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The Incidence of Malignant Growth of the Undescended Testicle: a Reply and Re-Evaluation
THE Jouru\~AL or,' Un.o.cOGl
Vol. 81, No. 5, May l!J5!l Printrd 1·n e.S .A.
THE I2\CIDE2\CE OF .1-\LALIGNANT GROWTH OF THE Ui\DESCE;';DED TESTICLE: A REPLY AND RE-EVALUATION HORACE E. CAMPBELL
In 1927 """'""0""' wrote, "No greater divc,rsit:' of opinion probably exists concerning anything in medicine tlmn the qrn,stion of malignancy in the undescended testis." In 1940 the definitive ancl unequivocal ans1yer to this problem was [umished Gilbert ancl Hamilton when they a collected series of over 7000 cases of malignancy of the trsticle among which 840 had the malignancy in an undescended testide, an incidence of something undc,r 12 per cent. Among 9,7,11,097 military rel'ruits, 22,665 had umlrsccndecl testicle, an inc:idenC'e of 0.23 per cc,nt. These authors wrote, "That 1 l pc,r cent of all testicular tumors occur in the 0.23 per cent of the malrs who arc cryptorchid proYes that m:opla~tic growth is found for more commonly in the ectopic than in the scrotal about 48 times more often tlmn expected by clmn<:e aswc:iation." (Sec table 1.) In 1942 Campbrll, in ,l sirnihr study but with a collcl'tc,d scric,s of only 1 c:asc,s of testicular malignancy, found that lfi:5 of these had the tumor in an undescenckd an incidence of J 1.6 pGr cent. His conclusion 1n1s, "The difference' hctm::Pn 0.2:-l ± 0.001 :S prr cent and 11.0 ± 0.3 per C'Pnt is so significant that it may be concluded 1Yithont foar of controYersion that the malignant process is more likely to affect thr maklrscrnded organ." Thr statistical significance of the clifferencc between these t\yo perc:c-mtages is enormous, or as Gill1ert nncl Hamilton it, ''f1bout 48 tinws more oftcn than expectecl chanC'e association." (Campbell, '41; IIill) This conclusion has been 1Yiddy accepted. One of the most distinguishrcl contributors to the likmture of m,dignancy in tbe undrscrndecl , in collaboratesticlc, Sir Gordon tion with Xonrnm R Yryndham, it this \Vay, "If the frequency of malignant disease \Vern in no 1Yay reh1tf'rl to non-descent of the organ, then only 0.23 per cf'nt of any series of testicubr neoplasm ought to implicate undC'scendc,d testes." On the othcr hancl, R,t least one dissident voice Acc.cpkd for pnlilication _\ugust 10, 1958.
has been raised, that of 1Y.• \. C:.1rroll of San Francisco. In the course oI a \vidcning a.nee among urologists throughout the it has become apparent that many have rca.d Carroll's 1949 paper and have hfr, theses. These may be stntecl succinctly to br. A. The data upon 1Yhich Gilbf'rt and Hnmilton, Campbell, and others bnsc their conclu. sions are so variable as to br unreliable, and J3. Fndescended testicle is n. rather common anomaly. If cancer affects tlw undrscendecl organ so much more frequently, then all of u.s should sec many more malignancies of the descended testicle. Actually, a. urologists have nrver seen a case. In an effort to resolve the controversy and to stabilize:: the thinking of the profession on this perennially confusing topic, the prf'sent writer has checked thr references given by Carroll and has found that at least six of them hc1ve been misquoted or incompletely quoted. _\nd thrse are six of the seven references he as 1clence of Yalidity of his thesis "A". FurthermorP . many physicians are not aware of the rncognizc:cl methods by whicb statistical nrnterial is nwasnrcd ancl irn~c'iiSed. The discussion that follows will be in tbrce general diYisions: I. The investigation ancl correction of tbc
II. An cYaluation of Yariabilit,1" of data Gt anrl (b) in thr field or· umlcsccmled testick, III. The significarn;e of Carroll's smYey m which 76 per cent of thr, rnl,ncnRt~ who rcspondcd to his questionnaire, had nevct' of seen or trea te, l a case of the undescended testicle. I
THE ERROR lK CERTATI, QTJOTATIONS FROM THE LTTERA TURJ,
Carroll apparently felt tlmt the "oYcr 11" givc'n by Gilbert ancl "nearly 12" giYen by Campbell, as tlrn incidrn<:e of nomlrsC'ent nmong those ksticln:
664
HORACE E. CAMPBELL TABLE
1. Incidence of nondescent of testicle in Army recruits Recruits \Vith Nondescent
Number Recruits Examined
Author
Marshall (1828) Rennes (1831) Myrdacz (1887) Love and Davenport (1920) Southam and Cooper (1927) Selective Service System (1947)
I I I
10,800 3,600 6,962,543 2,754,154 10,000 2,794,727
Source
British and French Armies French Army Austrian Army (1870-1882) American Drafted Army (1917-1918) Scottish Recruits (1916-1917) Selective Service Registrants (19401944)
Number
Per cent
12 6 14,057 8,538 52 12,426
0.11 0.16 0.20 0.31 0.52 0.44
----
Total. . . . . . . . . . . . Over-all Percentage. Standard Error.
12,535,824 ...
....
. . . ....
showing malignant change was too high. He wrote, "The published incidence of malignant cryptorchidism in relation to testicular malignancies as a whole varies from 8 to 15 per cent; i.e., Campbell 8 per cent, J\1acKcnzie and Ratner 8 per cent, Gilbert and Hamilton 9 per cent, Rubaschow 11 per cent, Hinman 12.2 per cent, Dean 13 per cent, Chevassu 13.7 per cent and again 11 per cent, and Scott 15 per cent. In opposition to these figures Cunningham reports 1 in 67 cases, Eccles none in 854 cases, Kocher 1 in 1000 cases and Coley none in 1357 cases." (His quoting Campbell's figure as 8 instead of 11.6 per cent, and Gilbert and Hamilton as 9 per cent instead of "over 11" has served to confuse things unnecessarily, is rather involved technically, and will not be untangled here.) For the record, however, the variability of these data is even wider than Carroll has inIicated. He did not refer to the 1938 paper of Gordon-Taylor and Till where a series of 50 cases of testicular malignancy personally observed by Sir Gordon over a period of thirty years involved the undescended testicle in 15 cases, 8 abdominal and 7 inguinal, an incidence of 30 per cent. And then there is the 1947 report by Murray and Ewert showing an incidence of 28 per cent. At this point in our discussion, however, we are concerned primarily with the "opposition figures." The Cunningham figure is correct and will enter the discussion later. The quotations from Eccles, Kocher, and Coley are erroneous. Eccles wrote, "In a close examination of
35,091 0.28 ±0.0015
48,000 males with hernia, 854 had imperfect descent of one or both testes, or one in every 56, and none of these presented any form of malignant disease". Clearly, this series has nothing to do with the incidence of malignant cryptorchism in relation to testicular malignancies as a whole. Coley wrote in 1919, "In the Out-Patient Department of the Hospital for Ruptured and Crippled from 1890 to 1918 there have been observed 80,736 cases of inguinal hernia in the male of which 1,357 of 1.68 per cent were associated with undescended or mal-descended testis." This is indeed interesting, but this series has nothing to do with the incidence of malignant cryptorchism in relation to testicular malignancy as a whole. Elsewhere in this same paper, Coley mentions 64 cases of "sarcoma" of the testis, in 12 of which the tumor was in the undescended testis, 18.7 per cent; but Carroll does not mention this. Kocher's 1000 cases were of undescended testicles, not testicular malignancy. His series, and those of Eccles and Coley, too, would be relevant as regards the incidence of malignancy in a series of undescended testicle, but is not relevant as regards the incidence of nondescent in a series of testicular malignancy. There is a difference. Carroll has introduced in opposition a series of percentages from another category. Carroll next sought to cast doubt upon the figure of 0.23 per cent as the incidence of nondescent in the adult male. He wrote, "The uncertainty as to the true incidence of crypt-
INCIDENCE OF MALIGNANT GROWTH OF UNDESCENDED TESTIS
orchidism deepens when the published statistics are enumerated, i.e. Marshall 0.1 per cent, Hempel 0.2 per cent, Gilbert and Hamilton 0.23 per cent, World War I records 0.31 per cent, Howard 0.6 per cent, Baumrucker 0.75 per cent and Coley 4. 7 per cent; a variation from 1 in a 1,000 to 75 in a 1,000." (The latter figure should be "to 47 in a 1,000" and has been corrected in his reprints.) It should be pointed out and understood that the figures of Marshall, Hempel, and from World War I all went into the series of Gilbert and Hamilton and are a part of his composite figure of 0.23 per cent. The figures of Howard, Baumrucker, and Coley have no relation here, as we shall now indicate. Here is what Howard actually wrote: "In the 20 years, about 110,000 male patients have been admitted to the [London] Hospital, and of these only 65 were suffering from malignant disease of the testis, or about 0.06 per cent of all male patients." He has nothing to say concerning the incidence of undescended testicle among these 110,000 male patients. Farther along in the paper he states that 57 of the malignant cases were verified by the microscope, and of these, 9 cases (15.7 per cent) occurred in the retained testis. Carroll does not quote this significant figure. Note that Howard's figure is 0.06, not 0.6 as given by Carroll. But this of no concern, for Howard's series is irrelevant in any case. Thus, Carroll's use of it is mistaken on two counts. Carroll quotes Baumrucker as reporting an incidence of 0.75 per cent. Baumrucker's words are: "Among 10,000 men, 75 had one or both testes undescended. Of these, 15 had abdominal testes, 14 unilateral and one bilateral. Of the 75 individuals, 60 had inguinal testes. Two of these had assumed a position in the canal following inguinal herniotomy from an original scrotal position .... The high incidence of undescended testicles may be explained by the fact that our material consisted of a certain percentage of previous rejections back for reclassification." This last sentence, to which Carroll makes no reference, makes this series unsuitable as an index to the general adult male population, despite the great value of the series in other respects. Coley is quoted as reporting an incidence of nondescent as high as 4.7 per cent. Here is what
665
Coley wrote: "Of 1,040 cases of hernia in adults operated upon at the Memorial Hospital by Dr. William A. Downes and the writer, 49 or 4.71 per cent were associated with undescended testis." Coley does not anywhere imply that one thousand cases of hernia are to be considered typical of 1000 males generally, as far as the incidence of undescended testicles is concerned. Thus it is seen that the three percentages cited by Carroll as so widely divergent as to cast doubt upon the incidence of 0.23 per cent are either misquoted or irrelevant. This is not to imply that the figure of 0.23 per cent is absolute. Perhaps it is not an exaggeration to say that nothing in the field of statistical analysis is absolute. The figure of 0.23 per cent has already to be altered by the addition of figures from World War II (table 1). Now let us consider the importance of variability as it affects reliability. II. VARIABILITY AND RELIABILITY OF DATA
The theory of probability will not be elucidated here. It is suggested that every physician should read carefully the (conveniently little) book by Bradford Hill. The writer made an effort to bring the rudiments of statistical method to the attention of the medical profession in 1941, at the time of his study of the problem of malignancy of the undescended testicle. Carroll has pointed out that the published figures vary. The statistically trained observer knows that they vary, but does not spend his time quoting the various series. He measures and assesses the variability. He knows that a percentage based upon 7000 cases is eminently more reliable than a percentage based upon 67 cases, and is therefore more concerned with the size of the series than the percentage itself. This was the reason that Gilbert and Hamilton collected from the literature over 7000 cases of testicular malignancy. This included the series which varied all the way from 1.5 per cent (Cunningham) up to 30.0 per cent (GordonTaylor and Till). Thus the "highs" were balanced against the "lows" in their proper proportions and there emerged the eminently reliable percentage which Gilbert and Hamilton conservatively reported as "over 11 per cent." The same kind of thinking was employed in arriving at the incidence of undescended testicle
0, 0, 0,
TABLE
2. Report of physical examinations of selective service registrants, Nov. 1940-Dec. 1944 based on approximately a 20 per cent sample. Does not include reports of second and subsequent examinations, to avoid possible duplication data. United States: All registrants (Negroes included) Age Groups
All Ages I
18 through 25 years
26 through 29 years
Total Result of examination Total Result of examination Total physi- - - - - - - - - - - - - physi- - - - - - - - - - - - - physicall¥ ed_- General Limited Discally ea.- General Limited Discall:y amme service service qualified amme service service qualified ammec
ey
Total Examined Total Defects.
.. ;, 794, 727 1,576,242 3,126,096 1,145,679
289, 702 928, 783 1,524,890 1,003,881 509,666 1,470,751 1,475,977 662,060
129,839 220,570
391, I 70 593,347
30 years and over
I I
428,439 538,947
Result of examination Total - - - - - - - - ~ - - - 1 physiGeneral I Limited Discall:y ed.service service qualified amme 229,421 197,129
I
55,413 106,921
143,605 841,398 234,897 l,lll,172
I
Result of examination
General Service
Limited service
Disqualified
342,940 286,490
104,450 182,175
394,008 642,507
~
0
~
C"l
i'1
A. Principal Defect of Examined Registrants by Result of Examination and Age Group
i'1 3enitalia Absence or atrophy of testicle .. Undescended testicle. Varicocele " Other genital defects ....
C"l
:,-.
5,457
4,880
225
343
2,995
2,766
IOI
128
8,323 29,837
I, 893 27,348
2,727 1,818
3,703
671
5,236 20,198
1,241 18,945
1,657 962
, ::: I
17,687
11,825
2,888
2,974
10,430
7,906
1,402
I, 122
870
52
46
1,494
1,253
72
169
I, 236 4,883
295 4,306
420 448
521 129
I, 851 4,756
357 4,097
650 408
844 251
2,862
1,872
570
420
4,395
2,047
916
1,432
9J
I
B. All Recorded Defects of Examined Registrants by Result of Examination and Age Group -
Genitalia Absence or atrophy of testicle . Undescended testicle . . Varicocele Other genital defeels.
I 12, f,42
7,857
1,798
2,987
6,023
4,214
666
1. 143
12,426 63,547
2,799 44,518
3,576 9,116
6,051 9,913
7,389 38,758
1,798 29, 725
2,108 4,446
40,222
19,849
8,492
11,881
21,555
12,832
3,886
I
I
2,350
1,393
459
498
4,269
2,250
673
I, 34n
3,483 4,587
1,960 11,231
429 7,145
594 2,211
937 1,875
3,077 13,558
572 7,648
874 2,450
1, 5:31 3,451
4,837
7,298
3,316
I, 931
2,051
11,369
3,701
2,675
4,993
;::: 'ti td
i'1
t< t<
IKCUHJNCE OF MALIGNAN'l' GROWTH OF UNDESCENDED TESTIS
among the adult male population (table 1). The pcn:tcntage varied here from 0.11 (Marshall) to 0.52 (Southam and Cooper). One need not discard these data, saying that they are too variable to be of use in forming a concept as to the frequency of undescended testide. ),clcl them all togethn, the small series of 3,600 contributing its effect along with the massive series of 6,9G2,543 recruits. YVith the addition of the 2,794,727 recruits from World War II, among whom the incidence of nonclescent was 0.44 per cent (table the general percentage is raised to 0.28 per cent from the previous 0.23 per cent. The weight of the massive series of 1887 will always makes itself felt. It is interesting to note that the percentagt'S have increased gradually with the passage of time. This may mean that the race is changing somewlmt, or that examinations arc more carefully done. It is likely that the pccrcentl1gc will never go above 0 ..5, but that it will hover around 0.30, so that ,ve may say quite confidently that about 3 men per thousand have nonrlescent of the testis. One of the most important uses of a rate, e.g., 11 percentage, is to compare it with another rate to see if some difference, e.g., a causal infiuencc, is present. To do this meaningfully, one must know how much this rate might have varied quite by chance, without the influence of some causative influence. Here, again, the physiBradford Hill of much cian will find the book help in coming to realizr that mud1 of truth is a matter of probability, and that one should not be misled into thinking that a final figure will ever he obtained. If the difference between two percentages is three times its standard error, the chances are only 1 in :no that a difference this large could orcur by chance. The difference between 11.0 ± 0.3 per cent and 0.28 ± 0.0015 per cent is 35 times its standard error, and it is almost a certainty that the unclescenclccl testicle is more likely to undergo malignant change than is the normally descemlecl organ. III. THJG SURVEY COKDUCTF,D BY CARROLL
Carroll circulated a questionnaire and learned that 503 members of the American Urological Association (7G per cent of those who responded to his questionnaire) had never seen a malignant m1dcscenclecl testicle. The present writer confossrs that he can not recall having seen one, either.
In this connection it is of interest to read that arres in thrc:e and one-half yc,ars of vatc practice has seen five cases of of the testis, and three of the ffrc were in descended testes, 60 per cent. One oc:c:mTed witb torsion in an abdominal testis and ,1nothcr seven years after orchiopexy. Kiefer, in fl, cent personal communication, tells of nine cases of tumor in undescended testes; and one of the most remarkable series of all is of Gordon-Taylor and Till. The fact that 503 urologists had never seen or treated a malignant undescenclecl testicle; proves simply that it is a rare disease. Dy no stretch of logic does it prove anything; as to whether the undescended testicle is more or less liable to malignant change. As a case rn point, the records of the: Peter Brnt Brigham Hospital for 27 years (1913~39) contained 2 cases of malignant undescended testicle. 11Iost of the residents in urology during that JJeriod did not see a case of malignant undescended testicle And yet, of all the testicular malignancie11 encountered at that institution in those 27 yearn (19 cases), 10 ..5 per cent were in unclesr:ended testicles. There are those (including the present who would like to sec a study made of the incidence of malignancy in a. series of males fol lowed from youth through adult lifo, givmg the incidence of malignancy in those of the scrir:s with normally descended and abnormally de scendecl testes. This study is in progress with vVorlcl War II material. Up until .January HHS over a. thousand cases of testicular had developed among those examined at the beginning of the war (Dixon and . ;\R the years proceed, we ma,y expect relevant data to emerge from this study. But while we aw waiting, sound clinical guides are afforded the data now recorded. 1Ve may conelucle again, "From the data reconfod in the literature it can now be sti1kd unequivocally that the undesccnclecl testicle is more liable to malignant change than the nor mally placed testicle and that the r,bclomin:i.l testicle is more liable to malignant change tlrnn the inguinal."
-w
587 Republic Bldg., Denver 2,-Colorado.
668
HORACE E. CAMPBELL
REFERENCES BAUMRGCKER, G. 0.: Incidence of testicular pathology. Bull. of U.S. Army Med. Dept., 5: 312-314, 1946. CAMPBELL, H. E.: Incidence of malignant growth of the undescended testicle. Arch. Surg., 44: 353-369, 1942. CAMPBELL, H. E.: The statistical method. A vital tool in clinical medicine. Surgery, 9: 825-831, 1941. CARROLL, W. A.: Malignancy ln cryptorchidism. J. Urol., 61: 396-404, 1949. COLEY, W. B.: Operative treatment of the undescended or maldescended testis, with especial reference to end results. Surg., Gynec. & Obst., 28: 452-459, 1919. DIXON, F. J.AND JVIooRE, R. A.: Testicular tumors. A clinicopathological study. Cancer, 6: 427454, 1953. EccLES, W. M.: The Imperfectly Descended Testis. New York: W. Wood & Co., 1903. GILBERT, J. B. AND HAMILTON, J. B.: Incidence and nature of tumors in ectopic testes. Surg., Gynec. & Obst., 71: 731-743, 1940. GoRDON-TAYLOR, G. AND TILL, A. S.: Malignant disease with special reference to neoplasms
of undescended organs. Brit. J. Urol., 10: 1-45, 1938. GORDON-TAYLOR, G. AND WYNDHAM, N. R.: On malignant tumors of the testicle. Brit. J. Surg., 35: 6-17, 1947-1948. GRoss, R. E. AND JEWETT, T. C. JR.: Surgical experiences from 1,222 operations for undescended testes. J.A.M.A., 160: 634-641, 1956. GROVE, J. S.: The cryptorchid problem. J. Urol., 71: 735-741, 1954. HILL, A. B.: Principles of Medical Statistics, ed. 2. London: The Lancet, Ltd., 1939. (A recent edition is available.) How ARD, R.: Malignant disease of the testes. Practitioner, 79: 794-810, 1907. KIEFER, J. H.: Personal communication. KocHER, T.: Die Krankheiten der mannlichen Geschlechtorgane. In Billroth, T. and Luecke, A.: Deutsche Chirurgie. Stuttgart: Ferdinande Enke, 1887, pt. 50b, pp. 414-532. MURRAY, 0. B. AND EWERT, E. E.: Malignant disease in undescended testes. Surg. Clinics of N. Amer., 27: 709-713, 1947. Selective Service System, Periodic Reports of Physical Examination vols. 4 & 15, 1947. WARRES, H. L.: Carcinoma ln maldescended testes. J. Urol., 72: 252-255, 1954.
Vol. 81, No. 5, May l!J5!l Printrd 1·n e.S .A.
THE I2\CIDE2\CE OF .1-\LALIGNANT GROWTH OF THE Ui\DESCE;';DED TESTICLE: A REPLY AND RE-EVALUATION HORACE E. CAMPBELL
In 1927 """'""0""' wrote, "No greater divc,rsit:' of opinion probably exists concerning anything in medicine tlmn the qrn,stion of malignancy in the undescended testis." In 1940 the definitive ancl unequivocal ans1yer to this problem was [umished Gilbert ancl Hamilton when they a collected series of over 7000 cases of malignancy of the trsticle among which 840 had the malignancy in an undescended testide, an incidence of something undc,r 12 per cent. Among 9,7,11,097 military rel'ruits, 22,665 had umlrsccndecl testicle, an inc:idenC'e of 0.23 per cc,nt. These authors wrote, "That 1 l pc,r cent of all testicular tumors occur in the 0.23 per cent of the malrs who arc cryptorchid proYes that m:opla~tic growth is found for more commonly in the ectopic than in the scrotal about 48 times more often tlmn expected by clmn<:e aswc:iation." (Sec table 1.) In 1942 Campbrll, in ,l sirnihr study but with a collcl'tc,d scric,s of only 1 c:asc,s of testicular malignancy, found that lfi:5 of these had the tumor in an undescenckd an incidence of J 1.6 pGr cent. His conclusion 1n1s, "The difference' hctm::Pn 0.2:-l ± 0.001 :S prr cent and 11.0 ± 0.3 per C'Pnt is so significant that it may be concluded 1Yithont foar of controYersion that the malignant process is more likely to affect thr maklrscrnded organ." Thr statistical significance of the clifferencc between these t\yo perc:c-mtages is enormous, or as Gill1ert nncl Hamilton it, ''f1bout 48 tinws more oftcn than expectecl chanC'e association." (Campbell, '41; IIill) This conclusion has been 1Yiddy accepted. One of the most distinguishrcl contributors to the likmture of m,dignancy in tbe undrscrndecl , in collaboratesticlc, Sir Gordon tion with Xonrnm R Yryndham, it this \Vay, "If the frequency of malignant disease \Vern in no 1Yay reh1tf'rl to non-descent of the organ, then only 0.23 per cf'nt of any series of testicubr neoplasm ought to implicate undC'scendc,d testes." On the othcr hancl, R,t least one dissident voice Acc.cpkd for pnlilication _\ugust 10, 1958.
has been raised, that of 1Y.• \. C:.1rroll of San Francisco. In the course oI a \vidcning a.nee among urologists throughout the it has become apparent that many have rca.d Carroll's 1949 paper and have hfr, theses. These may be stntecl succinctly to br. A. The data upon 1Yhich Gilbf'rt and Hnmilton, Campbell, and others bnsc their conclu. sions are so variable as to br unreliable, and J3. Fndescended testicle is n. rather common anomaly. If cancer affects tlw undrscendecl organ so much more frequently, then all of u.s should sec many more malignancies of the descended testicle. Actually, a. urologists have nrver seen a case. In an effort to resolve the controversy and to stabilize:: the thinking of the profession on this perennially confusing topic, the prf'sent writer has checked thr references given by Carroll and has found that at least six of them hc1ve been misquoted or incompletely quoted. _\nd thrse are six of the seven references he as 1clence of Yalidity of his thesis "A". FurthermorP . many physicians are not aware of the rncognizc:cl methods by whicb statistical nrnterial is nwasnrcd ancl irn~c'iiSed. The discussion that follows will be in tbrce general diYisions: I. The investigation ancl correction of tbc
II. An cYaluation of Yariabilit,1" of data Gt anrl (b) in thr field or· umlcsccmled testick, III. The significarn;e of Carroll's smYey m which 76 per cent of thr, rnl,ncnRt~ who rcspondcd to his questionnaire, had nevct' of seen or trea te, l a case of the undescended testicle. I
THE ERROR lK CERTATI, QTJOTATIONS FROM THE LTTERA TURJ,
Carroll apparently felt tlmt the "oYcr 11" givc'n by Gilbert ancl "nearly 12" giYen by Campbell, as tlrn incidrn<:e of nomlrsC'ent nmong those ksticln:
664
HORACE E. CAMPBELL TABLE
1. Incidence of nondescent of testicle in Army recruits Recruits \Vith Nondescent
Number Recruits Examined
Author
Marshall (1828) Rennes (1831) Myrdacz (1887) Love and Davenport (1920) Southam and Cooper (1927) Selective Service System (1947)
I I I
10,800 3,600 6,962,543 2,754,154 10,000 2,794,727
Source
British and French Armies French Army Austrian Army (1870-1882) American Drafted Army (1917-1918) Scottish Recruits (1916-1917) Selective Service Registrants (19401944)
Number
Per cent
12 6 14,057 8,538 52 12,426
0.11 0.16 0.20 0.31 0.52 0.44
----
Total. . . . . . . . . . . . Over-all Percentage. Standard Error.
12,535,824 ...
....
. . . ....
showing malignant change was too high. He wrote, "The published incidence of malignant cryptorchidism in relation to testicular malignancies as a whole varies from 8 to 15 per cent; i.e., Campbell 8 per cent, J\1acKcnzie and Ratner 8 per cent, Gilbert and Hamilton 9 per cent, Rubaschow 11 per cent, Hinman 12.2 per cent, Dean 13 per cent, Chevassu 13.7 per cent and again 11 per cent, and Scott 15 per cent. In opposition to these figures Cunningham reports 1 in 67 cases, Eccles none in 854 cases, Kocher 1 in 1000 cases and Coley none in 1357 cases." (His quoting Campbell's figure as 8 instead of 11.6 per cent, and Gilbert and Hamilton as 9 per cent instead of "over 11" has served to confuse things unnecessarily, is rather involved technically, and will not be untangled here.) For the record, however, the variability of these data is even wider than Carroll has inIicated. He did not refer to the 1938 paper of Gordon-Taylor and Till where a series of 50 cases of testicular malignancy personally observed by Sir Gordon over a period of thirty years involved the undescended testicle in 15 cases, 8 abdominal and 7 inguinal, an incidence of 30 per cent. And then there is the 1947 report by Murray and Ewert showing an incidence of 28 per cent. At this point in our discussion, however, we are concerned primarily with the "opposition figures." The Cunningham figure is correct and will enter the discussion later. The quotations from Eccles, Kocher, and Coley are erroneous. Eccles wrote, "In a close examination of
35,091 0.28 ±0.0015
48,000 males with hernia, 854 had imperfect descent of one or both testes, or one in every 56, and none of these presented any form of malignant disease". Clearly, this series has nothing to do with the incidence of malignant cryptorchism in relation to testicular malignancies as a whole. Coley wrote in 1919, "In the Out-Patient Department of the Hospital for Ruptured and Crippled from 1890 to 1918 there have been observed 80,736 cases of inguinal hernia in the male of which 1,357 of 1.68 per cent were associated with undescended or mal-descended testis." This is indeed interesting, but this series has nothing to do with the incidence of malignant cryptorchism in relation to testicular malignancy as a whole. Elsewhere in this same paper, Coley mentions 64 cases of "sarcoma" of the testis, in 12 of which the tumor was in the undescended testis, 18.7 per cent; but Carroll does not mention this. Kocher's 1000 cases were of undescended testicles, not testicular malignancy. His series, and those of Eccles and Coley, too, would be relevant as regards the incidence of malignancy in a series of undescended testicle, but is not relevant as regards the incidence of nondescent in a series of testicular malignancy. There is a difference. Carroll has introduced in opposition a series of percentages from another category. Carroll next sought to cast doubt upon the figure of 0.23 per cent as the incidence of nondescent in the adult male. He wrote, "The uncertainty as to the true incidence of crypt-
INCIDENCE OF MALIGNANT GROWTH OF UNDESCENDED TESTIS
orchidism deepens when the published statistics are enumerated, i.e. Marshall 0.1 per cent, Hempel 0.2 per cent, Gilbert and Hamilton 0.23 per cent, World War I records 0.31 per cent, Howard 0.6 per cent, Baumrucker 0.75 per cent and Coley 4. 7 per cent; a variation from 1 in a 1,000 to 75 in a 1,000." (The latter figure should be "to 47 in a 1,000" and has been corrected in his reprints.) It should be pointed out and understood that the figures of Marshall, Hempel, and from World War I all went into the series of Gilbert and Hamilton and are a part of his composite figure of 0.23 per cent. The figures of Howard, Baumrucker, and Coley have no relation here, as we shall now indicate. Here is what Howard actually wrote: "In the 20 years, about 110,000 male patients have been admitted to the [London] Hospital, and of these only 65 were suffering from malignant disease of the testis, or about 0.06 per cent of all male patients." He has nothing to say concerning the incidence of undescended testicle among these 110,000 male patients. Farther along in the paper he states that 57 of the malignant cases were verified by the microscope, and of these, 9 cases (15.7 per cent) occurred in the retained testis. Carroll does not quote this significant figure. Note that Howard's figure is 0.06, not 0.6 as given by Carroll. But this of no concern, for Howard's series is irrelevant in any case. Thus, Carroll's use of it is mistaken on two counts. Carroll quotes Baumrucker as reporting an incidence of 0.75 per cent. Baumrucker's words are: "Among 10,000 men, 75 had one or both testes undescended. Of these, 15 had abdominal testes, 14 unilateral and one bilateral. Of the 75 individuals, 60 had inguinal testes. Two of these had assumed a position in the canal following inguinal herniotomy from an original scrotal position .... The high incidence of undescended testicles may be explained by the fact that our material consisted of a certain percentage of previous rejections back for reclassification." This last sentence, to which Carroll makes no reference, makes this series unsuitable as an index to the general adult male population, despite the great value of the series in other respects. Coley is quoted as reporting an incidence of nondescent as high as 4.7 per cent. Here is what
665
Coley wrote: "Of 1,040 cases of hernia in adults operated upon at the Memorial Hospital by Dr. William A. Downes and the writer, 49 or 4.71 per cent were associated with undescended testis." Coley does not anywhere imply that one thousand cases of hernia are to be considered typical of 1000 males generally, as far as the incidence of undescended testicles is concerned. Thus it is seen that the three percentages cited by Carroll as so widely divergent as to cast doubt upon the incidence of 0.23 per cent are either misquoted or irrelevant. This is not to imply that the figure of 0.23 per cent is absolute. Perhaps it is not an exaggeration to say that nothing in the field of statistical analysis is absolute. The figure of 0.23 per cent has already to be altered by the addition of figures from World War II (table 1). Now let us consider the importance of variability as it affects reliability. II. VARIABILITY AND RELIABILITY OF DATA
The theory of probability will not be elucidated here. It is suggested that every physician should read carefully the (conveniently little) book by Bradford Hill. The writer made an effort to bring the rudiments of statistical method to the attention of the medical profession in 1941, at the time of his study of the problem of malignancy of the undescended testicle. Carroll has pointed out that the published figures vary. The statistically trained observer knows that they vary, but does not spend his time quoting the various series. He measures and assesses the variability. He knows that a percentage based upon 7000 cases is eminently more reliable than a percentage based upon 67 cases, and is therefore more concerned with the size of the series than the percentage itself. This was the reason that Gilbert and Hamilton collected from the literature over 7000 cases of testicular malignancy. This included the series which varied all the way from 1.5 per cent (Cunningham) up to 30.0 per cent (GordonTaylor and Till). Thus the "highs" were balanced against the "lows" in their proper proportions and there emerged the eminently reliable percentage which Gilbert and Hamilton conservatively reported as "over 11 per cent." The same kind of thinking was employed in arriving at the incidence of undescended testicle
0, 0, 0,
TABLE
2. Report of physical examinations of selective service registrants, Nov. 1940-Dec. 1944 based on approximately a 20 per cent sample. Does not include reports of second and subsequent examinations, to avoid possible duplication data. United States: All registrants (Negroes included) Age Groups
All Ages I
18 through 25 years
26 through 29 years
Total Result of examination Total Result of examination Total physi- - - - - - - - - - - - - physi- - - - - - - - - - - - - physicall¥ ed_- General Limited Discally ea.- General Limited Discall:y amme service service qualified amme service service qualified ammec
ey
Total Examined Total Defects.
.. ;, 794, 727 1,576,242 3,126,096 1,145,679
289, 702 928, 783 1,524,890 1,003,881 509,666 1,470,751 1,475,977 662,060
129,839 220,570
391, I 70 593,347
30 years and over
I I
428,439 538,947
Result of examination Total - - - - - - - - ~ - - - 1 physiGeneral I Limited Discall:y ed.service service qualified amme 229,421 197,129
I
55,413 106,921
143,605 841,398 234,897 l,lll,172
I
Result of examination
General Service
Limited service
Disqualified
342,940 286,490
104,450 182,175
394,008 642,507
~
0
~
C"l
i'1
A. Principal Defect of Examined Registrants by Result of Examination and Age Group
i'1 3enitalia Absence or atrophy of testicle .. Undescended testicle. Varicocele " Other genital defects ....
C"l
:,-.
5,457
4,880
225
343
2,995
2,766
IOI
128
8,323 29,837
I, 893 27,348
2,727 1,818
3,703
671
5,236 20,198
1,241 18,945
1,657 962
, ::: I
17,687
11,825
2,888
2,974
10,430
7,906
1,402
I, 122
870
52
46
1,494
1,253
72
169
I, 236 4,883
295 4,306
420 448
521 129
I, 851 4,756
357 4,097
650 408
844 251
2,862
1,872
570
420
4,395
2,047
916
1,432
9J
I
B. All Recorded Defects of Examined Registrants by Result of Examination and Age Group -
Genitalia Absence or atrophy of testicle . Undescended testicle . . Varicocele Other genital defeels.
I 12, f,42
7,857
1,798
2,987
6,023
4,214
666
1. 143
12,426 63,547
2,799 44,518
3,576 9,116
6,051 9,913
7,389 38,758
1,798 29, 725
2,108 4,446
40,222
19,849
8,492
11,881
21,555
12,832
3,886
I
I
2,350
1,393
459
498
4,269
2,250
673
I, 34n
3,483 4,587
1,960 11,231
429 7,145
594 2,211
937 1,875
3,077 13,558
572 7,648
874 2,450
1, 5:31 3,451
4,837
7,298
3,316
I, 931
2,051
11,369
3,701
2,675
4,993
;::: 'ti td
i'1
t< t<
IKCUHJNCE OF MALIGNAN'l' GROWTH OF UNDESCENDED TESTIS
among the adult male population (table 1). The pcn:tcntage varied here from 0.11 (Marshall) to 0.52 (Southam and Cooper). One need not discard these data, saying that they are too variable to be of use in forming a concept as to the frequency of undescended testide. ),clcl them all togethn, the small series of 3,600 contributing its effect along with the massive series of 6,9G2,543 recruits. YVith the addition of the 2,794,727 recruits from World War II, among whom the incidence of nonclescent was 0.44 per cent (table the general percentage is raised to 0.28 per cent from the previous 0.23 per cent. The weight of the massive series of 1887 will always makes itself felt. It is interesting to note that the percentagt'S have increased gradually with the passage of time. This may mean that the race is changing somewlmt, or that examinations arc more carefully done. It is likely that the pccrcentl1gc will never go above 0 ..5, but that it will hover around 0.30, so that ,ve may say quite confidently that about 3 men per thousand have nonrlescent of the testis. One of the most important uses of a rate, e.g., 11 percentage, is to compare it with another rate to see if some difference, e.g., a causal infiuencc, is present. To do this meaningfully, one must know how much this rate might have varied quite by chance, without the influence of some causative influence. Here, again, the physiBradford Hill of much cian will find the book help in coming to realizr that mud1 of truth is a matter of probability, and that one should not be misled into thinking that a final figure will ever he obtained. If the difference between two percentages is three times its standard error, the chances are only 1 in :no that a difference this large could orcur by chance. The difference between 11.0 ± 0.3 per cent and 0.28 ± 0.0015 per cent is 35 times its standard error, and it is almost a certainty that the unclescenclccl testicle is more likely to undergo malignant change than is the normally descemlecl organ. III. THJG SURVEY COKDUCTF,D BY CARROLL
Carroll circulated a questionnaire and learned that 503 members of the American Urological Association (7G per cent of those who responded to his questionnaire) had never seen a malignant m1dcscenclecl testicle. The present writer confossrs that he can not recall having seen one, either.
In this connection it is of interest to read that arres in thrc:e and one-half yc,ars of vatc practice has seen five cases of of the testis, and three of the ffrc were in descended testes, 60 per cent. One oc:c:mTed witb torsion in an abdominal testis and ,1nothcr seven years after orchiopexy. Kiefer, in fl, cent personal communication, tells of nine cases of tumor in undescended testes; and one of the most remarkable series of all is of Gordon-Taylor and Till. The fact that 503 urologists had never seen or treated a malignant undescenclecl testicle; proves simply that it is a rare disease. Dy no stretch of logic does it prove anything; as to whether the undescended testicle is more or less liable to malignant change. As a case rn point, the records of the: Peter Brnt Brigham Hospital for 27 years (1913~39) contained 2 cases of malignant undescended testicle. 11Iost of the residents in urology during that JJeriod did not see a case of malignant undescended testicle And yet, of all the testicular malignancie11 encountered at that institution in those 27 yearn (19 cases), 10 ..5 per cent were in unclesr:ended testicles. There are those (including the present who would like to sec a study made of the incidence of malignancy in a. series of males fol lowed from youth through adult lifo, givmg the incidence of malignancy in those of the scrir:s with normally descended and abnormally de scendecl testes. This study is in progress with vVorlcl War II material. Up until .January HHS over a. thousand cases of testicular had developed among those examined at the beginning of the war (Dixon and . ;\R the years proceed, we ma,y expect relevant data to emerge from this study. But while we aw waiting, sound clinical guides are afforded the data now recorded. 1Ve may conelucle again, "From the data reconfod in the literature it can now be sti1kd unequivocally that the undesccnclecl testicle is more liable to malignant change than the nor mally placed testicle and that the r,bclomin:i.l testicle is more liable to malignant change tlrnn the inguinal."
-w
587 Republic Bldg., Denver 2,-Colorado.
668
HORACE E. CAMPBELL
REFERENCES BAUMRGCKER, G. 0.: Incidence of testicular pathology. Bull. of U.S. Army Med. Dept., 5: 312-314, 1946. CAMPBELL, H. E.: Incidence of malignant growth of the undescended testicle. Arch. Surg., 44: 353-369, 1942. CAMPBELL, H. E.: The statistical method. A vital tool in clinical medicine. Surgery, 9: 825-831, 1941. CARROLL, W. A.: Malignancy ln cryptorchidism. J. Urol., 61: 396-404, 1949. COLEY, W. B.: Operative treatment of the undescended or maldescended testis, with especial reference to end results. Surg., Gynec. & Obst., 28: 452-459, 1919. DIXON, F. J.AND JVIooRE, R. A.: Testicular tumors. A clinicopathological study. Cancer, 6: 427454, 1953. EccLES, W. M.: The Imperfectly Descended Testis. New York: W. Wood & Co., 1903. GILBERT, J. B. AND HAMILTON, J. B.: Incidence and nature of tumors in ectopic testes. Surg., Gynec. & Obst., 71: 731-743, 1940. GoRDON-TAYLOR, G. AND TILL, A. S.: Malignant disease with special reference to neoplasms
of undescended organs. Brit. J. Urol., 10: 1-45, 1938. GORDON-TAYLOR, G. AND WYNDHAM, N. R.: On malignant tumors of the testicle. Brit. J. Surg., 35: 6-17, 1947-1948. GRoss, R. E. AND JEWETT, T. C. JR.: Surgical experiences from 1,222 operations for undescended testes. J.A.M.A., 160: 634-641, 1956. GROVE, J. S.: The cryptorchid problem. J. Urol., 71: 735-741, 1954. HILL, A. B.: Principles of Medical Statistics, ed. 2. London: The Lancet, Ltd., 1939. (A recent edition is available.) How ARD, R.: Malignant disease of the testes. Practitioner, 79: 794-810, 1907. KIEFER, J. H.: Personal communication. KocHER, T.: Die Krankheiten der mannlichen Geschlechtorgane. In Billroth, T. and Luecke, A.: Deutsche Chirurgie. Stuttgart: Ferdinande Enke, 1887, pt. 50b, pp. 414-532. MURRAY, 0. B. AND EWERT, E. E.: Malignant disease in undescended testes. Surg. Clinics of N. Amer., 27: 709-713, 1947. Selective Service System, Periodic Reports of Physical Examination vols. 4 & 15, 1947. WARRES, H. L.: Carcinoma ln maldescended testes. J. Urol., 72: 252-255, 1954.