W. Kenneth Cuyler

Intraepithelial (Stage O) cancer of the cervix

Abstract The concepts of the detection, diagnosis, and treatment of intraepithelial cancer in our clinic are presented. The data are based on 485 patients with intraepithelial cancer of the cervix studied during the past 13 years from Jan. 1, 1947, through Dec. 31, 1959.

Clinical problems in stage 0 (intraepithelial) cancer of the cervix

Abstract A report is given of 275 patients with intraepithelial (Stage 0) squamous-cell cancer of the cervix or cervical stump, who have had diagnosis and treatment in our clinic during the past eight and one-half years. An attempt is made, by the use of descriptive tables, to place Stage 0 cancer in its proper perspective in the entire problem of malignancies of the female generative tract, as these malignancies are seen by our group. From this small series, we can draw no valid conclusions. This series is simply the basis for consideration of an attempt to formulate how properly to manage the problem of Stage 0 cancer. A review of the clinical material, as shown in the various tables, adds little noteworthy data to those of the 1952 report. Although the figures are not of statistical value, Table I shows that the incidence of intraepithelial cancer in the gynecologic patients was 0.58 per cent and in the obstetric patients the incidence was 0.57 per cent. No significant alterations are found for age (Tables III and IV), for race and economic status, for marital status, or parity (Tables V, VI, and VII). Table VIII shows clearly that Stage 0 cancers were found in cervices and in cervical stumps in which no clinical manifestations of disease were apparent to the examiners. If evidences of disease were present, they were in no way pathognomonic of Stage 0 cancer. A comparison of treatment Tables IX, X, and XI in the original report of 1952 with treatment Tables X and XI in this present report shows among the clinicians of our department a definite trend to vaginal hysterectomy with conservation of the ovaries in our younger age groups. The majority feels that vaginal hysterectomy with removal of an adequate vaginal cuff is the operation of choice. It should be noted in Table X that of 237 gynecologic patients with intraepithelial cancer of the cervix, 57 are being followed with no further definitive treatments than multiple punch biopsies for 7 patients and cold-knife cone biopsies for 50 patients. Discrepancies between the total figures for certain categories in the treatment Table X in this report and those in the treatment Tables IX and X in the original 1952 report are due to elimination from this series of a number of patients treated and followed elsewhere (uncontrolled and lost). Table XI shows that of 38 obstetric patients with intraepithelial cancer of the cervix, 10 have received no more definitive treatments than multiple punch biopsies and 11 no more definitive treatments than cold-knife conizations. The figures in Tables X and XI state a calculated risk we have assumed in following these patients who have not had definitive treatment. Another expression of this assumed risk is found in Table XII which shows that 7 gynecologic patients with Stage 0 cancer of the cervix were permitted to become pregnant one or more times before definitive treatments were given. It is important to note that only one of these 7 patients has continued to show genital smear atypicalities. This patient had multiple biopsies only and not cervical conization. Table XIII gives the data on the 11 patients, in a total of 38 obstetric patients who had Stage 0 cancer, who became pregnant after the diagnosis was established. Of these 11 patients, but 3 at the present time had had definitive operative treatment. Eight patients are being followed. One obese, hypertensive patient died following vaginal hysterectomy. No other significant complications occurred as a result of operations for diagnosis or treatment of Stage 0 cancer. Resuturing of the cervix for hemostasis was done in several patients who continued to bleed following cold-knife conization. Routine soundings control the problem of cervical stenosis. One patient, of the 275 patients, had a depressive psychosis prior to diagnosis and definitive therapy and committed suicide despite psychiatric care. It is not felt that the diagnosis and treatment hastened her action. No patient in this series has developed drug addiction. In the discussion, an effort is made to show some of the problems of Stage 0 cancer as they involve many of the specialists of hospital technical practice as well as those of our own service. A short summary is given of the clinical records of two patients in whom invasive squamous-cell cancer of the vagina was demonstrated years after definitive diagnosis and hysterectomy for intraepithelial cancer of the cervix. These two patients are subjects for many varied speculations. To our knowledge none of the patients who are being followed without definitive treatment has developed invasive squamous-cell cancer of the cervix. The follow-up is an important feature in the study of Stage 0 cancer of the cervix or of the cervical stump. It is essential that all patients whether they have had conservative or definitive treatment be followed with adequate diagnostic techniques. Heavy obligations are assumed by anyone who elects to treat the lesion whether by conservative or definitive therapeutic methods. The “pooling” of data from many clinics must be expedited in order to clarify the confusion which now exists in criteria both for diagnosis and for the methods of treatment. Data are presented on the number of follow-up visits and the duration of the follow-up periods for 60 of 75 patients who have Stage 0 cancer and who have had but multiple punch biopsies and cold-knife cervical conizations. The number of follow-up visits per patient ranges from 1 to 14, totaling 289 for the 60 patients. The duration of the follow-up periods ranged from 2 months to 6 years. No patient in this series who has had definitive treatment for Stage 0 cancer of the cervix continues to show atypicalities in genital smears. Three gynecologic and 2 obstetric patients who had multiple punch biopsies or coldknife cervical conizations of the cervix have persistent cytologic atypiae. The two obstetric patients have recently delivered and 2 of the gynecologic patients desire further pregnancies. The third gynecologic patient is 74 years of age and has severe cardiac disease. It is important that two groups of patients in this series be followed closely for academic as well as for clinical reasons. The first group is comprised of those patients who had microscopic foci of invasion found in tissue specimens subjected to multiple block sectioning. There were 7 of these patients, 6 gynecologic and one obstetric. To date, none of these patients has clinical evidence of invasive cancer. The second group is comprised of those patients who have not yet had definitive treatment. Patient 4 in Table XII is an outstanding example in this category. Faithful in follow-ups and with understanding, she refuses further diagnostic or treatment procedures. The diagnostic multiple punch biopsies were made just four years ago. The patient remains adamant in her intention to have another child. Periodic infertility on the husbands part has increased the difficulty of the situation.

Genital cytology in obstetric and gynecologic patients. A four-year study☆☆☆

Abstract 1. 1. Cytologic interpretations were made on 51,022 smears from 15,217 obstetric and gynecologic patients in a four-year study. 2. 2. Technical procedures and classification of cytology are substantially those of Papanicolaou and colleagues. Classification of cervical cytologic atypicalities as studied in smears from pregnant women is recommended. 3. 3. Only 12.3 per cent of the women studied had what were judged to be normal elements in smear preparations whereas some degree of benign abnormalities was encountered in 80.4 per cent. 4. 4. False-negative and false-positive percentages of error are given. Various methods of calculating the false-positive error are illustrated and criticized. 5. 5. A total of 594 genital cancers was studied by smear preparations, of which 447, or 75.2 per cent, consisted of squamous-cell carcinoma of the cervix. Adenocarcinoma of the uterus comprised 80, or 13.4 per cent of the total number. Thirty-two (29 squamous-cell and 3 adenocarcinomas), or 6.8 per cent of the cervical cancers, occurred in cervical stumps. 6. 6. Ninety-five intraepithelial carcinomas of the cervix were studied. These represent 0.62 per cent of all patients studied, 0.65 per cent of the patients who did not have malignancy, and 17.5 per cent of the neoplastic squamous lesions of the cervix. The ratio of intraepithelial carcinoma to squamous-cell carcinoma of the cervix was 1:4.7. 7. 7. Cold-knife conization of the cervix is considered to be the method of choice to provide adequate material for the diagnosis of intraepithelial and early invasive carcinoma of the cervix. The punch biopsy method missed 18.5 per cent of the lesions. 8. 8. The number of patients who had intraepithelial and squamous-cell carcinoma of the cervix are presented graphically according to age groups. 9. 9. The importance of correlating smear interpretations with corresponding pathologic studies is emphasized. 10. 10. The cost of cytologic studies is estimated to be as follows:

The metabolism and utilization of progesterone given intramuscularly to women

0.90 per smear;

The diagnosis of genital malignancy by vaginal smears

3.00 per new patient;

Effects of estrogenic therapy upon ovarian function

2.00 per visit;

STUDIES OF THE METABOLISM OF ANDROGENS IN WOMEN1,2

75.00 per malignancy studied. 11. 11. It is suggested that many intraepithelial carcinomas of the cervix will not be detected unless women as young as 20 years of age have routine cytologic studies made. 12. 12. It is strongly suggested that efforts be made to standardize reports of cytologic interpretations, the staining procedure, classification, and the statistical methods employed. 13. 13. The method is of value for broad screening purposes, providing the interpretations are properly controlled. The detection of early cervical neoplasms is, perhaps, its greatest value. The identification for future study of the cervices which exfoliate benign but definite atypicalities of the epithelium is important.

Pregnanediol determinations in gynecology and obstetrics

Abstract Studies have been reported upon the endometriotropic responses of 23 patients with functional irregularities of uterine bleeding during 99 of 117 cyclic series of therapy with progesterone alone or combined with estrogens. During 30 cycles of 4 of these patients, and during 10 cycles of an additional group of 3 patients, similarly treated, urinary titers of sodium pregnandiol glucuronide were determined. The endometriotropic data warrant the conclusion that crystalline progesterone, when administered intramuscularly in oil to women with functional irregularities of uterine bleeding, is inefficiently utilized. Six of the 7 patients studied were also unable to utilize efficiently their intrinsic progestin despite the existence of evidence that it was being metabolized normally. The intramuscular administration of crystalline progesterone to these patients resulted not only in no increases in their urinary titers of the pregnandiol-complex but also in apparent decreases. These observations suggest that incomplete metabolism occurred. Some of the various factors which may influence the metabolism and utilization of progesterone are discussed.

Rationale of Estrogenic Therapy in Functional Dysmenorrhea1

Abstract Six thousand, seven hundred fifty-three smears on 1,709 patients have been studied. The smears were obtained, stained, and classified by the methods of Papanicolaou and Traut. One hundred fourteen patients with genital malignancy were diagnosed by smears out of a group of 124 diagnosed by pathology; a percentage error of 8.1. False positive diagnoses were made in 34 of 1,585 patients; a percentage error of 2.1. Nine patients have been presented who illustrate the diagnosis of genital carcinoma by the vaginal smear method. These include squamous celled carcinoma of the cervix, 5; squamous celled carcinoma of the vulva, 1; sarcoma of the uterus, 1; and chorionepithelioma, 1. Those patients having squamous celled carcinoma of the cervix show that the diagnosis of malignancy sometimes may be made earlier by smears than by the biopsy method. Primary adenocarcinoma of the oviduct was revealed in the vaginal smears of one patient. One patient with adenocarcinoma of the endometrium in which smears were negative even when they were obtained from the tumor surface is reported to show a weakness of the smear method. Salient features, good and bad, of the vaginal smear method in the diagnosis of genital cancer have been presented. It is thought that this procedure will become routine in the complete physical examination of women, but that treatment for malignancy should not be instituted prior to pathologic tissue confirmation.

ORAL USE OF PREGNENINONOL IN FUNCTIONAL MENO-METRORRHAGIA

T HE ability of adequate estrogenie therapy to transform normal progestational cycles of women to estrogenic (and presumably anovulatory) ones has been verified in the preceding communication.l It would appear most unlikely that therapy of this kind and order is capable of restoring normal progestational cycles in women with ovarian failure of anovulatory type. An investigation, however, of the end results of estrogenic therapy in association with anovulatory failure seemed advisable for several reasons : (1) to confirm or to deny the dictum that, regardless of our ability to substitute for the endocrine deficienry of ovaries with intrinsic ovarian principles no salvage of physiologic functions, i.e., return of the fertile state, results; and (2) to confirm or to deny the theory that the salvage of ovarian function which has been described as following cyclic estrogenprogesterone therapy in a large group of women with prolonged or excessive estrogenic bleeding results solely from t,he estrogenic fraction of the therapeutic schedule. The commercial availability of a cheap, potent,, and orally active nonhormonal est,rogen (diethylstilbestrol) requires a clear definition of the role of estrogens in the treatment of ovarian failure. Methods Sixteen patients whose ages ranged from 15 to 35 years (average age 21.6 years) were selected for this investigation. These patients had presumed anovulatory ovarian failure predicated upon the occurrence of episodes of estrogenic bleeding. The bleeding cycles were commonly irregular and often of prolonged duration. Each patient selected had received from one to three endometrial biopsies prior to initiation of therapy. Two hormonal estrogens, estriol glucuronidet and estradiol in the form of its benzoatet and dipropionate,§ and an nonhormonal estro*Part I of this article was included in the February issue. ?Estriol glucuronide (emmenin) supplied by Ayerst, Montreal, Canada. McKenna and Harrison.