Thorax 1981 ;36:901-905

Reactive mesothelial proliferation: a necropsy studyCD SHELDON, AMANDA HERBERT, PJ GALLAGHER

From the Department ofPathology, Southampton University General Hospital, Southampton

ABSTRACT To establish a histological standard against which surgical biopsy material could becompared, the degree of mesothelial proliferation was studied in 100 unselected necropsies. A minordegree of mesothelial hyperplasia was identified in 10 cases, usually close to areas of fibrous ad-hesions. Pleural plaques were present in 33 patients but there was no evidence of associatedmesothelial proliferation. No mesothelial changes were noted in patients with empyema or pleuralmetastases. These findings indicate that the degree of mesothelial hyperplasia in common disordersof the pleura is relatively slight. Significant mesothelial proliferation in needle biopsies shouldtherefore be viewed with considerable suspicion and, where clinically appropriate, be followed byfurther investigation.

The extensive use of asbestos in the Southamptonarea over a period of at least 25 years has led to ahigh local incidence of pulmonary and pleuralfibrosis and malignant mesothelioma. Over 150pleural biopsies are examined in our surgicalpathology laboratory annually but the evaluation ofmesothelial proliferation is a recurrent histologicalproblem. Although cytological examination ofpleural fluid is often useful in the investigation ofpulmonary carcinoma,3 the cytological diagnosis ofmalignant mesothelioma from pleural aspirates isnotoriously difficult.6 7We were primarily concerned that mesothelial

proliferation associated with common disorders suchas fibrous adhesions, pleural plaques, or empyematamight be a source of diagnostic confusion. To pro-vide a standard against which surgical biopsymaterial might be compared we have made a de-tailed histological study of the mesothelium in 100unselected necropsies.

Methods

The pleural and peritoneal cavities, the lungs andvisceral pleura, both surfaces of the diaphragm, andthe splenic capsule were examined in 100 necropsies.The number, size, and position of any lesions wererecorded and samples of normal and abnormaltissue taken for histology. Three levels of a block ofthe right lower lobe of the lung were cut at 15 ,umand examined unstained for asbestos bodies.

Address for reprint requests: Dr PJ Gallagher, Departmentof Pathology, Southampton University General Hospital,Southampton S09 4XY.

Using a four-point scale (nil, slight, moderate, andmarked) the degree of mesothelial hyperplasia,vasodilatation and fibrosis was assessed in both thevisceral and parietal pleural sections of each case.In addition a record was made of the nature anddensity of any associated inflammatory infiltrates.

Results

The causes of death of the patients studied are shownin table 1. The mean age of the 64 men was 66-6

Table 1 Causes ofdeath ofpatients studied

Cause of death Number ofpatients

Ischaemic heart disease 23Chronic cardiac failure 12Other cardiovascular causes 8Respiratory tract infections 14Pulmonary embolism 6Bronchial carcinoma 7Tumours other than bronchial carcinoma 8Renal disease 5Cerebrovascular accidents 4Septicaemia 4Trauma 3Others 6

Table 2 Frequency of macroscopic changes in pleuralcavities and splenic capsules

Macroscopic change Frequency (%)

Pleural plaques 33Fibrous pleural adhesions 22Areas of pleural fibrosis (not plaques) 10Inflammatory changes 14Secondary tumour deposits 8Hyalinised areas on splenic capsule 13No macroscopic abnormalities 33

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years (range 26-98 yr) and the 36 women 73-1 years(range 24-95 yr).MACROSCOPIC FINDINGSThe changes identified are summarised in table 2. In33 cases no abnormalities were detected. Fibrousplaques were present in 30 men and three women.They were most frequent in the posterolateralportions of the chest wall and tended to follow thesurfaces of the lower five ribs more than the inter-costal spaces. Lesions ranged from 0 5 x 0 5 cm. to10 x 12 cm. Of the 33 patients with pleural plaques17 had plaques alone, 12 plaques and fibrous ad-hesions, seven hyalinised areas on the splenic capsule,three associated pleural inflammation, and onemetastatic carcinomatous deposits. There was nosignificant statistical association between the pres-ence of pleural plaques and fibrous adhesions (X2 =2-6, p > 0 1) or pleural plaques and hyalinised areason the splenic capsule (X2 = 0-003, p > 0-5).

Fourteen patients had macroscopic evidence ofpleural inflammation. In one a large empyema had

Fig 1 Diagrammatic representation of the structure ofnormal parietal pleura (see text for details). p: parietalpleura, arrows: connective tissue bands (thin linescollagen, thick lines elastic), at: adipose tissue, sm:skeletal muscle.

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formed and in another extensive bilateral fibrinousexudates were present in both pleural cavities. Thechanges in the remaining 12 cases were relativelyslight.

MICROSCOPIC CHANGES

Normal pleural cavitiesNormal pleural histology is illustrated in figs 1 and2. The mesothelium is present as a single layer in allportions of the thoracic cavity and in many sectionsis barely discernible. A band of compressed connec-tive tissue, up to 100 ,um in thickness, separates themesothelium from the underlying adipose tissue.Between the adipose tissue layer and the intercostalskeletal muscles is a further compressed band ofconnective tissue (usually 80-120 um) containingrelatively more elastic tissue than the submesotheliallayer.

Mesothelial proliferationIn 90% of cases the mesothelium was entirelynormal. Mesothelial hyperplasia was identified in 10cases (seven men, three women; mean age 71-3 yr,range 62-87). In eight of these the hyperplasticchanges were seen close to areas of pleural fibrosisor fibrous pleural adhesions. Even in the most florid

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Fig 3 Slight hyperplasia of visceral pleural mesotheliumclose to an area ofpleural fibrosis. H and E, x 245.

cases (figs 3 and 4) there was only slight nuclearpleomorphism, and although nucleoli were occasion-ally conspicuous (fig 4) no mitoses were seen. Themesothelium rarely exceeded two layers in thicknesseven in areas close to fibrous adhesions (fig 4).Multilayering could usually be attributed to histo-logical artefact.

Pleural plaquesThe idealised structure of a pleural plaque is shownin fig 5. In the vast majority of the plaques sectionedthe mesothelial covering was incomplete. There wasno evidence of mesothelial hyperplasia or regener-ation, even in the three cases in which the mesothe-lium was intact. Occasional clusters of mixed chronicinflammatory cells were present at the periphery ofplaques. The central collagenous core was relativelyacellular and generally had a characteristic basketweave appearance. Plaque thickness varied between0 3 and 9 0 mm (mean 2-5 mm). Plaques greater thanabout 3 mm in thickness often had focal areas ofcalcification.

Asbestos bodiesIn 17 patients one or more asbestos bodies were

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Fig 4 Hyperplasia ofparietal pleural mesothelium in anarea ofpleural fibrosis. Some of the multilayering can beattributed to histological cutting artefact. H and E,x 125. Inset: conspicuous nucleoli of hyperplasticmesothelial cells. H and E, x 500.

identified in the sections of the right lower lobe. In11 of these cases pleural plaques were present, threehad areas of pleural fibrosis, one a primary bronchialcarcinoma, one pleural metastatic deposits, and onea normal pleural cavity. There was a significantassociation between pleural plaques and the presenceof asbestos bodies (X2 = 7 7, p < 0 01). There wasan occupational history of asbestos exposure in twoof the 10 male patients, but none of the seven women.

Fig 5 Diagrammatic representation of structure of apleural plaque (see text for details). Note central mass ofdense connective tissue protruding through mesothelialcovering (arrows).

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Fig 7 Parietal pleural deposit of metastatic bronchialcarcinoma. The mesothelial covering is barely discernible.HandE, x 145.

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Fig 8 Parietal pleura of a patient with an empyema.The mesothelium is partially necrotic (arrow). H and E,x 90.

Other microscopic changesNo mesothelial abnormalities were detected aroundtumour deposits or areas of pleural dust pigment-ation (figs 6 and 7). Acute inflammatory changeswere present in the pleura of 10 patients and chronicinflammation in six. When inflammation was exten-sive the mesothelium was often absent or necrotic(figs 8 and 9). A minor degree of mesothelial hyper-plasia was identified in one patient only.Discussion

The purpose of this study was to define the degree ofmesothelial proliferation that occurs in commondisorders of the pleural cavity. A clear-cut result wasobtained. Florid mesothelial proliferation was neverrecognised. A minor degree of hyperplasia wasidentified in 10% of cases, usually close to areas ofpleural fibrosis.

In any investigation of this nature it is importantto consider whether the patients studied were repre-sentative of the population that might be found inthe relevant clinical setting. Our cases, like thoseseen in most pulmonary units, were predominantlymale, and were elderly. Furthermore the incidence ofcommon macroscopic abnormalities, such as pleuralplaques, was similar to other and sometimes largernecropsy surveys.2 510

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Fig 9 Parietal pleura close to a fibrous adhesion. Manyfibrinous strands have formed but there is no associatedmesothelial hyperplasia. H and E, x 125.

Pleural biopsy often enables a diagnosis ofpulmonary carcinoma to be firmly established. Intwo recent series the rate of positive diagnosis inbiopsies from patients subsequently shown to havepulmonary carcinoma at operation or necropsy was

48% and 70%.1"' Our own experience is that thediagnosis of malignant mesothelioma from needlebiopsies of the pleura is far more difficult than thatof bronchial carcinoma. Klima and Gyorkey em-

phasised that binucleation and hyperchromaticitywere consistent findings in the mesothelium ofpatients who were later shown to have malignantmesothelioma.4 However Rosai and Dehner reporteda wide variety of histological abnormalities, in-

cluding mitotic activity and multinucleation, in aseries of 13 cases of mesothelial hyperplasia in ab-dominal hernial sacs.8 Despite this report we con-sider that the results of our study, coupled with thefindings of Klima and Gyorkey,4 indicate thatmesothelial changes such as nuclear hyperchroma-tism, atypia, or mitotic activity must not be lightlydismissed. They are unlikely to occur in non-neoplastic disorders of the pleura. Such patients,particularly those with an occupational history ofasbestos exposure, or an unusual pattern of pul-monary illness should be rebiopsied, and appropriatefurther investigation or follow-up planned.

We thank the Department of Teaching Media,University of Southampton for preparing the art-work and Miss Margaret Harris for typing themanuscript.

References

1 Deluccia VC, Reyes EC. Percutaneous needle biopsy ofparietal pleura. Analysis of 50 cases. NY State J Med1977;77:2058-61.

2 Francis D, Jussey A, Mortensen T, Sikjaer B, Viskum K.Hyaline pleural plaques and asbestos bodies in 198randomised autopsies. Scand J Respir Dis 1977;58:193-6.

3 Frist B, Kahan AV, Koss LG. Comparison of the diagnos-tic values of biopsies of the pleura and cytologic evalu-ations of pleural fluids. Am J Clin Pathol 1979;72:48-51.

4Klima M, Gyorkey F. Benign pleural lesions and malignantmesothelioma. Virchows Arch 1977 ;376:181-93.

5 Meurman L. Asbestos bodies and pleural plaques in aFinnish series of autopsy cases. Acta Pathol MicrobiolScand 1966; Supplement 181.

6 Naylor B. The exfoliative cytology of diffuse malignantmesothelioma. J Pathol Bacteriol 1963 ;86:293-8.

Roberts GH, Campbell GM. Exfoliative cytology ofdiffuse mesothelioma. J Clin Pathol 1972;25:577-82.

Rosai J, Dehner LP. Nodular mesothelial hyperplasia inhernia sacs. A benign reactive condition simulating aneoplastic process. Cancer 1975 ;35:165-75.

Rous V, Studeny J. Aetiology of pleural plaques. Thorax1970 ;25 :270-84.

10 Robinson JJ. Pleural plaques and splenic capsular sclerosisin adult male autopsies. Arch Pathol 1972;93 :118-22.

Van Hoff DD, Li Volsi V. Diagnostic reliability of needlebiopsy of the parietal pleura. A review of 272 biopsies.Am J Clin Pathol 1975;64:200-3.

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