Cervix. The mainstay of screening for uterine carcinoma is the Papanicolaou (Pap) smear. For Pap examination of the cervix, material is best obtained directly from the cervix by some type of scraping technique. Vaginal irrigation or vaginal pool smears are reported to be only 50%–75% as accurate as cervical scrape for detection of cervical carcinoma. A single scrape smear has a false negative rate of about 30% (literature range, 5%–50%). Some reports indicate that the false negative rate can be reduced by one half or more by obtaining two successive cervical scrape specimens at the same examination or by obtaining both a cervical scrape specimen and an endocervical aspiration or endocervical swab specimen (making another smear with the endocervical specimen, either on the same slide as the scrape material or on another slide). Care should be taken not to contaminate the cervix area with water or lubricating jelly, both of which distort the tissue cells.

There have been several significant changes since 1980 in diagnosis of uterine cervix abnormalities. First, there has been reclassification of how degrees of cervix histologic abnormality are reported. This was previously graded in terms of degrees of dysplasia (or atypia, often used as a synonym for dysplasia, although some use atypia to describe nuclear abnormality and dysplasia to describe both nuclear and architectural abnormality). Grading of histologic abnormality included degree of dysplasia from I to III, based on abnormal changes in the lower third of the squamous cervical epithelium (dysplasia degree I), the lower third plus involvement of the middle third (dysplasia degree II), and both the lower and middle thirds plus incomplete involvement of the upper third (dysplasia degree III). Involvement of the entire thickness of the epithelium was named carcinoma in situ (CIS). The newer system was based on the concept of cervical intraepithelial neoplasia (CIN) from a philosophy that any cytologic abnormality of the cervix was potentially cancer and should not be ignored, even though the response of the physician in follow-up or treatment modality would vary. This in turn was based on studies using culposcopy that biopsied lesions from which Pap smears interpreted as Class II “nonspecific inflammation” or minimal atypia were obtained. These biopsies disclosed a substantial number of patients (12%–25%) who had what is now classified as varying categories of CIN, even including CIN III. In the past, if a patient had a class II Pap smear, the physician would follow the patient with periodic cytology specimens. However, an increasing number of investigators point toward substantial false negative rates on repeat cytology (similar to false negative initial cytology) and recommend culposcopy or cervicography after the first abnormal Pap result regardless of the degree of abnormality. In the CIN system, the previous dysplasia degree III and CIS were combined into the single category of CIN III. This eliminated the “gray zone” between total replacement of the epithelium by abnormal nuclei and replacement of nearly full thickness except for only one or two layers or rows of cells at the surface.

Another significant change was a new system of reporting cytologic changes. The long-established Pap report was based entirely on 5 categories (see the box on this page) that were primarily morphologic (with some interpretive implications). Additional interpretative comments or information that could affect interpretation were optional.

The new system was developed at a 1988 conference in Bethesda and revised in 1991. The 1991 revision of the Bethesda reporting system is shown in the box. This system mandates reporting of various technical factors or other findings that could affect interpretation (predominantly those that could produce false negative results, the presence or absence of various types of infection, and specific identification of various types of “reactive” changes. It also reduced interpretation of definite cytologic abnormality to two categories: low grade (formerly Pap Class III, mild dysplasia, CIN I) and high grade (formerly Pap Class IV and V, moderate or severe dysplasia, or CIN II and III). This implies more importance to a somewhat lesser degree of cytologic abnormality. Unfortunately, there still exist borderline or gray areas in the classification that depend on subjective decisions by the cytologist. It cannot prevent false negative results because material was not obtained from the lesion (sampling error) or because abnormal cells were missed when the slide was examined (interpretive or laboratory error).

There have also been some advances in detection of cervical abnormality. Methods have been devised to make monolayer specimen cell preparations for Pap examination. These preparations permit better staining and prevent overlooking abnormal cells in overlapping cell clumps or masses or in blood. Most of the reported methods improved overall Pap sensitivity to greater or lesser degree. Cervix specimen collection using various brushes rather than swabs or wooden spatula-type instruments have generally been reported to increase overall Pap sensitivity. Culposcopy (direct visual examination of the cervix through a viewing device called a culposcope) and cerviography (photography of the entire visually available cervix with an instrument called a cerviscope) have both been reported to increase detection of cervical lesions compared to “blind” cytology. Some investigators report better results than others for the monolayer cytologic methods, sampling devices, and viewing techniques; a few investigators found relatively little overall differences between the old and new methods.

Standard Papanicolaou Classification
Class I
Absence of atypical or abnormal cells
Class II
Atypical cytologic changes but no evidence of malignancy
Class III
Cytologic changes suggestive of, but not conclusive for, malignancy
Class IV
Cytologic changes strongly suggestive of malignancy
Class V
Cytologic changes conclusive for malignancy

Revised Bethesda System (1991)
Adequacy of the specimen
Satisfactory for evaluation
Satisfactory for evaluation but limited by . . .(specify reason)
Unsatisfactory for evaluation . . . (specify reason)
General Categorization (optional)
Within normal limits
Benign cellular changes: See descriptive diagnosis
Epithelial cell abnormality: See descriptive diagnosis
Descriptive Diagnoses
Benign cellular changes
Infection
Trichomonas vaginalis
Fungal organisms morphologically consistent with Candida spp.
Predominance of coccobacilli consistent with shift in vaginal flora
Bacteria morphologically consistent with Actinomyces spp.
Cellular changes associated with herpes simplex virus
Other
Reactive changes
Reactive cellular changes associated with:
Inflammation (includes typical repair)
Atrophy with inflammation (“atrophic vaginitis”)
Radiation
Intrauterine contraceptive device
Other
Epithelial Cell Abnormalities
Squamous cell
Atypical squamous cells of undetermined significance: Qualify*
Low-grade squamous intraepithelial lesion encompassing: HPV† mild dysplasia/CIN I
High-grade squamous intraepithelial lesion encompassing: moderate and severe dysplasia, CIS/CIN 2 and CIN 3
Squamous cell carcinoma
Glandular cell
Endrometrial cells, cytologically benign, in a postmenopausal woman
Atypical glandular cells of undetermined significance: Qualify*
Endocervical adenocarcinoma
Endometrial adenocarcinoma
Extrauterine adenocarcinoma
Adenocarcinoma, NOS
Other Malignant Neoplasms: Specify
Hormonal Evaluation (applies to vaginal smears only)
Hormonal pattern compatible with age and history
Hormonal pattern incompatible with age and history: Specify
Hormonal evaluation not possible due to: Specify
_______________________________________________________
*Atypical squamous or glandular cells of undetermined significance should be further qualified as to whether a reactive or a premalignant/malignant process is favored.
†Cellular changes of human papillomavirus (HPV)—previously termed koilocytosis, koilocytotic atypia, or condylomatous atypia—are included in the category of low-grade squamous intraepithelial lesion.

Considerable evidence has accumulated linking cervical infection by human papillomavirus (HPV) types 16 and 18 with cervical epithelial cell atypia, premalignant changes, and progression to carcinoma (Chapter 17). HPV changes can be seen in squamous epithelial cells on biopsy and on Pap smears, but the virus type cannot be specified. Nucleic acid probe is more sensitive than either visual microscopy or cytology and in addition is specific for the viral type for which the probe is constructed.

Endometrium. Screening for endometrial carcinoma can be done using endometrial suction biopsy, endometrial aspiration for cytology, endometrial washing methods, endometrial brushing, and cytology specimens taken from the endocervix or vaginal pool. Endometrial sampling methods are somewhat difficult to evaluate due to a considerable number of methods that can vary in detection rate but that are frequently lumped together in the literature. Endometrial biopsy using the Vabra aspirator generally is reported to detect about 96% (literature range, 80%–100%) of endometrial carcinomas. Endometrial biopsy with the Novak suction curette has been reported to detect about 91% of cases (range, 77%–94%). Endometrial cavity aspiration for cytology with a device known as the Isaacs cell sampler detects about 92%–94% of cases (range, 78%–100%). Endometrial lavage methods (e.g., Gravlee cell wash) detect about 80%–85% of cases (range, 66%–100%). Endometrial mechanical cell dislodgement methods, such as the MiMark and Endopap devices, are reported to detect more than 90% of carcinomas. Endometrial brush methods (another way to dislodge cells mechanically) are reported to detect 57%–92% of cases. In methods depending predominantly on cytology, hyperplasias and abnormalities other than tumor are not as easily identified as they can be with tissue specimens provided by biopsy. Endocervical aspiration detects endometrial carcinoma in about 70% of cases (range, 14%–90%). Smears from the vaginal pool in the posterior fornix of the vagina detect 30%–50% of cases (range, 18%–90%). Specimens from the cervix detect only about 35% (range, 25%–55%) of advanced endometrial carcinoma.

Follow-up of abnormal Papanicolaou smear. Abnormal or definitely positive Pap smears should be followed up with a biopsy of the site indicated to confirm the diagnosis and determine the extent and histologic characteristics of the neoplasm. For the cervix, colposcopic examination with biopsy is becoming the most widely used technique. For the endometrium, dilatation and curettage should be done.