Diseases of the Vagina, Vulva, Perineum, and Anus
THE VAGINA
Normal Cytology
Except for the mucus-secreting Bartholin’s glands, discussed below, the vagina is lined by squamous epithelium that is identical to that lining the outer surface of the uterine cervix. Normal cytology consists of squamous cells and their variants, identical to those described in Chapter 8.
Benign Abnormalities
Inflammatory Disorders
The inflammatory disorders and their causes, observed in the vagina, are generally the same as in the uterine cervix (see Chap. 10). Ulceration of the vaginal epithelium may occur under a variety of circumstances, such as the presence of a pessary. Wilbur et al (1993) described vaginal ulcers in a rare disorder of unknown etiology, the Behçet’s disease. In the case described, abnormal squamous cells, mimicking cancer, were observed in cervicovaginal smears. Cases of malakoplakia of the vagina were reported by Lin et al (1979) and by Chalvardjian et al (1985). For further discussion of this rare disorder, see Chapter 22.
Melanosis of vagina, i.e., accumulation of melanin in the epithelium, is a very uncommon benign condition that may mimic a malignant melanoma (Karney et al, 2001). Malignant melanoma is discussed in Chapter 17.
Infections and Hormonal Status
The responses of the vaginal squamous epithelium to events in the normal menstrual cycle and under the impact of hormonal medication are discussed in Chapters 8 and 9. The susceptibility of the vagina to infectious agents depends on the hormonal status of the squamous epithelial lining: absence of epithelial maturation before puberty and after the menopause favors the proliferation of infectious agents (see Chap. 10).
Posthysterectomy Glandular Cells
Glandular cells of endocervical type have been observed in vaginal smears after hysterectomy (Bewtra, 1992; Tambouret et al, 1998). The origin of these cells is not clear but the authors postulated focal glandular metaplasia or adenosis, occurring in the vaginal epithelium after treatment by radiotherapy or 5-fluorouracil (for further discussion of vaginal adenosis, see below.)
Fistulous Tracts
Fistulous tracts between the vagina and an adjacent organ, such as the rectum (recto-vaginal fistula), or the bladder (vesicovaginal fistula), may result in the presence of epithelial cells of urothelial or intestinal origin in vaginal smears.
In rectovaginal fistulae, the tall, columnar, mucus-producing colonic epithelial cells may be recognized in cervicovaginal smears because of their large size and columnar configuration. These cells usually occur in compact sheets or clusters with basal nuclei and smooth luminal epithelial surface. The differential diagnosis is with vaginal adenosis (see below) and with endocervical or endometrial benign or malignant cells, which are usually smaller. The endocervical-type cells that have sometimes been observed in vaginal smears in posthysterectomy patients may also be confused with colonic cells. The colonic cells are often accompanied by bowel contents in the form of fecal material, often containing indigested muscle or vegetable fibers and plant cells originating in the colon (see Chap. 8). Because the nuclei of the plant cells are large and dark they may be mistaken for cancer cells. For further discussion of plant cells and their identification in sputum, see Chapter 19.
In vesicovaginal fistulae, the multinucleated, large urothelial umbrella cells, derived from the epithelium of the bladder, can sometimes be identified in cervicovaginal smears. These cells can be mistaken for cancer cells (see Chap. 22 for a detailed description of these cells).
Foreign Bodies
A variety of foreign material and foreign bodies, described in Chapter 8, may be found in the vagina and, hence, in cervicovaginal smears.
Benign Tumors and Tumorous Conditions
Except for condylomata acuminata and vaginal adenosis (to be discussed below), benign tumors and tumorous conditions are infrequent in the vagina and of very limited significance in diagnostic cytology. Endometriosis, cysts or benign tumors of Gartner ducts, and very uncommon benign tumors, such as leiomyomas or rhabdomyomas, occur in the wall of the vagina, do not produce any perceptible abnormalities in the vaginal epithelium and, hence, cannot be recognized cytologically, except by aspiration biopsy.
Vaginal and Cervical Adenosis
Natural History
A synthetic compound with estrogen-like effect, diethylstilbesterol (DES), was extensively used for prevention of abortions and other complications of pregnancy during the late 1940s and early 1950s. About 20 years later, it became apparent that the use of this drug adversely affected the offspring of the patients so treated.
In some of the male offspring, cysts of the epididymis and abnormal spermatogenesis were observed, a finding of limited cytologic significance (Gill et al, 1976). In the female offspring, vaginal and cervical adenosis has been observed, a disorder caused by a replacement of vaginal squamous epithelium by glandular epithelium, that on inspection appear as red patches in the upper reaches of the vagina and adjacent cervix. In about 40% of the affected females, there are also abnormalities in the gross configuration of the vagina and the cervix, described as ridges. Most importantly, adenocarcinomas and squamous carcinomas and precursor lesions were observed in a small subset of females with vaginal adenosis. These lesions are discussed below.
It has been shown by Sonek et al (1976) that DES administered between the seventh and eighth weeks of pregnancy resulted in 100% of adenosis in the offspring; if the drug was administered later during pregnancy, the frequency of adenosis was reduced but remained at about 70%.
Although there has been considerable speculation as to the mechanism of formation of adenosis, the evidence currently available strongly suggests that DES inhibits the transformation of the müllerian cuboidal epithelium into squamous epithelium that normally takes place during the last stages of the fetal life. A similar mechanism, although on a very limited scale, must be evoked in reference to cervical eversion or ectropion (see Chapter 10). Thus, adenosis may be conceived as a very large eversion of the endocervical epithelium, affecting the outer portions of the uterine cervix and the adjacent vagina. This has been confirmed by ultrastructural studies (Fenoglio et al, 1976). Experimentally, adenosis can be induced in mice by estrogen treatment (Forsberg, 1976). Vaginal adenosis was also reproduced in the female offspring of the monkey, Cebus apella, exposed to DES during pregnancy (Johnson et al, 1981).
It is of interest, though, that exposure to DES is not a mandatory event in vaginal adenosis. Robboy et al (1986) reported 41 patients with this disorder who had no DES exposure. Adenosis of the vagina has also been observed after treatment with 5-fluorouracil and carbon dioxide laser, usually for extensive condylomas of the vulva and vagina (Sedlacek et al, 1990; Goodman et al, 1991; Bernstein et al, 1983). A case of vaginal adenosis in a patient on Tamoxifen therapy was reported by Ganesan et al (1999).
Histology
In adenosis, areas of proximal vagina and adjacent outer rim of the uterine cervix are lined by mucus-producing glandular epithelium, usually of the endocervical type, replacing the normal squamous epithelium. Occasionally, the epithelium resembles that of the endometrium or the fallopian tubes. The glandular epithelium also forms tubular glands of endocervical type in the lamina propria that may reach the muscularis (Fig. 14-1A,B).
All changes commonly observed in the endocervical epithelium may be observed in adenosis: tubal metaplasia, squamous metaplasia, and malignant transformation leading to adenocarcinoma, epidermoid carcinoma and its precursor lesions, or both.
With the discontinuation of the use of DES for prevention of obstetrical difficulties, adenosis has become a rare disorder, limited to those few women, daughters of DES-exposed mothers, now in their 50s or 60s, and the rare
women who develop it spontaneously or after treatment (see above). Nonetheless, for the sake of completeness, we have retained the description of the cytologic manifestations of this disorder.
women who develop it spontaneously or after treatment (see above). Nonetheless, for the sake of completeness, we have retained the description of the cytologic manifestations of this disorder.
 Figure 14-1 Vaginal adenosis. A. Endocervical type epithelium lining the surface of the vagina. B. Residual endocervical type glands underneath the squamous epithelium lining the vagina. C. Vaginal scrape smear containing scattered endocervical type cells next to squamous cells. D. Scrape of adenosis. The dominant cells are parabasal cells from squamous metaplasia. |
Cytology
The purpose of cytologic examination of the vagina in children and women at risk is to determine the presence of adenosis and of malignant changes, if any, by non-invasive methods. Unfortunately, in uncomplicated adenosis, the cytologic techniques are not very efficient because the glandular epithelium does not desquamate easily. The best method is based on direct scrapes of the lesions under visual control; this approach is applicable only to adult women. In children and virginal adolescents, a vaginal pool smear obtained by a small pipette is the only method available.
Vaginal Pool Smears
Adenosis is characterized by mucus-secreting columnar endocervical cells of various sizes, occurring singly or in clusters, or endocervical cells showing transition to squamous metaplasia (Fig. 14-1C,D). The diagnosis is possible because the finding of normal endocervical cells in vaginal smears is otherwise exceptional. The finding of small squamous cells (“metaplastic cells”), unless in company of columnar mucus-secreting cells, is of a very limited diagnostic value because such cells may also originate in normal squamous epithelium. The efficacy of diagnosis of adenosis in vaginal pool smears is low.
Direct Scrape Smears From Areas of Adenosis
This is the sampling method of choice in adult women at risk. Bibbo et al (1975) advocated taking four separate scrape smears from the four quadrants of the proximal vagina. This may be supplemented by direct smears of the outer portio of the uterine cervix, preferably under visual control. Prior to cytologic sampling, the accumulated mucus should be removed with a gauze sponge.
Direct vaginal scrape smears from cases of adenosis contain
either secure or presumptive evidence of disease. Secure evidence of disease is either the presence of glandular cells of endocervical type or glandular cells showing transition to squamous metaplasia. The presence of small squamous cells, singly or in clusters (“metaplastic cells”), cannot be considered as secure evidence of adenosis. Other cell types listed by Bibbo et al (1975), such as anucleated squamous cells or dyskaryotic squamous cells (dysplastic cells), have no specificity whatsoever for adenosis. Applying these criteria to Bibbo’s series of 66 patients with known adenosis, the cytologic diagnosis of this disorder could be securely established in nine patients and a presumptive diagnosis of adenosis based on “metaplastic cells” in an additional 33 patients. The limited value of cytology in the diagnosis of uncomplicated adenosis was also emphasized by Robboy et al (1986), who could establish the diagnosis of adenosis in only 22% of 575 such patients.
either secure or presumptive evidence of disease. Secure evidence of disease is either the presence of glandular cells of endocervical type or glandular cells showing transition to squamous metaplasia. The presence of small squamous cells, singly or in clusters (“metaplastic cells”), cannot be considered as secure evidence of adenosis. Other cell types listed by Bibbo et al (1975), such as anucleated squamous cells or dyskaryotic squamous cells (dysplastic cells), have no specificity whatsoever for adenosis. Applying these criteria to Bibbo’s series of 66 patients with known adenosis, the cytologic diagnosis of this disorder could be securely established in nine patients and a presumptive diagnosis of adenosis based on “metaplastic cells” in an additional 33 patients. The limited value of cytology in the diagnosis of uncomplicated adenosis was also emphasized by Robboy et al (1986), who could establish the diagnosis of adenosis in only 22% of 575 such patients.
Confirmation of the Cytologic Diagnosis of Adenosis
This is best accomplished by colposcopy. The colposcopist can clearly identify the extent of adenosis and, more important perhaps, examine the large and sometimes multiple transformation zones for evidence of possible neoplastic lesions. If colposcopy is not available, Schiller’s test will disclose iodine-negative areas of glandular mucosa within the vagina and the outer cervix.
Clinical Significance
Melnick et al (1987) estimated the risk of adenocarcinoma at 1 case per 1,000 women with adenosis through the age of 34 years. The peak incidence was at 19 years of age but tumors have been observed in children as young as 7 and in women age 30 (Herbst and Bern, 1981). Tuboendometrial type of epithelium appears to be the most common source of adenocarcinomas (Robboy et al, 1982, 1984). By far more common in adenosis are the precursor lesions of squamous cancer in the vagina and the adjacent cervix (see below).
Follow-up of many thousands of patients with adenosis disclosed the very high probability of self healing. The glandular epithelium undergoes squamous metaplasia which becomes mature and identical to normal squamous epithelium. Thus, unless there is evidence or suspicion of malignant transformation, it appears safe to observe these patients without treatment. Adenocarcinomas and premalignant or malignant squamous lesions observed in patients with adenosis are discussed below.
Malignant Tumors
The most common primary malignant tumors of the vagina are carcinomas of squamous derivation and type. Since the appearance of adenosis on a large scale, increased attention has been devoted to adenocarcinomas associated with this disorder. Primary adenocarcinomas, in the absence of adenosis, are very uncommon, although they have been repeatedly observed. Rare tumors, including malignant melanomas, sarcomas, and metastatic tumors to the vagina are discussed in Chapter 17. Postradiation carcinoma in situ (dysplasia) of the vagina is discussed in Chapter 18.
Squamous Carcinoma
Invasive squamous carcinomas of the vagina and their precursor lesions are usually observed in women past the age of 40. In approximately 50% of these patients, there is evidence of a synchronous or metachronous squamous carcinoma of the uterine cervix that may be invasive or in situ (Kanbour et al, 1974; Murad et al, 1975; Lee and Symmonds, 1976). Bell et al (1984) also observed vaginal cancer in several patients after hysterectomy for allegedly benign disease. Norris et al (1970) reported a case of vaginal squamous carcinoma in an infant.
Association of vaginal carcinomas with other malignant tumors of the female genital tract may also occur. We have personally observed synchronous or metachronous tumors of the vagina, vulva, and occasionally of the endometrium, tube, and ovary. Thus, the presence of a vaginal carcinoma should automatically trigger the search for other malignant lesions. Conversely, follow-up of patients with carcinoma or precancerous states of the epithelium of the uterine cervix and the vulva must include periodic examinations of the vagina.
Observations pertaining to the possible role of human papillomavirus (HPV) in the genesis of cervical carcinoma are also applicable to squamous carcinomas of the vagina and vulva (see Chap. 11). The proof of viral presence in the relatively uncommon vaginal lesions is not nearly as extensive as for the cervical and vulvar squamous carcinomas and their precursor lesions. Still, there is no doubt that the vaginal neoplastic disorders follow the pattern of cervical disease and share identical cytologic, histologic, and biologic backgrounds (Okagaki et al, 1984).
Histology
Most squamous carcinomas of the vagina are keratin-producing, both on the surface of the epithelium of origin and within the invasive and metastatic foci. Occasionally, such lesions have thick layers of keratin on their surfaces and may bear considerable similarity to the warty (verrucous) carcinomas of various organs (Fig. 14-2). The tendency to keratin formation is also observed in precancerous lesions (see below). Nonkeratinizing (epidermoid) carcinomas of the vagina made up of medium-size cells or small cells may also occur (Fig. 14-3). Small cell carcinomas with endocrine features were described by Albores-Saavedra et al (1972) and by Chafe (1989). In a case reported by Colleran et al (1997), the tumor was shown to be secreting ACTH and causing a Cushing’s syndrome.
The term microinvasive carcinoma of the vagina was discussed by Peters et al (1985), based on experience with six patients with invasion up to 2.5 mm in whom the results of surgical treatment by partial or total vaginectomy were uniformly good. In our experience, however, even superficially invasive vaginal carcinomas are capable of forming metastases. Two territories of lymph nodes may be involved: carcinomas of the distal third of the vagina usually form metastases to the inguinal lymph nodes; carcinomas of the proximal third may metastasize to pelvic lymph nodes; carcinomas of the middle third may metastasize to either or both of these two groups of
lymph nodes. The reasons for the very aggressive behavior of carcinomas of the vagina are not clear. Presumably, the lack of a thick muscularis and the abundance of lymphatics in the vaginal wall account for the striking differences in behavior when compared with the superficially invasive carcinomas of the uterine cervix (see Chap. 11).
lymph nodes. The reasons for the very aggressive behavior of carcinomas of the vagina are not clear. Presumably, the lack of a thick muscularis and the abundance of lymphatics in the vaginal wall account for the striking differences in behavior when compared with the superficially invasive carcinomas of the uterine cervix (see Chap. 11).
 Figure 14-2 Keratinizing squamous carcinoma of the vagina. A. Keratinized carcinoma in situ from which well-differentiated squamous carcinoma shown in B was derived. C,D. Various aspects of small squamous cancer cells in a vaginal smear. |
We have also observed a case of a bulky vaginal tumor with features of pseudosarcoma. On the surface of the lesion, there was a squamous carcinoma in situ. The stroma of the tumor was composed of spindly cells mimicking a sarcoma with focal differentiation into an invasive squamous carcinoma (Fig. 14-4). This tumor was identical to the uncommon tumors of this type observed in the esophagus and adjacent organs described in Chapter 25.
Squamous Carcinoma In Situ and Related Lesions (Vaginal Intraepithelial Neoplasia; VAIN)
Carcinomas in situ and noninvasive epithelial lesions with lesser degrees of abnormality (“dysplasias”) have been grouped as vaginal intraepithelial neoplasia (VAIN) that can be graded I, II, III as initially proposed for similar lesions of the uterine cervix (see Chap. 11). Although the Bethesda nomenclature (see Chap. 11) has not been extended to the vagina, it appears reasonable to classify VAIN I as low-grade lesions (mild dysplasia with features of condyloma) (Fig. 14-5) and VAIN II and III as high-grade lesions. This suggestion gained support from a study by Sherman and Paull (1993) who documented better reproducibility of diagnoses, using the binary system. Logani et al (2003) reported that most of the precancerous lesions of the vagina contain high risk HPV, contrary to vulvar lesions. These authors also noted that staining with proliferation antigen M1B1 helps in distinguishing benign from potentially malignant epithelial changes.
The clinical appearance of these lesions depends on the level of keratinization: the heavily keratinized lesions appear as white patches (leukoplakia), whereas the poorly differentiated (epidermoid) lesions with limited keratin formation may appear as red areas in the vagina (Hummer et al, 1970).
Predictably, the low-grade lesions resemble structurally normal squamous epithelium, except for the presence of nuclear enlargement, hyperchromasia, and mitotic activity (Fig. 14-5). In the presence of koilocytes, the lesions are identical to the so-called flat condylomas observed on the surface of the uterine cervix (see Chap. 11). Keratin deposits are often present on the surface. The low-grade lesions may occur as multiple condylomas that form small elevations of the vaginal epithelium (condylomatous colpitis) and are often associated with similar lesions on the vulva; although these lesions are difficult to eradicate, they are not considered threatening to the patient. They have been observed in children, presumably as a consequence of sexual abuse. More important is the single low-grade
lesion. Although many of these lesions may disappear, presumably spontaneously or after treatment, there is at least some evidence, based on personal experience, that the vaginal low-grade lesion may progress to invasive cancer more rapidly and more frequently than similar lesions in the uterine cervix. This observation has received support from a follow-up study of untreated VAIN by Aho et al (1991) who also observed the progression of a low grade lesion to invasive cancer.
lesion. Although many of these lesions may disappear, presumably spontaneously or after treatment, there is at least some evidence, based on personal experience, that the vaginal low-grade lesion may progress to invasive cancer more rapidly and more frequently than similar lesions in the uterine cervix. This observation has received support from a follow-up study of untreated VAIN by Aho et al (1991) who also observed the progression of a low grade lesion to invasive cancer.
 Figure 14-3 Poorly differentiated squamous carcinoma of the vagina. A,B. The surface lesion (A), which became invasive (B). C,D. Small cancer cells in vaginal smears. |
The high-grade lesions fall into two groups: kerat-informing lesions, that may show remarkable similarity to low-grade lesions except for the presence of abnormal cells throughout the thickness of the epithelium (see Fig. 14-2A); and nonkeratinizing lesions that are similar to high-grade lesions of the endocervical canal, composed of smaller malignant cells and show little or no keratin formation on the surface (see Fig. 14-3A). Anecdotal evidence has been accumulated that these lesions, particularly the classical carcinoma in situ, have the ability to progress to invasive squamous cancer (Rutledge, 1967; Benedet and Sanders, 1984; Aho et al, 1991), although the frequency of progression remains unknown because few of these lesions are followed without treatment.
Cytology
The customary source of diagnosis of vaginal carcinoma is the smear obtained by aspiration of the vaginal pool. Occasionally, however, cancer cells of vaginal origin may be observed in cervical smears.
If cervical and/or vaginal smears contain evidence of squamous carcinoma or a related precancerous lesion and there is no evidence of disease in the uterine cervix, the vagina must be investigated. Direct scrape smears of the vaginal wall may be used initially to confirm the diagnosis. On occasions when there is no visible mucosal abnormality, we have recommended mapping smears, i.e., taking multiple, separately labeled smears from separate vaginal sites to identify the source of the abnormal cells for biopsy.
Invasive Carcinoma
Invasive keratinizing epidermoid carcinomas of the vagina closely resemble invasive squamous carcinomas of the uterine cervix. Most tumors shed relatively highly differentiated squamous cancer cells of various sizes with thick, yellow or orange cytoplasm (see Fig. 14-2). Keratin “pearls” of malignant type and bizarre cell types (tadpole cells, spindly cells) are common. Koilocytes may be observed, suggesting
the origin of such lesions from “flat condylomas.” Necrosis, which is so commonly present in invasive cancer of the cervix, is often absent. Inflammation and trichomoniasis are commonly observed.
the origin of such lesions from “flat condylomas.” Necrosis, which is so commonly present in invasive cancer of the cervix, is often absent. Inflammation and trichomoniasis are commonly observed.
 Figure 14-4 Pseudosarcomatous squamous carcinoma of the vagina. The polypoid lesion with smooth surface was clinically protruding into vaginal lumen. A. Squamous carcinoma in situ on the surface of a tumor composed of spindly cells, shown in B. C. Focus of squamous differentiation in the invasive spindly component of the tumor. D. A vaginal pool smear from a similar case showing well-differentiated squamous cancer cells. |
Invasive nonkeratinizing carcinomas are made up of smaller cancer cells with less evidence of keratin formation (see Fig. 14-3). Occasionally, only small, undifferentiated cancer cells are present. Other features of such smears are similar to those described above.
Cytologic findings in a case of small-cell neuroendocrine carcinoma of vagina were described by Ciesla et al (2001). Numerous small cancer cells, some with nuclear molding, were observed and illustrated.
Precursor Lesions of Vaginal Squamous Carcinoma (VAIN)
Low-Grade Lesions (VAIN Grade I, Mild Dysplasia, Flat Condylomas)
The cytologic presentation of these lesions, shown in Figure 14-5D, consists of superficial and intermediate dyskaryotic (dysplastic) squamous cells and koilocytes, characterized by a delicate, transparent cytoplasm and enlarged, irregular, hyperchromatic nuclei, often surrounded by a clear zone. The underlying tissue abnormality (Fig. 14-5B) is very similar to that of low-grade lesions occurring on the uterine cervix (see Chap. 11).
High-Grade Lesions (Carcinoma In Situ, VAIN Grade II or III)
Precursor lesions of epidermoid carcinoma often follow, or are synchronous with, similar lesions of the uterine cervix, most often the keratin-forming type. Two types of high-grade lesions (carcinoma in situ) may be observed in the vagina. The uncommon small cell type is characterized by the presence of small cancer cells, occurring singly or in clusters (see Fig. 14-3C,D). These lesions and their cytologic presentation usually follow and are akin to the “classic” small cell carcinoma in situ of the uterine cervix (see Chap. 11).
More common are the keratin-forming high grade lesions (keratinizing carcinomas in situ (Fig. 14-6). These lesions shed dyskaryotic (dysplastic) and squamous cancer cells of variable sizes, some with opaque, thick, keratinized cytoplasm and large pyknotic nuclei. Koilocytes with a wide perinuclear clear zone are commonly present. The tissue, however, may disclose a high-grade lesion capable of invasion, showing residual evidence of a condyloma (Fig. 14-6D). These lesions are clear examples of malignant
transformation of low-grade (condylomatous) lesions that may be particularly dangerous in the vagina. One should not be misled by the presence of koilocytes into believing that the lesion will disappear without treatment.
transformation of low-grade (condylomatous) lesions that may be particularly dangerous in the vagina. One should not be misled by the presence of koilocytes into believing that the lesion will disappear without treatment.
 Figure 14-5 Low-grade condylomatous-type lesion of the vagina in a child. A,B. Low and higher magnification views of the lesion which consists of thickened, folded squamous epithelium with numerous koilocytes in the upper layers. C. In situ hybridization of the same lesion with antibodies to HPV 11. The black nuclei show positive reaction. D. Vaginal smear from a similar lesion showing well differentiated dyskaryotic (dysplastic) intermediate squamous cells, one of which shows perinuclear halos consistent with koilocytosis. |
High-grade VAIN lesions are not infrequently observed in postmenopausal women with atrophic smear pattern. As was discussed in Chapter 11 in reference to similar lesions of the uterine cervix, the recognition of cancer cells in dry, atrophic smears may be fraught with difficulty, particularly because the feature of nuclear hyperchromasia is not readily evident in dry cancer cells spread on the slide. In such smears, the nuclear size and the nucleocytoplasmic ratio become the principal criteria of recognition of cancer cells: the nuclei are substantially larger than those of benign squamous cells in the same smears, and the nucleocytoplasmic ratio is altered in favor of the nucleus. Reviving the epithelium with estrogen may be quite helpful in the diagnosis.
It is quite evident that there are significant cytologic similarities between the low-grade lesion shown in Figure 14-5
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