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Evaluation of the cytologic test in the early diagnosis of cancer
Original EVALUATION
Communications
OF TEE CYTOLQ&ZC TWJT IN TEE EARLY DIA&WWHS OF C2kNWR
A Two-Year Survey of the Routine Use of the Smear Tech&que M.D., NEW YORK, N. ‘I’.
?JOSEPH SKAPIER, (From
the Strnvy
Cnno~r
Prewntion Cmcrr
C!linir and
of Allied
YpmoriaT Hospital 1)issa.w.~)
for
thr
Tr~ccfm~ni
of
INCE Papanicolaou and Traut’ reported their observations on the diagnostic value of vaginal smears in carcinoma of t,he uterus, this method has been widely accepted. This technique was first introduced by I,‘Esperance* for screening in cancer prevention clinics. The diagnosis of this method is based on the principle that malignant cells, due to their high proliferative attirity, exfoliate into the body fluids long before t,he lesion is recognized clinically. An appropriate term for this study is “exfoliative .cytology. “:+ Meigs et ZII.,~Ayre and Graham,” Jones et al,” and Fremonth-Smith’ have conclusively confirmed the value of exfoliative cytology in the diagnosis of cancer of the female genital tract. Gates and Warren8 have pointed out t,he different applications of l-he vaginal smear method in diagnosis of ut,erine cancer : 1. for the study of obscure conditions, such as borderline lesions of uncertain significance and those that cannot be diagnosed by the usual methods ; 2. for diagnosis in selected cases; 3. for determination of the sensit,ivity to irradiation o-f pancer of the uterus in individual cases; 4. As a routine test in general physical examinations; 5. as an adjunct t,o biopsy in diagnosis of gynecologic casesgenerally. In addition to the vaginal fluid, this method may be used with various types of body fluids which contain the exfoliated cells. The fluids may be bronchial secretions, gastric contents, urine sediment, sputum, and others. The recent. reports of Papanicolaou, Marshall, and Cooper,” Herbut and Clerf,“’ Woolner and McDonald,l* Hunter and Rirllardson,‘Z and Campbell and GrimmIS are very encouraging.
S
Material and Method The purpose of this paper is to evaluate the routine use of the cytologic test in the diagnosis of early cancer of the uterus from data obtained in 1946 and 1947, in the Strang Clinic. Approximately 8,000 asymptomatic women had vaginal and cervical smears for the detection of early cancer of the genital tract. In every case a minimum of two smears were taken, a vaginal and a cervical. The vaginal fluid was aspirated with a glass pipette attached to a rubber bulb aft&r it had been carefully placed in the posterior fornix. No lubricants were 366
Volume 53 Number 2
CYTOLOGIC
TEST
IN
EARLY
CANCER
367
DIAGNOSIS
used in this procedure. The fluid was then spread on a slide and fixed immediately in equal parts of 95 per cent alcohol and ether for at least one hour. The cervical smear was obtained by gently swabbing the external OS with a cotton swab. The -fluid on the swab was spread on a slide and fixed in the same manner.
Fig.
L-Vaginal
Fig. Fig. Fig.
Z.-Isolated 3.-Cluster
smear
showing
normal
2.
malignant of malignant
superficial
epithelial
cells.
(X540)
Fig.
3.
cell. (X540) cells. (X540)
Fundal carcinoma can be ruled out with more accuracy by using an endometrial aspiration in addition to the vaginal smear. This is performed with a sterile infant laryngeal cannula introduced beyond the internal OS; with moder-
368
SKAPIER
ate suction the fluid is obtained. Frequently, in elderly postmenopausal women or those with atrophic vaginitis, the vaginal and cervical secretions are scanty. In such cases, the procedure should bc repeated until adequate material is obtained for staining, for not too infrequent false negative reports mav bn the result of this neglect. If t,he fluid remains scanty, washings of the vagina ma> be used. This is done with a solution of equal parts of saline and 10 1~ cent, alcohol. The washings thus obtained arc centrifuged, and a portion of the setliment is placed on an albumin-coated slide and fixed as already described. 7%~ remainder of the sediment can be prcscrved for additional smears it’ neetled. All smears are prepared and stained according to the tcchniqur 01’ l’al)anic*Oli1011.'4
Fig.
4.-Cluster
of malignant cells showing overcrowding cell carcinoma of the cervix, biopsy
and loss of pattern. included. (X540)
Case of squamous-
In our series, the diagnosis of malignancy in some instances was based on the findings from t,he cervical smear while the corresponding vaginal smear was negative ; therefore, it is advisable to take adequate vaginal and cervical mat,erial from each patient. Vaginal aspiration alone is not the best procedure to follow for optimum results. The menstrual history of the patient at the time when the smears are taken, a history of hormone therapy, irradiation, or pelvic surgery are important for the evaluation of atypical cells. Smears should be examined under high as well as low magnification. Isolated suspicious or positive cells may be easily overlooked if only low power is used. The time required to examine a slide adequately varies with the experience of the examiner, Screening of slides can be done by trained personnel, leaving only suspicious and positive slides to the cytologist. Wit.11 proper experience one may examine, on an average, four to six cases per hour.
yzgr
“2”
CYTOLOGIC TEST IN EARLY CANCER DIAGNOSIS
c!riteti
of
369
gf&wnt CMS
The correct diagnosis of a smear requires a thorough acquaintance with the normal cytology of the material being studied (Fig. 1). One cannot overemphasize that the accuracy and dependability of the test depend upon a correct interpretation of the findings. The criteria of the malignant cells as seen in the vaginal smear have been described in detail.*? I5 The most significant of these are: 1. the tendency of the nucleus to be unusually large in proportion to the cytoplasm ; and 2. the nuclear richness in chromatin content, i.e., hyperchromatism, also fragmentation and irregularities of the nucleus with thickening of the Aberrent cells suggestive nuclear membrane and prominence of the nucleoli. of carcinoma may be found either singly or in clusters (Figs. 2 and 3). The loss of pattern and overcrowding of cells is of particular importance in the cluster forms (Figs. 4 and 5). These aberrations are characteristic of epidermoid carcinoma of the cervix as well as adenocarcinoma of the fundus. In adenocarcinoma an abnormal vacuolization of the cytoplasm is seen, in which the vacuoles are frequently infiltrated by leucocytes (Fig. 6). Vacuolization of the cytoplasm in cervical cells has no significance for malignancy. Thickening of the nuclear membrane is quite often seen in cancer cells, but this is not specific for malignancy because it is also seen with chronic inflammation and irritation.
Fig.
5.-Vaginal
smear
of a case of intraepithelial
carcinoma
of the cervix.
(X540)
There are certain features which are not pathognomonic of malignancy, but may add supporting evidence to suspicious findings. These may be an excessive number of degenerated cells or the presence of many active histiocytes. However, a histiocytic reaction may also be found in inflammation and normally in the postmenstrual period, or following coitus; however, in the absence of these, their presence in exdess is suggestive of a malignant process. Bleeding which cannot be attributed to known causes may also be considered suspicious for malignancy. With the present state of our knowledge of exfoliative cytology, we have no criteria which could be applied in the diagnosis of precancerous lesions. IEpidermization is considered by some as precancerous. Atypical cells are often
I 0 c s 1’ 0
Laboratory
and Clinical
Data
L)uring 1946 and 1947, 7,777 asymptomatic !\‘1m1(‘1~ lvet~’ ttsarlliu~~(l III oil 1 clinic, 4,160 in 1946 and 3,617 jn 19-1;. Among tllcxst., t.wcnt?‘-r wo ~.:ir(.inutn;ls T\v-ellt~--w oi’ thenc twwt~~-l \Tc, (‘aws of the female genit,al tract were dcteplctf. ‘I‘his is shown were proved to be positive first by sm~‘itr and then 1)~ biopsies. in Table II. These findings give us approximat,elp ant’ l)ositivc caase per 35-l women examined. The laboratory and clinical data :IW also show71 in Table TT
Volume Number
58 2
Fig.
CYTOLOGIC
B.--Vaginal
smear
Fig.
‘I.-Smeat
TEST
and biopsy
showing
IN
EARLY
CANCER
of a case of adenoearcinoma
a case of infection,
371
DIAGNOSIS
Class
of the uterus.
II.
(X540)
(X5401
__-~
CHART NUMBER
2,220 C. H. 2,847 D. M. 4,850 C.R. 4,999 M. J. 5,409 S. B *
TABLE: II. FINDINGSON FIRST GYN.
erosion
I,::,46 IV
l/15/46 III 8/47
erosion
4/
8/
OF SMEARS 12/U/46 IV 8,' 8/46 IV 1/ 2/46 IV l/23/46 III l/11/46 IV
DATEAND CLASSIFICATIOW
LABORATORY AND CLINICAL TRACT PROVED BY VAGINAL
Cervical cervicitis
EXAM Cervical erosion
35 Chronic erosion
42
AGE
40 Granular
Noue
47 None
42
45 Cervical Cervical
erosion
erosion
49 48 Cervical
erosion
5,465 E. 8. 5,499 A. s. 5,500 G. B. 45
Cervical
3/‘&G
6,516 J. F. 40
4/16/46 III
III
6,720 H. H.
--._--
__~--__
BIOPSY
l/23/!&6 Intraepithelial ca. 8/ s/4; Epidermoid ea. Grade l/26/46 ca. Intraepithelial
4/ 4/4G 4/17/-16 Int rsepithelial ca. 4/16/16 1?/23/47 cerriei& Uwoitic
-.------
5/14/‘&T Intraepithelial ea. 10/19/46 Epidermoid ea. Grade l/29/46 Intraepithelial ca. l/23/46 Intraepithelial ca. l/11/46 ca. Grade Epidcrmoid
II
II
II
DATA IN 21 CASES OF CARCINOMA OF THE GENITAL SMEARS AND CONFIRMED LIY BIOPSIES FCRTHER VAGINAL SMEARS
3/20/47 IV None 2/14/46 IV 10/31/46 III Nvne None None 2/ l/46 Z/26/46 IV l/28/47 III 11/10/4T III 12/12/a; IV
up
TREATMENT AXD CLI~NICALCOTRSE
follow
Hyatereetomv
No
Hgsterectom~
Hysterectomy
No
follow
follow
up
up
up
.
-.
hnit3 t >
No
follow
Irradiatiou tiuhsequent negative Irradiation
No
-_-___-..
Hpaterrctomy Epidermoid ca. Grade III.
.--.
T-
Cervical
40
61
5,716 H. D.
9,085
3/26/47 IV 12/16/47 III
37
50
12,086 M. c.
12,425 L. N. 16,420 M. J.
35
III
39
Laceration of cervix Cervical erosion
None
3/
6/47
1,&47 III 2/13/47 III
llD?3? L. A.
Laceration of cervix Cervical erosion
51
10/25/46
g/13/46 III
44
erosion
polyp
erosion
bleeding
S/20/46 III g/13/46 III S/13/46 III
M. R. 11,380
Cervical
Vaginal
erosion
6/13/46 IV
10,412
R. M.
Cervical
56
8%: fJ. K.
Cervical
49
8,020
Cervical polyp and erosion
44
7,676 F. S.
III
6/46
12/22/47 TV
None
3/24/47 IV
11/26/47 V
None
None
12/
None
7/12/46 IV None
None
l/16/46
1 l/26/46 ca. Grade l/22/47 Epidermoid ea. Grade 11/11/47 11/26/47 Int.raepithelial ca. 3/ 7/47 Intraepithelial ca. 3/24/47 Epidermoid
Fa. 3/22/47 Spindle-cell sarcoma
Intraepitl~eliai
II
II
ea. 7/13/46 Epidermoid ca. Grade III 3/ 5/47 Adenocarcinoma, fundus g/13/46 9/ 2/46
Intraepitheliai
6/U/46 6/24/46 follow
up
follow
follow
follow
No
follow
Hysterectomy
No
No
No
up
up
up
up
Operation for retroperitoneal tumor, metastases uterus No follow up
Hysterect,omy
Hysterectomy
No
Hysterectomy
Y w
374 Among these 21 cases the first smear was reported as Class III in 12 eases (57 per cent) and Class IV in 9 cases (43 per cent). On subsequent, smears, some of the original Class III were reclassified as IV and one as V. On reviexving the clinical data it is of interest to see that in three cases (14 per cent,) the findings were negative on physical examination, while the remaining eighteen cases (86 per cent) showed some evidence of pathology. On further exploration. nineteen cases (90 per cent) proved to hc carcinoma of the cervix one case (5 per cent) adenocarcinoma of the fundus, and 1 case (5 per cent) a metastatic: spindle-cell sarcoma. Of the cervical carcinomas, 12 cases (63 per cent,! rcvealed intraepithelial carcinoma, i.cl., raknoma in situ, five cases (26 per cenl J epidermoid carcinoma (:rade II. nncl two eases ill per cclnt \ epidermoid aarcdinoma G-rade III. -_TYPE
NUMBER
Intraepithelial epidermoid carvinorr::~ Epidermoid carcinoma Grade II Epidermoid carcinoma Grade 11 I Adenocarcinoma, fundus Metastatic windle-cell sarcoma. uterus TABLE AGE (YEARS) 35 to 39 40 to 49 50 to 59 61
IV.
PERCENT
12 .-I ,> r I
AGE INCIDENCE -.-
5; “‘j d. 10 3 .i
OF CASES IN TABLE II. -.. .--___-. ---_l_ -
NUMBER
---
PEBCEKT 19 62
---zzx _---.
-. --
3 1
There are two additional cases which bring out the problems of false positive and negative reports. Case No. 13,928 (M. H.) reported Class III on one occasion and Class IV on four subsequent examinations, has not as yet been eonfirmed by biopsy. This case is not considered closed, and further exploration may confirm or disprove our diagnosis. Case No. 8,716 (H. D.) had three negative reports on smears, but biopsy was reported as positive for intraepithelial carcinoma. Following a total hysterectomy, the surgical specimen was reported as adenosis of the cervix without cancer.
1. In 1946 and 1947, in the Strang Clinic of Memorial Hospital, approximately 8,000 asymptomatic women had routine vaginal and cervical smears for the detection of cancer of the genital tract. The method as applied in the clinic is discussed. 2. The significant features of the -criteria of malignancy as seen in cytologic studies are evaluated. 3. A classification of the findings on smears as applied to the diagnosis of malignant neoplasm is presented. 4. Our findings result in twenty-two positive cases of carcinoma of the female genital tract, which is approximately one case per 354 asymptomatic women examined. Twenty-one cases were substantiated by biopsies. The re-
Volume 58 Number 2
CYTOLOGIC
TEST
IN
EARLY
CANCER
DIAGNOSIS
375
maining case continues positive smears in spite of repeated negative cervical biopsies. One case showed negative smears prior to the positive cervical biopsy although the surgically removed uterus showed only adenosis. Conclusion The results obtained in 1946 and 1947 with the routine use of the cytologic test in the detection of cancer of the female genital tract have been very encouraging. Other body fluids, namely, sputum, gastric contents, urine sediment, prostatic, fluid, and rectal mucus are now being subjected to cytologic studies in our clinic, as a screening method for the early detection of cancer. References 1. 2. 3. 4.
6. 6. 7.
8. 9. 10. 11. 12. 13. .14. .15.
Papanicolaou, G. N., and Traut, H. F.: AM. J. OBST. & GYNEC. 42: 193, 1941. L’Esperance, Elise 8.: Bull. New York Acad. Med. 23: 394,1947. Papanicolaou, G. N.: Atlas of Exfoliative Cytology, to be published. Meigs, J. V., Graham, R. M., Fremont-Smith, M., Kapnick, I., and Rawson, R. W.: Surg., Gynec. & Obst. 77: 449, 1943. Meigs, J. V., Graham, R. M., Fremont-Smith, M., Janzen, L. T., and Nelson, C. B.: Surg., Gynec. & Obst. 81: 337, 1945. Ayre, J. E.: Canad. M.A.J. 51: 17, 1944. Ayre, J. E., Bauld, W. A. G., and Kearns, P. J.: Aaa. J. OBST. & GYNEC. 50: 102, 1945. AM. J. OBST. & GYNEC. 51: 743, 1946. Ayre, J. E.: Jones, C. A., Neustaedter, T., and Mackenzie, L. L.: AM. J. OBST. & GYNEC. 49: 159, 1945. Fremont-Smith, M., Graham, R. M., and Meigs, J. V.: New England J. Med. 237: 302, 1947. Fremont-Smith, M., Graham, R. M., and Meigs, J. V.: New England J. Med. 238: 179, 1948. A Handbook for the Diagnosis of Cancer of the Uterus by Gates, 0.: and Warren, 8.: the Use of Vaginal Smears, Harvard University Press, 1947, pp. 63-66. Papanicolaou, G. N., and Marshall, V. E.: Science 101: 519,1945. Papanieolaou, G. N.: J. Urol. 57: 375, 1947. Papanicolaou, G. N,, and Cooper, W. A.: J. Nat. Cancer Inst. 7: 357, 1947. Herbut, P. A., and Clerf, L. H.: J. A. M. A. 130: 1006, 1946. Woolner, L. B., and McDonald, J. R.: Proe. Staff Meet. Mayo Clin. 22: 369, 1947. Surg., Gynec. & Obst. 85: 275, 1947. Hunter, W. C., and Richardson, H. L.: Campbell, J. P., and Grimm, H. A.: Rev. Gastroenterol. 15: 21, 1948. Papanicolaou, G. N.: Science 95: 438, 1942. Papanicolaou, G. N.: J. A. M. A. 131: 372, 1946.
Communications
OF TEE CYTOLQ&ZC TWJT IN TEE EARLY DIA&WWHS OF C2kNWR
A Two-Year Survey of the Routine Use of the Smear Tech&que M.D., NEW YORK, N. ‘I’.
?JOSEPH SKAPIER, (From
the Strnvy
Cnno~r
Prewntion Cmcrr
C!linir and
of Allied
YpmoriaT Hospital 1)issa.w.~)
for
thr
Tr~ccfm~ni
of
INCE Papanicolaou and Traut’ reported their observations on the diagnostic value of vaginal smears in carcinoma of t,he uterus, this method has been widely accepted. This technique was first introduced by I,‘Esperance* for screening in cancer prevention clinics. The diagnosis of this method is based on the principle that malignant cells, due to their high proliferative attirity, exfoliate into the body fluids long before t,he lesion is recognized clinically. An appropriate term for this study is “exfoliative .cytology. “:+ Meigs et ZII.,~Ayre and Graham,” Jones et al,” and Fremonth-Smith’ have conclusively confirmed the value of exfoliative cytology in the diagnosis of cancer of the female genital tract. Gates and Warren8 have pointed out t,he different applications of l-he vaginal smear method in diagnosis of ut,erine cancer : 1. for the study of obscure conditions, such as borderline lesions of uncertain significance and those that cannot be diagnosed by the usual methods ; 2. for diagnosis in selected cases; 3. for determination of the sensit,ivity to irradiation o-f pancer of the uterus in individual cases; 4. As a routine test in general physical examinations; 5. as an adjunct t,o biopsy in diagnosis of gynecologic casesgenerally. In addition to the vaginal fluid, this method may be used with various types of body fluids which contain the exfoliated cells. The fluids may be bronchial secretions, gastric contents, urine sediment, sputum, and others. The recent. reports of Papanicolaou, Marshall, and Cooper,” Herbut and Clerf,“’ Woolner and McDonald,l* Hunter and Rirllardson,‘Z and Campbell and GrimmIS are very encouraging.
S
Material and Method The purpose of this paper is to evaluate the routine use of the cytologic test in the diagnosis of early cancer of the uterus from data obtained in 1946 and 1947, in the Strang Clinic. Approximately 8,000 asymptomatic women had vaginal and cervical smears for the detection of early cancer of the genital tract. In every case a minimum of two smears were taken, a vaginal and a cervical. The vaginal fluid was aspirated with a glass pipette attached to a rubber bulb aft&r it had been carefully placed in the posterior fornix. No lubricants were 366
Volume 53 Number 2
CYTOLOGIC
TEST
IN
EARLY
CANCER
367
DIAGNOSIS
used in this procedure. The fluid was then spread on a slide and fixed immediately in equal parts of 95 per cent alcohol and ether for at least one hour. The cervical smear was obtained by gently swabbing the external OS with a cotton swab. The -fluid on the swab was spread on a slide and fixed in the same manner.
Fig.
L-Vaginal
Fig. Fig. Fig.
Z.-Isolated 3.-Cluster
smear
showing
normal
2.
malignant of malignant
superficial
epithelial
cells.
(X540)
Fig.
3.
cell. (X540) cells. (X540)
Fundal carcinoma can be ruled out with more accuracy by using an endometrial aspiration in addition to the vaginal smear. This is performed with a sterile infant laryngeal cannula introduced beyond the internal OS; with moder-
368
SKAPIER
ate suction the fluid is obtained. Frequently, in elderly postmenopausal women or those with atrophic vaginitis, the vaginal and cervical secretions are scanty. In such cases, the procedure should bc repeated until adequate material is obtained for staining, for not too infrequent false negative reports mav bn the result of this neglect. If t,he fluid remains scanty, washings of the vagina ma> be used. This is done with a solution of equal parts of saline and 10 1~ cent, alcohol. The washings thus obtained arc centrifuged, and a portion of the setliment is placed on an albumin-coated slide and fixed as already described. 7%~ remainder of the sediment can be prcscrved for additional smears it’ neetled. All smears are prepared and stained according to the tcchniqur 01’ l’al)anic*Oli1011.'4
Fig.
4.-Cluster
of malignant cells showing overcrowding cell carcinoma of the cervix, biopsy
and loss of pattern. included. (X540)
Case of squamous-
In our series, the diagnosis of malignancy in some instances was based on the findings from t,he cervical smear while the corresponding vaginal smear was negative ; therefore, it is advisable to take adequate vaginal and cervical mat,erial from each patient. Vaginal aspiration alone is not the best procedure to follow for optimum results. The menstrual history of the patient at the time when the smears are taken, a history of hormone therapy, irradiation, or pelvic surgery are important for the evaluation of atypical cells. Smears should be examined under high as well as low magnification. Isolated suspicious or positive cells may be easily overlooked if only low power is used. The time required to examine a slide adequately varies with the experience of the examiner, Screening of slides can be done by trained personnel, leaving only suspicious and positive slides to the cytologist. Wit.11 proper experience one may examine, on an average, four to six cases per hour.
yzgr
“2”
CYTOLOGIC TEST IN EARLY CANCER DIAGNOSIS
c!riteti
of
369
gf&wnt CMS
The correct diagnosis of a smear requires a thorough acquaintance with the normal cytology of the material being studied (Fig. 1). One cannot overemphasize that the accuracy and dependability of the test depend upon a correct interpretation of the findings. The criteria of the malignant cells as seen in the vaginal smear have been described in detail.*? I5 The most significant of these are: 1. the tendency of the nucleus to be unusually large in proportion to the cytoplasm ; and 2. the nuclear richness in chromatin content, i.e., hyperchromatism, also fragmentation and irregularities of the nucleus with thickening of the Aberrent cells suggestive nuclear membrane and prominence of the nucleoli. of carcinoma may be found either singly or in clusters (Figs. 2 and 3). The loss of pattern and overcrowding of cells is of particular importance in the cluster forms (Figs. 4 and 5). These aberrations are characteristic of epidermoid carcinoma of the cervix as well as adenocarcinoma of the fundus. In adenocarcinoma an abnormal vacuolization of the cytoplasm is seen, in which the vacuoles are frequently infiltrated by leucocytes (Fig. 6). Vacuolization of the cytoplasm in cervical cells has no significance for malignancy. Thickening of the nuclear membrane is quite often seen in cancer cells, but this is not specific for malignancy because it is also seen with chronic inflammation and irritation.
Fig.
5.-Vaginal
smear
of a case of intraepithelial
carcinoma
of the cervix.
(X540)
There are certain features which are not pathognomonic of malignancy, but may add supporting evidence to suspicious findings. These may be an excessive number of degenerated cells or the presence of many active histiocytes. However, a histiocytic reaction may also be found in inflammation and normally in the postmenstrual period, or following coitus; however, in the absence of these, their presence in exdess is suggestive of a malignant process. Bleeding which cannot be attributed to known causes may also be considered suspicious for malignancy. With the present state of our knowledge of exfoliative cytology, we have no criteria which could be applied in the diagnosis of precancerous lesions. IEpidermization is considered by some as precancerous. Atypical cells are often
I 0 c s 1’ 0
Laboratory
and Clinical
Data
L)uring 1946 and 1947, 7,777 asymptomatic !\‘1m1(‘1~ lvet~’ ttsarlliu~~(l III oil 1 clinic, 4,160 in 1946 and 3,617 jn 19-1;. Among tllcxst., t.wcnt?‘-r wo ~.:ir(.inutn;ls T\v-ellt~--w oi’ thenc twwt~~-l \Tc, (‘aws of the female genit,al tract were dcteplctf. ‘I‘his is shown were proved to be positive first by sm~‘itr and then 1)~ biopsies. in Table II. These findings give us approximat,elp ant’ l)ositivc caase per 35-l women examined. The laboratory and clinical data :IW also show71 in Table TT
Volume Number
58 2
Fig.
CYTOLOGIC
B.--Vaginal
smear
Fig.
‘I.-Smeat
TEST
and biopsy
showing
IN
EARLY
CANCER
of a case of adenoearcinoma
a case of infection,
371
DIAGNOSIS
Class
of the uterus.
II.
(X540)
(X5401
__-~
CHART NUMBER
2,220 C. H. 2,847 D. M. 4,850 C.R. 4,999 M. J. 5,409 S. B *
TABLE: II. FINDINGSON FIRST GYN.
erosion
I,::,46 IV
l/15/46 III 8/47
erosion
4/
8/
OF SMEARS 12/U/46 IV 8,' 8/46 IV 1/ 2/46 IV l/23/46 III l/11/46 IV
DATEAND CLASSIFICATIOW
LABORATORY AND CLINICAL TRACT PROVED BY VAGINAL
Cervical cervicitis
EXAM Cervical erosion
35 Chronic erosion
42
AGE
40 Granular
Noue
47 None
42
45 Cervical Cervical
erosion
erosion
49 48 Cervical
erosion
5,465 E. 8. 5,499 A. s. 5,500 G. B. 45
Cervical
3/‘&G
6,516 J. F. 40
4/16/46 III
III
6,720 H. H.
--._--
__~--__
BIOPSY
l/23/!&6 Intraepithelial ca. 8/ s/4; Epidermoid ea. Grade l/26/46 ca. Intraepithelial
4/ 4/4G 4/17/-16 Int rsepithelial ca. 4/16/16 1?/23/47 cerriei& Uwoitic
-.------
5/14/‘&T Intraepithelial ea. 10/19/46 Epidermoid ea. Grade l/29/46 Intraepithelial ca. l/23/46 Intraepithelial ca. l/11/46 ca. Grade Epidcrmoid
II
II
II
DATA IN 21 CASES OF CARCINOMA OF THE GENITAL SMEARS AND CONFIRMED LIY BIOPSIES FCRTHER VAGINAL SMEARS
3/20/47 IV None 2/14/46 IV 10/31/46 III Nvne None None 2/ l/46 Z/26/46 IV l/28/47 III 11/10/4T III 12/12/a; IV
up
TREATMENT AXD CLI~NICALCOTRSE
follow
Hyatereetomv
No
Hgsterectom~
Hysterectomy
No
follow
follow
up
up
up
.
-.
hnit3 t >
No
follow
Irradiatiou tiuhsequent negative Irradiation
No
-_-___-..
Hpaterrctomy Epidermoid ca. Grade III.
.--.
T-
Cervical
40
61
5,716 H. D.
9,085
3/26/47 IV 12/16/47 III
37
50
12,086 M. c.
12,425 L. N. 16,420 M. J.
35
III
39
Laceration of cervix Cervical erosion
None
3/
6/47
1,&47 III 2/13/47 III
llD?3? L. A.
Laceration of cervix Cervical erosion
51
10/25/46
g/13/46 III
44
erosion
polyp
erosion
bleeding
S/20/46 III g/13/46 III S/13/46 III
M. R. 11,380
Cervical
Vaginal
erosion
6/13/46 IV
10,412
R. M.
Cervical
56
8%: fJ. K.
Cervical
49
8,020
Cervical polyp and erosion
44
7,676 F. S.
III
6/46
12/22/47 TV
None
3/24/47 IV
11/26/47 V
None
None
12/
None
7/12/46 IV None
None
l/16/46
1 l/26/46 ca. Grade l/22/47 Epidermoid ea. Grade 11/11/47 11/26/47 Int.raepithelial ca. 3/ 7/47 Intraepithelial ca. 3/24/47 Epidermoid
Fa. 3/22/47 Spindle-cell sarcoma
Intraepitl~eliai
II
II
ea. 7/13/46 Epidermoid ca. Grade III 3/ 5/47 Adenocarcinoma, fundus g/13/46 9/ 2/46
Intraepitheliai
6/U/46 6/24/46 follow
up
follow
follow
follow
No
follow
Hysterectomy
No
No
No
up
up
up
up
Operation for retroperitoneal tumor, metastases uterus No follow up
Hysterect,omy
Hysterectomy
No
Hysterectomy
Y w
374 Among these 21 cases the first smear was reported as Class III in 12 eases (57 per cent) and Class IV in 9 cases (43 per cent). On subsequent, smears, some of the original Class III were reclassified as IV and one as V. On reviexving the clinical data it is of interest to see that in three cases (14 per cent,) the findings were negative on physical examination, while the remaining eighteen cases (86 per cent) showed some evidence of pathology. On further exploration. nineteen cases (90 per cent) proved to hc carcinoma of the cervix one case (5 per cent) adenocarcinoma of the fundus, and 1 case (5 per cent) a metastatic: spindle-cell sarcoma. Of the cervical carcinomas, 12 cases (63 per cent,! rcvealed intraepithelial carcinoma, i.cl., raknoma in situ, five cases (26 per cenl J epidermoid carcinoma (:rade II. nncl two eases ill per cclnt \ epidermoid aarcdinoma G-rade III. -_TYPE
NUMBER
Intraepithelial epidermoid carvinorr::~ Epidermoid carcinoma Grade II Epidermoid carcinoma Grade 11 I Adenocarcinoma, fundus Metastatic windle-cell sarcoma. uterus TABLE AGE (YEARS) 35 to 39 40 to 49 50 to 59 61
IV.
PERCENT
12 .-I ,> r I
AGE INCIDENCE -.-
5; “‘j d. 10 3 .i
OF CASES IN TABLE II. -.. .--___-. ---_l_ -
NUMBER
---
PEBCEKT 19 62
---zzx _---.
-. --
3 1
There are two additional cases which bring out the problems of false positive and negative reports. Case No. 13,928 (M. H.) reported Class III on one occasion and Class IV on four subsequent examinations, has not as yet been eonfirmed by biopsy. This case is not considered closed, and further exploration may confirm or disprove our diagnosis. Case No. 8,716 (H. D.) had three negative reports on smears, but biopsy was reported as positive for intraepithelial carcinoma. Following a total hysterectomy, the surgical specimen was reported as adenosis of the cervix without cancer.
1. In 1946 and 1947, in the Strang Clinic of Memorial Hospital, approximately 8,000 asymptomatic women had routine vaginal and cervical smears for the detection of cancer of the genital tract. The method as applied in the clinic is discussed. 2. The significant features of the -criteria of malignancy as seen in cytologic studies are evaluated. 3. A classification of the findings on smears as applied to the diagnosis of malignant neoplasm is presented. 4. Our findings result in twenty-two positive cases of carcinoma of the female genital tract, which is approximately one case per 354 asymptomatic women examined. Twenty-one cases were substantiated by biopsies. The re-
Volume 58 Number 2
CYTOLOGIC
TEST
IN
EARLY
CANCER
DIAGNOSIS
375
maining case continues positive smears in spite of repeated negative cervical biopsies. One case showed negative smears prior to the positive cervical biopsy although the surgically removed uterus showed only adenosis. Conclusion The results obtained in 1946 and 1947 with the routine use of the cytologic test in the detection of cancer of the female genital tract have been very encouraging. Other body fluids, namely, sputum, gastric contents, urine sediment, prostatic, fluid, and rectal mucus are now being subjected to cytologic studies in our clinic, as a screening method for the early detection of cancer. References 1. 2. 3. 4.
6. 6. 7.
8. 9. 10. 11. 12. 13. .14. .15.
Papanicolaou, G. N., and Traut, H. F.: AM. J. OBST. & GYNEC. 42: 193, 1941. L’Esperance, Elise 8.: Bull. New York Acad. Med. 23: 394,1947. Papanicolaou, G. N.: Atlas of Exfoliative Cytology, to be published. Meigs, J. V., Graham, R. M., Fremont-Smith, M., Kapnick, I., and Rawson, R. W.: Surg., Gynec. & Obst. 77: 449, 1943. Meigs, J. V., Graham, R. M., Fremont-Smith, M., Janzen, L. T., and Nelson, C. B.: Surg., Gynec. & Obst. 81: 337, 1945. Ayre, J. E.: Canad. M.A.J. 51: 17, 1944. Ayre, J. E., Bauld, W. A. G., and Kearns, P. J.: Aaa. J. OBST. & GYNEC. 50: 102, 1945. AM. J. OBST. & GYNEC. 51: 743, 1946. Ayre, J. E.: Jones, C. A., Neustaedter, T., and Mackenzie, L. L.: AM. J. OBST. & GYNEC. 49: 159, 1945. Fremont-Smith, M., Graham, R. M., and Meigs, J. V.: New England J. Med. 237: 302, 1947. Fremont-Smith, M., Graham, R. M., and Meigs, J. V.: New England J. Med. 238: 179, 1948. A Handbook for the Diagnosis of Cancer of the Uterus by Gates, 0.: and Warren, 8.: the Use of Vaginal Smears, Harvard University Press, 1947, pp. 63-66. Papanicolaou, G. N., and Marshall, V. E.: Science 101: 519,1945. Papanieolaou, G. N.: J. Urol. 57: 375, 1947. Papanicolaou, G. N,, and Cooper, W. A.: J. Nat. Cancer Inst. 7: 357, 1947. Herbut, P. A., and Clerf, L. H.: J. A. M. A. 130: 1006, 1946. Woolner, L. B., and McDonald, J. R.: Proe. Staff Meet. Mayo Clin. 22: 369, 1947. Surg., Gynec. & Obst. 85: 275, 1947. Hunter, W. C., and Richardson, H. L.: Campbell, J. P., and Grimm, H. A.: Rev. Gastroenterol. 15: 21, 1948. Papanicolaou, G. N.: Science 95: 438, 1942. Papanicolaou, G. N.: J. A. M. A. 131: 372, 1946.