THE INTERPRETATION OF INFLAMMATORY REACTIONS IN THE VAGINA, CERVIX, AND ENDOCERVIX BY MEANS OF CYTOLOGIC SMEARS

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1 THE INTERPRETATION OF INFLAMMATORY REACTIONS IN THE VAGINA, CERVIX, AND ENDOCERVIX BY MEANS OF CYTOLOGIC SMEARS GEORGE L. WIED, M.D. Department of Obstetrics and Gynecology, University of Chicago and the Chicago Lying-in Hospital, Chicago, Illinois During the first gynecologic examination, it is generally difficult to ascertain the extent and type of an inflammatory reaction. From the clinical standpoint alone, it is difficult to decide whether this reaction acute or chronic, advanced or slight is diffuse or localized to the vagina, the cervix, or the endocervix. The diagnosis is usually established during a period of clinical observation with test-therapy, or by histology, or both. A technic with an adequate degree of diagnostic accuracy that provides a means of distinguishing the factors governing such a reaction is of practical value in obstetrics and gynecology. Assuming that certain technical details are observed, exfoliative cytology provides information that may be used for the localization and differentiation of inflammatory reactions. It is the author's purpose to describe the technic of preparation and interpretation of cytologic smears, with reference to localization and further differentiation of inflammatory reactions of the vagina, cervix, and endocervix. PREPARATION OF SMEARS The cytologic smears are prepared in the usual manner from the female reproductive tract. In every instance, smears are prepared from (1) the vaginal wall, (2) the external os of the uterine cervix, and (3) the endocervix. These 3 smears are prepared on 1 slide (Fig. 1) in such a manner that the smear from the vaginal wall is on the part of the slide closest to the frosted end, the cervical smear in the middle of the slide, and the endocervical smear on the part of the slide furthest from the frosted end. For the preservation of accuracy in the examination, it is important that the smears be properly placed and prepared. It is not advisable to prepare the smears on 3 separate slides, inasmuch as this makes the comparative study considerably more time-consuming. The smears are fixed in alcohol-ether prior to drying, and are then stained according to the technic suggested by Papanicolaou. The interpretation should not be made if the smears are permitted to dry prior to fixation. METHOD OF INTERPRETATION The interpretation of smears for localization and differentiation of inflammatory reactions is based on the observation and comparison of (1) the relative number of leukocytes, (2) the stage of preservation of leukoc3'tes, (3) the presence Received, March 28, 1957; accepted for publication May 16. Dr. Wied is Assistant Professor of Obstetrics and Gynecology, and is in charge of the Cytology Laboratory of the University of Chicago Clinics. This work was supported by an Institutional Grant of the American Cancer Society and the Goldblatt Cancer Research Fund. 233

2 234 WIED Vol. 28 VAGINAL SHEAR ^ \ END0CEBV1CAL SMEAR FIG. 1. Sketches to illustrate the preparation of smears: (1) an ordinary wood spatula is used to obtain the specimen without any scraping on the mucosa of the lateral wall of the vagina, and then the material is spread on the portion of the slide adjacent to the frosted end; (2) a second wood spatula is used to scrape the mucosa of the uterine cervix (or any recognizably abnormal area), and then spread on the middle portion of the slide; (3) a cotton-swab applicator (preferably pre-moistened) is inserted into the cervical canal and rotated slightly, and then the material is spread on the portion of the slide farthest from the frosted end. of histiocytes or foreign body giant cells, and (4.) the inflammatory changes in the epithelial cells. The evaluation is determined by a relative assessment of all of the above factors, and not from any one criterion. Number of Leukocytes An initial observation is made in order to decide which of the 3 smears has the highest number of leukocytes, and which contains relatively few leukocytes, or none. In a patient with localized vaginitis (Fig. 2), the vaginal smear con- FiG. 2 (upper row). Inflammatory reaction localized to the vagina. The photomicrograph on the left illustrates the vaginal material, with numerous, slightly degenerated leukocytes and cells of Trichomonas vaginalis. The middle photomicrograph represents the cervical specimen; there are fewer leukocytes, and they are more degenerated than those observed in the vaginal material. The endocervical specimen (photomicrograph on the right) contains highly degenerated leukocytes, and the epithelial cells illustrated do not have unusual cytologic features. Papanicolaou method. X 360. FIG. 3 (middle row). Inflammatory reaction localized to the cervix uteri. The photomicrograph on the left represents the vaginal material, with only few leukocytes, and all of them are degenerated. Two normal epithelial cells and 2 highly degenerated nuclei of leukocytes are illustrated in the picture. The middle photomicrograph was prepared from the cervical portion of the specimen; there are abundant, rather well preserved leukocytes and squamous epithelial cells with a slight degree of atypia as a result of the inflammation. The endocervical specimen (photomicrograph on the right) has greatly degenerated leukocytes and some normal epithelial cells. Papanicolaou method. X 360. FIG. 4 (lower row). Inflammatory reaction localized to the endocervix. The photomicrograph on the left represents the vaginal specimen, with normal squamous epithelial cells and no leukocytes. The middle photomicrograph was prepared from the cervical specimen; a normal squamous epithelial cell and well preserved leukocytes are illustrated. The remainder of the material consists of nuclear debris, probably from degenerated leukocytes. The material from the endocervix is illustrated in the photomicrograph on the right. There is an abundance of leukocytes and epithelial cells with a moderate degree of atypia, probably resulting from the inflammation. Papanicolaou method. X 360.

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4 236 WIED Vol. 28 tains an abundance of leukocytes, as compared with the cervical and endocervical smears. There may be a moderate number of leukocytes present in the cervical and even in the endocervical smears. On the other hand, they are of minor importance, and manifest more advanced degeneration than that observed in the vaginal smear. Similarly, the smears from patients with localized cervicitis and endocervicitis have the greatest numbers of leukocytes, respectively, in the cervix (Fig. 3) and the endocervix (Fig. 4). An abundance of leukocytes usually signifies an advanced inflammatory reaction, rather than a slight infection, except for the physiologic occurrence of leukocytes, such as that observed during menstrual periods. Stage of Degeneration of Leukocytes The state of preservation or of degeneration of the leukocytes is the next consideration in the interpretation of the smears. The presence of exceptionally well-preserved leukocytes generally indicates a more acute inflammatory reaction (Fig. 5) than does the presence of extremely degenerated leukocytes, such as those observed in senile vaginitis (Fig. 6). The stage of degeneration of leukocytes is also of significance in determining the sites of localization of inflammatory reactions. The leukocytes found at the chief site of infection manifest relatively few degenerative changes, as compared with those in the smear farthest from the center of the infection; leukocytes in the latter location have a relatively higher degree of degeneration (Figs. 2 to 4). The comparative stage of degeneration of leukocytes may be helpful in determining the primary site of infection if the comparative observation on the numbers of leukocytes does not yield significant results. In other words, if an abundance of leukocytes is found in equal amounts in all 3 smears, the smear that is prepared from the chief site of the inflammatory reaction usually contains leukocytes in the best state of preservation. Histiocytes, Foreign Body Giant Cells Histiocytes of various sizes and shapes are frequently observed in smears from patients with advanced inflammatory reactions (Fig. 8). Foreign body giant cells are sometimes found in the vaginal smears of patients with traumatic FIG. 5 (upper left). This photomicrograph was prepared from material from a patient with acute vaginitis, and it illustrates several, well preserved leukocytes, as well as normal squamous epithelial cells. Papanicolaou method. X 360. FIG. 6 (upper right). This photomicrograph was prepared from the vaginal specimen of a patient with senile vaginitis, and it illustrates extremely degenerated leukocytes (nuclear debris), as well as normal epithelial cells from the parabasal layers. Papanicolaou method. X 360. FIG. 7 (lower left). A histiocyte and a foreign body giant cell, as well as several slightly degenerated leukocytes, bacteria, and a normal squamous epithelial cell, are illustrated. This photomicrograph was prepared from vaginal material from a patient with vaginitis. The woman was using a pessary as treatment for prolapse of the uterus. Papanicolaou method. X 360. FIG. 8 (lower right). Relatively abundant, small histiocytes, as well as slightly degenerated leukocytes, are illustrated in this photomicrograph that was prepared from an endocervical specimen from a patient with cervicitis and endocervicitis. Papanicolaou method. X 360.

5 Sept CYTOLOGIC EXAMINATIONS FIGS

6 238 WIED Vol. 28 reactions in the tissue, e.g., patients who use pessaries for the treatment of prolapse of the uterus (Fig. 7). Inflammatory Changes in the Epithelial Cells Epithelial cells frequently manifest slight atypia in smears from patients with inflammatory reactions. This atypia is generally evidenced by the presence of so-called hyperactive and hypertrophic cells, of the parabasal cell (Fig. 9) or endocervical cell variety (Fig. 10), and by the presence of squamous epithelial cells from various layers of the mucosa (Fig. 11). In the cytologic differentiation of the sites of inflammatory reaction, most of these changes in epithelial cells are expected in the smear that is prepared from the chief site of the inflammatory reaction (Figs. 3 and 4). By means of this technic, it is then possible to differentiate the inflammatory reactions into: 1. Inflammatory reaction localized to the vagina. 2. Inflammatory reaction localized to the cervix. 3. Inflammatory reaction localized to the endocervix. 4. Diffuse inflammatory reaction. 5. Apparently mild inflammatory reaction. 6. Apparently marked inflammatory reaction. 7. Apparently acute inflammatory reaction. 8. Apparently chronic inflammatory reaction. The individual findings for the above conditions are briefly summarized, as follows:./. Inflammatory reaction localized to the vagina (Fig. 2). In this condition, the vaginal smear contains the greatest number of leukocytes, and in the best stage of preservation. In some instances, there may be an atypia of the squamous epithelial cells as a result of the inflammatory reaction (Figs. 9 and 11). Small histiocytes and foreign body giant cells may also be observed in the vaginal part of the smear. If the findings of slight epithelial atypia and histiocytes are present, they are more likely to be observed in the smear prepared from the vaginal wall than in the smears from the other sites. FIG. 9 (upper left). This photomicrograph illustrates 6 atypical, dark parabasal cells with intracellular vacuolization and dark nuclei, as well as several, well preserved leukocytes and 2 normal squamous cells from the superficial portion of the mucosa. The specimen was collected from the cervix of a patient with dysplasia of that structure. Papanicolaou method. X 360. FIG. 10 (upper right). A cluster of dense, dark endocervical cells with a slight degree of anisokaryosis and several, slightly degenerated leukocytes are illustrated in this photomicrograph. The specimen was collected from the endocervix of a patient with advanced endocervicitis and endocervical dysplasia. Papanicolaou method. X 360. FIG. 11 (lower left). Inflammatory cellular changes are illustrated in this photomicrograph that was prepared from vaginal material collected from a 26-year-old patient with acute vaginitis. There are several, slightly degenerated leukocytes, bacteria, and normal squamous cells from the superficial, intermediate, and parabasal layers. The presence of squamous epithelial cells from the various layers is usually observed in smears of material from patients with inflammatory reactions. Papanicolaou method. X 360. FIG. 12 (lower right). A squamous epithelial cell with 2 nuclei and a cluster of immature epithelial cells from a deep layer are illustrated in this photomicrograph prepared from material from the cervix of a patient with dysplasia of that structure. Papanicolaou method. X 360.

7 Sept CYTOLOGIC EXAMINATIONS &*tt 4 5 SJ^ l^>i* PIGS

8 240 WTED Vol Inflammatory reaction localized to the cervix {Fig. 3). Similarly, an inflammatory reaction localized to the cervix is evidenced by the presence of atypical epithelial cells, sometimes also by histiocytes, and the greatest number of wellpreserved leukocytes in the cervical smear. In addition to these findings, the cervical smears sometimes manifest findings that are suggestive of eversion of the cervix and the epidermization of glands (Fig. 12). 3. Inflammatory reaction localized to the endocervix (Fig. 4). An inflammatory reaction localized in the endocervix, similarly to that described for the cervix, is characterized by the presence of the greatest number of well-preserved leukocytes, and the occasional presence of histiocytes in the endocervical smear. In addition to these findings, patients with localized inflammatory reactions in the endocervix usually have some hyperactive endocervical cells or slightly atypical squamoid cells, such as those usually observed in epidermization of glands. 4- Diffuse inflammatory reaction (Fig. 13). In this discussion, the term diffuse inflammatory reaction refers to inflammatory reactions that are apparently equally advanced in the vagina, the cervix, and the endocervix. It does not include the possible presence of infections of the parametria, the adnexa, or the intrauterine cavity. The inflammatory reaction is referred to as diffuse, provided there is no significant difference in the numbers of leukocytes present, the stage of preservation of the leukocytes, the presence of histiocytes, and the presence of inflammatory changes in epithelial cells. Generally, the term is used only for advanced inflammatory reactions, and not for those situations in which there are moderate numbers of leukocytes in all 3 of the smears. 5 and 6. Mild and marked inflammatory reactions. Patients with a slight inflammatory reaction have moderate numbers of leukocytes that manifest beginning degeneration, few or no histiocytes, and few or no inflammatory changes as evidenced by epithelial cells. Patients with advanced inflammatory reactions have abundant leukocytes, frequently well preserved, sometimes histiocytes, and, very frequently, inflammatory changes in the epithelial cells. 7 and S. Apparently acute or chronic inflammatory reaction. The classification of inflammatory reactions into acute and chronic is an aspect of the evaluation that does not yield significant results in all instances. The distinction is based on the assumption that the more acute the inflammatory reaction, the better preserved and more numerous are the leukocytes (Figs. 5 and 6). The most significant differences may be observed in some instances of cervical ectropion with an acute inflammatory reaction, where abundant and well-preserved leukocytes are present, as compared with the chronic inflammatory reaction in senile vaginitis, where extremely degenerated leukocytes are observed. RESULTS This technic for evaluating the chief site of an inflammatory reaction has been used at Chicago Lying-in Hospital for the past 3 years, and it has proved to be useful in the diagnosis and treatment of vaginal, cervical, and endocervical infections. The diagnostic information obtained on 500 patients with leukorrhea is summarized in Table 1.

9 Sept CYTOLOGIC EXAMINATIONS 241 FIG, 13. The photomicrographs illustrate the diffuse inflammatory reaction in smears of 3 specimens from a patient with vaginitis (associated with Trichomonas vaginalis), eversion of the cervix, and epidermization of the endocervic.il glands. Abundant numbers of leukocytes, in similar stages of preservation, are observed in all 3 of the specimens. The moderate degree of atypia in the epithelial cells probably results from the inflammation. Papanicolaou method. X 360. TABLE 1 FINDINGS ON 500 GYNECOLOGIC AND OBSTETRIC PATIENTS WHO HAD LEUKORWIEA Site of Inflammatory Reaction* Doderlein's Bacillus Mixed Bacteria Cocci Fungi Trichomonads No inflammatory reaction found in any of the 3 smears Localized vaginal infection Localized cervical infection Localized endocervical infection Diffuse inflammatory reaction s IS IS S 52 Totals * The localization of an inflammatory reaction, together with the microbiologic evaluation, provides a useful guide to the type of treatment required. SUMMARY AND CONCLUSIONS The potentialities of the cytologic examination of smears are discussed with reference to (1) the localization of inflammatory reactions in the vagina, the cervix, and the endocervix, and (2) the classification of these inflammatory conditions into mild, marked, acute, and chronic reactions. The technic of preparation and the interpretation of such smears is described..1. If smears from (1) the vaginal wall, (2) the external os of the cervix uteri, and (3) the endocervix are prepared separately on one slide for every gynecologic and obstetric patient, it is possible, by means of cytologic studies, to categorize the reaction as diffuse, or localized to any one of the 3 sites, i.e., the vagina, the cervix, or the endocervix.

10 242 WJ.ED Vol In addition to determining the localization of the chief inflammatory reaction, the cytologic interpretation may provide information pertaining to (1) the degree of the infection slight or advanced inflammatory reaction and (2) whether or not the inflammatory reaction is seemingly acute or chronic. 3. The differentiation results from the comparative evaluation of the leukocytes present in the 3 smears, their stage of preservation, the presence or absence of histiocytes, and, finally, the presence or absence of inflammatory changes in epithelial cells. SUMMARIO IN INTERL1NGUA Le potentialitates del examine cytologic de frottis es discutite con referentia a (1) le localisation del reactiones inflammatori in vagina, cervice, e endocervice, e (2) le classification de iste conditiones inflammatori como leve, marcate, acute, e chronic. Es describite le technica del preparation e interpretation de tal frottis. 1. Si frottis ab (1) le fornice vaginal, (2) le orificio externe del cervice uterin, e (3) le endocervice es preparate separatemente super un sol lamina pro omne patiente gynecologic e obstetric, il deveni possibile per medio de studios cytologic categorisar le reaction como diffuse o como localisate in un del 3 sitos, i.e., vagina, cervice, o endocervice. 2. A parte que le interpretation cytologic determina le localisation del principal reaction inflammatori, illo pote provider informationes in re (1) le grado del infection leve o avantiate reaction inflammatori e (2) le character apparentemente acute o chronic del reaction inflammatori. 3. Le differentiation resulta ab le evalutation comparative del leucocytes que es presente in le 3 frottis: lor stadio de preservation, le presentia o absentia de histiocytos, e finalmente le presentia o absentia de alterationes inflammatori in cellulas epithelial.