Document vBQkEa0n26KoBJE8eYjdZnZR6

nrrcnce e chest ^ ippears ^ distant .-T "ntment factory, >n. Mirgerjr. The Detection and Growth of Intrathoracic Neoplasms The Lower Limits of Radiographic Distinction, the Antemortum Size, the Duration, and the Pattern of Growth as Determined by Direct Mensuration of Tumor Diameters from Random Thoracic Roentgenograms the Ex- :!.irr, S.: v Meta*sarcoma >43, 1952. '-Donald. ~c Malig5.1950. lalignant ' Tistue '>45. 124 The purpose of this investigation "'as to and 1961 and having 2 or more thoracic explore the appiirabililv of rrju-liiiw- non-.' ri lent gem >grams showing intrathoracic pri s'multaneous anti nonsvstcmatic mensuration mary or metastatic cancers were included in >f the roentgen shadows of malignant neo^ the study. When multiple thoracic roentgeno plasms in the lung to the betterment of our grams were taken on the same day, only the understanding of the growth and behavior of best study was considered. Roentgenograms malignant neoplasms in man and a better taken by some technique other than the stand X* definition of the limitations of the roentgeno- ard 72 in. target-film distance, posterior- grnphic detection of pulmonary tumors. anterior projection, were excluded. Cases Material Consecutive patients attended at the Kllis Fischel State Cancer Hospital between 1'10 , Submitted for publication July 20, t%2. Chief Surgeon, Ellis Fischel State Guirrr Hos pital and Advanced Clinical Fellow of the American Cancer Society (Dr. Spratt); Professor of Rndio- meeting the initial conditions included 21 patirnts having 22 primary pulmonary cancers and 176 patients with cancers metastatic to lung. All roentgenograms were reviewed, and all of the primary cancers and 138 of the metastatic Cancers showed circular radiopacities having diameters measurable simply rhysics, Mallinckrodt Institute of Radiology. Wash ington University School of Medicine (Dr. Ter-Poeossian); Surgeon, Ellis Fischel State Cancer Hospital (Dr. Long). Supported by USPHS Grant No. CS-9741. with dividers and a millimeter scale (Table 1, Fig. 1). That these circular radiopacities measured on posterior-anterior projections were in fact spheres could be ascertained in 125 BCG273f.'f'TJ;' 'vv '--rrn by 6113 18091 284 ARCHIVES OF SVRCh.H, Tabi.f. 1.--Histological Typrs cl M> iijih.i oe Intrathoraeic Neoplasms Observed and Number of Posterior-Anterior Thor 0,1c Roentgenograms Taken per Patient' Type* of Intratho- raue Neoplums No. ol I* A 1 liorstcic Koentgonncrain* per Patient 12 IS Totals * AdeaatmlDoma TrintTUonel Ca. Epidermoid Ca. Soft Tlmue Sare. Ouaoua Sare. Lymphdmaa Melanoma Unclualfled Ca. Subtotal for Metast. Primary l'ulm. Ca.f Totals * No. of patients, t Kef. 4. many cases by observing that these opacities were also circular on lateral projections, and the diameters of the circles were the same in both views. The reasons why 38 of the met astatic cancers were not measurable are given in Table 2. The tumors of the patients wereObserved on from 2 to 13 separate thoracic roentgeno grams taken on different dates at intervals of time between dates varying from 1 to 1,200 days, with a median interval between 31 and 100 days and a wide disjicrsion of the num bers of days within various intervals. N'o system has governed how frequently thoracic roentgenograms'were ordered in the follow up of cancer patients attended at lillis Fischd during the 21 years of the study. Many uf the primary pulmonary cancers ind the pul monary metastases Were obsei-ved during jieriods when the host was free of symptoms, though the development of symptoms pr&6ably inlluenced the obtaining of some exami nations. The diameters of the primary pulmonary' cancers were measurable at 92 di ferent times. Among the 138 patients with measurenbie intrathoraeie metastatic cancers (Table 11.1' patients had but 1 metastasis'measured. -W patients had 2 distinct and separate nretasta>es, 10 patients had 3 metastases, and I AilMocvrfBomr tiraaac ' Larga Boaral Hemaek : Kldoejr - Eraiocaatrlum . 1`rwtaia 1 Bubtotal |E(jMirmok Cu Ml 1`alata CrrrU , . ,Jp tfolHOUl MelanacarCnoni t'lbraannauia Lsraphoaaa i liodskln* Diar jrLympiuMnreoii W LymptiocjrUs i Subtotal Ormoti Tout rito. mlaalnitfn l (UiaMerayoaiu OMwcnleawc ittaHardnai .Cborloole ' " 'Taut j I^S-had 4 i _t': distril [.nr^mnts. ligand f 656 di fmctastabcs are fifativc relative Fig. 1.--Frequency dis tribution of the measure ments of the seriated diameters of intrathoranc neoplasms of man dr served repeatedly but randomly by 72 in. i-atcrior-anterior (hot** roentgenograms: bib in dependent mcasurctntrii of 1 or more intratlwrao: metastasis in 138 period, and 92 independent meatnremeuts of 22 prinuii pulmonary cancers met made. Fig. 2.--Cumul. frequency t measurements ot various j (tuied success!l^.hiKar and log [ probability paper - hunxotital lines (tot indicate tl tuuidenee limitaurinal or Gauss I- tnbution. Linen Wtler approximr L'laeen the 95% c< R,: hmits on tlie loj ft' Winy plot, su jit wocikc of a log b-j rbslnbution. - Vol. S6, Feb., M3 E: BCC2736 SpratI, 6113 18092 1'fc. OF SURGERY -d and 'HATHORACIC NF.OPLASMS Table 2.--Types of Immeasurable Pulmonary Metastases Observed on Sequential Thnrneic Rocntarnonrams 2:15 Touts Typo o( Cancer liifTtiv nr I.ympimnciti*' Reason Metasnise* Immensurntile I'lPiiral KiTusion Indistinct Combination Total thMeuetnomiw limit UmBml -lemaeh Kidney fndotnetrium rmtate IS* Fills Fischel, dy. Many of and the pul- 1 during mptoms. ns prol>some exami- -rH-rmold Carcinomas soft Paiata c-rrlt Up *ubtotal M*]tnoerc`noiu fibrosarcoma Irmphomu Hodtfcias Dbwasa Lyrapboeartoma Ltntphoeyltc Laukemlo fnbtotai *tnd Total Hint raising from flies Rhabdomyosarcoma Ofteocente sarcoma Adenocarcinoma, large bowel Cborionle cm., uterus Total n 1 1 1 1 2 in i \ i : I J I 1 a 73 i 7 1 l 5 12.8 ", nfr:ier<t y pulmonary tTerent times, asureable inTable 1), 87 icasured. 40 ate metasta sises, and 1 -ent had 4 tnetastases measured. Tlu- tre- diameters are plotted successively on linear ncy distributions of the 2 diametric and logarithmic probability paper in Figure 2. uurements of primary ptilmotiarv c.-mrrrs_ The closer a probability paper plot of the of 656 diametric measurement*- f ihc cumulative relative frequency of a distribu -.istases are given in Figure 1. 'I'he ettmti- tion of events approaches a straight line, the 1 vr relative frequencies of the nq >c<t ive closer is the frequency distribution of the I ''rcqucncy disr` the measure, the seriated i intratlior.irir of man nl>. watedly Imt y 72 in. pos. !or thoracic 'ams: 656 inmeasurements "C intrathoracic n 138-persons, nendent meas. L^2 primary ^Hbtrs 2.--Cumulative relr frequency of the uiiremcnts of tumors various diameters led successively on ar and logarithmic lability paper. The 2 -dental lines on each t indicate the 95% -tidcnce limits of a tnal or Gaussian dis"ition. Linearity is Icr approximated he wn the 95% confidence its on the lot- prohaty plot, supporting -*rncc of a log normal tributjon. 1063 126 Sprait et at. 1 6113 18093 BCC2737 2S86 . IwKcCilullVmliSs Oor SmL /,(. .* events to a normal nr Gaussian tlisiiilnitinn* tive" initially and were still interpreted Linearity is approximated better in the log- "negative" at tin review. The time betwera probability plot of Figure 2, amijlie equa- the taking of the thoracic roentgenogram & tions of a Gaussian distribution were used terpreled as "negative" and the taking of m to demanine the parameters of a log normal lirst examination showing tumor varied i:.c distribution of the diameters ( Table 3);5 11 to 1,200 days with a median inten.il oi The'diagnostic acumen of the radiologists 300 days. ,' was tested in 2 ways. One test was made by the random placement, upon the posterior and anterior thorax, of balls of Incite having a Comment j > I/ The diameters of spherical intratliorant! radiodensity approximating that of solid neoplasms observed by the repetitive jai tumors and ranging in diameter from 1.6 to nonsystematic menstir ition of the slu'l. 12 mm. rosterior-nnterior thoracic roent of these tumors seer on standard 72 ia. genograms were taken of each arrangement target-film distance (osterior-anlerior1 tiu of the lucite spheres at 72 in. largct-hlm' racie roentgenograms have been slwwii a distance, 70 kv., 200 ilia., and 0.05 sec. The Figures 1 and 2 to approximate a lug-aura^ radiologists then examined these films, at frequency distribution. If the cancers *fit tempting to locate the circular shadows. The observed randomly Iftwcen the limiPii second method of testing the acumen con radiographic distinction at one extreme sisted of having the roentgenologists examine antemortem size at the other extreme. films that had been interpreted as normal if the cancers grew bv a geometric pmgiw before the location of the tumors Invame evi -ion in size, (lieu observations of size bctitta dent on subsequent examinations. the 2 limiting conditions might be exported a The radiologists could locate the opacities distribute into a normal or Gaussiandistrie- of lucite balls 10-12 mm. in diameter regularly lion on a size scale of geometric"progres>* regardless of the location. They could locate i.e.. a logarithmic scale. Since no sy?u the radiopacities of balls 6 mm. in diameter seems t<^ have determined how freqwafj only when the opacities were located in inter "chest x-rays" were irdcred at litlis Tis>ir costal spaces contrasted against aerated lung. during the (last 21'years and since tln-fe* They could distinguish the radiopacities of such a wide dispersion of the span ui tea 3 mm. diameter balls from normal putmniiary liei ween examinations, there is every rca* shadows in these same areas of favorable con to suppose that we have collected a groups! trast only when they were shown precisely where to look. Radiopacities of balls smaller than 3 mm. in diameter were indistinguishable from anatomical pulmonary radiopacities. No single primary pulmonary cancer nor single pulmonary metastasis smaller than <> mm. in diameter was interpreted as an abnor mal shadow initially by the radiologist. Kv the review of earlier films taken lielore the location of tumors had become evident, the smallest primary cancer detectable was 12.( mm. in diameter, and the smallest metastasis was 3.5 mm. in diameter, both of these meas urements being equivocal. Kven after this review there remained a group of <10 patients having had thoracic roentgenograms which were taken before the location of tumors hr came evident and which were read as "nrg.i i.uidom measurements. That the fns,ucn>-j di-irilmtioii of these tiieasurements i'.ura*; log iiormnl distribution is in sup|mrt <>: Uc { concept that these inlrathoracic cancer* W j matt were indeed growing by a gem.-rfr* progression in size as postulated by G'Kx* *J However, other as yet unrecognized u.trtj could have produced the log normal >1.1 lion. The parameters of the log normal- -* billion of tbe measurements is given m !-j i 3. Tlie-e |iaramelers state that the prnlu! y* of observing on a standard thoracic :e*| grriogram a tumor smaller than <> u.::. *j diameter would be 0.025 and smaller '.:~i-1 mm. would lie 0.005. This is in agree..**] u itli the direct tests of the radiolugi-t-' no-tic acumen bv using the Incite lialls*i.ib I V'ol. 86, Feb., l%.i a I ri?c*ku 1review: [ffler t t Iff 6113 18094 Tfc 'ES OF SURGERY , `STRATllORAClCNV.Ori.ASMS ' 2S7 till interpreted a* The time lictwcen T/unr. 3.--The Parameters of the ! on Normal Distribution of the Diameters of Randomly Measured Primary Pulnumaty Lancers and Pulmonary Metastases* . roentgenogram in- t'ririnrv I'uliiiiin'arjr CiinM-rs T-iilmonw/ Mctnstnim <1 the taking of the 'umor varietl from median interval of at rical mtrntlinrncir Mmn --3 S.O. f Mean --2 P.l). Mean Mr-in 4 2 P.!>. Mmn4SS.li. v.D. !. | ik(ril<1Motl * Dlant<Mtr Mm. n linn O.T'W * (i :mh 2.5 - 3 - - 354 3*1 m I/O* Distribution* 0.4*77 0.5030 1.4336 2.0542 2.37ttt 0.31.53 Dlimctcr Mm. 107 3S 27.1 IlS.t 239.S %oi An Observation* t i1 SS at SI 1p `lie re|H'titivr and ti of the shadow* o standard 72 in. -CsleulMcil from nrtfcrliil in Ficw- i snn>t:ird drvtalion. 'rior-anterior thn- 'viewing films previou-.lv l :i' negative 0 been shown in ''irr the locations of Inmor- were known. mate a log-nonn.il The parameters in Table a aUn '.(ate that the cancers were 'Sf prnbaliilify of observing a primarv pnl- en the limits of `inary cancer larger than J1'*1 mm. or an t one extreme and itrathoracic metastasis larger than lib mm. kextreme, and vmM lie less than 0,025. The largest cnttccr fctric prngre*- id metastasis observed iiciv re-.|K-rtivelv ms of size between '.23 mm. and 200 mm. in diameter. I-argcr ght be expected to -nors were not observed Imcate-v the patients tlaussian distribu- '"n died, and intrntlioracie i.iuiit* diet ween nctric progression. 12and 20 cm. in diameter mav be considered Since no system Htemnrtem size, requiring eilbcr definitive 1 how frequently `-crapy or the death of the ln>--i. -d at Ellis Fischel P.v expressing cancer si/e by the number and since there is : neoplastic ceils rather than bv diameters, a the span-of time nicer of f> mm. in diameter cmiiaiiis almut re is every reason 1.13X10* cells, a cancer of 125 mm. in di ilected a group of verter nl*ctit 0.7X10" cells, and a cancer of hat the frequency .'>) itmi. iii diameter alHiiii | So IIP2 cells. Mremcnts forms a If growth occurs predominant I v bv llir rnn- :n support of the 'nin division of the cancer cells followed oracic cancers of `v a period of growth of the daughter cells g by a geometric iated by Collin*.** -veogntzed factor* g normal ilistrib'i log normal di-lri- 'approximately' the si/e of the parent cells More cellular division again occurs, then ,!t<c cancers are equivalent respectively to .''>7, 59.8, and 50.8 binarv divisions or ''tihlings" of a single eell. We then have "Iciice that the duration of an iniialboiat ic * is given in Tablp -'plasm between the lnvur limit of radio- ' hat the probability C'aphic visibilitv i f> mm. in di.nueleri and 'd thoracic roent* 'temortom size (2('0mm di nuclei I would i 6 mm. in Vequal lo no more Ilian I I bin.uv divisions aller than 3 f the cells originally within a vancer (i mm. t agreement - diameter (40.X--26.7 14.1 i. The maxi- radiologists' dine- -tint duration of the life of llie untreated iucite balls and be '-M*t lietwecn these same limning conditions would therefore lie equal to the time required for all the cells to divide once, i.e., the doubling time, multiplied by 14. For undiffer entiated and epidermoid cancers of the lung having mean doubling times of about 90 days,* the duration of the life of the untreated host lietwcen the limits of radiographic visi bility and antemortem size of the intrathorncic tumor would lie about 1,260 days, or 3.45 years. Among the metastases measured in this study the most rapid doubling time observed was 5 days. For this tumor the life expectancy of the host would not and did not much exceed 70 days after the appearance of the metastasis (5 day doubling time X14 doubling intervals = 70 days). Collins has re lated measurements of doubling times of metastases in the same hinge as observed for metastases in this study,1-3-8 and from iliesc the prognosis placed on the life of the host by more slowly growing metastases can lie estimated similarly. Summary and Conclusion The frequency distribution by seriated lumor diameter of 92 random, repetitive, and nonsimultaneous radiographic measurements on 22 primary pulmonary cancers and 656 '"'I' measurements of 1 lo 4 pulmonary melasiases in 138 consecutive patients having mriasinsiziiig cancers and Sarcomas of differcni types is reported. The distribution of the mi-asuremeols of tumors of different sizes is randomized in a log normal distribution, and the parameters of this distribution are reimrted. A log normal distribution of random observations measured between the lower Feb., 1963 X Stratt et at. 2U . HitHIVES or SUKEl.i- limits of radiographic resolution ait'l die upper limits of morbid tumor size would l>e expected of tumors that grow by geometric progression. The lpwer limits of resolution achieved by standard thoracic radiographic teehniijuea is about 3 mm., but tumors are not generally diagnosed by the radiologist until their di ameter exceeds 6 mm., a size equivalent to the 26.7 doublings of a 1,000 cubic micron cell. A malignant intrathoracTc neoplasm that has attained a diameter of 200 mm., a size equivalent to 40.8 doublings of a 1,000 cubic micron cell, requires definitive therapy or else the cancer will generally kill the host during the next interval of the doubling of tumor volume. The maximum life ex|icclancy ot the untreated host between the radiographically visible size and the antemortem size of an intrathoracic tumor is equal to aUnti 40.8 doublings (200 mm. tumor) minus 2<>.7 doublings (6 mm. tumor) or almut 14 don blings multiplied by the doubling time of the cancer. We wi-ii to express our appreciation to Dr. t_. if. WiuW'HKr. 1'hief of Diagnostic Radiology at Ellis liachel State Cano r Hospital, for penniwift to review the accumulated radiographic files oi tl^t iii.uuuum .mil fur radiographic consultative lolm >. Spratt, Jr.. M.D., ttiief Surgeon. 'l' Dili. t iM-liel State Cancer Hosj ital, Columbia. V. -1 ' I : REFERENCES l 1. '.illms, V. P.; Koclller, R.. ind Tiers, It' (iliservaiiiius cm the Growth Kates of Human i* mot.. Amer. J. Kueiilgcnol. 6:988-101)0, I't.Vi i dllius. V. 1'.: Time of C ccurrencc of MiU taw iroiii Carcinoiha of Colon and Rectum, t ,in Is .isr-.t'ls. 1962. i ..i Spiegel, M. R.: < httlinc amt Theory and i'ahleno hi Statistics, New York. Scliaum I'tiNnl..: ; t a.. 1'itil. I spi.itt, J S., Jr.; Spjnt, II. J-, and Kn|*i.i I. I lie Kroiptency 1 listrilm.ion of tiie titna'-t. K.u,. ami tlie Estimated Duration ot l`rir..i\ I'liliuoiiaiy Carcinomas, Camer, in press. - l ii|.uhli.heil data on the growth rates w iw- tut hi.ti \ imtastasev iroiii limiian cancers and mi* ..... . ol.-crved at the Ellis Fisdid State Cairn Hospital. 1940-1961.