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Test case to show value of cervical cytology smear in uterine cancer diagnosis
TEST OASE TO SHOW V.A.LUE OF CEB.VIOA.L CYTOLOGY SMIAR IN UTBBINE CANCER DIAGNOSIS* J.
ERNEST
AYRE, M.D., W. A. G.
R\ULD,
1\f.D.,
.\ND
P. ,J.
KKAR)J8,
M.D.
MON'l'REAL, QUEBEC
(Fmm the De1Mrtment of Obstf'!rics an.d GtJntJcolnoy, Roy(ll Vi('tori{l Hoo·pital, j',f cGill F ni Pfrsity )
cytology smears ha\'e been found to detect uterine canCERVICAL cer in lesions so minute as to he missed by the examining finger, the eye, or even the biopsy knife. Such a statement seems fantastic at first, and yet the illustrations accompanying this article prove it is not impossible. The explanation lies in the fact that any cancer lesion large enough to c~use ''spotting'' desquamates specifie (•ancer celts which appear in the blood and discharge, gathering at the external cervical os, to be spilled down into the vaginal secretions below. Papanicolaou and Trauti wer-e the first to describe specific cancer cells in the vaginal secretions of uterine malignancies. Meigs 2 corroborated their findings, confirming the high degree of accuracy described by the original investigators. Both groups admitted that the search for cancer cells was arduous and prolonged in some cases, at times n•quiring a study of three separate smeaJ•s to arrh,e at the correct diagnosis. One of us ( J. E. A.) 8 has t·eeently described a modification of the technique whereby smears taken routinely from the external cervical os showed larger concentrations of cancer eells. The search for the diagnostic cancer cells was, therefore, facilitated and aceelerated, rendering the test more efficient. The cytology of smears prepared from the cervical os is different from that found in the vaginal smear. This is true of normal cases as well as in cancer. In the normal eases, larger numbers of cervical cells, squamous and glandular, and of the endometrial eells from above are found in the secretions at the cervical portal. Most <~anecr of the genital tract arises from either the cervix or the fundus uteri. Therefore, it seems only natural that larger concentrations of the telltale malignant cells may be found at the external os, the souree of th(l spill. Thert>fore, small early growths manifesting only occasional desquamation and spotting, which may require prolonged study for diagnosis hy the vaginal smear, yield a. more speed;\; decision in the rapid det~:..ction of cancer cells in the cervical cytology smear. While three slides may l~e required to diagnose some cases by thP vaginal smear one is usually sufficient in the cervical cytology smt>al'.
Case :&~port The patient, a 42-year-old AJP.erican woman, was admitted. to. the Women's Pavilion of the Royal Victoria Hospital on April 9; 1944. She gave a history of having been delivered of a child by. instrum~mts eighteen months previously. A year later a checkup revealed a small erosion from which a biopsy was taken by her physician in New Yo:rk *Aided by a grant from the Banting H•·"•'n.rch Foundation.
102
AYRE ET AL. :
CERVICAL CYTOLOGY SMEAR
103
State. The biopsy was reported as showing a cervical malignancy, and the patient was referred to Dr. W. A. G. Bauld, head of the Cancer Clinic of the Women's Pavilion. Pelvic examination, on admission, revealed a moderately enlarged mobile uterus attached to a hypertrophic. freelv movable cervix. Dr. Bauld stated at this time that he could find ·no cervical lesion demonstrable clinically, other than the usual small circular erosion about the external os. Cervical cytology smears were taken alid studied. The first smear was reported positive for cancer. On the basis. of the smear findings, coupled with the history of the eervieal biopsy, ~ 1t}anhysterectomy was performed. •
Fig. 1.-Showlng cells found in cervical os smear. Note variable size and conformation of nuclei, also some vacuolation In cancer cells.
Pathologic Report.-Grossly the specimen consisted of a generally enlarged uterus with cervix attached, measuring 18 by 13 by 8 em. The cervix appeared hypertrophic with a small circular eroded area surrounding the external os. Repeated sections of the cervix showed no ulcerated or indurated portion. In view of the suspicion of cancer aroused by the history and the vaginal smear findings, four separate cervical biopsies were taken at 12, 3, 6, and 9 o'clock, respectively. None of these exhibited any gross evidence of cancer. The other organs showed no relevant disease. The microscopic findings were of interest. The first segment of cervix examined showed evidence of cystic cervicitis with a normal .appearing squamocolumnar junction (Fig. 2). The second segment examined, however, showed a different picture. The squamous epithelium appeared normal up to a point approaching the squamocolumnar area. Here the character of the squamous eqithelium exhibited a distinct and abrupt change, the epithelium becoming thicker and the cells showing an hyperplastic appearance. The cytology of this area exhibited a tendency to immaturity, the cells presenting many large and numerous small pyknotic nuclei. Some of these showed evidence of mitosis. · There was no marked invasion of the cervical stoma, but the subepithelial tissues in the hyperplastic zone showed a definite round-cell infiltration (Fig. 3) . The other pelvic tissues showed no evidence of involvement, although the myometrium showed an independent lesion in the nature of a deeply spreading adenomyosis. Dr. Bauld, in replying to the physician who had referred the patient to him, summarized the case as follows: ''Mrs. L. referred by you has been treated by hysterectomy. I confirmed your diagnosis prior to operation by vaginal (cervical) smears which showed definite cancer cells. I could not localize the site of the lesion as the cervix was perfectly healthy in appearance. On this reasoning, I felt that operation would complete the treatment more effectively than radiation. I did a total hysterectomy and bilateral salpingo-oophorectomy. Test of the cervical tissue postoperatively showed a very minute superficial cancerous lesion of the cervix, one of the earliest in our records. I think we can look forward to an almost certain -cure. ' ' •we usually make it a practice to confirm smear findings by the biopsy before resorting to operation or radiotherapy.
104
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
l<'ig-. 2.-First eervical
biop~y
showing cystit' cervicitis with nnnnal rt PPH'I.I'in)!· columnar junction .
sqtHlnHl-
-·
. ·~
Fig. 3.-Second cervical biopsy showing change in charact er of squamous epitheNote s uperficial n oninvasivP. eancP.r lium approaching .•quamocolumn a r junction. (Rowen's disease).
Fig. 4.-High-power pbotomicrograi>h of cancerous area. Note resemblance or cells In smear to those along the surface.
AYRE ET AI,.:
CERVICAL CYTOLOGY SMEAR
105
Criteria. of Diagnosis Considerable study of normal and abnormal vaginal and cervical cytology is necessary to enable one to accurately differentiate the cancer cell from the benign cell. In general, the criteria as outlined so beautifully by Papanicolaou and Traut in their monograph• have been followed. In brief, the finding of blood and pus cells scattered among normal squamous cells with more or less numerous atypical cancer cells showing specific nuclear changes (multilobulation, ruultinucleation, anisocytosis, pyknosis, and multiple chromatin granulations) is significant. The morphology of the cancer cells found in different cases is extreruely variable. But the cells from any one case are usually found to be similar to the cells found in the actual tissue biopsy in that case (Figs. 1 and 4).
Technique The technique is that described in "A Simple Office Test :£or Uterine Cancer Diagnosis.' ' 3 The cervical cytology smear is taken, using a curved glass pipette following exposure with a bivalve speculum. The mucous and blood present at the external os of the cervix or from the surface of the lesion is drawn up into the pipette by suction. This is transferred to a glass slide suitably labeled. The mucus is spread over the slide to prevent the smear bein~r too thick. The slide is then immediately immersed in a solution . of ether and alcohol 9fi per cent (equal parts). Up to this stage, the test may be taken in the office or clinic, wherever the patient is first seen. The bottle containing the smears is then sent to the cytology laboratory for the more complicated process of staining and expert interpretation. The simplicity of the test is important, as the inevitable delay associated with an advisement of hospitalization for biopsy is eliminated. Therefore, the case arousing only suspicion of malignant possibilities in the physician's mind is given the benefit of a "surface biopsy" without waiting until signs of more advanced growth indicate that hospitalization and biopsy have become an obvious and imperative conclusion.
Observation The opinion of the chief gynecologic pathologist (P. J. K.) is that the lesion is an early superficial squamous-cell carcinoma, which at this early stage is still noninvasive. This would appear to fall into the group of early cancer lesions described as "Bowen's disease." Some pathologists have argued that the lesion is not cancer until there is invasion. It is our conception, however, that lesions so early and so minute as this one appears to be should be considered as cancer in a preinvasive :form. No doubt if the disease were diagnosed very early ruore often, it would be found to be in this relatively benign preinvasive stage.
Summary A case has been presented in which an early cervical cancer was detected by the cervical cytology smears while the lesion was so localized as not to be detectable by the trained eye or the finger, and 50 per cent of the surgical biopsies failed to show it. It would appear that the vaginal and cervical cytology smears are of definite value in the diagnosis of very early as well as advanced eases of uterine malignancies.
References
1. 2. 3. 4.
Papanicolaou, G. N., and Traut, H. F.: AM. J. 0BST. & GYNEc. 42: 193, 1941. Meigs, J. V., et al.: Surg., Gynec. & Obst. 77: 449, 1943. Ayre, J. E.: Canad. M.A. J. 51: July, 1944. Papanicolaou, G. N., and Traut, H. F.: Diagnosis of Cancer by Vaginal Smears, New York, 1943, Commonwealth Fund. DRUMMOND MEDICAL BUILDING
ERNEST
AYRE, M.D., W. A. G.
R\ULD,
1\f.D.,
.\ND
P. ,J.
KKAR)J8,
M.D.
MON'l'REAL, QUEBEC
(Fmm the De1Mrtment of Obstf'!rics an.d GtJntJcolnoy, Roy(ll Vi('tori{l Hoo·pital, j',f cGill F ni Pfrsity )
cytology smears ha\'e been found to detect uterine canCERVICAL cer in lesions so minute as to he missed by the examining finger, the eye, or even the biopsy knife. Such a statement seems fantastic at first, and yet the illustrations accompanying this article prove it is not impossible. The explanation lies in the fact that any cancer lesion large enough to c~use ''spotting'' desquamates specifie (•ancer celts which appear in the blood and discharge, gathering at the external cervical os, to be spilled down into the vaginal secretions below. Papanicolaou and Trauti wer-e the first to describe specific cancer cells in the vaginal secretions of uterine malignancies. Meigs 2 corroborated their findings, confirming the high degree of accuracy described by the original investigators. Both groups admitted that the search for cancer cells was arduous and prolonged in some cases, at times n•quiring a study of three separate smeaJ•s to arrh,e at the correct diagnosis. One of us ( J. E. A.) 8 has t·eeently described a modification of the technique whereby smears taken routinely from the external cervical os showed larger concentrations of cancer eells. The search for the diagnostic cancer cells was, therefore, facilitated and aceelerated, rendering the test more efficient. The cytology of smears prepared from the cervical os is different from that found in the vaginal smear. This is true of normal cases as well as in cancer. In the normal eases, larger numbers of cervical cells, squamous and glandular, and of the endometrial eells from above are found in the secretions at the cervical portal. Most <~anecr of the genital tract arises from either the cervix or the fundus uteri. Therefore, it seems only natural that larger concentrations of the telltale malignant cells may be found at the external os, the souree of th(l spill. Thert>fore, small early growths manifesting only occasional desquamation and spotting, which may require prolonged study for diagnosis hy the vaginal smear, yield a. more speed;\; decision in the rapid det~:..ction of cancer cells in the cervical cytology smear. While three slides may l~e required to diagnose some cases by thP vaginal smear one is usually sufficient in the cervical cytology smt>al'.
Case :&~port The patient, a 42-year-old AJP.erican woman, was admitted. to. the Women's Pavilion of the Royal Victoria Hospital on April 9; 1944. She gave a history of having been delivered of a child by. instrum~mts eighteen months previously. A year later a checkup revealed a small erosion from which a biopsy was taken by her physician in New Yo:rk *Aided by a grant from the Banting H•·"•'n.rch Foundation.
102
AYRE ET AL. :
CERVICAL CYTOLOGY SMEAR
103
State. The biopsy was reported as showing a cervical malignancy, and the patient was referred to Dr. W. A. G. Bauld, head of the Cancer Clinic of the Women's Pavilion. Pelvic examination, on admission, revealed a moderately enlarged mobile uterus attached to a hypertrophic. freelv movable cervix. Dr. Bauld stated at this time that he could find ·no cervical lesion demonstrable clinically, other than the usual small circular erosion about the external os. Cervical cytology smears were taken alid studied. The first smear was reported positive for cancer. On the basis. of the smear findings, coupled with the history of the eervieal biopsy, ~ 1t}anhysterectomy was performed. •
Fig. 1.-Showlng cells found in cervical os smear. Note variable size and conformation of nuclei, also some vacuolation In cancer cells.
Pathologic Report.-Grossly the specimen consisted of a generally enlarged uterus with cervix attached, measuring 18 by 13 by 8 em. The cervix appeared hypertrophic with a small circular eroded area surrounding the external os. Repeated sections of the cervix showed no ulcerated or indurated portion. In view of the suspicion of cancer aroused by the history and the vaginal smear findings, four separate cervical biopsies were taken at 12, 3, 6, and 9 o'clock, respectively. None of these exhibited any gross evidence of cancer. The other organs showed no relevant disease. The microscopic findings were of interest. The first segment of cervix examined showed evidence of cystic cervicitis with a normal .appearing squamocolumnar junction (Fig. 2). The second segment examined, however, showed a different picture. The squamous epithelium appeared normal up to a point approaching the squamocolumnar area. Here the character of the squamous eqithelium exhibited a distinct and abrupt change, the epithelium becoming thicker and the cells showing an hyperplastic appearance. The cytology of this area exhibited a tendency to immaturity, the cells presenting many large and numerous small pyknotic nuclei. Some of these showed evidence of mitosis. · There was no marked invasion of the cervical stoma, but the subepithelial tissues in the hyperplastic zone showed a definite round-cell infiltration (Fig. 3) . The other pelvic tissues showed no evidence of involvement, although the myometrium showed an independent lesion in the nature of a deeply spreading adenomyosis. Dr. Bauld, in replying to the physician who had referred the patient to him, summarized the case as follows: ''Mrs. L. referred by you has been treated by hysterectomy. I confirmed your diagnosis prior to operation by vaginal (cervical) smears which showed definite cancer cells. I could not localize the site of the lesion as the cervix was perfectly healthy in appearance. On this reasoning, I felt that operation would complete the treatment more effectively than radiation. I did a total hysterectomy and bilateral salpingo-oophorectomy. Test of the cervical tissue postoperatively showed a very minute superficial cancerous lesion of the cervix, one of the earliest in our records. I think we can look forward to an almost certain -cure. ' ' •we usually make it a practice to confirm smear findings by the biopsy before resorting to operation or radiotherapy.
104
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
l<'ig-. 2.-First eervical
biop~y
showing cystit' cervicitis with nnnnal rt PPH'I.I'in)!· columnar junction .
sqtHlnHl-
-·
. ·~
Fig. 3.-Second cervical biopsy showing change in charact er of squamous epitheNote s uperficial n oninvasivP. eancP.r lium approaching .•quamocolumn a r junction. (Rowen's disease).
Fig. 4.-High-power pbotomicrograi>h of cancerous area. Note resemblance or cells In smear to those along the surface.
AYRE ET AI,.:
CERVICAL CYTOLOGY SMEAR
105
Criteria. of Diagnosis Considerable study of normal and abnormal vaginal and cervical cytology is necessary to enable one to accurately differentiate the cancer cell from the benign cell. In general, the criteria as outlined so beautifully by Papanicolaou and Traut in their monograph• have been followed. In brief, the finding of blood and pus cells scattered among normal squamous cells with more or less numerous atypical cancer cells showing specific nuclear changes (multilobulation, ruultinucleation, anisocytosis, pyknosis, and multiple chromatin granulations) is significant. The morphology of the cancer cells found in different cases is extreruely variable. But the cells from any one case are usually found to be similar to the cells found in the actual tissue biopsy in that case (Figs. 1 and 4).
Technique The technique is that described in "A Simple Office Test :£or Uterine Cancer Diagnosis.' ' 3 The cervical cytology smear is taken, using a curved glass pipette following exposure with a bivalve speculum. The mucous and blood present at the external os of the cervix or from the surface of the lesion is drawn up into the pipette by suction. This is transferred to a glass slide suitably labeled. The mucus is spread over the slide to prevent the smear bein~r too thick. The slide is then immediately immersed in a solution . of ether and alcohol 9fi per cent (equal parts). Up to this stage, the test may be taken in the office or clinic, wherever the patient is first seen. The bottle containing the smears is then sent to the cytology laboratory for the more complicated process of staining and expert interpretation. The simplicity of the test is important, as the inevitable delay associated with an advisement of hospitalization for biopsy is eliminated. Therefore, the case arousing only suspicion of malignant possibilities in the physician's mind is given the benefit of a "surface biopsy" without waiting until signs of more advanced growth indicate that hospitalization and biopsy have become an obvious and imperative conclusion.
Observation The opinion of the chief gynecologic pathologist (P. J. K.) is that the lesion is an early superficial squamous-cell carcinoma, which at this early stage is still noninvasive. This would appear to fall into the group of early cancer lesions described as "Bowen's disease." Some pathologists have argued that the lesion is not cancer until there is invasion. It is our conception, however, that lesions so early and so minute as this one appears to be should be considered as cancer in a preinvasive :form. No doubt if the disease were diagnosed very early ruore often, it would be found to be in this relatively benign preinvasive stage.
Summary A case has been presented in which an early cervical cancer was detected by the cervical cytology smears while the lesion was so localized as not to be detectable by the trained eye or the finger, and 50 per cent of the surgical biopsies failed to show it. It would appear that the vaginal and cervical cytology smears are of definite value in the diagnosis of very early as well as advanced eases of uterine malignancies.
References
1. 2. 3. 4.
Papanicolaou, G. N., and Traut, H. F.: AM. J. 0BST. & GYNEc. 42: 193, 1941. Meigs, J. V., et al.: Surg., Gynec. & Obst. 77: 449, 1943. Ayre, J. E.: Canad. M.A. J. 51: July, 1944. Papanicolaou, G. N., and Traut, H. F.: Diagnosis of Cancer by Vaginal Smears, New York, 1943, Commonwealth Fund. DRUMMOND MEDICAL BUILDING