Prognostic Significance of Histopathologic Subtype and Stage in Small Cell lung Cancer A. E. FRAIRE, MD, E. H. JOHNSON, MD,* R. YESNER, MD, X. 6. ZHANG, MD,t H. J. SPJUT, MD, AND S. D. GREENBERG, A study of 149 light

microscopic

with recorded

diagnoses

initial

tissue slides

from

(114 cases) and undifferentiated

carcinoma

taken to test the reproducibility

and prognostic

histopathologic

of SCLC proposed

subclassification

ogy Panel of the International Cancer (IASLC). of clinical pathologists were

to test the impact The tissue slides

as SCLC or non-SCLC

with no knowledge

by a panel of five

of the initial diagnosis.

into the three subtypes

of a new

by the Pathol-

for the Study of Lung

This study was further designed

reclassified

divided

thology

Association

impact

outlined

The SCLCs

by the IASLC

panel: small (classic or pure), mixed (small cell/large

and combined

(small cell/squamous

nocarcinoma).

Small cell lung cancer was clinically

regional,

or distant. Consensus

carcinoma

diagnosis

at least three of the five pathologists)

staged as local, as agreement

was achieved

and 20 were classified

as non-SCLC.

for the small, mixed.

and combined

203 days, respectively

The median lengths of survival

were regional,

lengths

of survival

staging data were avail-

sociation was highly significant significantly

longer

(P = .OOOl). We conclude

of survival in SCLC. Mixed times were

men, and the survival time difference significant

longer between

(P = .0028). We found no significant

vival according

and

This

as-

that stage

for women

sub-

than for

to age or race. HUMPATHOL 23:520-528. :c: 1992 by W.B. Saunders Company

rvho

with

in sur-

Copyright

adcqu;~tr

had been identificcl

xwkmrd

rhr 147

men and women was differences

tremor rrgistry of thy HCYI‘l‘auh (;rner;d to I !)Mi. These I47 patients r-eprcsentrct patirnts

subtypes had

survival times than the small or combined

types (P = .025). Survival

prom

and 74 (60.2%) were distant for the local, regional,

AND METHODS

LYr wtrospecti\rl~ r-viewed light niicroh~opic tissue stidc l-k!) cat3 (qmr~~~dtyrhI-re slides/cxse: 430 slicks Iotal) wrrespontlin~ (0 I-15 mses acccssionecl as .X:1.(: from the

123 SCLC cases, 27 (21.9%)

distant stages were 428, 25 1, and II 1 days, respectively. is the major determinant

MATERIALS

subtypes were 225, 1,110, and

(P = .025). Adequate

(17.9%)

stage. The median

as SCLC

and four [3.2%] combined)

able in 123 of the 124 SCLC cases. Ofthe were local, 22

by

in 144 (96.6%)

of the 149 cases. Of these 144 cases, 124 were reclassified (115 [92.80/o] small, five [4.0%] mixed,

pacell),

or small cell/ade-

(defined

reports of long-ter111 survival have appeared in thr metficaf literature. ’ most reports cite median lengths of survival of only 7 IO 15 months.“~’ The clinical diversity of SCIX: i-effected 1~ these wrvirig Imgths of‘ survival has long been reccqzjiized and kuftipfe clinical, histopathologic, ant1 therapeutic factors that intluenw oucome have been studied.“~“’ This stud!; was geared priinarifv to test ttw refm~ducit~ifity arid prognostic impact of ttii new fiistof~~~tfiofogi~ subcfassiti~atiorl 0L‘ X1,(: fm)posed ty the f~a~liofo~gy flanef 01‘ the Iriternational Ahscdacion fi)r tlir Study of I .r~rig Cancer (IASIC), whicfi mx~guizts three subtyes: small (classi< or pure), mixed, and combirlcd. Tfus study also anafyres the prognostics iniportance of‘ clinical stage. age, sex, arid race on survival. ratlic

(SCLC)

(35 cases) was under-

stage. age, sex, and race on survival.

were blindly

147 patients

of small cell lung cancer

MD

follow-up

xitl

Hospital

xfequate

I

~IXJIII I !)7

I

7H.?u/(sof’ 188 Serforn~etl 1)) thv log r-ank md generalized Wikoscm tests on SAS diwarr (S:Yi Institute. Inc. (Lrey. IN).” th Kaplant~q~~~xletl

table

test,“’

md

thr

arld

k sa111ple

tr.st’4

(I’
R&ice et al the histopathofogic diagnosis was made by two pathologists,‘” while in the study by Hirsch et al the diagnosis was made by only one pathologist.“’ In another study. the issue of validation of diagnosis by ;I secmnd 01’ ;I third fmthologist was not addressed at aff.” For our study. howe\:er. a cliqqlosis was riot accef>ted unless supported hi three or more of the five pathologists. In addition, vardon of the percentage component of large cells required by the various investigators to make the diagnosis may Asoresult in variations of the reported frequency of’the mixed subtype. In our study, we were not able to support previous reports of‘ mixed subtypes having a poorer prognosis than the small cell subtype. ’ ‘.“w In fact, the median length of survival for the mixed suhtyfle (1,l 10 days) was longer than that for the sn~fl cell subtype (225 days). This was significant (k sample test 2 cff, P = ,025). A recent study by Aisner et al involving 628 patients (550 with histologic material) also failed to corroborate shortened lengths of surGval in patients with mixed (small cell/large cell) subtypes.“” In their study of 550 f>atients, Aisner et al reported that the initial review by one pathologist showed that 526 (95.6%). 24 (4.3%). a

TABLE 4.

Historic Evolution of Classification

FIGURE ponent variant fication

7. Undifferentiated large cell carcinoma with a comof smaller darker cells simulating a small cell/large cell of small cell carcinoma. (Electron microscopy, magnix4,700.) (Reproduced with permission.34)

aild 0 (0%) fmtieilts had small c,rll, mixed. mid c-ombiut‘(l suhlypes, resf)ec.ti\.cly.‘:’ On 1.m iew h), ;I secotitl ftat hologist, :!isner d al rrf)or(d I WJm a~rc’c’1nc’n1 L’or (he small c,ell subtyf,e.‘” Ho\vcvc~-, the ;igrecmm rate I,ctweeii the two f~afhologists fi)r the mixed subtype 1~;~s 0nfJ. -f:i.X% (1 1 of ‘11 casrs). There wc’i‘t’ uo detecUbfe differences ol~scm~l in the nlctliau lengths of’ survivals between the smdl cell subtyfle (44.6 weeks) mtl first review noised subtvpcs (53.1 weeks) or belween the snlall and the conc.orcl;int crc~mcl cell suhtypc (M.6 b~ks) suhtylxs (52.5 weeks).‘” Therefore, lfiese review IJllXed investigators c~cmcluttecl that the rare (4.4%) mixed sub ‘yf” does iiot carry it Lv’or-seprognosis.“” Altfiough our sur\:icaf findings mtl those of the Aisner rt al study are similar, the design of tfie two stiitfies tlift‘ers ccmsicle&l~ since. ;is stated earlier, our study recfuired agreement by three of five f>athologists before a case woulrl hc ;I(‘cepted as mixed, whereas the Aisner et al study reyuirecl OUI agreement by only two f)athofogists. Furthernlorc. findings sh& a Itbnger. statistically significant length of‘ survival for the mixed subtyf>e as comfm-ed with thy showed srnalf cell subtype, whereas the Aisnrr et al stu& no difference in length of‘ survival between t’he small and mixed subtypes. BefIler et al also tailed to corrohorate shorter survival times a~~tfworse prognosis for the mixed subtyf>e.‘“’ These investigators strdiecf ‘L4I) patients with SC1.C and subclassified the tumors into three liistopa~hofogic subgroups: oat cell, fmre intermediate (without small cell/large cell features). mcf mixed small/ large cell subtype. No significant differences in remission

of Small Cell Lung Cancer Histopathologic

Subtypes

PROGNOSIS

f

)I \;I113i\;1l 1LIlC \\c’l‘(’

ti~lllltl

;llllollg

chew

OF SMALL CELL LUNG CANCER

ch1w

In

111~’

s;lud!.

et al)

shcming tncthocls ol’di;Ignostic \~;Ilirl;It io1I as writ as SIII‘t \ iwl tlif?twncc~s, is fw3rtited in .I at)lc~ 5. f~‘onrbiwtl .\ll/)f~,iw.Thy rare combined stIt)tyfl(b (sn1;Ill C-ell f,fus bqttatiiotts cxx~inoni;i 01 ~itl~t~oc~~t~-c~i~~oti~~i~ has txwi estim;ttr(t to rrf)wsent It5s than I”;. 01‘ untrcatc’d %:I X:4 ~intl ha\ bren r~f~ortetl to ti;Ivc ;I slll;lll CYII(‘0111f1011rnt. \\liic.li ma\ be f~t‘on~inent 01 mittor.” III our hcries. f’our crises (‘3.%) were diaqiowtl 34 c~o1r1t~inetl; iti tliree of’tlicse fout~ 04es, IlIe tliag:lrosis \\;Is uIatle of1 hiof)sy tissue. nr:Itrri;Il. We arc’ not ;i\vxt’ 4 )I :itlj studic.s that have ;Ittetnf)ted to cluantitatc the cstt31t ot rht- dilkt-~~iti;itetl ~~oi~~f~on~~ntin three co11it~iii~~~lc;Ircii1011I;I~. 111our cases. the differentiatetl ~onif~ot1c‘nts (squamorIs ~141(.;Irciiiot11;I or ~Idr~~o~a~-c~it1o~11;I) dicl 1101mc34 5’P. M’c bCficb\,c, 110wc~e1~, that the fm3encc’ 01 at!, c~o1nfX~urtit of‘ cliffer~11tiated ~~arc.inonia wottld jttrttfy the diagnosis 01 cx~tiibined subtype. The true frtGlwiic\~ of the (.onibint‘d subt!.f>c is not kno~~ti t)ut tl~~f~euds on sc‘vc1~;II \ ariables: ( I ) how large the biof)s\ is, (2) honv tnm~ tksuc t1locks ;irc tafmi. (3) whether utItc’)f,~v01‘sui~gic;il iu;tlet~i~tl is hcilig cotisitleI~rd, ;ttid (4) \~ari;Itio~i in t~rntit1oIogs. ‘1‘tius, tti(~ ti-w Creq11t31(.) of combi~it~tl subtyfX3 n1;i); br cluitr difhcult to asc.ertaiti. ‘l‘his ditfictilt~ ilr rrfklt~tl I)\ the \vitlr ratigc of rcf,oi-(4 frecltIt~i1c.ie~.““~‘” .2t ttIe I!)?!) IiIectiug of the. .-\nierit an (k~llcgc ol (:tiest 1% sicims. l’rstier tat al, r~portirig on the rvolutioti c)fS(:Li ., noted tliat at ;iutof~\, 16 (8%~)of 200 S(:I.lus difl’~reniiatetl (squa111ous c;Ircinon1;I or ~Ideno~ar-c.i1iottl~I) cornponm1ts. TuIIIO~ showitig features of squ;Itnous carcinoma ,Itrd ade110~~~i11011~I (withresent, fm)gnostic data for thv cotubinecl S(:lA: subtyf>e me not available froni our rc\,ier\ of the lite1.ature or from our study findings. Thus, for the n1onient. dete1~niination of its true frequency arid prognostic sigiiificancr~ niust await clarificatio1i b> turtlirr stud&.

sub

Hq>ler c’t al, tIi(b tissrtc. slide5 \vc~rc’ 1x9 icwtl with regard to agrec111ent ratrs and, tlius. it is tiot f>ossiblc’ to d~trrn1ine how mm\’ 01‘ the I :I (5%) of the Y!l tumors that were c~l;~ssifietl as tiiixetl (st11;tll c_cll,/l~I1~~~cell) wc’17 initi:Ill\~ diagnosctl I)\ ;t cxm(‘01tl:itit (f~;itholog+t) fXIi1. 01’ I+ the third f~;1tltofo~i~t. In OIII‘ sttid~~. xsc f;)untl si~t1ificm1t. lo1Iger SUI-ki\al timex liji tl~s tnisc~cl (st~~all CYII./large c.efl) rtibt!l>t~ 3s c0111p~iretl \iitli the otltlet~ stIbtvfK4 (P = .OOL’Hb\ log 1Xlh md I’ = 00X-l b! gcmer~tlkd M’ifcoxon test’). We txwral~oxl \ui \i\;Il bv Iii~tof~;itl~oIo~ic~ CCII suhtvfx using the fog r;i111\tt-51. 51t~;Itil\.i11~ f’or st;Iq. and the histof~;Itliologi~~ cxdl I\ pc 011 sttr\k~tl rrtiiained significant (I’ = .O 1 19). In ;itltlition. 12(’ ~1t1;11~~z~d tt1~ :Issoc.i;itioii bet\ttWI histof~~ItIrologic c-t.11subtvf,ct aid ht;rge (six [WV] 01‘ tiinr c;I\c~ 01’ tiii\ecl ;intl c~ot11hitirtl siIbt!.fX4 M’C‘I’C Ioc;iI 01’ t-cgicm;It tshilr l!) [ 43’71 of‘ I 1-I c’;iscs 01’ stdl crll 01. c,l:Issi, 4ubt\f>c. wt’rc IocA or region;il) ~tttd tottttd th;lt 111~tliflrrrnc~e Iwt\\wn thc.sc. two grotrf)s \v;ts ttot sixtiili(xlt (I’ 1 I I,. Fisliei.‘s rsac’t test. ~RX)tailed). Thf3e fitiditlgs stqp3t that ttw longer feng:th of’ sttr\,ival ti)r ttit, tnixtxl ~tibtkfw is ttot ;I rcllection oflimitrtl (local or regiotl;tl) SI;I~C AOIW. Nonrthctfess, \\t‘ interfxet the Iongct~ length 01’ stir\ i\,;il fi)t- the mixed subt\f)e with c3ittio11 hec;Iust* 01 (1 1 the stnall nuuIbe1~ of (Xzs (11 = .G) at~tl (L’) tlir f;rct that it1 c3c.h of ttit. five cases the tliaposis L\:IS ti1;Ide I)\, cot1st~ns11s and it1 no ir1static.e was Itit, diapiosir iiiade tw majority or tmx~imitv. In cxmIrast. 101. tlics t 15 wiafl &II subtypes. ;I diagnosis was aticl unatiit11it~~ it1 .Ic~lIic\(~d I)\ ~~onsensu~. tiiajoritv, 13.3% ;)f the cases. *-esf~ecti;~el). .3).3C~i. 37.3’%, and ‘l‘hus. it is ;If,f,;Ire11t that although the overall rate of ;tgt~ee111mt itI our series was \.erv high (96.6%). fmthologists 111or(’ rc3tlilv agree with cme another wherl maIyAng fxirc or c Iaasic small cell subtypes as 0pf)osed to tht, mixed and ccm1bined subtypes (Table 2). Larger 4trIdies wit II diagnoses ~~~ilitlated by fXIthofo&T panels (with dis~fosiirc~ of agreement rates ;m~cmg thr panel to final diagnoses retitkretl bv t1lc’n1brrs . ;I\ opposed or final diagnoses made by ;I individual fxithologists, third fxithologist in cases of discordant pairs) and apfmqkate fI)flow-uf) will be needed to clarif? 111~issues of true frecluetrcy ancl survival rates of‘ the tnised cell atbtvfws. ?~onrtheless. our study demonstrates that in wtltr;tst to the s111allcell subtype, the diaCgnosis of mixed sttbtvp is C~diffic1Ilt diagnosis. with 0111) tlirev of five f~;Ithologists agreeing mith the diagnosis 111each of five (‘axes of the tnixrd subtype. Our study suppot-ts f,revious 4~bservatiot1.s that the true frequency of mixed subtypes IS nowhere near the I!% to 11.8% frequency cited in e;I1-licr stlld,iczs.“,“z, ‘r’Furthermore. our findings support .\isnel et al‘s contetltion that mixed subtype n1orpholo~ does not infer a11 inferior survival rate and concur with thrir sugge:>tion that patients with mixecl XIX: subtypes should he mmagcd with regimens and a f,hilosoph, si111il;Ir to that used in patients with the classic or pure of published studies of small suhtlil)e.‘ii A summary %‘I.( 1 misc4 aubtvpes fro111 the medical literature, i\f)c.4.“’

(Faire

In

Clinical Stage ‘I‘he prognostics impact of tunior stage in no1i-SCL(~ is well ~tI;ir~I~teri/.etl.~‘.~~ For rhr staging ot’nott-%I.(:. 525

HUMAN PATHOLOGY TABLE 5. S~,urc~/‘Yc;lt

Small Cell Lung Cancer: Literature No. of (;;Ls(.\

Volume ‘23,No. 5 (May 1992) Review of Mixed Small Cell Lung Cancer Subtypes

\‘alici;~iion of l)i;ly~o~ia”

Sur-viI;dt

Signilic a~( t

KtWLlId.\

Not ‘it;Ilr(l

I’ < ,005

I’ < .Ol

NS

NS

I’ = .OO!)

the TNM system, according to guidelines established 1~) the American Joint Committee, has been most commonly applied. “X However, this TNM system can he only modestly applied to SCLC and, as a result, other staging systems have been used.“’ The most widely used system, proposed first by the VA Lung Cancer Study Group, categorizes SCLC as either “limited’* (ie, confined to one hemithorax, including ipsilateral positive hilar and scalene lymph nodes) or “extensive” (including all other patients with disease beyond the chest cavity and with nonresectable disease).“” In a study of 214 SCLC patients, Hansen et al evaluated the prognostic impact of stage, performance status, sex, age, and histopathologic subtypes and concluded that only stage and performance status appeared to have clinical importance.“’ In this study, Hansen et al found no statistically significant association between prognosis and sex, age, or histopathologic subtype.“” Subsequent studies further documented the critical importance of stage in prognosis.“,“” In our study, TNM data were available only in the latter years of the study. Thus, we chose to use clinical and radiographic data that divided patients into local, regional, and distant stages. Although not commonly applied to SCLC, this type of staging is well known to most clinicians and can be compared with the currently favored limited or extensive stages, with the local and regional stages together corresponding to the limited stage and the distant stage corresponding to the exten526

sive stage. Our findings showing median lengths of’ SUI‘viva1 for local, regional, and distant stage patients of 428, 251, and 11 1 clays, respectively (k sample test, 2 df, 1’ = .OOOl), stress the importance of stage on survival. Nonetheless, most reports in the medical literature cite survival figures in terms of limited versus extensive disease. For this reason, we grouped the 10~x1and regional stage cases together and compared their length of survival with the length of survival of patients with distant (ie, extensive) disease by the log rank statistic. This corn-parison also showed significant differences between these two groups (P = .0015). Thus, we conclude that our findings amply support the critical importance of stage on survival in SCLC patients. Age,

Sex, and Race

Available information concerning the impact of age, sex, and race on length of survival in patients with SCLC is scanty and often conflicting. Osterlind et al and Johnson et al have reported that women survive longer than men.J.H.!~ However, Hirsch et al found no correlation between age or sex and length of survival in their study of 200 patients.” Bepler et al also reported no differences with regard to age and sex.“” while other investigators did not address these parameters in their rrports.“‘,“” Our study identified a longer, statistically significant survival in women compared with men (P =

PROGNOSIS

OF SMALL CELL LUNG CANCER

.OOL’S).at~d sul)pc)rts earliet- asserlioris that wottten survi\,types (sitiall cell, tnixecl, ;ttt(l cotttl~itted). and to d~tertnin~ its prognostic signific~;ittc.~.Thl:~ ovc~all level of consensus diagnosis aniong the fivr p;ifl~o1o~isls was high (14-l of 131) cast‘s /!Qj.S%]), suggt3titig rhal tlic IASI,(: classificatioti is ;i workable and rqm~clttcil~lr systetti. The level of agreetitetrt aittong the five paLhologists was best f’or the small cell s&type, wltich constituted !)Z.H%~of all cases. However, in none 01 the tive ttiixctl subtvpes md in none of’the four contbiticd suhtylle5, ;I dia&cbsis was made by unmiinity. Of lhc

124

c‘;ises ret-lassified

by the

pad

as XI.e is suppot-ti\:e of‘ .\istter et at’s c~ottclusion that this ;I rare I utt~ot wthnt. with ;I frequeucy much lower than the I !!$ to I4.XV pt-r\iousl!, stt~~estecl.“.“~,~~~ ,4nrong the thr_Ct, ttist~~~p;ttliologi~ subtypes, survival times were Iottger f’or the tttixed subtypes. Although significant, WY incerprt.t (Iris longer survival with caution hrcmse of chc%sntall nutnt~rt- (II = .5) of mses and because ;I majorit\ 01 utiattititilv diagnosis was not attained in anv of the fi\r castes. l~&hertttc~re, the lack of niajority or kutiniit\ tli;igtio:;rs iii alI of 0111.five accepted cases of mixed suhr\pw suggests rhat this is ;I difficult histop;tttloloSi~ cli;~gnosia. Future, larger studies with diagnoses validated t)\ pathology panels and with disclosure of agreement t.;;les ;IS opposed 10 diagnoses made by individual pathotogists should also help to deterniiiie the true frequency attcl progttosis of the mixed subtype. At present. littIc> or no data exist with regard to the true frec~uettc~~ 01’ prognosis of the cotrtbined subtypes. Of 1I!3 case\ with adequate staging data, 2 1.748, 17.7$, and 5-l.6% were local, regional, and distant, respectively. ‘l2tt~ dift‘ermces hetweeti these stages were highI\- signihcattt. ittdicAng that clinical stage is a powrt.ful prrcl.ic.tot~ of survival. Our data further shows ;I longer, sigitific.attt survival for women cmnparecl with IIWI~. I‘lw~~e were no significant differences of length of sur\~i\~al wi rh rqarct 10 age ot- race.

527

(Fraire et al)

HUMAN PATHOLOGY

Volume 23. No. 5 (May 1992)

528

Prognostic significance of histopathologic subtype and stage in small cell lung cancer.

A study of 149 light microscopic tissue slides from 147 patients with recorded initial diagnoses of small cell lung cancer (SCLC) (114 cases) and undi...
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