Studies on the distribution of abnormal cells in cytological smears. VII. Cervical brush versus plastic and wooden spatulas.

A model system of exfoliated normal human cervicovaginal squamous cells, exfoliated rodent tumor cells, and acellular, viscous, mucuslike material was used to investigate cell deposition on smear preparations made with three different instruments: plastic spatulas, wooden spatulas, and brush-tipped collectors. The total number of exfoliated cells and the total number of tumor cells present within the randomly distributed holes were then recorded for 41 smear preparations. For smears done with the brush, a total of 47,146 exfoliated cells were recorded; with wooden spatulas, 4517 cells; and with plastic spatulas, 7648 cells. When the brush was used, 6905 tumor cells were recorded. When wooden or plastic spatulas were applied, 563 and 1132 tumor cells were found, respectively. Thus, the brush yielded 12.2 and 6.1 times more tumor cells than plastic and wooden spatulas, respectively.

Effect of combined treatment with phenylpropanolamine and estriol, compared with estriol treatment alone, in postmenopausal women with stress urinary incontinence.

Twenty-nine postmenopausal women with slight to severe stress urinary incontinence and estrogen deficiency symptoms in the urogenital tract were treated with estriol, p.o. 4 mg once daily, and either phenylpropanolamine (PPA), p.o. 50 mg twice daily, or placebo for periods of 6 weeks according to a randomized double-blind crossover schedule. At urodynamic recordings the maximum urethral closure pressure increased by 22% with combined treatment (p less than 0.001) and an additional effect of PPA to estriol was shown (p = 0.022). The pressure transmission ratio increased, by about 15%, with both treatments (p less than 0.07). The number of leakage episodes was reduced by 28% with combined treatment (p = 0.007), but not with estriol alone (p = 0.08). Both combined treatment and estriol alone reduced significantly (p less than 0.01) the urinary incontinence complaints. Twelve women (43%) preferred combined treatment, while 7 (25%) preferred estriol alone. In women with initially slight to very severe urine loss, combined treatment reduced also (p = 0.02) the amount of urine loss, measured at a standardized physical stress test. Signs of estrogen deficiency in vulva, vagina and urethra were reduced, 75% (p less than 0.001) or 65% (p = 0.001) with estriol given in combination with PPA or alone. Maturation index of both urethral and vaginal epithelium displayed significant changes. It is concluded that the combined treatment, PPA + estriol, by affecting both the muscular and mucosal factor of the urethra, is more effective than estriol alone for treatment of female stress urinary incontinence in the postmenopausal ages.

Evaluation of the urethral mucosa before and after oestrogen treatment in postmenopausal women with a new sampling technique.

Using a new type of nylon brush (Cytobrush) for sampling of cells, the state of the urethral mucosa was evaluated before and after oestrogen treatment in 10 patients suffering from urinary incontinence. In 4 other patients the results obtained were compared with those using the conventional cotton swab technique. The brush specimens were found to be much more cellular and consequently more informative than those obtained with the conventional technique. The cytologic examination based on brush samples also demonstrated that oestrogen treatment within 3 weeks induced a proliferation of the atrophic urethral mucosa in postmenopausal women suffering from urinary incontinence.

Screening for endometrial carcinoma by endouterine aspiration cytology with analysis of tumor markers in the aspirates. Development and application of a new screening technique.

A new endometrial aspiration technique for office screening of endometrial carcinoma without an anesthesia was studied. In patients without apparent signs of cervical canal stenosis, all of whom were 50 years of age or older, the aspiration attempt was successful in 96%. The aspirates were used for cytologic study and tumor marker assays. The results indicate that screening for endometrial carcinoma should be based on the determination of biochemical tumor markers in the uterine fluid. Lactate dehydrogenase (LD) is recommended as a primary marker, determined as total LD and as LD isoenzyme activity. Endometrial cytology is recommended as a supplementary screening technique in selected cases.

Adenoma of the nipple. An unusual diagnosis in aspiration cytology.

The cytology of adenoma of the nipple in a fine needle aspirate has so far not been reported. Such a case is described, and the very important cytologic distinction of this lesion from Paget's disease is emphasized.

Studies on the distribution of abnormal cells in cytologic preparations. VI. Pressure exerted by the gynecologist during smearing.

A model system consisting of exfoliated abnormal cells and acellular viscous, mucus-like material was used to investigate the effect of the pressure exerted during smearing on the number of abnormal cells present in the preparations. Smears were made with a cotton swab applicator from left to right with parallel strokes, without overlapping smearing and without rotating the instrument of cell collection. Light and heavy pressures done during smearing procedure were recorded by the aid of an automatic scale. By means of the smearing technique, a gradual decrease in the total number of cells was recorded along the pathway of smearing. By using heavy pressure, however, cell accumulation also occurred at the end of the pathway of the last smearing strokes. Smears made with heavy pressure contained 13% more tumor cells than those made with light pressure. It is concluded that the pressure exerted by the operator during smearing may be an important parameter influencing both the number and the distribution of abnormal cells on smear preparations. These considerations may be of significance in screening programs for tumor cell detection.

Cytologic atypias in the uterine fluid of intrauterine contraceptive device users.

A peculiar cell pattern, characterized as an atypical glandular cell cluster (AGCC), was found in the uterine fluid from women using intrauterine contraceptive devices (IUDs). This atypia can mimic adenocarcinoma. Since the atypical cells were present in much higher frequency in the uterine fluid than in the cervical mucus, it is suggested that they originated in the endometrium.

PIP: In a current research program on intrauterine cytology, an effort was undertaken to describe and quantitate the atypical glandular cell cluster (AGCC) observed in uterine fluid from IUD users. Uterine fluid was sampled and cervicovaginal smears taken from 54 healthy women of reproductive age with regular menstrual periods. 34 of the patients had used an IUD (TCu 200, Recip, Sweden) for 1-1/2 to 3 years. 20 patients did not use IUDs or oral contraceptives (OCs). Within each group, samples were taken in the proliferative phase (8th-16th day of the cycle) and in the luteal phase (17th-30th day of the cycle). The uterine fluid was aspirated with a sterile pediatric feeding tube. A low aspiration vacuum minimized the trauma to the endometrial mucosa, and thus a blood free sample could be obtained. Papanicolaou, AGCCs were counted on both slides, and the sum was given as the number/mcl. The number of inflammatory cells/mcl of uterine fluid was also calculated for each sample. AGCCs were present in the uterine fluid smears from 22 of the 34 IUD users. They occurred similarly in the proliferative and luteal phases. In these 22 samples, a mean of 5.1 clusters/mcl was found. Each cluster consisted of 3-40 cells; the individual cells varied morphologically but were generally characterized by enlarged nuclei, with coarsely granular, irregularly distributed chromatin, occasionally a marked nuclear border, and conspicuous nucleoli. Some cells even revealed marked clumping of the chromatin and macronucleoli. It is thus understandable that these cells can mimic endometrial adenocarcinoma. This was further stressed by the inconstant presence of cytoplasmic vacuoles and signet ring cells. In May-Grunwald-Giemsa stained smears, many mononuclear cells revealed a considerable amount of reddish brown pigmentation, with granules about 1 mcm-2 mcm in diameter in thenucleus as well as in the cytoplasm. In the distinct macrophages, this finding was less common. The granules were not easily seen in Papanicolaou stained specimens. AGCCs were absent in all but 1 of the samples in the control group. Normal endometrial cells were found in all the other samples. ACGGs were present in the cervicovaginal smears from 2 of the 34 IUD users. AGCCs were also found in the uterine fluid from these 2 patients. AGCCs were not present in any of the 20 cervicovaginal smears from the control group. The data strongly suggest an endometrial origin for the AGCCs since they were found much more frequently in the uterine fluid than in the cervical mucus.

Age at menarche, urine estrogens and breast cancer risk.

In 511 nulliparous women aged 15-19 years and 347 aged 30-39, an analysis has been undertaken of the relationship of urine concentrations of the three principal estrogens to age, age at menarche and Quetelet's index of adiposity. The analysis was undertaken by means of multiple regression, controlling for each of the 12 centers from which the data originated, as well as for the other study variables. In the younger women, age was strongly and positively related to concentrations of E1 and E2 and less so to E3. In the age group 30-39, follicular phase specimens showed positive relationships with age for all three fractions but luteal specimens did not. Age at menarche showed inverse relationships to levels of E1 and E2 which were significant in the younger but not in the older age group. The associations of estrogens with Quetelet's index were weak and not statistically significant. The data suggest that women whose menarche occurs early not only have a longer duration of exposure to estrogens during years which are probably important in the initiation of breast cancer but, in addition, their exposures are at a higher level during those years and probably at later ages also. These observations support the hypothesis that the mechanism of the association of early menarche with breast cancer risk is via the association of both with estrogen stimulus.

Enzyme cytochemical studies of the mononuclear phagocytic cells in human uterine fluid.

Mononuclear phagocytic cells were present in normal uterine fluid. All transitional forms between monocytes and mature macrophages could be distinguished. The content of lysosomal enzymes in these cells was found to be identical to that of blood monocytes, which validates the hypothesis of their origin. Mononuclear phagocytic cells were more numerous in the uterine fluid aspirated from women with an intrauterine device (IUD). Furthermore, the activity levels of lysosomal enzymes in these cells were higher in the group of IUD users than in the nonusers, indicating a higher phagocytic activity of such cells in the IUD group, possibly secondary to the inflammatory process.

PIP: The investigation purposes were to characterize the mononuclear phagocytic cells present in human uterine fluid according to their content of lysosomal enzymes and to compare the enzymatic activities of such cells in uterine fluid obtained from IUD users and nonusers. Uterine fluid was obtained from 15 healthy and normally menstruating women attending the clinic at the Malmo General Hospital in Malmo, Sweden. 10 of the women had use an IUD (TCu 200) for 6 months to 3 years; 5 used neither an IUD nor oral contraceptives (OCs). The fluid was aspirated using a sterile pediatric feeding tube. Only samples that were not contaminated with blood or cervical mucus were used. Aliquots of each sample were smeared on 5 separate glass slides. 1 smear was stained with May-Grunwald-Giemsa stain. The remaining smears were stained for the following lysosomal enzymes: alpha-naphthyl acetate esterase (ANAE); napthol AS-D chloroacetate esterase; acid phosphatase; and alkaline phosphatase. Blood smears were obtained from 5 healthy volunteers and stained identically for comparative purposes. Estimation of the content of each enzyme was based on the staining intensity in 20 randomly selected mononuclear phagocytic cells from each smear of uterine fluid or blood. Uterine fluid smears obtained from IUD nonusers contained only a few granulocytes and mononuclear phagocytic cells. These cells occurred in much higher numbers in the uterine fluid from IUD users. In May-Gunwald-Giemsa stained smears, some of the mononuclear phagocytic cells were morphologically similar to blood monocytes; they had round to oval nuclei, pale and finely granular chromatin, nearly invisible nucleoli, and a dusky blue cytoplasm that occasionally contained a few azurophilic granules. This finding was more common in the IUD group. The mononuclear phagocytic cells in uterine fluid obtained from both IUD users and nonusers showed strong ANAE activity, but the strongest activity was found in macrophages in the IUD group. Acid phosphatase activity was strong in many mononuclear phagocytic cells in uterine fluid from both IUD users and nonusers. The activity was strongest in mature macrophages in smears from IUD users. Granulocytes were strongly chloroacetate-esterase positive in uterine fluid as well as in blood smears. Positive stained material was often found in the cytoplasm of macrophages in uterine fluid, especially in the IUD group. Alkaline phosphatase activity was observed neither in blood monocytes nor in mononuclear phagocytic cells in uterine fluid.

Cyclic variation of the cellular components in human uterine fluid.

Endometrial glandular cells and mononuclear phagocytic cells dominated the samples of undiluted uterine fluid obtained at different stages of the menstrual cycle whereas granulocytes were present in much lower numbers. Mast cells were occasionally found. The number of each cell type was significantly decreased in the luteal phase as compared to the midcycle and premenstrual phases. Phagocytic activity of the mononuclear cells was also significantly decreased in the luteal phase. Low numbers of inflammatory cells and low phagocytic activity during the luteal phase may be important for survival of the blastocyst in the event of conception.

The cellular composition of uterine fluid in IUD users - a quantitative study.

The cellular composition of uterine fluid was studied quantitatively in 75 IUD users and 48 non-users. In the IUD group the number of granulocytes was increased about 300 times above that of the non-IUD group, whereas the numbers of mononuclear phagocytic cells and lymphocytes were increased by a factor of 30. Endometrial glandular cells were not quantitatively affected by the presence of an IUD. Granulocytes constituted nearly two-thirds and mononuclear phagocytic cells nearly one-third of the total cell count in the IUD group. Mast cells wee found more frequently and eosinophilia occurred more often in the uterine fluid of IUD users.

Screening of endometrial carcinoma by lactate dehydrogenase isoenzyme analysis of uterine fluid.

Determination of total activity for lactate dehydrogenase (LD) as well as electrophoretic separation and quantitative determination of the individual LD-isoenzymes was performed in 431 samples of uterine fluid obtained by the Gravlee Jet Wash technique or a described simple device for endouterine aspiration. The isoenzyme pattern for each menstrual phase was characteristic. The study population included 18 patients with endouterine neoplasia. All these malignancies were characterized by increased total LD-activity and/or abnormal distribution of the individual LD-isoenzymes compared to proliferative phase and would consequently have been discriminated at postmenstrual or postmenopausal examination. The LD-enzyme technique proved to be more accurate than cytology with approximately the same number of false positives.

Screening of endometrial carcinoma by jet wash and endouterine aspiration cytology.

The results obtained from the use of a new instrument designed to simplify endometrial aspiration were compared to those obtained by Gravlee Jet Wash. The observed difference in accuracy in the diagnosis of endometrial neoplasia between Jet Wash (95 per cent) and endouterine aspiration (91 per cent) is discussed. It is concluded that endometrial cytology by either method is a valuable complement to the Panpanicolaou smear in asymptomatic postmenopausal women. The new endouterine aspiration instrument is recommended because of its greater simplicity.

Early diagnostic signs in the development of a fallopian tube carcinoma.

A woman is presented in whom cellular atypia and signs of abnormal fibrinolysis in a jet washing caused persistent suspicion of malignancy after a benign curettage. Nearly 3 years later a fallopian tube carcinoma was diagnosed. The value of determination of biological markers of neoplasia in addition to the cytologic interpretation of uterine fluid is emphasized.

A study of cryosurgery for dysplasia and carcinoma in situ of the uterine cervix.

We studied 22 patients with a histopathological diagnosis of severe dysplasia and 89 patients with a diagnosis of carcinoma in situ of the uterine cervix. Twenty patients (18 per cent) had negative cervical smears for four to six years after diagnosis by biopsy of the cervix. The 91 patients with persistently abnormal smears were treated by cryosurgery, using a double freeze technique with nitrous oxide. Seventy-four (86 per cent) had persistently normal cervical smears after one treatment and eight after a second treatment while nine patients required conization for recurrently abnormal cervical smears. The duration of follow-up was five or six years in 48 patients (53 per cent). In a subsidiary study, material was obtained for histological examination from 72 patients with normal smears by endocervical curettage and multiple biopsies of the cervix; 8 showed slight atypia and 2 had residual carcinoma in situ.