Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura.

Thorax(1976),31, 15

Pleuropneumonectomy in the

management

of

diffuse malignant mesothelioma of

the pleura

Experience

with 29

patients

E.

G.

BUTCHART,

T.

ASHCROFT1,

W. C.

BARNSLEY,

and M. P.

HOLDEN

Departmentof Cardiothoracic Surgery, Shotley Bridge General Hospital andDepartmentof Pathology, University of NewcastleuponTyne

Butchart,E. G.,Ashcroft,T.,Barnsley,W. C., and Holden, M. P. (1976). Thorax, 31, 15-24. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experiencewith 29 patients. An analysis is made of the results of pleuropneumonectomy for diffuse malignant pleural mesothelioma in 29 patients and acomparison is made withthe

resultsof non-surgicaltreatmentinafurther17patients. Asystemoftumourstaging is

pro-posed, and the resultsarecorrelatedwithtumour stageand withhistologicaltype. Pleuropneu-monectomydoesnotappear materiallyto affect thecourse ofthe disease incasesofmixed

epithelial and mesenchymalhistologicaltype. However,stageIcasesofpureepithelial

histo-logicaltypeappeartocarry abetter prognosis, especiallythosewhosehistologicalstructure

consistsentirely of abundant oedematous mucoidstromawithloosely arrangedtumourcells. It is suggested therefore that only epithelial cases should besubjected to pleuropneumon-ectomy. Means ofreducing operative mortality are discussed and alternative methods of

treatmentdescribed.

Diffuse malignant mesothelioma of the pleura is a highly malignanttumour, the course of which aver-ages nine monthsfromdiagnosis todeath (Wagner, 1971)or 13 to 14monthsfromfirstsymptom to death (Elmes,1973a).Veryfewpatients survivelonger than twoyearsirrespectiveofthe treatment they receive. Thishas ledto aconservative attitudetothe manage-mentofmesothelioma, exemplified byarecentreview oftherapeutic alternatives(Elmes, 1973b)inwhichthe conclusion was that all forms of treatment were valueless and that onlysymptomatic treatment was justified. In

particular,

reviewing

surgically

treated cases, Elmes could find no authenticated case of prolonged survival.

Asbestos exposure on Tyneside occurs in many industries, notably shipbuilding (Ashcroft, 1973), and ourresulting experience with arelatively large series of patients with diffuse malignant meso-thelioma leads us to dispute this conservative ap-proach. A study of our surgical and pathological

'Present address: Department of Pathology Leighton Hospital, Crewe,Cheshire

experience enables us to make a reappraisal of the place ofpleuropneumonectomy.

MATERIAL AND METHODS

SURGICAL PATIENTS Twenty-nine patients (20 men and 9 women) underwent pleuropneumonectomy between 1959 and 1972. Themean ageatoperation was 52 4 (range 35-63) years. Mostpatientsgave a historyofasbestoscontact,oftenover morethan 30 years before developingsymptoms. Thecommonest

presenting symptoms were pain and dyspnoea, sometimes associated withafeeling ofheaviness on theaffected sideof the chest. Their chestradiographs showedeitherapleural effusionorpleural thickening. The time between onset ofsymptoms andoperation averaged9 5months(range2monthsto 4years).

In 17 patients, the disease involved the right pleura, and in 12patients theleft.

NON-SURGICALPATIENTS Seventeen

patients

(16

men and 1

woman)

received various combinations of medical treatment:

E.G. Butchart, T.Ashcroft, W. C. Barnsley, and M. P. Holden Pleuralaspiration only 6patients

Intrapleural cytotoxic drugs 2patients Intrapleural radioactive gold 1 patient Intrapleuralcytotoxic drugs 1 patient

and radioactivegold

Intrapleuralcytotoxic drugs 1 patient andradiotherapy

Norecord of treatment given 6patients Because of incomplete records and the small numbers of cases involved, no attempt has been made toassesstheresults of any specific form of treatment. Instead, they have been used as a relatively homo-genous groupofnon-surgical cases for the purpose of comparison.

The mean age at onset of symptoms was 58-5 (range 47-73) years.

DIAGNOSIS Inthesurgical patients, the diagnosis was suggested by thecombination ofasbestos exposure andradiographic evidence of pleural pathology and in some cases confirmed by pleural fluid cytology and needle biopsy ofthe pleura. In many patients, however, theradiologicalappearance ofthe charac-teristicpleural thickeningwasregardedassufficiently pathognomonic, and the diagnosis was confirmed atoperation by frozen section histology.

All the non-surgical patients had the diagnosis confirmedatnecropsy.

SURGICALTECHNIQUE Thesurgical approach for all cases was a standard posterolateral thoracotomy throughthe bed of the excised 6thrib. Blunt dissection wasbegunextrapleurally,and theparietal pleurawas

stripped off the chest wall. From the apex, the mediastinal pleura was stripped down towards the hilum, taking the paratracheal nodes en bloc. The internal mammary vessels were ligated at the apex and inferiorly, and the lymph nodes in relation to thesevesselsweredissected offthe chest wall with the pleura.

Anteriorly, the pericardium was opened and ex-cised widely asitwas frequently involvedby direct extension of tumour.

Posteriorly, the extrapleural dissection was con-tinued to the hilum, dissecting out subcarinal and paraoesophagealnodes. Thepericardiumwasopened posteriorlyoverthe leftatrium.

Hilar structures were dealt with in a standard fashion asin any intrapericardial pneumonectomy. The diaphragm in most cases was completely excised, the tumour often being thickestatthispoint.

In five cases with minimal diaphragmatic involve-ment,itwaspossibletodevelopaplaneof dissection between thediaphragmatic muscle and the perito-neum, leaving the latter almostentirelyintact.

The surgical specimen therefore consisted of pleura, lung, lymph nodes, ipsilateral pericardium, and diaphragm. In 24 cases, it was necessary to reconstruct the diaphragm using industrial nylon or Dacron-reinforced

Silastict

which was sutured to the chest wall or a rim of healthy diaphragm and the inferior pericardium withacontinuous suture. In the remaining five cases, the diaphragmatic peritoneum wasclosed, producingasatisfactory barrier between the chest andabdomen.

In 15

cases,

thepericardial defect was patched with nylon or Dacron-impregnated Silastic, and in the remaining 14 cases it was left open.

PATHOLOGY The histological diagnosis was re-viewed and confirmed in all 46 cases by one of us (T.A.). The tumours were classified histologically into three types: pureepithelial,mixedepithelialand mesenchymal, and puremesenchymal (TableI). The histological criteria were those generally accepted (McCaughey, 1958 and 1965; Hourihane, 1964; Ashcroft, 1973). Wedid notsubdivide theepithelial groupinto anundifferentiatedpolygonal type anda

tubopapillary type, as suggested by Whitwell and Rawcliffe

(1971),

because boththese types occurred incombinationin some cases.

TABLE I

HISTOLOGICAL CLASSIFICATION OF DIFFUSE MALIGNANT MESOTHELIOMA

Surgical Non-surgical

Histology Patients Patients Total

Epithelial 11 7 18 (39-1%)

Mixed 17 7 24 (52-2%)

Mesenchymal 1 3 4 (8-7%)

Total 29 17 46

However, we were able to

identify

a

histological

variant within the

epithelial

group showing a dis-tinctive histological structure, characterized by abundant oedematous mucoidstromaand

relatively

small

numbers ofloosely

arranged

tumourcellswith poorly formed tubules, clefts, and sometimes

cystic

spaces (Figs. 1 to

3).

This variant occurred in pure form in threepatientsandwasclassifiedas

epithelial

typeA.Epithelialcasesshowingnoevidence of these featureswereclassifiedas

epithelial

typeB, andthose showingthe featuresof type A in

varying

proportions

with the moreusual

tubopapillary

structure astype AB(Table

II).

Thejustificationforthis subclassifica-tion is its apparent

prognostic significance,

which is discussedbelow.

In addition, in order to facilitate

analysis

of the

'DowCorningCorporation, Midland,Michigan,USA,48640

Pleuropneumonectomy in themanagementof

diffuse

malignant mesothelioma 17

7t,,

j$

-

~~~~~~-'d

-

j

L::

.t..-... *.t, p5>7-st~~~~~~.. --c~~~~~~~~~~~~~~~~~~~-N...

FIG. 1. Case 11 (see Table VI). Showsoedematousmucoid stroma, separating irregular spaces which arepartlyfilled with tumour cells (Haematoxylin and eosin x 85).

Vr

4. 'K 'Jr.

... O.~

9F

FIG.2. Case2(seeTable VI). Shows similartissueto Fig. 1 including poorly formed tubules (HandEx85).

E. G. Butchart, T.

iX

Ashcroft, W. C. Barns/ey,and M. P. Holden

secwWF

| e.k, '#.

i~~~~~li

_* -...A..

V t#>.<, a Vs^ , i;^ wX v :.. A s... v ._ y: *! *~~~~~~~~~~~~~~~~~~~~~~~~~~~~~w #f w 8 °* -t F' '.v:A x + ^ a W.'sjb

w~~~~~~~~~

44.4.

}..s.s;<k.s.s...X

^ ft

z~~~~~~~~

A:W+' ,' ::X -a]A*w4...a v .

FI.*Y 3. Cas 34

(see

Tal IX) Slow a eino eeaos vain inatuou... cotinn

otei tye (HandE x180)

TABLE II

SUBCLASSIFICATION OF THE EPITHELIAL GROUP

Surgical Non-surgical

Type Patients Patients Total

A 3 0 3(16 7%)

AB 2 2 4(22-2%/0)

B 6 5 11 (61 1/)

Total I1 7 18

results, a system of tumour staging is proposed (TableIII).

TABLE III

CLINICOPATHOLOGICALSTAGINGOF DIFFUSE

MALIGNANT MESOTHELIOMA

Stage ClinicopathologicalStaging

I Tumour confined to homolateral pleura, lung, and

pericardium

It Tumourinvading chest wallor involvingmediastinal

structures, eg,oesophagus, heart,opposite pleura

Lymph nodeinvolvement within the chest

1It Tumourpenetrating diaphragmtoinvolveperitoneum

directly

Lymph node involvement outsidethechest

IV | Distant blood-bornemetastases

100 5 so 50 \ c 25 0 6 12 8 24 30 36 Survival (months)

FIG.4. Overallpostoperativesurvival. Thesteepfall of the graphrepresentshospital mortality.

whole series was 31

%

and that only three patients (10-3

%)

survived two years or longer. However,

twoofthesethreepatientsarealive and wellwithno

evidence of recurrence 3j and 6 years respectively afteroperation.

Immediate results Hospital mortality showed a marked increaseoverthe ageof 60 years(Table IV). Analysisof thehospital mortality (TableV)revealed that seven of the nine deaths could have been pre-ventedbybettercaseselection,alterationin

surgical

technique,orbetterpostoperativemanagement.

Inadditiontothe ninedeaths, four other

patients

experiencedsignificantpostoperative

complications:

three patients suffered thromboembolic

complica-tions and one patient required reoperation for a

RESULTS

SURGICAL CASES The postoperative survival curve

(Fig. 4) shows that the hospital mortality for the 18

Pleuropneumonectomy in themanagementof difluse malignant mesothelioma TABLE IV

HOSPITAL MORTALITY RELATEDTO AGE

No. of No. of

Age Group Cases Deaths Mortality

30-39 2 0 0

40-49 10 3 30

50-59 9 2 22 2

60-69 8 4 50

TABLE V

ANALYSIS OF HOSPITAL MORTALITY (9 CASES)

Respiratory failure 3cases

Respiratory failure+bronchial

fistula Icase

Pneumonia in remaininglung 1case

Theoretically Pulmonary oedemafollowing preventable resuscitation from cardiacarrest

due tomassive haemorrhage 1case

Secondary haemorrhage into

pneumonectomy spacefollowing

anticoagulants I case

'Unpreventable' Massive pulmonary embolism 1case

Myocardial infarction 1case

chylothorax. The total complicationratewas44-8%. In two patients dying from respiratory failure, complications related to the prosthetic diaphragm

werecontributory factors. Inonepatient, ineffective

suturing of the prosthesistothechest wall permitted the stomach to herniate into the pneumonectomy

space posteriorly, necessitating reoperation. In

another patient,abronchialstumpfistula developed during prolonged artificial ventilation, and air under tension in thepneumonectomyspaceescaped between

the diaphragmatic prosthesis and the chest wall to

presentdramaticallyas atensionpneumoperitoneum.

Lateresults Tables VIand VIIpresentthe relevant

data for epithelialcasesandcasesof mixed epithelial

and mesenchymal type respectively. There was no

statistically significant difference in theagesof these

two histological groups. Only one case of pure

mesenchymal type was encountered in the surgical

series, and the patient unfortunately died in the immediatepostoperative period.

Table VIII relates survival to tumour stage and histological type.Statistical analysis of the results in patients who survived operation shows that:

1. Comparing all epithelialcases and all casesof

mixed epithelial and mesenchymal type, a

significantly higher survivalrate(p<0-01) in the epithelial group can be demonstrated only at

sixmonths after operation.

2. Comparing all patients with stage I tumours,

significantly more of the epithelial group

(p <005) survived oneyear or more.

3. Comparing patients of epithelial type, sig-nificantly more patients with type A tumours

(p<0'05) survivedmorethantwoyears. NON-SURGICAL CASES Table IX shows the survival time from theonsetofsymptomsuntil death in each histologicalgroup.Nocasesof mixedtypeor

mesen-chymaltypesurvivedlonger thantwoyears,whereas threepatients with epithelial typetumours (42-9 %) lived three years or longer. Some patients with epithelialtumoursobviously haveabetterprognosis,

buttaking thegroup as awhole, there isnostatistically

significant differenceinsurvival between thepatients with epithelial tumours and those with mixed or

mesenchymal tumours.

Table X shows the pathological staging of the

tumour at necropsy in each histological group.

Small numbers make statistical analysis unhelpful butit isinterestingto notethat 100%ofmesenchymal

TABLE VI

DETAILED ANALYSIS OF 11 CASES OF EPITHELIAL TYPE

Subsequent

Total Radiotherapy

Case Ageat Sub-type Tumour Lymph Diaphragm Chest Post- Survival

Operation Stage Node Pene- Wall operative (months) Time

Involve- tration Involve- Survival 1st Interval Reason

ment ment (months) symptom (months)

todeath 1 63 B I 0 0 0 0 4 2 60 A I 0 0 0 0 36 3 62 AB II + 0 0 6 8 4 48 B III 0 + 0 7 12 5 60 B III 0 + 0 11 23 6 35 B I 0 0 0 15 5 12 Recurrence inscar 7 57 B I 0 0 0 16 19 8 56 B 11 + 0 0 17 23 9 60 B IX 0 0 + 21 24 10 49 A I 0 0 0 411 651 | 57 A I 0 0 0 751 1231

'Patients still alive.

E.G.Butchart,T. Ashcroft, W. C.Barnsley,and M. P. Holden TABLE VII

DETAILED ANALYSIS OF 17 CASES OFMIXED EPITHELIAL AND MESENCHYMAL TYPE

Subsequent

Total Radiotherapy

Age at Tumour Lymph Diaphragm Chest Post- Survival

Case Operation Stage Node Penetration Wall operative (months) Time

Involvement Involvement Survival (I st Interval

(months) symptom after Reason

todeath) Operation (months) 12 61 1 0 0 0 0 11 13 63 II 0 0 0 12 14 49 I 0 0 0 0 ? 15 59 1 0 0 0 0 9 16 45 II 0 0 0 8 17 52 II 0 0 0 2 18 55 1 0 0 0 3 5 19 47 1I 0 0 3 8 20 53 1 0 0 0 3 9 21 50 1 0 0 0 3 9 22 44 1 0 0 0 4 14 3 _claviculir Supra-lymphnode Irretastases 23 47 I 0 0 0 4 6 24 60 I 0 0 0 4 16 3 Tumour recurrence inwound 25 44 it 0 0 8 1 1 26 54 1 0 0 0 9 13 27 38 1 0 0 0 22 30 28 43 1 0 0 0 24 48 16 Tumour recurrence in chestwall TABLE VIII

ANALYSIS OF POSTOPERATIVE SURVIVAL RELATED TO

fHISTOLOGICAL TYPE AND TUMOUR STAGE (HOSPITAL

DEATHS EXCLUDED) TumourStage Epithelial TypeA 411 751 Type AB 6 TypeB 15 16 17 21 7 11

Mixedepithelialand 3 3 3 4 4 3 8

mesenchymal 4 9 22 24

'Still aliveand well.

Thefigures in the tablerepresent thesurvival in months for each

patient.

tumourshad alreadyreached stageIV atthetime of death,whereastwoof theepithelialtumours(28-6%)

werestillin stageIinspiteof long histories. Inboth of these patients, death was accelerated by right heart failuresecondarytobulk of tumourin thelung and massivepleuraleffusion.

COMPARISON OF SURGICAL AND NON-SURGICAL CASES

Analysing data from Tables VI, VII, and IX and comparing survival times from first symptom to death in surgical and non-surgical cases, it is not

surprising to find that there is no statistically sig-nificant differencein thesurvival ofthetwogroups,

TABLE IX

DETAILEDANALYSIS OF THE NON-SURGICAL

NECROPSY SERIES

Total

Tumour Survival

Age at Stage (months)

Case Histology Death atDeath (1st

symptom todeath) 30 E B 62 IV 10 31 E AB 65 IV 10 32 E B 48 1I 11 33 E B 60 III 12 34 E AB 76 I 36 35 E B 75 IV 96 36 E B 67 1 144 37 EM 66 IV 5 38 EM 62 IV 8 39 EM 58 IV 12 40 EM 52 IV 13 41 EM 60 III 18 42 EM 56 II 20 43 EM 62 IV 24 44 M 60 IV 5 45 M 55 IV 8 46 M 61 IV 24

either overallorwhenanalysedforeachof the

histo-logical types. Operative deaths wereexcluded from

theanalysis.

Insufficient information is available from the

hospital records of the medically treated cases to

make any comparison of morbidity in the two

groups.

Pleuropneumonectomy in the management of difjuse malignant mesothelioma TABLE X

TUMOUR STAGE AT NECROPSY (NON-SURGICAL CASES)

RELATED TO HISTOLOGICALTYPE

Tumour Stage

Histological Type I |I III IV

Epithelial 28*6% 14-3% 14-3° 42.9%

Mixedepithelial and

mesenchymal 14-3% 14-3% 714%

Mesenchymal 100%

DISCUSSION

Sincediffuse malignant mesothelioma of thepleura

wasfirst recognizedas aclinical entity there has been

controversyabout the best form oftreatment,and the

presentmultiplicity oftreatmentregimens testifiesto

the lackofsuccessofmostof them.

Theforms oftreatmentcurrently practisedcanbe

classified as palliative or radical. Most forms of

palliativetreatment seekto relieve dyspnoea by the prevention of recurrent pleural effusion. Methods advocated forproducing pleural symphysis include thoracotomy and poudrage (Prorok and Nealon, 1968), pleuroscopy and poudrage (Scarbonchi and Razzouk, 1967), and simple pleurectomy(Merlier, le Brigand, and Wapler, 1968; Lanitis and Waridel, 1973), the latterhaving the additional advantage of pain relief. However, themostsatisfactorymeansof

achieving pleural symphysis appears to be tube drainage with maintained suction and the intro-duction of cytotoxicagents (Leininger, Barker, and Langston, 1969; Anderson, Philpott, and Ferguson, 1974), the latter causing adhesion largely by their irritant action on the pleural surfaces. Pain due to

chest wallinvolvement ismosteffectively relieved by palliative radiotherapy(Schliengeretal., 1969).

The termradical treatment implies the complete elimination oftumourinthehope of achievingacure.

High dose radiotherapy is often referredtoasradical

or 'aggressive' treatment but, although tumour

shrinkage has been reported insome cases(Eschwege

and Schlienger, 1973), complete elimination of tumourhasneverbeen achieved, and the high doses

required have a very detrimental effect on lung

function whichprogressesfor 6-12 months. High dose

radiotherapy should probably be regarded onlyas a

methodof obtaining slightly longer-term palliation. The only treatmentfor this disease which can be

termedtruly radical, therefore, issurgery.Eiselsberg

(1922)wasthe firsttorecommendradicalsurgeryfor

diffuse malignant mesothelioma of the pleura but, owing tothe limitations ofthoracic surgeryat that time, he didnotremovethewhole lung. Subsequent authors(Harris, Hyman, and Nevins, 1959; Saltzer, 1959; Jagdschian, 1962 and 1970) advocated

pleuro-pneumonectomy as the treatmentof choicefor this condition, and the first pleuropneumonectomy for diffusemalignant mesothelioma in this clinic andalso probably the first in this country was performed by Mr. G. A. Mason in February 1949 (because of incomplete records the patient was not included in the present series).

Thefact thattwopatientsinthe series arestill alive and well and free from recurrence 3j and 6 years respectively afterpleuropneumonectomyshows that the operation can be successful. Nevertheless, the generally poor results obtained in this series andin others (Ehrenhaft, Sensenig, and Lawrence, 1960; Porter and Cheek, 1968; Hertzog and Toty, 1968; Merlier etal., 1968;Seliverstov,1970;Bartoszewicz, 1971; Lanitis and Waridel, 1973) necessitate a re-appraisal of the place of pleuropneumonectomy. Some authors (Hertzog and Toty, 1968; Merlieretal., 1968; Schlienger et al., 1969; Herrmann and Herr-mann, 1972) havecondemned the operation on the groundsofitshigh immediate mortality,thedifficulty in achieving tumour clearance, the risk of seeding tumour in the chest wall, and the poor long-term survival figures. The unsubstantiated view that surgical treatment may result in distant metastases (Elmes,1973b) has been refuted by Whitwell (1973). Previous authors have not related their results to histological type or to tumour stage, and,with the exception of Elmes(1973a and 1973b), who studied casesfrom several centres inGreat Britain and cases from theliterature,allauthors drawconclusionsfrom personal experience of small numbers ofcases, the largest series being thatofI{ertzog and Toty(1968), whoreported six cases.

Withpersonal experienceofamuchlargernumber of cases, certain points emerge which enable an attempt to be madeto answerthecriticisms against radicalsurgery:

1. High mortality alone should not condemn an operation but should stimulate thought into meansofreducingthemortality. In ourseries, seven out of nine deaths were considered preventableby better case selection, improved surgical technique or better postoperative management.

2. The margin of tumour clearance in pleuro-pneumonectomy is necessarily small but in many cases ofdiffusemalignantmesothelioma this isadequateasthe disease remains confined to the pleura for a long time, showing little inclination to invade the adjacent skeletal muscle of the chest wall (Jagdschian, 1970). Where chest wall invasion has taken place multifocally the patient is not suitable for pleuropneumonectomy.

E. G. Butchart, T.Ashcroft, W. C. Barnsley, and M. P. Holden 3. Studying survival in relation to histological

type and pathological staging and planning management accordingly is now practised for most tumours, and mesothelioma should be no exception.

When this procedure is applied to meso-thelioma it is possible to identify a group of patients whose prognosis justifies the applica-tion of radicalsurgery.

SIGNIFICANCE OFHISTOLOGICALTYPING Innecropsy

studies, Whitwell and Rawcliffe (1971) found distant metastases from epithelial tumours much less frequent than from tumours containing mesen-chymal elements. These findings correlate well with our ownnecropsyseries (TablesIXandX). Although further work is necessary on the subject,it appears from our results that the mesenchymal element of mesothelioma, whether occurring in pure form or mixed with theepithelial element, renders the tumour more malignant. The epithelial element when it occursinpureform appears to carry a better prog-nosis, particularly when it is composed entirely of type A.Onlythree casesoftype Aepithelialtumours were seen(TableVI) in thesurgical series; all three hadlong histories before operationand the two who survived operationare bothalive and well with no recurrence. Itisinterestingthat no case of pure epi-thelial type A was encountered in the non-surgical necropsyseries andthat the two long-termsurvivors (cases 35and36)wereboth oftype B.

There seems little doubt that mesenchymal tumours, pure ormixed,have a poor prognosisand do not justify radical surgery. Examination of a larger series of epithelial cases is required to clarify the association of type A tumours withprognosis, and it is our opinion, therefore, that all stage I epithelialtumours should be given the opportunity of radical surgery.

CLINICAL STAGING OF MESOTHELIOMA Mediastinal lymph node involvement can be assessed by medi-astinoscopyand macroscopical diaphragmatic pene-tration by radiology of the undersurface of the diaphragm using artificial pneumoperitoneum. Al-though there are no reports in the literature ofthe latter technique being used in diffuse malignant mesothelioma, itsvalue inoutlining other diaphrag-matic pathology has been reported (Trimble and Leftwich, 1955; Stevens and McCort, 1964; Meyers, 1973). Extensive or multifocal chest wall invasion shouldcontraindicate radical surgery. However, we areinagreement withJagdschian (1970) in believing that the tumour is rarely locally inoperable in this way.

MANAGEMENT OF THE INDIVIDUAL CASE Thefollowing plan of management (Fig. 5) issuggested for patients presenting with diffuse malignant mesothelioma of thepleura: Patients Pane ts under bO

overt

Fir Unfit Stage Staqe I IIor III E M;

Pleuro- Hiqhdose Tubedrainaqe pneumonectomy Radiotherapy +suction

+cytotoxics

FIG. 5. Schematic representation of the management of diffuse malignant mesothelioma ofthe pleura: E = epi-thelial type; ME=mixed epithelial and mesenchymal

type; M= mesenchymal type.

1. Exclude patients over the age of 60, unless exceptionally fit, from consideration for radical surgery, because of the high mortality rate inthis age group.

2. Inpatients under60, carry out detailed assess-ment of respiratory and cardiac status. The patient'saccountof his exercise tolerance before the onset ofsymptoms is important. Evidence ofischaemicheart disease, moderateor severe chronicbronchitis,emphysema, excessive obes-ity or any diseaselikelytoaffectthefunctionof the remaining lung should contraindicate surgery and high dose radiotherapy. These patients should receive palliative treatment. 3. In those patients considered fit for major

surgery,proceedto:

(a) mediastinoscopy. Obtain mediastinallymph nodes for biopsy. Involved lymph nodes should contraindicate pleuropneumonec-tomy.

(b) artificialpneumoperitoneum andradiology of the undersurface of the diaphragm. This should have a smooth concavesurface and anything to suggest

penetration by

tumourshouldcontraindicatesurgery. 4. If the investigations above suggest that the

tumour has not progressed beyond stage I, proceed to open pleural biopsy and frozen section histology. An accurate

histological

diagnosis,identifyingthetype of

mesothelioma,

requires a large sample of tumour

(needle

biopsyistherefore

unsuitable),

asit is

possible

Pleuropneumonectomy in the management of

diffuse

malignantmesothelioma for some partsof the tumour to appearentirely

epithelial and others mesenchymal.

5. Proceed to pleuropneumonectomy only if frozensection histology shows the tumourtobe of pureepithelialtype.

6. Inallfitpatients with mixed andmesenchymal histological type and in stage II cases of epi-thelial type, the useof high dose radiotherapy maybeworth while to achieve somewhat longer-termpalliation.

7. In those patients unfit for either surgery or

high-dose radiotherapy,thebest form of pallia-tion appears to be a combination of tube drainage with maintained suction and intra-pleural cytotoxic drugs.

PREVENTION OFHOSPITAL MORTALITY AND MORBIDITY

If pleuropneumonectomyis to be recommended for selected cases of diffuse malignant mesothelioma, means of reducing the operation's present high mortality and morbidity must be sought. Careful cardiorespiratoryassessment and exclusion of high-riskpatients as detailed above should substantially reduce the incidence of respiratory failure post-operatively. Further reduction in the complication rate can be achieved only by attention to operative technique and postoperative management.

During the operation care should be taken to secure haemostasis as theoperation proceeds, rather than leaving haemostasis until the specimen is removed. Inthisway verylargeblood losses and the risks of rapid blood transfusion can be avoided. Particular attention should be paid to haemostasis during the separation of the diaphragm from its peripheral attachments or large amounts of blood may drain into the peritoneal cavity and remain unaccounted for. If haemostasis is incomplete in this situation, bleeding into the peritoneal cavity maycontinuepostoperatively toproduceunexplained hypovolaemia.

Soundsuturingof thediaphragmaticprosthesis to the chest wall is essential and is moreeasily accom-plished if the prosthesis is sited higher than the original diaphragm.

Postoperativemanagement shouldbeundertaken in a cardiothoracicintensive care unit. Everyeffort should be made to achieveoptimumhaemodynamic status, ventilation, and acid-base balance within the first few hours after surgery, if necessaryinstituting artificialventilation until the dayafteroperation.

CONCLUSIONS

Pleuropneumonectomy is a formidableoperationand our results show that it cannot be justified as the treatment ofchoice for all cases of diffusemalignant mesotheliomaof thepleura.However,ifthehospital

morbidity and mortality can be reduced, it seems justified to recommend the operation for stage I

casesofpureepithelialtype.

We are indebted to Mr. R. A. McNay and Mr. J. A. Furness for statistical advice, to Dr. Heinz Neef, Martin Luther University SurgicalClinic,Halle-Saale, East Germany, for translating the many German papers referred to, and to Miss M. I. Appleton for typing the manuscript.

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(1973b). Therapeuticopenings in the treatment of mesothelioma. In Biological Effects of Asbestos, pp.277-280.TheInternational Agency for Research

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Eschwege, F. andSchlienger, M. (1973). Laradiotherapie des mesotheliomes pleuraux malins. Journal de Radiologie, d'Electrologie et de MedecineNucleaire, 54,255.

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