1303

Screening for Disease *

CANCER SCREENING BY CYTOLOGY

KEITH J. RANDALLPathology Department, Orpington Hospital, Orpington,

Kent

FOR a number of sites it has been suggested thatcytology, used as a selective screening procedure,could identify cancer at an early and theoreticallycurable stage. Five of these sites will be consideredin this brief review-uterine cervix, bronchus, blad-der, stomach, and oral cavity. The accessibility ofthe uterine cervix made it the first target for the

diagnosis of preinvasive cancer by cytology. Indeed,as will be seen, only the cervix can satisfy the criteriaoutlined in the opening article of this series: carci-noma at this site carries a high mortality; effectiveand acceptable treatment, by conisation of the cervixor hysterectomy, is available and practicable; and

screening can alter the natural history of the diseasein a significant proportion of those investigated.

CERVIX UTERI

There is little doubt that an adequate cervical smearcan detect carcinoma-in-situ of the cervix. However,several workers (notably Yule’) have shown that asmany as one-fifth of true-positive cases may be missedby a single examination. This has prompted cytolo-gists to suggest that all women entering a screeningprogramme should have their first two tests done close

together-within, say, a year.Few people would now accept the view that

carcinoma-in-situ as picked up by cytological methodsis a separate disease from invasive cancer (a contro-versy lately reviewed by Langley 2). Work by Wake-field et al.3 adds weight to the contention that theyare closely related; they found a close correlationbetween positive smears and mortality from invasivecarcinoma when both are analysed with reference tothe husband’s occupation. However, we still do notknow what percentage of preinvasive cervical lesionsprogress to invasive disease 2 In 1971 Spriggs’ out-lined a follow-up study of women with positive smearswho refused treatment, and this approach could pro-vide useful information about the natural history ofcervical cancer.Although screening has been used in many parts

of the world for a number of years, it is only lately thatresults which show a fall in the incidence and mor-

tality for invasive disease have appeared. In BritishColumbia 80% of women over 20 years of age havebeen screened, and the corrected mortality of this

group fell from 11-4 per 100,000 in 1958 to 6-9 per100,000 in 1970.5 However, the incidence of clinicalcarcinoma in the screened group was still 14% ofthat in the unscreened population, and this suggeststhat the maximum benefit to this screened populationis the reduction of clinical carcinoma to about one-

*A report of this series will be available early in 1975 (seeLancet, Nov. 2, p. 1092).

seventh of its previous rate. In the city of Aberdeçn,6where cervical screening covers 90% of the at-risk

population, the rate of clinical carcinoma in 1971was less than half the rate 10 years earlier, and between1961 and 1971 the mortality-rate for carcinoma of thecervix fell by nearly 30% (the corresponding fall forEngland and Wales being about 10%). In Finland’ 7

screening is offered to women between 25 and 60

years of age in a total female population of 2,400,000,and the attendance-rate for the country as a wholeis 78 %. . The incidence and mortality for cervicalcancer for those under 60 years of age fell by abouta third.

These results, and others from different countries,suggest that cervical cytology offered as a selective

screening procedure can significantly reduce the mor-tality from carcinoma of the cervix. However, cer-vical screening is frustrated by the fact that thosemost at risk are the least likely to attend regularly, orat all, for testing. A valuable survey of the attitudesof women at risk has been reported by Wakefield andhis colleagues in Manchester.8As many as 30% of positive smears are now being

found in women under 35. This may be due to

changes in patterns of sexual behaviour or to the useof non-barrier forms of contraception. It seems

reasonable to suggest that steps now being taken toidentify and treat these cases should prevent a risein the incidence and mortality of cervical carcinomathat otherwise might be expected 10 years from now.The cost benefit of cervical screening is unknown.

6 years ago Knox 9 estimated that the cost of pre-venting a case of clinical carcinoma might be El 000.However, at a recent meeting of the British Societyfor Clinical Cytology the Aberdeen workers 10 whohave carried out a detailed study of costs presentedfigures to show that in their area, at least, the averagecost of detecting and treating a preclinical carcinomaof the cervix is, at the present time, f417 comparedwith f882 for a clinical case. These figures, theyrightly claim, justify the expense of a screening pro-gramme. Although a lot of work has been done withautomative procedures, no reliable and potentiallymore economic alternative to manual screening hasyet been developed.

BRONCHUS

Among the malignant diseases, carcinoma of the bronchuscarries the highest mortality-rate in Britain and manyother countries; there were 31,659 such deaths in Englandand Wales in 1972.

In 1966 Canti 11 described the significance of intra-

epithelial carcinoma of the bronchus of heavy smokers,and pointed out that a positive result for cytology inthe absence of radiological evidence of a tumour was notuncommon; he also stated that the proportion of patientswith positive findings who progressed to invasive bronchialcancer was unknown. Nasiell 12 suggested that heavysmokers with productive cough could be screened for

malignant cells in their sputum, and this view is held

by others.13,14 Saccomanno and his colleagues 15 have beenstudying the sputum of uranium miners since 1957 andhave detected several intraepithelial bronchial tumours.

They stated that both uranium mining and cigarettesmoking are associated with the development of carcinoma-in-situ and invasive disease, and they suggested that suchat-risk groups be screened annually.

1304

It may be difficult or impossible to localise the site ofa tumour that is cytologically positive but radiologicallyand bronchoscopically negative. None the less, screeningmay be worth while because some cases, notably amongheavy smokers, might be reversible if smoking were

stopped.15-17No work has yet been reported on population screening

with follow-up of cytology positive cases who have stoppedsmoking, and it is doubtful if such a programme couldbe staged in Britain at the moment; most cytologists wouldwish to look at three specimens (12 slides) at each annualscreening of every participant. However, the developmentof cell dispersal methods and the automation of screeningcould play a part in making such a programme feasible,both for those who are heavy smokers or at high riskbecause of their occupation 1a

BLADDER

It has been known for many years that certain industrialprocessess are associated with a high incidence of bladdercancer. a and 0 naphthylamine, benzidine, magenta, andauramine manufacture were among those incriminated,and the manufacture and use of bladder carcinogens arenowadays carefully controlled. Crabbe et a1.19 used

cytology over a 5-year period to screen an industrialpopulation of dyestuff workers, and concluded that cytologywas useful in indicating the presence of bladder tumoursat an early stage, before symptoms or other urinary ab-normalities are present. They stated that cytology wasindispensable in any factory where a hazard from industrialbladder tumours might exist, and that it is the methodof choice in such a high-risk -industrial population. Sucha screening scheme is in use in Britain for workers in boththe dyestuff and rubber industries. Urinary cytologynow has an established place as a selective screeningprocedure for those at high risk and also for patientspresenting with any symptoms suggestive of neoplasia inthe urinary tract.

STOMACH

Gastric cytology is a cumbersome and time-consumingprocedure and causes discomfort to the person beingexamined. It requires the collection of material from thestomach of a fasting person, the stomach being washedout with saline or proteolytic enzyme. Schade, 20--22 whointroduced this technique and identified carcinoma-in-situin the stomach using cytology, suggested that it might beused to screen annually those at high risk for gastriccarcinoma-namely, patients with pernicious anaemia orchronic gastritis, and in a recent review 23 Schade con-cluded that gastric cytology should be used in patientswith gastric disease but not for mass screening. Workersin Japan, where the incidence of gastric carcinoma is

very high, supplemented cytological techniques with thefibre-optic gastroscope and gastric camera in an effort toidentify early preinvasive disease.24,25 However, subse-

quent reports on the diagnosis of presymptomatic gastriccancer have been less optimistic.26,27 Tumours detectedwere not early cases, and 282 cases of pernicious ansemiaexamined every 6 months for 3 years revealed only 2inoperable gastric carcinomas and 1 benign gastric polyp.

ORAL CAVITY

Several reports have advocated the use of cytologyas a selective screening process for oral cancer. Allegraand his colleagues,28 for instance, reported its use in 6448patients attending dentists and oral-cancer detectionclinics: among 74 cases of oral carcinoma diagnosedcytologically 19 were in clinically non-suspicious lesions.

Allegra et al. maintain that cytology should be part ofa total clinical evaluation by dentists and by oral surgeons.

However, the value of cytology in this area is far from

proved, and much more work needs to be done.

CONCLUSION

Results now appearing for cervical cytology shouldconvince the epidemiologists of its value. Cytologyalready has a role as a selective screening procedurefor carcinoma of the bladder, and a similar use maybe found in the future in relation to lesions in thestomach, lung, and, possibly, the oral cavity.The National Conference on Cancer Prevention

and Detection, held in Bethesda, Maryland, in March,1973, covered several topics discussed in this article.A summary of recommendations, published as an

addendum to the conference proceedings, toucheson the breast and the colon besides the lung andcervix uteri, and the procedures mentioned includeradiographic techniques as well as cytology. Several

techniques are deemed to be at a research stage, butspecific recommendations include the following: forthe breast, self-examination monthly and periodicexamination by a doctor or other health worker andperiodic mammography for women at high risk; forthe lung, radiographic and cytological investigation atleast once a year for high-risk groups with routinescreening for cigarette smokers only; for cervix uteri,Papanicolaou smears periodically; and for colon,periodic examination for faecal blood-loss and procto-scopy for people over 40 years of age and radiographicinvestigations for high-risk groups.

REFERENCES

1. Yule, R. Acta cytol. 1972, 16, 389.2. Langley, F. A. Br. J. Hosp. Med. 1974, 12, 73.3. Wakefield, J., Yule, R., Smith, A., Adelstein, A. M. Br. med. J.

1973, ii, 142.4. Spriggs, A. I. Lancet, 1971, ii, 599.5. Boyes, D. A., Knowlden, J., Phillips, A. J. Bull. Cancer, 1973,

11, 4.6. McGregor, J. E., Teper, S. Lancet, 1974, i, 1221.7. Timonen, S., Nieminen, U., Kauraniemi, T. ibid. p. 401.8. Wakefield, J. (editor). Seek Wisely to Prevent. H.M. Stationery

Office, 1972.9. Knox, E. G. Screening in Medical Care; p. 52. London, 1968.10. Thorn, J., Swanson, K., Macgregor, J. E., Russell, E. Unpublished.11. Canti, G. in Symposium on Carcinoma of the Bronchus. King

Edward VII Hospital, Midhurst, 1966.12. Nasiell, M. Nord. Med. 1965, 74, 746.13. de la Rue, N. C., Pearson, F. G., Thompson, D. W., van Boxel, P.

Geriatrics, 1971, 26, 130.14. Sagiroglu, N. Saglderg, 1972, 46, 18.15. Saccomanno, G., Archer, V. E., Auerbach, O., Sanders, R. P.,

Brennan, L. M. Cancer, 1974, 33, 256.16. Auerbach, O., Stout, A. P., Hammond, E. C., Garfinkel, L. New

Engl. J. Med. 1962, 267, 111.17. Doll, R., Hill, A. B. Br. med. J. 1964, i, 1399.18. Guardian, Aug. 22, 1974.19. Crabbe, J. G. S., Cresdee, W. C., Scott, T. S., Williams, M. H. C.

Br. J. ind. Med. 1956, 13, 270.20. Schade, R. O. K. Acta cytol. 1959, 3, 7.21. Schade, R. O. K. Gastric Cytology: Principles, Methods and

Results. London, 1960.22. Schade, R. O. K. Acta cytol. 1964, 8, 129.23. Schade, R. O. K. J. Am. med. Ass. 1974, 228, 890.24. Yamada, T., Matsumoto, S., Sankawa, H., Seino, Y. ibid. p. 27.25. Inokuchi, K., Inutsuka, S., Furusawa, M., Soejima, K., Ikeda, T.

Ann. Surg. 1966, 164, 145.26. McDonald, W. C., Brandborg, L1. L., Taniguchi, L., Beh, J. E.

Rubin, C. E. Cancer, 1964, 17, 163.27. Boon, T. H., Schade, R. O. K., Middleton, G. D., Reeve, M. F.

Gut, 1964, 5, 269.28. Allegra, S. R., Broderick, P. A., Corvese, N. Acta cytol. 1973,

17, 42.29. Proceedings of National Conference on Cancer Prevention and

Detection. Cancer, 1974, 33, suppl.