You get a call from woman patient/friend/relative, who tells you she has had an abnormal Pap smear and wants your opinion about it. She says the interpretation is ASCUS, Atypical Squamous Cells of Undetermined Significance. If doing Pap smears is not part of your practice, or you haven't reviewed the subject in the last five years, you may find yourself completely confused by this question. This categorization is part of the Bethesda System (TBS) of Pap Smear reporting, which was adopted in the U.S. in the early 1990s.

Let me give you the direct answer on ASCUS first. Ask whether the report gives a further description of the cells. The cytopathologist may characterize the cells as reactive/inflammatory or dysplastic/neoplastic, or there may be no further characterization offered. If the description favors a reactive process, the Pap should be repeated in four to six months. If there are any symptoms or signs of vaginitis, that condition should be treated before the repeat Pap.

If the report of ASCUS is noncommital or favors dysplasia, the patient's physician may have recommended a Pap in two to three months. If your caller is postmenopausal, local treatment with estrogen may be advised, because sometimes atrophic changes in the squamous epithelium can mimic dysplasia. The Pap would then be repeated after this treatment.

Probably the most important advice that you can give at this juncture is that the patient involved must follow up as recommended. In the majority of instances the follow-up cytology will be normal. In around 20- 25%, the repeat Pap will have ASCUS or a more dysplastic categorization, and further testing, i.e., colposcopy with biopsy must be done.

What has happened to the Pap test terminology and what is it? Starting in December of 1988 the National Cancer Institute held a number of meetings charged with addressing problems with Pap smear interpretation. The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses was the result of this effort, as reported in 1989.(1) It is abbreviated TBS. Follow-up workshops were convened to monitor the efficacy of this system and recommend refinements.

The Bethesda System makes a broad distinction between normal cells/benign cellular changes (like inflammation) and epithelial cell abnormalities that may or may not have neoplastic significance. It then groups the epithelial cell abnormalities into categories that have a similar natural history in terms of malignant potential and therefore require the same management.

Let me give you some examples (Table 1, which follows, summarizes these categories):

In the original Papanicalaou classification, benign atypical cellular changes and other types of atypia were both Class II; in the Bethesda system, atypical cells that are abnormal but not categorized, are called ASCUS (atypical squamous cells of undetermined significance), and as we see from the introductory example, are treated with more frequent follow-up.

The rest of the cellular abnormalities are divided into three broad categories: Low-grade Squamous Intraepithelial Lesion, LSIL; High-grade Intraepithelial Lesion, HSIL; and invasive carcinoma.

LSIL includes mild dysplasia and very importantly the cellular characteristics caused by Human Papilloma Virus, HPV. Studies have shown that these two types of changes progress to malignancy and similar rates,(2) making it logical that the management strategies should be similar. As with ASCUS, a repeat Pap in four to six months is the usual initial recommendation.

HSIL encompasses the rest of the superficial neoplastic changes in the squamous epithelium. This category includes moderate and severe dysplasia, cervical intraepithelial neoplasia 2 and 3 (CIN2 and CIN3), and carcinoma in situ, CIS. Again, because of similar natural history, all of these lesions are investigated by colposcopic biopsy and definitive local therapy where indicated.

Specimen Adequacy

Another important aspect of the change to the Bethesda System, has been the inclusion of a notation of specimen adequacy in the Pap report. Cervical cancer arises in the zone of cells between the squamous epithelium of the vagina and the columnar epithelium of the endocervix. This is called the transformation zone, an area of metaplastic epithelium thought to be most vulnerable to carcinogenic influences. The goal of the Pap smear is to sample this metaplastic area. The presence of endocervical cells in the specimen provides assurance that the transformation zone was sampled. Currently, most practitioners use the cytobrush to sample cells from the surface of the cervix near the os and the endocervical canal.

Notes About Follow-Up

Despite the fact that the Bethesda System has simplified the follow-up recommendations by grouping the cytological changes into more logical pathological categories as denoted by the heavier line in Table 1, there are reasons to modify follow-up procedures from standard. The basic guidelines for follow-up are shown in Table 2.

Table 2. Follow-Up of the Pap Report.

If Report	Repeat Pap	Colposcopy-Directed Bx*
HGSIL		Yes
LGSIL
Reliable Pt	4-6 mos.	ORSN
Unreliable or High-risk Pt.		Yes
ASCUS
No Comment	2-3 mos.	ORSN
Favor Reactive	4-6 mos.	ORSN
Unreliable or High-risk Pt.		Yes

* Punch biopsies or small loop cone (outpatient)
History of prior atypical/positive Pap smears or precursor diagnosis.
ORSN = Only if repeat suggests neoplasia

Adapted from the ACS Newletter.(1)

Source: Shingleton et al

Risk categories: Women who have HIV or HPV infection, have a previous history of an abnormal Pap, or are smokers are at higher risk for developing cervical neoplasia. Onset of sexual activity in the teens and more than one sex partner are also considered risk factors. If a Pap comes back ASCUS or LSIL, colposcopy and biopsy are recommended if the patient has any of these risk factors.

Reliability: Another reason to go straight to biopsy with lower category lesions (ASCUS and LSIL) is if you have any concern about whether the patient will come back for the recommended follow-up. A look at previous records may reveal that an established patient makes routine appointments at very long intervals. A new patient should be questioned about the likelihood that she may relocate before she has had time to come back for a repeat Pap. In any event, whether you go for immediate biopsy or follow up Pap, make sure you have a flagging and notification system in your records to indicate that follow-up is due. This is a good risk management measure and it will reduce the likelihood of a high category Pap at too long an interval.

Patient Management Guidelines

There are a number of ongoing studies looking at the outcomes of various management strategies using TBS. Pending the results of these studies National Cancer Institute workshop participants have formulated interim guidelines on management.(4) These will be updated as more information becomes available. ASCUS and LSIL are the most common, potentially serious abnormalities detected by the PAP smear. The great majority of these revert to normal on further testing. The main goal is to develop a management plan that detects progressing lesions without offering complex procedures to those that will regress.