27 June Bmnly L. WALTER ET AL.: RESPONSE OF CERVICAL CANCERS TO IRRADIATION

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1 27 June 1964 Bmnly MEDICAL JOURNAL L. WALTER ET AL.: RESPONSE OF CERVICAL CANCERS TO IRRADIATION x 1,638.) FIG. 2.-Foci of sme tumour s in Fig. 1 contining vible tumour cells with scnty cytoplsm, reltively lrge nuclei with prominent nucleoli nd distinct chromtin pttern; n pprently norml mitosis is present. (H. nd E. X625.) FIG. 3.-Section from n irrdited tumour showing smll vible cells, degenertions, nd bizrre bnorml mitotic figures. (H. nd E. x 625.) FIG. 1.-Section from n irrdited tumour showing bizrre non-vible cells in the form of two mononuclete monster cells nd multinuclete tumour gint cell, some degenerting cells, nd kertinizing cells with condenstion of the cytoplsm nd well-defined cell wlls. (H. nd E.

2 BRTSH MEDICAL JOURNAL 27 June 1964 L. WALTER ET AL.: RESPONSE OF CERVICAL CANCERS TO IRRADIATION FIG. 4.-Showing some of the bnorml mitoses seen in Fig. 3 t higher mgnifiction. Two degenerte cells () undergoing chromtolysis lso seen. (H. nd E. X 2,340.) C e re b b FIG. 5.-Section from sme irrdited tumour s Figs. 3 nd 4, showing numerous vible cells with scnty cytoplsm nd intct nuclei (); bnorml mitoses with clumped (b) or scttered (c) chromosomes; degenerting cells in the stge of pyknosis (d); nd chromtolysis (e) nd mononuclete nd multinuclete monster cells. (H. nd E. X 645.)

3 27 Junr~e 1964 MEDICAL JOURNAL 1673 Assessment of Response of Cervicl Cncers to Irrdition by Routine Histologicl Methods Brit. med. J'., 1964, 1, L. WALTER,* M.B., B.S., D.M.R.E.; C. V. HARRISON,+ M.D. A. GLUCKSMANN,4 M.D.; C. P. CHERRY,t M.B., CH.B. The purpose of this pper is to show tht vluble prognostic informtion cn be obtined from ordinry routine exmintion of seril biopsies tken from ptients undergoing rdiotherpy for cncer of the uterine cervix. The originl method of exmining seril biopsies from tumours before nd during rdiotherpy ws devised in order to determine whether the erly histologicl chnges induced by irrdition could serve s mens of ssessing the rdiocurbility of the individul tumour (Glucksmnn, 1941). Since this reserch project ws strted it hs been shown repetedly tht such histologicl method gives relible indiction of the locl response to rdiotherpy of the tumour in individul ptients (Glucksmnn nd Sper, 1945; Glucksmnn, 1946, 1947, 1952, 1958, 1961; Glucksmnn nd Wy, 1948; Wood nd Bog, 1950; McGrrity nd Grvn, 1961; Merrill, Wood, nd Zippen, 1961). In the erly descriptions of the method cell counts in selected comprble res of seril biopsies were dvocted. It hs since been proved tht cell counts re unnecessry nd tht modified nd simplified form of the originl technique gives s relible n ssessment of the locl rdition response. Procedure A full clinicl exmintion of the ptient is mde, nd the extent of the tumour is ssessed s ccurtely s possible, so determining the clinicl stge. A provisionl pln of tretment is decided on, but this my be modified when the ptient is exmined under n nesthetic, nd further digitl nd visul exmintion of the cervix cn be supplemented by cystoscopy. In the series to be discussed in this pper the tretment consisted of three pplictions of rdium, either lone or supplemented by x-ry therpy. In deciding on the exct pln for ny one ptient, the extent of the locl disese, the type of tumour, nd the ge nd generl condition of the ptient were ll tken into considertion. Whether the ptient hs hd biopsy for dignosis or not, pre-rdition biopsy is tken under n nesthetic t the time of the first rdium insertion, nd this one is used by the pthologist for comprison with the lter biopsies. Further specimens re obtined t the time of subsequent rdium pplictions, gin under nesthetic. In the series under discussion the intervl between the first nd second biopsies ws week, nd tht between the second nd third vried from one to three weeks. If technique of tretment using one or two rdium pplictions is used biopsy should be tken week fter completion of the rdium tretment, nd if necessry nother fter further week. These lter biopsies * Consultnt Rdiotherpist, Hmmersmith Hospitl, London. Professor of Morbid Antomy, Postgrdute Medicl School, University of London. Working with grnt from the British Empire Cncer Cmpign t the Strngewys Reserch Lbortory, Cmbridge. D [WITH SPECIAL PLATE] cn be tken without n nesthetic if the cervix is exposed in good light. To void the possibility of misunderstnding it is necessry for the clinicin nd the pthologist to hve greed on the criteri to be used in ssessing the response to rdition., These criteri re discussed lter. In the method recommended the pthologist hs first to clssify the histologicl type of the tumour before irrdition. Secondly, in biopsies tken during nd fter irrdition he hs to note certin cytologicl chnges nd to mke direct comprisons between biopsies tken before nd fter rdiotherpy. A prognosis bsed on rdition chnges seen in seril biopsies cn be given only if the dose nd the time intervl between beginning rdiotherpy nd the tking of the biopsies is known. The pthologist in ll probbility will not be given these fcts; nor is it necessry, s the ultimte interprettion of the chnges is in the hnds of the clinicin, who will hve ll these detils. Technicl Procedure In order to determine the effect of the rdition on the tumour it is essentil for biopsy smples to include growing tumour foci. These re found t the mrgin of the tumour, where the blood supply is dequte, nd the biopsy should be tken from this re to include the growing edge of the tumour nd mrgin of the djcent tissue. If the growth is of prolifertive type n dequte smple cn be obtined with biopsy punch, but if it is -of the infiltrting ulcertive type it is better to cut wedge with knife. The specimen should be plced in fixtive immeditely. The extent of the disese nd the exct site of the prerdition biopsy should be crefully recorded (reference to the clock fce is convenient wy of doing this), nd subsequent biopsies should be tken from the neighbouring re, gin tking the mrgin of the lesion. Necrotic tissue from the centre of the tumour or the surfce of n ulcer is useless in evluting the rdition response. For the ssessment of rdition chnges in seril biopsies it is essentil to hve well-fixed mteril. Formol-sline should be voided s it gives unstisfctory cytologicl detil, nd fixtion in Sus solution (three hours is dequte for the verge-sized biopsy followed by trnsfer to 80% lcohol) gives excellent results, nd it is simple for the hospitl stff to use s it is supplied in form redy for immedite use. Lendrum's fixtive (mercuric chloride in commercil formlin) lso is simple to use nd gives very good cytologicl detil. It my hve n dvntge over Sus solution s overfixtion does not occur nd specimens cn be left for 24 hours in the fixtive. This my be more convenient for the hospitl stff. Our own specimens hve ll been fixed in one or other of these two fixtives.

4 June 1964 Cervicl Cncers-Wlter et l. Fixtion is followed by dehydrtion in lcohol in the usul wy nd then by routine prffin-embedding. Hemtoxylin nd eosin stining of sections is quite dequte for ssessing rdition chnges. Essentils for the Pthologicl Report Histologicl Clssifiction of Tumour For prcticl purposes cervicl cncers cn be divided into three groups: (1) squmous crcinoms, including every grdtion from the highly kertinized type to those in which kertiniztion is miniml nd limited to few cells; (2) denocrcinoms of vrying grdes of differentition but ll showing t lest some mucin production; nd (3) nplstic tumours showing no sign of either kertin or mucin production nd usully of nplstic or even bizrre cytology. Criteri to be Reported To enble the clinicin to interpret the prognosis the pthologist's report must contin informtion on the three following points: Presence of Vible Tumour Cells.-Cells tht re degenerting or proceeding to kertiniztion (Specil Plte, Figs. 1 nd 5) re of no importnce. It is the vible cells tht must be recognized. In ordinry hemtoxylin nd eosin sections these cells hve scnty bsophilic cytoplsm nd reltively lrge nd often hyperchromtic nucleus which my be drk-stining but with the nucler structures distinct (Specil Plte, Figs. 5 nd 2). It is not necessry to count the number of vible cells present in sections of the postrdition biopsy, but the report must stte whether there re mny, few, only occsionl, or no vible cells present. Presence of Norml-looking Mitoses.-Bizrre nd bnorml mitotic figures (Specil Plte, Figs. 3 nd 4) hve striking ppernce nd usully ctch the eye. They cn be disregrded s they led to cell deth nd therefore re not of importnce for the interprettion of the prognosis. On the other hnd, it is essentil for the clinicin to know whether or not norml-looking mitoses re present in the post-rdition sections. Perceptible Difference in Degree nd Extent of Differentition Between the Pre- nd Post-rdition Sections.-This is the lest importnt criterion, especilly if much vible tumour persists for week or more fter beginning rdiotherpy. However, in tumours of squmous type mrked increse in the degree nd extent of kertiniztion between pre-rdition nd the first post-rdition specimen, nd between the ltter nd second post-rdition biopsy, cn be guide in ssessing prognosis. The sme pplies to increses in the mount of mucin nd the number of mucin-producing cells in irrdited denocrcinoms. Some of the tumours ppering initilly nplstic my show some kertiniztion or mucin production nd occsionlly both ctivities fter irrdition. In the presence of vible cells it is not relevnt to mention whether n inflmmtory rection, necrosis, foreign-body gint cells, or kertinized debris re seen in the post-rdition sections. In the bsence of ny vible tumour such findings my indicte good response to tretment, nd thus cn be of help to the clinicin. Interprettion of Pthologicl Findings The prognosis bsed on the response to irrdition refers, obviously, to the locl disese only. The finl prognosis must depend on the distnt spred s well. BRATUS MEDICAL JOURNAL An unfvourble response to tretment is indicted if the first post-rdition biopsy contins mny vible tumour cells, nd especilly if there re norml-looking mitoses. The occurrence of only minor increse in differentition is lso evidence of poor response but is of less importnce. The presence of lrge or bizrre cells is of no rel prognostic vlue. A fvourble response to tretment is indicted when, in the first post-rdition biopsy, norml-looking mitoses in tumour cells cnnot be found nd when vible tumour cells re scnty. An increse in the degree nd extent of kertiniztion between the first nd second post-rdition biopsies is lso good sign. In minority of cses the rdition responses my hve to be recorded s doubtful. Sometimes the post-rdition biopsy contins no recognizble tumour but only necrotic debris or inflmmtory exudte. Sometimes there my be tumour present, but its response my be intermedite between the good nd bd responses described bove. Correltion Between Histologicl Prognosis nd Five-yer Results of Tretment In series of 210 cses of crcinom of the uterine cervix in clinicl stges 1-4 treted by Dr. L. Wlter t Hmmersmith Hospitl pre-rdition biopsy nd one or two dditionl biopsies tken during therpy were vilble nd were submitted for ssessment of the rdition effect. Informtion on rdition dose nd the time intervl between given dose nd the biopsy excision ws supplied to the Strngewys Reserch Lbortory, Cmbridge, cell counts were done on the mteril, nd the prognosis ws bsed on the quntittive nlysis. The sme mteril ws submitted to the Pthology Deprtment of the Postgrdute Medicl School, Hmmersmith, nd ws reported on routinely without informtion on the dose of rdition or the time in reltion to rdition tretment of the biopsy excision. The reports on the post-rdition specimens specified whether or not vible tumour cells nd norml-looking mitoses were present nd whether or not there ws n increse in differentition of the tumour tissue s compred with the pre-rdition biopsy. The reports were sent to Dr. L. Wlter, who judged the prognosis in the following wy: if seven dys fter beginning rdium tretment mny vible cells nd norml-looking mitoses were reported the prognosis ws considered to be unfvourble; the bsence of mitoses nd the predominnce of differentited or degenerting tumour cells ws tken s n indiction of fvourble response to tretment. At both centres no definite prognosis could be given in 105 cses. In the mjority of instnces this ws becuse the postrdition smples contined no tumour tissue or, less often, becuse of mbiguous cellulr chnges. In the nlysis these cses were regrded s hving doubtful prognosis. Of the other 105 cses with definite prognosis, 23% were fvourble nd 77% unfvourble ccording to the Postgrdute Medicl School, while the corresponding figures for the Strngewys Reserch Lbortory were 12% nd 88% respectively. The Tble compres the clinicl result in the 210 cses with the prognosis given t the Postgrdute Medicl School nd t the Strngewys Reserch Lbortory. It shows tht for both centres the five-yer survivl rte for cses given Prognosis Fvourble Unfvourble.. Doubtful Five-yer Survivl Postgrdute Med. Sch. Strngewys Res. Lb. No. of Cses 0 No. of Cses I 1.. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ± ±

5 27 June 1964 Cervicl Cncers-Wlter et l. NMICAO.,ikL 1675 fvourble prognosis is significntly higher thn for those with n unfvourble prognosis, while tht for ptients in whom definite prognosis could not be given is intermedite between the other two groups. Similr differences in survivl rtes between the three groups re seen if n nlysis is mde for clinicl stge 1 nd 2 cses seprtely nd for stges 3 nd 4 combined. (See histogrm bsed on the dt obtined t the Postgrdute Medicl School.) c/c No ' o F U? F U? F U? STAGE Histogrm showing the reltion of prognosis to five-yer survivl for clinicl stges 1, 2, nd 3 plus 4. F = Fvourble. U = Unfvourble.?= Doubtful. No. = Number of cses. An overll survivl rte of bout 50% in the cses with doubtful prognosis (see Tble) suggests tht the bsence of tumour tissue or mbiguous chnges in the post-rdition specimen did reflect rdio-curble tumour in bout hlf of these ptients. In some of these cses it might hve been possible to give definite prognosis if second post-rdition biopsy hd lwys been vilble. This is borne out in series of 700 cses treted by Mr. S. Wy in Newcstle in which second post-rdition biopsy reduced the incidence of doubtful prognoses to 12%. As cn be seen from the Tble the correltion between the prognosis nd the five-yer survivl rtes re very similr for the two methods used in ssessing the response to rdition, *nd the differences in the fvourble nd in the unfvourble cses between the two centres re not sttisticlly significnt. In eight cses the prognosis given t the two centres ws in complete disgreement; the Postgrdute Medicl School gve fvourble prognosis in seven nd n unfvourble prognosis in one, while the reverse ws given t the Strngewys Reserch Lbortory. In four cses ech centre gve the correct prognosis. In further five cses the Postgrdute Medicl School gve fvourble prognosis while the response ws considered doubtful t the Strngewys Reserch Lbortory. In nother five cses the prognosis ws regrded s unfvourble t the Strngewys Reserch Lbortory nd doubtful t the Postgrdute School. The high degree of greement between prognoses bsed on quntittive nlysis nd those bsed on pthologicl reports of rdition chnges seen in seril biopsies shows tht the histologicl ssessment need not be lborious procedure nd is well within the scope of routine pthology deprtment. The fct tht t the Postgrdute Medicl School four different pthologists shred the reporting on rot nd yet chieved results comprble with those from single reserch investigtor indictes tht the method outlined is esily reproducible. The striking differences in the clinicl result for cses with n unfvourble nd fvourble prognosis indicte tht the ssessment of rdition chnges in seril biopsies cn be of use to the therpist in deciding on dditionl tretment in individul ptients. Summry The response of cncers of the uterine cervix undergoing tretment by irrdition cn be ssessed by compring biopsies tken before nd during the course of tretment. This hs previously been regrded s reserch technique, but by mking certin simple observtions it is possible to pply the method in ordinry routine prctice. The techniques necessry re described nd comprison is mde of the findings on the sme group of 210 ptients by reserch workers nd by deprtment crrying out routine reporting. The comprison of the histologicl reports with ech other nd with the clinicl results fter five or more yers indictes tht vlid results cn be obtined by routine deprtment. REFERENCES Glucksmnn, A. (1941). Brit. 7. Rdiol., 14, 187. (1946). Brit. med. Bull., 4, (1947). In Recent Advnces in Clinicl Pthology, edited by S. C. Dyke, pp Churchill, London. (1952). Brit. 7. Rdiol., 25, 38. (1958). Act Un. int. Cncr., 14, 358. (1961). IXth Interntionl Congress of Rdiology, pp Thieme, Stuttgrt. - nd Sper, F. G. (1945). Brit. 7. Rdiol., 1i, 313. nd Wy, S. (1948). 7. Obstet. Gynec. Brit. Emp., 55, 573. McGrrity, K. A., nd Grvn, J. M. (1961). In Rdiobiology, edited by P. L. T. Ilbery, pp Butterworth, London. Merrill, J. A., Wood, D. A., nd Zippen, C. (1961). Proceedings of Conference on Reserch on the Rdiotherpy of Cncer, 1960, pp Amer. Cncer Soc., New York. Wood, C. A. P., nd Bog, J. W. (1950). Reserches on the Rdiotherpy of Orl Cncer. Spec. Rep. Ser. med. Res. Coun. (Lond.), No H.M.S.O., London.