into three groups, and defined type Ias lymphocyte depleted, type II as benign lympho-cytic, and type III as malignant lymphoproliferative.All cases of classical Wegener's granulomatosis andsome of the limited form were of type I. The cases oflymphomatoid granulomatosis all fell into the thirdgroup. Type II was a more indolent condition, oftenoccurring in older patients and associated with arelatively good prognosis.

It is possible that lymphomatoid granulomatosis isthe result of long continued antigenic stimulus in anabnormal host. Pre-existing chronic disease has beenreported in a number of cases,43444 immune impair-ment is sometimes a feature,52 72 and the disease hasoccurred in renal transplant recipients.49 73 74 Im-munological and ultrastructural studies indicate anabnormal proliferation of B cells, which mayprogress to a malignant lymphoma.52 Parallels maybe drawn with Sjogren's syndrome and angio-immunoblastic lymphadenopathy, in which there isimmune deficiency, lymphoid proliferation, and anincreased incidence of lymphoma.4352There is now some doubt concerning the position

of lymphomatoid granulomatosis as a distinct entity.Malignant midline reticulosis, or polymorphicreticulosis, is one of the many disorders which causethe "lethal midline granuloma" syndrome.3 4Histologically it is identical to lymphomatoidgranulomatosis, and it has been suggested that thetwo conditions are essentially the same.3 75 76 Thesituation is further confused by reports of lympho-matoid granulomatosis affecting the upper respira-tory tract and abdominal organs.73 78-80

Churg-Strauss syndrome and polyarteritis nodosaare at the two ends of the systemic necrotisingvasculitis spectrum.20 Polyarteritis nodosa affectsonly medium-sized systemic arteries: the pul-monary vasculature is not involved. A history ofallergy and a peripheral eosinophilia are unusual.Nevertheless the two disorders are not completelyclear cut, and some patients have a vasculitis with thecharacteristics of both-the so-called "overlapsyndrome".20The aetiology of necrotising sarcoidal granulo-

matosis is unknown, although in one case Aspergillusfumagatus was demonstrated by immunofluor-escence.58 Some authorities regard it as a variant ofsarcoidosis,59 whereas Saldana80 is of the opinionthat it is a distinct pulmonary angiitis. Vascularinvolvement is common in typical pulmonarysarcoidosis,81 and nodular radiographic opacitiesmay be seen.8283 But on the other hand diffuseangiitis, necrosis, and absence of lesions in hilarlymph nodes and extrathoracic organs all suggest aseparate disease.Liebow included bronchocentric granulomatosis

among the granulomatous and angiitic lung diseases,but it now seems likely that this is basically a necro-tising bronchitis caused by hypersensitivity to fungiof the Aspergillus type: vascular involvement issecondary.6' Although correct in the context of theoriginal paper, the inclusion of this entity with thepulmonary vasculitides now seems inappropriate.To summarise then, the pulmonary angiitic and

granulomatous diseases are a heterogeneous groupin which the common theme is a disturbance of theimmune system. We need to know much more aboutthe precipitating factors and how they producechanges in the pulmonary vasculature and paren-chyma. Bronchocentric granulomatosis should per-haps be placed in a separate category, the existenceof a limited form of Wegener's granulomatosis as anentity is questionable, and the relationship ofnecrotising sarcoid granulomatosis to other con-ditions requires elucidation. Nevertheless, the presentclassification, although far from ideal, is a usefulaide-memoire to diagnosis and management, whichin the end is what clinical medicine and pathology isall about.

CW EDWARDSDepartment of Histopathology,

East Birmingham Hospital,Birmingham

References

Liebow AA. Pulmonary angiitis and granulomatosis. AmRev Respir Dis 1973;108:1-18.

2 Lie JT. Nosology of pulmondary vasculitides. Mayo ClinProc 1977;52:520-2.

3 Leu HJ. Pathergic granulomatoses. Pathomorphology ofclassical and limited form of Wegener's granulomatosis,of lymphomatoid granulomatosis and of eosinophilicgranulomatous angiitis. Vasa 1979;8:203-12.

4Deremee RA, Weiland LH, McDonald TJ. Respiratoryvasculitis. Mayo Clin Proc 1980;55:492-8.

5 Klinger H. Grenzformen der Periarteriitis nodosa.Frankfurt Z Pathol 1931 ;42:455-80.

6 Wegener F. Uber generalisierte, septische Gefasserkrank-ungen. Verh Dtsch Ges Pathol 1936;29:202-10.

7Wegener F. Ober eine rhinogene Granulomatose mitbesonderer Beteiligung des Arteriensystems. BeitrPatholAnat 1939;102:36-8.

8 Fahey JL, Leonard E, Churg J, Godman G. Wegener'sgranulomatosis. Am J Med 1954;17:168-79.

9 Godman GC, Churg J. Wegener's granulomatosis.Pathology and review of the literature. AMA Arch Path1954;58:533-53.

10 Walton EW. Giant cell granuloma of the respiratory tract(Wegener's granulomatosis). Br Med J 1958;2:265-70.

1 Israel HL, Patchefsky AS. Wegener's granulomatosis oflung: diagnosis and treatment. Experience with 12 cases.Ann Intern Med 1971 ;74:881-91.

12 Fauci AS, Wolff SM. Wegener's granulomatosis: studies ineighteen patients and a review of the literature. Medicine(Baltimore) 1973;52:535-61.

13 Patchefsky AS, Israel HL. Pulmonary Wegener's granulo-matosis. Ann Clin Lab Sci 1973;3:249-58.

14 Wolff SM, Fauci AS, Horn RG, Dale DC. Wegener's



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86

granulomatosis. Ann Intern Med 1974;81 :513-25.5 Deremee RA, McDonald TJ, Harrison EG, Coles DT.

Wegener's granulomatosis. Anatomic correlates, aproposed classification. Mayo Clin Proc 1976 ;51 :777-81.

16 Fauci AS, Wolff SM. Wegener's granulomatosis andrelated diseases. DM 1977;23:3-36.

17 Israel HL, Patchefsky AS, Saldana MJ. Wegener'sgranulomatosis, lymphomatoid granulomatosis, andbenign lymphocytic angiitis and granulomatosis of lung.Recognition and treatment. Ann Intern Med 1977;87:691-9.

18 Flye MW, Mundinger GH, Fauci AS. Diagnostic andtherapeutic aspects of the surgical approach to Wegener'sgranulomatosis. J Thorac Cardiovasc Surg 1979;77:331-7.

19 McDonald TJ, Deremee RA, Weiland LH. Wegener'sgranulomatosis and polymorphic reticulosis-twodiseases or one? Experience with 90 patients. ArchOtolaryngol 1981;107:141-4.

20 Fauci AS, Haynes BF, Katz P. The spectrum of vasculitis:clinical, pathologic, immunologic, and therapeuticconsiderations. Ann Intern Med 1978 ;89:660-76.

21 Maguire R, Fauci AS, Doppman JL, Wolff SM. Unusualradiographic features of Wegener's granulomatosis.AJR 1978;130:233-8.

22 Epstein DM, Gefter WB, Miller WT, Gohel V, BonavitaJA. Spontaneous pneumothorax: an uncommonmanifestation of Wegener's granulomatosis. Radiology1980;135:327-8.

23 Gohel VK, Dalinka MK, Israel HL, Libschitz HI. Theradiological manifestations of Wegener's granuloma-tosis. Br J Radiol 1973;46:427-32.

24 Gonzalez L, Van Ordstrand HS. Wegener's granuloma-tosis. Radiology 1973 ;107:295-300.

25 Landman S, Buirgener F. Pulmonary manifestations inWegener's granulomatosis. Am J Roentgenol RadiumTher Nucl Med 1974;122:750-7.

26 Farrelly C, Foster DR. Atypical presentation of Wegener'sgranulomatosis. Br J Radiol 1980;53:721-2.

27 Rosenberg DM, Weinberger SE, Fulmer JD, Flye MW,Fauci AS, Crystal RS. Functional correlates of lunginvolvement in Wegener's granulomatosis. Use ofpulmonary function tests in staging and follow-up. Am JMed 1980;69:387-94.

28 Hensley MJ, Feldman NJ, Lazarus JM, Galvanek EG.Diffuse pulmonary haemorrhage and rapidly progressiverenal failure. An uncommon presentation of Wegener'sgranulomatosis. Am J Med 1979;66:894-8.

29 Reed WB, Jensen AK, Konwaler BE, Hunter D. Thecutaneous manifestations in Wegener's granulomatosis.Acta Derm Venereol (Stockh) 1963 ;43:250-64.

30 Kraus Z, Vortel V, Fingerand A, Salavec M, Kotch V.Unusual cutaneous manifestations in Wegener'sgranulomatosis. Acta Derm Venereol (Stockh) 1965;45:288-94.

31 Drachman DA. Neurological complications of Wegener'sgranulomatosis. Arch Neurol 1963;8:145-55.

32 Oimomi M, Suehiro 1, Mizuno N, Baba S, Okada S,Kanazawa Y. Wegener's granulomatosis with intra-cerebral granuloma and mammary manifestations.Report of a case. Arch Intern Med 1980;140:853-4.

33 Shillitoe EJ, Lehner T, Lessof MH, Harrison DFN.Immunological features of Wegener's granulomatosis.Lancet 1974;1:281-4.

34 Conn DL, Gleich GJ, Deremee RA. Raised serum immuno-globulin E in Wegener's granulomatosis. Ann Rheum Dis1976 ;35 :377-80.

35 Howell SB, Epstein WV. Circulating immunoglobulincomplexes in Wegener's granulomatosis. Am J Med

1976;60:259-68.36 Horn RG, Fauci AS, Rosenthal AS, Wolff SM. Renal

biopsy pathology in Wegener's granulomatosis. Am JPathol 1974;74:423-33.

3 Carrington CB, Liebow AA. Limited forms of angiitis andgranulomatosis of Wegener's type. Am J Med 1966;41:497-527.

38 Bernier J, Charbonneau R, Sestier F. A propos d'une formelocalisee de granulomatose de Wegener. Union Med Can1969;98:44-54.

39 Asin HR, Wagenaar JPM, Swierenga J. The mitigatedform of Wegener's disease. Scand J Respir Dis 1972;53:367-74.

40 Davis RW, Fetter BF, Young WG. Wegener's granulo-matosis. Two patients presenting with solitary pulmonarylesions and review of eleven other cases. Ann Thorac Siirg1972 ;13:427-34.

41 Donald KJ, Edwards RL, McEvoy J DS. An ultrastructuralstudy of the pathogenesis of tissue injury in limitedWegener's granulomatosis. Pathology 1976 ;8:161-9.

42 Hsu JT. Limited form of Wegener's granulomatosis. Chest1976 ;70:384-5.

43 Liebow AA, Carrington CRB, Friedman PJ. Lymphoma-toid granulomatosis. Hum Pathol 1972 ;3 :457-558.

44 Katzenstein AL, Carrington CB, Liebow AA. Lympho-matoid granulomatosis. A clinicopathologic study of 152cases. Cancer 1979;43:360-73.

45 Herman PG, Hillman B, Pinkus G, Harris GC. Unusualnoninfectious granulomas of the lung. Radiology 1976;121:287-92.

46 Hicken P, Campbell Dobie J, Frew E. The radiology oflymphomatoid granulomatosis in the lung. Clin Radiol1979 ;30:661-4.

4 Saldana M, Patchefsky AS, Israel Hl, Atkinson GW.Pulmonary angiitis and granulomatosis. The relation-ship between histological features, organ involvementand response to treatment. Hum Pathol 1977;8:391-409.

48 Schj0oseth SA, Blom GP. Lymphomatoid granulomatosisof the lung, liver and spleen. Scand J Haematol 1978;21:104-8.

49 Hammar SP, Gortner D, Sumida S, Bockus D. Lympho-matoid granulomatosis: association with retroperitonealfibrosis and evidence of impaired cell mediated im-munity. Am Rev Respir Dis 1977;115:1045-50.

50 Kay S, Fu Y, Minars N, Brady JW. Lymphomatoidgranulomatosis of the skin: light microscopic andultrastructural studies. Cancer 1974 ;34:1675-82.

51 Gross PR. Lymphomatoid granulomatosis. Cuitis 1980;25:305-9.

52 Bender BL, Jaffe R. Immunoglobulin production inlymphomatoid granulomatosis and relation to other"benign" lymphoproliferative disorders. Am J ClinPathol 1980;73:41-7.

53 Churg J, Strauss L. Allergic granulomatosis, allergicangiitis and periarteritis nodosa. Am J Pathol 1951 ;27:277-301.

54 Chumbley LC, Harrison EG, Deremee AA. Allergicgranulomatosis and angiitis (Churg-Strauss syndrome).Mayo Clin Proc 1977;52:477-84.

55 Dicken CH, Winkelmann RK. The Churg-Strauss granu-loma: cutaneous, necrotising, palisading granuloma invasculitis syndromes. Arch Pathol Lab Med 1978;102:576-80.

56 Veevaete F, Van Der Straeten M, De Vos M, Roels H.Allergic granulomatous angiitis. Scand J Respir Dis1978 ;59:287-96.

5 Clausen KP, Bronstein H. Granulomatous pulmonaryarteritis. A hypereosinophilic syndrome. Am J ClinPathol 1974;62:82-7.



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58 Corrin B, Spencer H. Some aspects of pulmonary path-ology. In: Anthony PP, MacSween RNM, eds. Recentadvances in histopathology no 11. Edinburgh: ChurchillLivingstone, 1981.

59 Churg A, Carrington CB, Gupta R. Necrotising sarcoidgranulomatosis. Chest 1979 ;76:406-13.

60 Beach R, Corrin B, Scopes JW, Graham E. Necrotisingsarcoid granulomatosis with neurological lesions in achild. J Pediatr 1980;97:950-3.

61 Katzenstein AL, Liebow AA, Friedman PJ. Broncho-centric granulomatosis, mucoid impaction and hyper-sensitivity reactions to fungi. Am Rev Respir Dis 1975;111:497-537.

62 Olsen KD, Neel HB, Deremee RA, Weiland LH. Nasalmanifestations of allergic granulomatosis and angiitis(Churg-Strauss syndrome). Otolaryngol Head Neck Surg1980;88:85-9.

63 McGuirt WF, Rose EF. Lethal midline granuloma: apathological spectrum. J Laryngol Otol 1976;90:459-66.

64 Wetmore SJ, Platz CE. Idiopathic midface lesions. AnnOtol Rhinol Laryngol 1978 ;87:60-9.

65 Allen AR, Moen CW. Wegener's granulomatosis. JThorac Cardiovasc Surg 1965;49:388-97.

66 Novack SN, Pearson CM. Cyclophosphamide therapy inWegener's granulomatosis. N Engi J Med 1971 ;284:938-42.

67 Reza MJ, Dornfeld L, Goldberg LS, Bluestone R, PearsonCM. Wegener's granulomatosis. Long term follow-up ofpatients treated with cyclophosphamide. ArthritisRheum 1975;18:501-6.

66 Harrison HL, Linshaw MA, Lindsley CB, Cuppage FE.Bolus corticosteroids and cyclophosphamide for initialtreatment of Wegener's granulomatosis. JAMA 1980;244:1599-600.

69 Fuller P, Hafermann D, Byrd R, Jenkins D. Use ofirradiation in lymphomatoid granulomatosis. Chest1978 ;74:105-6.

70 Shank BB, Kelley CD, Nisce LZ, Nori D. Radiationtherapy in lymphomatoid granulomatosis. Cancer 1978;42:2572-80.

71 Ulbright TM, Katzenstein AL. Solitary necrotizinggranulomas of the lung. Differentiating features andetiology. Am J Surg Pathol 1980;4:13-28.

72 Cohen ML, Dawkins RL, Henderson DW, Sterrett GF,Papadimitrou JM. Pulmonary lymphomatoid granulo-matosis with immunodeficiency terminating as malignantlymphoma. Pathology 1979;11:537-50.

73 Gardiner GW. Lymphomatoid granulomatosis of thelarynx in a renal transplant recipient. J Otolaryngol1979;8:549-55.

74 Walter M, Thomson NM, Dowling J, Fox R, Atkins RC.Lymphomatoid granulomatosis in a renal transplantrecipient. Aust NZ J Med 1979 ;9:434-6.

7 Deremee RA, Weiland LH, McDonald TJ. Polymorphicreticulosis, lymphomatoid granulomatosis. Two diseasesor one? Mayo Clin Proc 1978;53:634-40.

76 Crissman JD. Midline malignant reticulosis and lympho-matoid granulomatosis. A case report. Arch Pathol LabMed 1979;103:561-4.

7 Chen KTK. Abdominal form of lymphomatoid granulo-matosis. Hum Pathol 1977 ;8:99-103.

78 Singh G, Hellstrom HR. Lymphomatoid granulomatosis:report of a case without pulmonary lesions and withischaemic colitis, probably a sequel to granulomatosis.Hum Pathol 1978;9:364-6.

79 Gupta S, Gupta OP. Lymphomatoid granulomatosis ofthe oropharynx. Ear Nose Throat J 1980;59:152-4.

80 Saldana MJ. Necrotizing sarcoid granulomatosis: clinico-pathologic investigations in 24 patients (abstract). LabInvest 1978;38:364.

81 Rosen Y, Moon S, Huang CT, Gourn A, Lyons HA.Granulomatous pulmonary angiitis in sarcoidosis. Am JClin Pathol 1977;67:213.

82 Sharma OP, Hewlett R, Gordonson J. Nodular sarcoido-sis: an unusual radiographic appearance. Chest 1973;64:189-92.

63 Onal E, Lopata M, Lourenco RV. Nodular pulmonarysarcoidosis. Clinical roentgenographic and physiologiccourse in five patients. Chest 1977;72:296-300.



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