J Clin Pathol 1992;45:295-298

Desmoplastic malignant mesothelioma: a reviewof 17 cases

G E Wilson, P S Hasleton, A K Chatterjee

AbstractAims: To identify the histological

features of desmoplastic mesothelioma,and to determine its incidence and prog-nosis.Methods: Two hundred and fifty five

cases of malignant mesothelioma wereexamined over seven years (1982-9) toidentify the desmoplastic variant. Sec-tions were cut at 5 um and stained withhaemotoxylin and eosin and withCAM 5 2(Dakopatts). Asbestos fibre counts werecarried out by light microscopy in 14cases using the potash digestion method.Results: Seventeen cases were iden-

tified as desmoplastic mesothelioma giv-ing an incidence of 6-6%. In 11 cases thecell type in more cellular areas wassarcomatous and in six others it wasbiphasic. The mean survival time fromonset of symptoms to death was 5-8months for the sarcomatous variant and6-8 months for the biphasic variant.Twelve of 16 patients had had previousoccupational exposure to asbestos, rang-ing from five months to 43 years. Thediagnosis of desmoplastic mesotheliomawas only accepted if acellular connectivetissue comprised 50% or more of thetumour bulk. Also seen was collagennecrosis, anastomosing bands of oftenhyalinised collagen with a prominentstoriform pattern, and where cellulardetail was present there were hyper-chromatic nuclei.Conclusions: Desmoplastic meso-

thelioma is a rare variant of malignantmesothelioma with a storiform collagenpattern, collagen necrosis, blandacellular collagen and focal cytologicalfeatures ofmalignancy. Though rare, it isimportant to recognise this variant anddistinguish it from a pleural plaque, non-specific reactive pleural fibrosis, pleurisy,rheumatoid disease, or, rarely, spindlecell sarcomas.

Although rare, malignant mesotheliomas haveassumed great importance during the past twodecades because of their increased incidence,especially among persons with previousexposure to asbestos.'2 Up to 90% of meso-theliomas are associated with asbestos withinoccupationally exposed groups" and becauseof the long latency period ofbetween 25 and 45years for the effects of exposure to asbestos todevelop into mesothelioma, it is expected thatthe number of cases will continue to increaseuntil 2000 and beyond.' 2 4

There is a subgroup of malignant meso-thelioma, termed desmoplastic malignantmesothelioma (DMM), in which 50% or moreof the tumour is fibrous and has a low cellcontent.67 The hypocellular, bland appearan-ces of such desmoplastic areas can be extremelydifficult to interpretate and the correct diag-nosis ofmalignancy may not be suspected. Thisis particularly the case when needle biopsy isperformed, and many cases of DMM are stillonly diagnosed at necropsy.

MethodsTwo hundred and fifty five cases of malignantmesothelioma were seen at or referred to theregional cardiothoracic centre between 1982and 1989.

Seventeen (6-6%) of these cases were con-sidered to be DMM-that is, more than 50%of the tumour was composed of dense hypo-cellular fibrous tissue. In seven patients thediagnosis was made during life by thoracotomyand biopsy. Post mortem examinations werecarried out in 16 of the 17 cases. Clinical andoccupational histories were taken from hospitalrecords or from the Medical Boarding Panel(Respiratory Diseases) notes. Relevant blocksof tissue were fixed in formalin and embeddedin paraffin wax. Sections (5 gm) were stainedwith haematoxylin and eosin for light micro-scopical examination. An average of sevenblocks of tumour per case were available forstudy (range two to 19). Immunohistochemicalstaining was done on formalin fixed tissue usingthe standard peroxidase method8 followed byapplication of the low molecular weight cyto-keratin antibody CAM 5-2 (Dakopatts).Counts of asbestos fibres were carried out bylight microscopy in 14 cases using the potashdigestion method.9The ages of 16 ofthe 17 patients were known

and ranged from 41-79 years (mean 60-1 years)at the time of diagnosis. Fifteen patients weremale and two female. In 11 the presentingcomplaints included pleural effusion in five,shortness of breath in three, and anaemia,pleuritic chest pain, and weight loss, respec-tively in three. The length of survival fromonset of symptoms was known in 12 cases, themean survival being 5-8 months in eightpatients with sarcomatous tumours and 6-8months in four patients with mixed tumours.Twelve of 16 patients had had previous

occupational exposure to asbestos. The dura-tion of exposure ranged from five months to 43years where it was known. Specific treatmentwas given in five cases and included pleuraldecortication in three, radiation in one, andchemotherapy in one.

Department ofPathology, RegionalCardiothoracicCentre, WythenshaweHospital, ManchesterM23 9LTG E WilsonP S HasletonMedical BoardingCentre (RespiratoryDiseases), ManchesterA K ChatterjeeCorrespondence to:Dr P S Hasleton.Accepted for publication23 September 1991

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Figure 1 Stonform pattern in a desmoplastic mesothelioma: note lack of nuche(haematoxylin and eosin).

ResultsGROSS PATHOLOGYIn 13 (72-2%) cases tumour was in tpleural cavity. In two cases pleuralwere bilateral, the other case being leThe site of one tumour was unknown.invariably encompassed the pleural ca~extension along the interlobar fissuretrating the underlying lung parench3affecting the mediastinal structures irthe pericardium. Spread to thechest.

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Figure 2 Nuclear hyperchromatism with tumour extending into adipose tissue.

also common. The tumour varied from 05 cmto many centimetres in thickness. The under-lying lung was often atelectatic.

In the 16 post mortem cases 14 (87-5%)showed evidence of metastatic disease. Thecontralateral lung was most commonly affected(75% of cases). Other affected organs includedliver (n = 4), thyroid (n = 3), kidney (n = 4),adrenal (n = 3), myocardium (n = 2), and bone(n = 3). Two patients had associated peritonealtumour deposits.

MICROSCOPIC PATHOLOGYIn 17 (6-6%) of 255 cases of mesotheliomareviewed there was hypocellular or sometimes

° acellular collagenous tissue, comprising morethan 50% of tumour bulk. In 11 of the 17(64-7%) patients, the associated cellular areaswere sarcomatous. In the remainder (35-3%)both sarcomatous and epithelial componentswere present. The arrangement ofthe collagen-ous areas varied. Most commonly there was acomplex network of anastomosing bands ofoften hyalinised collagen with a prominentstoriform pattern (fig 1). This was the pre-

ei dominant appearance in 10 (58-8%) cases. Insix (35-2%) tumours the storiform pattern waspresent in combination with more spindledareas, the latter with features similar to thebasket weave pattern seen in benign fibrouspleural plaques. These spindled areas, how-

the right ever, lacked the uniform pattern seen in atumours pleural plaque. Where cellular detail was asses-ft sided. sable, there was often nuclear hyperchromat-Tumour ism, enlargement, and irregularity indicative ofvity with neoplasia (fig 2). In one case the spindledes, infil- component was predominant. Cellular andyma and desmoplastic areas often merged impercept-ncluding ibly.wall was In 12 of 17 (705%) cases collagen necrosis

was present within desmoplastic areas (fig 3).In eight of 12 (66-6%) cases, necrosis wasprominent and easily identified. In four cases itwas focal. It was always bland withoutassociated inflammation and in haematoxylinand eosin stained sections resembled fibrinoidnecrosis. Mitoses were rare, with not more thanone mitosis per 10 high power fields in desmo-plastic areas. Tumour infiltration of lungparenchyma was usually seen together withvascular invasion. Away from tumour, theencased lung had varied features includingbronchopneumonia, thrombi, and intra-alveolar oedema. In four cases early asbestoslesions in the form of fibrosis in respiratorybronchiolar walls and subpleural fibrosis wereseen. There were no cases offrank asbestosis asassessed by the presence of interstitial fibrosisand many asbestos bodies. In all but one casecells within the desmoplastic component werepositive for low molecular weight cytokeratinCAM 5-2. In nine (52-9%) cases more than half

* r- the cells were positive.Asbestos fibres were counted in 14 of the 17

cases. In three lung tissue was unavailable foranalysis. In 12 of 14 (85-7%) cases the asbestosfibre count by light microscopy was more than50,000 per gram of dried lung tissue indicatingprevious asbestos exposure (table).

296

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Figure 3 Collagen necrosis shown between arrows (haematoxylin and eosin).

DiscussionMalignant mesotheliomas are divided intothree histological subtypes: epithelial, sar-comatous, and mixed or biphasic. These pat-terns are found in roughly 55%, 15%, and 30%of cases.34 10 In general terms the behaviour ofepithelial mesotheliomas is similar to that ofcarcinomas with local spread, large pleuraleffusions, and metastases to regional lymphnodes. Sarcomatous mesotheliomas areassociated more frequntly with distant metas-tases, little or no effusion, and shorter survival.Mixed mesotheliomas have intermediatefeatures.'" Among the biphasic and sar-comatous subtypes is a group of tumours inwhich more than 50% of the tumour consists ofdense, hypocellular collagenous tissue. Thesetumours have been termed desmoplastic malig-nant mesothelioma (DMM).67 In these studies,and in our own, there was a predominance ofsarcomatous mesotheliomas (sarcomatousDMM). Unlike Cantin,6 we found no realdifference in survival between cases of sar-comatous DMM (5-8 months) and biphasicDMM (6-8 months). Hillerdal,'2 in a review of4710 published cases of mesothelioma, foundthe survival in sarcomatous and biphasic typesto be five and 11 months, respectively. Theprognosis of our biphasic group with desmo-plasia was similar to that of sarcomatousmesotheliomas.

Asbestosfibre counts

No of asbestos fibres per gramof dried lung tissue(averagefrom two lobes) No of cases/14

20,000 0 (0%)20,000-50,000 2 (14-3%)50,000-100,000 5 (35-7%)100,000-1 x 10/6 6 (42-9%)

1 x 10/6 1 (7-1%)

Metastases were present in 87-5% of cases.These were frequently within the contralaterallung, but metastases were common at moredistant sites. Cantin6 found metastases in60 1% of DMM. Kannerstein7 also found ahigher incidence ofmetastases inDMMthan intheir general series of diffuse mesotheliomas.The survival time and the incidence of metas-tases, often at distant sites, strongly suggeststhat it is the sarcomatous component whichdictates outcome.

In all tumours the desmoplastic areas consis-ted predominantly or in part of dense bundlesofhyalinised collagen arranged in interweavingbundles, whorls, or a storiform pattern. Theirregular arrangement of the collagenous com-ponent is of diagnostic importance and waspresent to some extent even in spindled areaswhich appeared superficially similar to thebenign pleural plaque.

Collagen necrosis is a further diagnosticclue46 13 and was found in nearly 75% of cases.It was bland with no associated inflammationand often had a confluent geographical dis-tribution. If cytological atypia, in the form ofnuclear enlargement and hyperchromatism, isseen a diagnosis of malignancy is stronglysuggested. Invasion of lung parenchyma,adipose tissue, or chest wall confirms the diag-nosis. Because mitoses are only occasionallypresent in hypocellular areas, their absencedoes not preclude malignancy.The differential diagnosis ofDMM includes

non-specific reactive pleural fibrosis, as seen insome cases of tuberculosis, pleurisy, and

F rheumatoid disease.'4 Clinical history may behelpful. Diffuse pleural fibrosis,'14-6 associatedwith exposure to asbestos, has a basket weavepattern with little inflammation and no cellularfibroblastic proliferation. In all cases describedby Stephens et al'4 there was dense subpleuralparenchymal interstitial fibrosis and asbestosfibre counts were very high. Localised pleuralplaques should not cause diagnostic difficulty

f as the basket weave arrangement is regular andstoriform or whorled areas are absent. Solitaryfibrous tumours of the pleura (fibrous meso-thelioma) are unrelated to asbestos exposure

f and are usually well circumscribed.4 1720 Theyare composed of spindled cells resemblingfibroblasts and arranged in a haphazard,sometimes storiform, pattern. Foci of necrosismay be found, especially in larger tumours.

F The tumour cells are strongly positive forvimentin and negative for keratin. This con-trasts with malignant mesothelioma where thetumour cells are usually cytokeratinpositive.122 Though fibrous tumours of thepleura resemble the desmoplastic areas ofDMM, the macroscopic appearances andabsence of keratin should indicate the correctdiagnosis of fibrous tumour where this isconsidered. Primary sarcomas of the pleuralcavity are rare, and with occasional exceptions,22keratin negative.

Unfortunately, immunohistochemistry is ofno assistance in the more difficult diagnosticproblem of distinguishing sarcomatousmesotheliomas and DMM from pleural reac-

. tions characterised by abundant granulation

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tissue and fibrosis.25 This is because in reactivestates submesothelial spindle cells acquirecytokeratin intermediate filaments, usually oflow molecular weight, while retaining theirconnective tissue markers and so stain for bothcytokeratin and vimentin.132526 The same pat-tern of staining is seen in most sarcomatoidmesotheliomas.

In inflammatory pleural lesions there isusually active granulation tissue formationwith an acute and chronic inflammatory infil-trate and fibrosis. The fibrosis does not have astoriform or basket weave appearance andnuclear hyperchromatism is not a feature.Apart from malignant mesothelioma, other

epithelial and mesenchymal tumours may con-tain desmoplastic areas and, in these, there isgood evidence to indicate that this is theconsequence of stimulation of stromalmyofibroblasts.27 28 Many cells within the des-moplastic areas ofDMM are, however, positivefor cytokeratin, findings which are in accor-dance with those of Cantin.' Malignantmesothelial cells, in certain cases, seem toassume the functional capacity of fibroblastsand at least one study has shown that mesoth-elial cells can produce collagen in tissue cul-ture.29

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