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Atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion: Diagnostic criteria and management
Atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion: Diagnostic criteria and management Raymond H. Kaufmml, MD Houston, Texas Since institution of the Bethesda system for reporting cervical and vaginal smears, there has been an increase in the number of smears reported to demonstrate atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions. The cytologic changes associated with a smear reported to have these cells are discussed. It is apparent that the interpretation of the cellular changes defined as atypical squamous cells of undetermined significance are not clear and that there is a significant variation among cytopathologists as to the cytologic changes that should be incorporated under this classification. Data are presented on the frequency of this diagnosis in our laboratory and of the follow-up findings observed in a subgroup of patients whose smears were reported to demonstrated atypical squamous cells of undetermined significance. The cytologic and histopathologic changes observed with smears reported as demonstrating findings compatible with a low-grade squamous intraepitheliat lesion are also discussed. A follow-up algorithm for the management of such patients is presented. (Am J Obstet Gyneco11996;175:1120-8.)
Key words: Atypical squamous cells of u n d e t e r m i n e d significance, low-grade squamous intraepithelial lesion, cervical intraepithelial neoplasia, h u m a n papillomavirus
The 1988 Bethesda Workshop lead to the development of the Bethesda system for reporting cervical and vaginal cytologic diagnoses. 1 This was revised in 1991 and the currently used Bethesda system has resulted in a uniformity in the reporting of cervical and vaginal specimens that was not seen before this time. The majority of cytopathologists, and clinicians support this new reporting system, although there are those who have opposed it. One of the most common reasons given for opposing this new reporting system is the significant increase in the n u m b e r of cytologic reports of atypical squamous cells of u n d e t e r m i n e d significance and the "lumping" together of both h u m a n papillomavirus (HPV) changes and grade 1 cervical intraepithelial neoplasia u n d e r low-grade squamous intraepithelial lesion. Syrjanen et al. 2 have suggested that it is important that patients not be overdiagnosed and overtreated as a result of applying the Bethesda system. Lonky et al. s have recommended that the cytologic diagnoses of HPV change and grade 1 cervical intraepithelial neoplasia should be distinguished. What do these terms mean and how should the patient
From the Departments of Obstetrics and Gynecology and Pathology, Baylor Collegeof Medicine. Reprint requests: Raymond H. Kaufman, MD, Baylor College of Medicine, Department of Obstetricsand Gynecology, 6550 Fannin, Suite 701, Houston, TX 77030. Copyright © 1996 by Mosby-YearBook, Inc. 0002-9378/96 $5.00+ 0 6/0/69800 1120
whose smear demonstrates the above findings be followed up and managed? The current article will define the terms atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion, present the morphologic changes associated with these reports, and briefly discuss their significance and management. The frequency of smears reported to demonstrate atypical glandular cells of u n d e t e r m i n e d significance is small and will not be discussed.
The diagnosis of atypical squamous cells of undetermined significance Since the adoption of the Bethesda System for reporting cervical or vaginal cytologic results, many laboratories have seen a progressive increase in the percentage of smears with the designation of atypical squamous cells of u n d e t e r m i n e d significance. Most pathologists would agree that the proportion of smears with this designation should be <5%. However, there are laboratories where as many as 9% of smears are given this diagnosis? One complicating factor is that agreement is not uniform among cytopathologists as to what criteria should be used to make this diagnosis. Our designation of atypical squamous cells of undetermined significance refers to the presence of abnormalappearing squamous cells that do not meet criteria for defined epithelial abnormalities. There are several reasons for reporting a smear with this designation. In most instances the abnormal cells in the smear are degenerat-
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Fig. 1. Atypical squamous cells of undetermined significance. Degenerating atypical squamous cells. It is not possible to determine whether these represent degenerating normal or neoplastic cells.
Fig. 2. Atypical squamous cells of undetermined significance. Cells demonstrate nuclei that are enlarged and slightly hyperchromatic. These changes could represent metaplasia associated with repair or low-grade squamous intraepithelial lesion. ing a n d it is often difficult to d e t e r m i n e whether these represent d e g e n e r a t i n g n o r m a l or neoplastic cells (Fig. 1). Thus the cytopathologist is u n a b l e to fit the cellular abnormality into any specific epithelial disorder. A n o t h e r circumstance when it is difficult to evaluate cellular changes occurs in the presence of severe inflammation a n d repair. Although the changes associated with repair are easily identified in most instances, this is n o t always the case. Third, poor fixation or poor stains may also lead to cellular changes that the cytopathologist finds difficult to accurately interpret, thus leading to a designation of atypical squamous cells of u n d e t e r m i n e d significance. Finally, when the cytopathologist is n o t quite sure how to interpret the cellular changes noted, this cellular classification leaves a way out. The cytopathologist is aware of the penalty paid when cells difficult to interpret are classified as negative a n d the patient subsequently is f o u n d to have invasive carcinoma of the cervix. Unfortunately, there is n o uniformity of a g r e e m e n t a m o n g pathologists as to what constitutes atypical squa-
mous cells of u n d e t e r m i n e d significance. The College of American Pathologists Cytopathology Committee reviewed 13 cases of cerx~cal a n d vaginal smears that had b e e n designated as atypical squamous cells of undeterm i n e d significance. ~ An i n d e p e n d e n t diagnosis was rendered on each case by each committee member. The lack of uniformity a m o n g these pathologists was readily apparent, with only 62% interpreting the smears as atypical squamous cells of u n d e t e r m i n e d significance on review, whereas 8% felt the smears were n o r m a l a n d 20% felt they demonstrated reactive changes only, The College of American Pathologists Cytopathology Committee reviewed an additional 31 cases diagnosed as atypical squamous cells of u n d e t e r m i n e d significance in 1994. ~ Seventeen cytopathologists took part in this study. In only 7 of 31 cases (23%) was a review diagnosis of atypical squamous cells of u n d e t e r m i n e d significance obtained from >70% of the participants a n d in only 5 of 31 cases (16%) was a diagnosis of atypical squamous cells of u n d e t e r m i n e d significance made by >80% of the experts. No
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Table I. Frequency of atypical squamous cells of u n d e t e r m i n e d significance a n d low-grade squamous intraepithelial lesions (52,167 smears) Age 0-14 15-19 20-24 25-29 30-34 35+ All
No. of smea~
512 1,363 4,431 7,535 9,379 28,947 52,167
ASCUS and HPV
ASCUS
t2 32 128 139 179 453 943
(2.34) (2.35) (2.89) (1.84) (1.91) (1.56) (1.8)
1 2 10 14 20 36 83
(0-20) (0.15) (0.23) (0.19) (0.21) (0.12) (0.16)
HPV
8 57 143 161 166 318 853
(1-56) (4.18) (3.23) (2.14) (1.77) (1.10) (1.6)
Cervicalinlraepithegalneoplasia grade l and HPV
4 34 99 90 93 152 463
(0.78) (2.49) (2.03) (1.20) (1.0) (0.52) (0.89)
Invasive HGSIL
3 8 33 48 43 69 204
(0.59) (0.59) (0.74) (0.64) (0.45) (0.24) (0.39)
canc~
12 (0.023)
Values m parentheses are percents. ASCUS, Atypical squamous cells of undetermined significance; HGSIL, high-grade squamous intraepithelial lesions. Table II. Follow-up data on 118 patients whose smears were designated as atypical squamous cells of u n d e t e r m i n e d significance Diagnosis
Normal Cervical polyp Squamous metaplasia HPV LGSIL HGSIL CIN grade 2 CIN grade 3 Squamous cell cancer ?dS Adenocarcinoma
No.
17 8 40 31 9 11 0 1 1
%
14 7 34 26 8 9
0.85 0.85
LGSIL, Low-grade squamous intraepithelial lesions; HGSIL, high-grade squamous intraepithelial lesions; C/N, cervical intraepithelial neoplasia; AIS, adenocarcinoma in situ.
single case received this diagnosis by all the reviewing cytopathologists. 5 Thus, it is obvious that opinions a m o n g cytopathologists are highly variable as to what constitutes atypical squamous cells of u n d e t e r m i n e d significance. Following are some of the criteria utilized in our laboratory in making this diagnosis. There may very well be disagreem e n t with these criteria. The relatively low percentage of smears signed out by us as atypical squamous cells of u n d e t e r m i n e d significance may account for the finding of significant pathology, in a relatively high percentage of these individuals.
Cytologic criteria associated with the diagnosis of atypical squamous cells of undetermined significance T h e cellular changes most often observed in smears classified as atypical squamous cells of u n d e t e r m i n e d significance include a loss of tile n o r m a l nuclear/cytoplasm ratio, associated ~dth n u c l e a r enlargement. Nuclear detail is often poorly defined, a n d the nuclei may appear hyperchromatic. The cells may appear in clusters; however, single a b n o r m a l - a p p e a r i n g cells may also be observed (Figs. 2 to 5). Occasionally, cells with slight perinuclear clearing a n d slightly enlarged nuclei
may suggest the presence of koilocytes b u t are n o t diagnostic. During 1993, 52,162 smears were reviewed in our cytopathology laboratory at Baylor College of Medicine. Of these, 943 (1.8%) were designated as atypical squamous cells of u n d e t e r m i n e d significance a n d 83 (0.16%) as atypical squamous cells of u n d e t e r m i n e d significance associated with HPV changes. Thus slightly <2% of smears were given this diagnosis (Table I). What is the significance of a smear reported as atypical squamous cells of u n d e t e r m i n e d significance, and how should such a patient be followed up? We attempted to obtain follow-up data o n 146 patients whose smears were designated as atypical squamous cells of u n d e t e r m i n e d significance. Follow-up was successful in 118 (81%) of these individuals. Table II presents the follow-up data on these women. Of significance is the fact that 9% of these w o m e n (11 individuals) were f o u n d to have either cervical intraepithelial neoplasia grade 2 or 3 on follow-up biopsy. O n e patient (0.85%) was f o u n d to have a d e n o c a r c i n o m a in situ and one (0.85%) had invasive a d e n o c a r c i n o m a of the cervix. Thus almost 11% of these w o m e n were f o u n d to have significant disease in the cervix. O f additional interest is that 8% of the group (nine patients) were f o u n d on follow-up biopsy to have cervical intraepithelial neoplasia grade 1 a n d 26% to have changes compatible with HPV infection. These findings are similar to those reported by SidawT and Tabbara. 6 According to data acquired by the College of American Pathologist Interlaboratory PAP Program, the m e d i a n rate of atypical squamous cells of u n d e t e r m i n e d significance in 1992 in the laboratories surveyed was 2.9%, with 10% of these laboratories reporting rates >9.0%. 4 Follow-up of patients with atypical squamous cells of u n d e t e r m i n e d significance by these laboratories revealed a range of 10.3% to 43% with tile diagnosis of squamous intraepithelial lesion. Fewer than 6% of the cases, however, had a high-grade squamous intraepithelial lesion. In this study Davey et al. 4 c o m m e n t e d o n the different applications of criteria for atypical squamous cells of u n d e t e r m i n e d significance in different laboratories. The authors suggest that one m e t h o d of m o n i t o r i n g laboratories
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Fig. 3. Atypical squamous cells of undetermined significance. These cells with large, slightly hyperchromatic nuclei demonstrate some perinuclear clearing, yet they are degenerating. These changes suggest, but are not diagnostic of, HPV infection.
Fig. 4. Atypical squamous cells of undetermined significance. This cluster of degenerating cells is difficult to interpret. However, they cannot be ignored. is to compare the atypical squamous cells of undetermined significance/squamous intraepithelial lesion ratio. When a laboratory reports a high percentage of smears as atypical squamous cells of undetermined significance compared x~qth squamous intraepithelial lesion (high ratio), it can be anticipated that a relatively small proportion of these patients will actually exhibit a squamous intraepithelial lesion on f011ow-up. Conversely, a laboratory with a lower ratio would be expected to have more patients with squamous intraepithelial lesion on follow-up. Davey et alJ r e c o m m e n d that clinicians using a specific laboratory have this information because it may guide them regarding the management of patients with smears designated as atypical squamous cells of undetermined significance. Thus it may be reasonable to follow up some patients with repeat cytologic studies rather than move directly to colposcopy and biopsy. It is vitally important that clinicians communicate closely with the pathologist interpreting their cytologic smears so that they can gain insight as to the significance of a report of atypical squamous cells of u n d e t e r m i n e d
significance. As already discussed, criteria used to make this diagnosis vary significantly from laboratory to laboratory. The clinician should request that the pathologist qualify, a diagnosis of atypical squamous cells of undetermined significance and indicate whether the changes observed are believed to be "reactive" or "degenerative" or may represent a squamous intraepithelial lesion. Most pathologists do, in fact, currently follow this practice. However, many cytopathologists prefer not to because they feel that the diagnosis of atypical squamous ceils of undetermined significance should only be used for socalled "gray zone" lesions.
Cytologic changes associated with low-grade squamous intraepithelial lesion The cellular findings associated with HPV infection and cervical intraepithelial neoplasia grade 1 are closely related, with considerable overlap of the morphologic changes seen in each. It is for this reason that the two conditions are grouped together as low-grade squamous intraepithelial lesion in the Bethesda system. However,
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Fig. 5. Atypical squamons cells of undetermined significance. Atypical degenerating (glandular?) cells are noted. Nuclei are hyperchromatic and enlarged.
Fig. 6. Low-grade squamous intraepithelial lesion. A, Koilocyte is identified in this cluster of cells. Nucleus is enlarged and hyperchromatic, and there is distinct perinuclear clearing. Several other cells in the cluster also demonstrate enlarged hyperchromatic nuclei. B, Koilocytes are seen. Two cells with enlarged hyperchromatic nuclei with perinuctear clearing are seen.
there are those 2' ~ who feel that the biologic behavior of HPV infection differs f r o m that of cervical intraepithelial neoplasia of a low-grade type (grade 1). Lonky et a l ) r e c o m m e n d e d that " a l t h o u g h difficult and subjective, the descriptive demarkation between mild dysplasia and HPV cytopathologic changes has predictive significance
and should be preserved in reports to the clinician." Further long-term studies will be r e q u i r e d to see whether this is the case; however, what does r e m a i n true is that most cytopathologists are not able to clearly distinguish the two cytologically. 6 For the put-poses of this discussion, HPV changes and cervical intraepithelial neoplasia will
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Fig. 7. Low-grade squamous intraepithelial lesion. Dyskeratocytes are seen. These cells are mature squamous cells and have orangophylic cytoplasm. Nuclei are enlarged mad hyperchromatic. Several cells have more than one nucleus.
Fig. 8. HPV changes on cervical biopsy. Koilocytes are evident. Nuclei are enlarged and hyperchromatic.
be described separately a n d some of the subtle differences between them will be emphasized although this distinction may be of little practical value when it comes to patient m a n a g e m e n t . The cytologic criteria for the diagnosis of HPV changes include the presence of koilocytosis, dyskeratocytosis, parakeratotic cells, a n d binucleation. Properly defined, the koilocyte is a cell c o n t a i n i n g a large, hyperchromatic, flat nucleus with indistinct c h r o m a t i n structure. Perin u c l e a r clearing is p r o m i n e n t in a cell with a b u n d a n t cytoplasm (Fig. 6, A a n d B). The dyskeratocyte is a mature squamous cell with uniformly dense orangophylic cytoplasm (Fig. 7). Its nucleus is similar to that of the koilocyte. Often these cells are seen in clusters with overlapping. Schneider et al. 7 evaluated the sensitivity of using "classic" koilocytosis a n d dyskeratocytosis to identify the presence of HPV infection. With these criteria, the authors identified only 15 % of HPV deoxyribonucleic acidpositive cases ( d e t e r m i n e d by deoxyribonucleic acid-filter hybridization in situ). They observed that five " n o n classic" cytologic criteria for diagnosing the presence of
HPV infection were significantly more sensitive in correctly identifying 84% of the HPV-positive group. These criteria included "mild koilocytosis," mild dyskeratocytosis, hyperchromatic nuclei, binucleation a n d multinucleation, a n d cleared cytoplasm. The morphologic evidence of HPV infection as seen on biopsy is the koilocyte. These cells are m o s t c o m m o n l y seen n e a r the surface of the squamous epithelium in the more mature squamous epithelial cells (Fig. 8). The basal and parabasal cells appear relatively n o r m a l in most instances. The criteria c o m m o n l y used for a cytologic diagnosis of cervical intraepithelial neoplasia grade 1 include the presence of enlarged, irregular nuclei in mature squamous epithelial cells (Fig. 9). The nucleus has a regular, granular, or reticular appearance a n d the nuclear memb r a n e is uniform. There is an increased nuclear/cytoplasm ratio. These are all changes that may be seen in association with HPV infection a n d thus distinguishing between the two disorders is of n o practical value. Morphologically, the distinction between cervical intraepithelial neoplasia grade 1 a n d pure HPV changes can be
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Fig. 9. Low-grade squamous intraepithelial lesion. These changes suggest cervical intraepithelial neoplasia grade 1 in association with HPV changes. Nuclei are enlarged, hyperchromatic, and varied. Several cells with faint perinuclear clearing are also noted.
presence of a b n o r m a l mitotic figures in the biopsy specim e n (Fig. 10).
Management of atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion
Fig, 10. Cervical intraepithelial neoplasia grade 1 in cervical biopsy specimen. Abnormal cell proliferation begins deep in epithelium, and scattered abnormal mitoses are noted. Cells mature as they move toward surface, and koilocytes are seen in more superficial epithelial cells.
m a d e m o r e easily. In the presence of cervical intraepithelial neoplasia grade 1, the a b n o r m a l cellular changes begin in the d e e p e r layers of the epithelium, with maturation o f the a b n o r m a l cells o c c u r r i n g as they move to the surface. Koilocytes are often seen in the m o r e superficial epithelium. In contrast to the " p u r e " HPV infection, cervical intraepithelial neoplasia is associated with the
T h e r e c o m m e n d a t i o n s p r o p o s e d h e r e are similar to those r e c o m m e n d e d by K u r m a n et al. s as interim guidelines for m a n a g e m e n t of a b n o r m a l cytologic results. As discussed above, there is considerable interlaboratory variation in r e p o r t i n g smears as atypical squamous cells of u n d e t e r m i n e d significance. For this reason, which cann o t be emphasized enough, the clinician and the cytopathologist must c o m m u n i c a t e with one a n o t h e r clearly and frequently. W h e n possible, the cytopathologist should c o m m u n i c a t e to the clinician any suspicions regarding the changes o c c u r r i n g in the cervix w h e n a smear has b e e n r e p o r t e d as atypical squamous cells of u n d e t e r m i n e d significance. Does the cytopathologist believe that the smear represents d e g e n e r a t i o n of cells, repair, possible HPV infection, or even cervical intraepithelial neoptasia? T h e cytopathologist's view often will act as a guide for the clinician in the m a n a g e m e n t of the patient. Unless the cytopathologist indicates that the changes seen could r e p r e s e n t the presence of a significant abnormality (cervical intraepithelial neoplasia, invasive carcinoma), a satisfactory a p p r o a c h to m a n a g e m e n t is to have the patient return for a follow-up Papanicolaou smear in 3 to 4 months. If a second smear is designated as atypical squamous ceils of u n d e t e r m i n e d significance, the patient should then be seen for colposcopy and directed biopsies as indicated. In the presence of a r e p e a t negative smear, the patient should be seen at 6-month intervals until three consecutive negative smears have b e e n obtained. After this the patient can be seen on an annual basis. T h e r e are certain modifications to the above. In the pa-
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CIN I/HPV Changes on Pap Smear
,1 Repeat Smear in 3 Months
,l I f CIN I/HPV Changes Present
I f Negative
!
Colposcopy with biopsy
If Negative~
Y
S
j
/
i I f C1N I/HPV Changes Only
Follow with Smear Every 6 Months
Repeat Smear in 6 Months
IfHGSIL I f Negative x 3 Biopsies and Treat Annual Smear Fig. 11. Management of low-grade squamous intraepithelial lesion. C/N, Cervical intraepithelial neoplasia; HG:SIL, high-grade squamous intraepithelial lesion.
dent with diagnosed acute vaginitis, the infection should be adequately treated and the smear repeated in 3 months. The postmenopausal woman with severe atrophic vaginitis should be instructed to use systemic or topical estrogen until the vaginal mucosa is estrogenized, at which time the smear should be repeated. Occasionally women receiving chemotherapy may demonstrate cytologic changes that appear abnormal. Invariably these changes will regress after cessation of treatment. Further follow-up in the above instances will d e p e n d on the findings noted in the repeat smear. It is our policy to follow up patients with smears designated as low-grade squamous intraepithelial lesion (either HPV changes alone or in association with cervical intraepithelial neoplasia grade 1 in a conservative manner (Fig. 11). The patient is seen again in 3 months, and the smear is repeated. If similar changes are noted on the
repeat smear, the patient is seen for colposcopic examination and directed biopsies as indicated. If changes indicative of HPV or low-grade squamous intraepithelial lesion alone are found, the patient is then seen at 6-month intervals for follow-up smears. If there is a persistence of cytologic evidence of low-grade squamous intraepithelial lesion, when, if ever, should such a patient be treated? In our own experience 15% of women whose smears and biopsies demonstrate a low-grade squamous intraepithelial lesion will in fact have a high-grade lesion present in the cervix. However, it is reasonable to assume that if such a patient is followed up at regular intervals after the diagnosis of a low-grade lesion cytologic or colposcopic evidence will eventually demonstrate the presence of a high-grade lesion. Thus it is our policy to continue to follow up such patients with cytologic study until a high-grade lesion is found on the Papanicolaou
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smear or until three consecutive smears have b e e n reported as negative. The use of HPV screening has b e e n advocated to help select those patients demonstrating atypical squamous cells of u n d e t e r m i n e d significance or low-grade squamous intraepithelial lesions o n a Papanicolaou smear who may n e e d colposcopy2' 10 The theory has b e e n proposed that those individuals d e m o n s t r a t i n g a low-risk HPV type do n o t n e e d immediate colposcopy a n d biopsy a n d can be followed up conservatively. However, for those individuals with a high-risk HPV type, immediate colposcopy a n d biopsy should be performed. To date, however, there are n o data to suggest that this course of action has validity. O u r own findings n a n d those of Downey et al. 12 would suggest that using currently available HPV testing techniques is of little practical value as a means of patient triage. It is possible that new, more sensitive HPV screening tests may serve this purpose. Comment
Some researchers have opposed the Bethesda system because of its allegedly associated potential for overrep o r t i n g a n d overtreatment in cases of atypical squamous cells of u n d e t e r m i n e d significance a n d low-grade squamous intraepithelial lesion. Indeed, the p r o p o r t i o n of smears with the designation of atypical squamous cells of u n d e t e r m i n e d significance has increased since the adoption of the Bethesda system. Several reasons exist for reporting smears with this designation, i n c l u d i n g the presence of d e g e n e r a t i n g cells, the presence of severe i n f l a m m a t i o n a n d repair, a n d suboptimal fixation a n d staining. Pathologists do n o t agree o n what constitutes atypical squamous cells of u n d e t e r m i n e d significance. In our laboratory slightly <2% of smears in 1993 were given this designation. I n f o r m a t i o n regarding a particular laboratory's atypical squamous cells of u n d e t e r m i n e d signific a n c e / s q u a m o u s intraepithelial lesion ratio should be provided to the clinician for guidance in patient management. C o m m u n i c a t i o n between the cytopathologist a n d clinician is essential for d e t e r m i n i n g the significance of a report of atypical squamous cells of u n d e t e r m i n e d significance. T h e cellular changes associated with HPV a n d cervical intraepithelial neoplasia can be hard to distinguish from one another. O u r treatment guidelines in cases of atypical squamous cells of u n d e t e r m i n e d significance a n d low-grade squamous intraepithelial lesion closely parallel those set forth by K u r m a n et al. 8 Unless "high-grade" cervical intraepithelial neoplasia or invasive carcinoma is suspected, the patient with a r e p o r t of atypical squamous cells of u n d e t e r m i n e d significance can be asked to r e t u r n within 3 to 4 m o n t h s for a repeat
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Papanicolaou smear. If this second smear is r e t u r n e d as atypical squamous cells of u n d e t e r m i n e d significance, colposcopy and directed biopsy should be performed. If the second smear is negative, smears should be taken at 6-month intervals until three negative smears have b e e n obtained, after which a n n u a l visits suffice. Patients with vaginitis or who are postmenopausal with severe atrophic vaginitis require special treatment. Patients whose smears are reported as low-grade squamous intraepithelial lesion because HPV changes alone or in the presence of cervical intraepithelial neoplasia grade 1 should be treated conservatively, with repeat smears a n d colposcopy with directed biopsy if the second repeat smear contains the same abnormality. Patients with high-grade lesions should be treated immediately. REFERENCES
1. National Cancer Institute Workshop. The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262:931-4. 2. Syrjanen K, Kataja V, Liskoski M, et al. Natural history of cervical human papillomavirus lesions does not substantiate the biologic relevance of the Bethesda system. Obstet Gynecol 1992;79:675-82. 3. Lonky NM, Navarre GL, Saunders S, et al. Low-grade Papanicolaou smears and the Bethesda system: a prospective cytohistopathologic analysis. Obstet Gynecol 1995;85:71620. 4. Davey DD, Naryshkin S, Nielsen ML, Klein TS. Atypical squamous cells of undetermined significance: interlaboratory comparison and quality assurance monitors. Diagn Cytopathol 1994;11:390-6. 5. RobbJA. The "ASCUS" swamp. Diagn Cytopathol 1994;11: 319-20. 6. 8idauT MK, Tabbara SO. Reactive change and atypical squamous cells of undetermined significance in Papanicolaou smears: a cytohistologic correlation. Diagn Cytopathol 1993; 9:423-9. 7. Schneider A, Meinhardt G, De-Villiers EM, Gissmann L. Sensitivity of the cytologic diagnosis of cervical condyloma in comparison with HPV-DNA hybridization studies. Diagn Cytopathol 1987;3:250-5. 8. Kurman RJ, Henson DE, HerbstAL, et al. Interim guidelines for management of abnormal cervical cytology. JAMA 1994; 271:18660. 9. CoxJT, Lorincz AT, Shiffman MH, et al. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet G)mecol 1995;172:946-54. 10. Wright TC, Sun TW, KorelosJ. Comparison of management algorithms for the evaluation of women with low grade cytologic abnormalities. Obstet Gynecol 1995;85:202-10. 11. Kaufman RH, lcenogle J, Adam E, et al. The relevance of HPV screening in the management of cervical intraepithelial neoplasia. In: Proceedings of the Thirteenth International Papillomavirus Conference, Amsterdam, The Netherlands, October 8-12, 1994. Amsterdam: International Papillomavirus Conference, 1994. 12. Downey GP, Bovin PJ, Deery ARS, et al. Relation between human papillomavirus type 16 and potential for progression of minor-grade cervical disease. Lancet 1994;344:432-5.
Key words: Atypical squamous cells of u n d e t e r m i n e d significance, low-grade squamous intraepithelial lesion, cervical intraepithelial neoplasia, h u m a n papillomavirus
The 1988 Bethesda Workshop lead to the development of the Bethesda system for reporting cervical and vaginal cytologic diagnoses. 1 This was revised in 1991 and the currently used Bethesda system has resulted in a uniformity in the reporting of cervical and vaginal specimens that was not seen before this time. The majority of cytopathologists, and clinicians support this new reporting system, although there are those who have opposed it. One of the most common reasons given for opposing this new reporting system is the significant increase in the n u m b e r of cytologic reports of atypical squamous cells of u n d e t e r m i n e d significance and the "lumping" together of both h u m a n papillomavirus (HPV) changes and grade 1 cervical intraepithelial neoplasia u n d e r low-grade squamous intraepithelial lesion. Syrjanen et al. 2 have suggested that it is important that patients not be overdiagnosed and overtreated as a result of applying the Bethesda system. Lonky et al. s have recommended that the cytologic diagnoses of HPV change and grade 1 cervical intraepithelial neoplasia should be distinguished. What do these terms mean and how should the patient
From the Departments of Obstetrics and Gynecology and Pathology, Baylor Collegeof Medicine. Reprint requests: Raymond H. Kaufman, MD, Baylor College of Medicine, Department of Obstetricsand Gynecology, 6550 Fannin, Suite 701, Houston, TX 77030. Copyright © 1996 by Mosby-YearBook, Inc. 0002-9378/96 $5.00+ 0 6/0/69800 1120
whose smear demonstrates the above findings be followed up and managed? The current article will define the terms atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion, present the morphologic changes associated with these reports, and briefly discuss their significance and management. The frequency of smears reported to demonstrate atypical glandular cells of u n d e t e r m i n e d significance is small and will not be discussed.
The diagnosis of atypical squamous cells of undetermined significance Since the adoption of the Bethesda System for reporting cervical or vaginal cytologic results, many laboratories have seen a progressive increase in the percentage of smears with the designation of atypical squamous cells of u n d e t e r m i n e d significance. Most pathologists would agree that the proportion of smears with this designation should be <5%. However, there are laboratories where as many as 9% of smears are given this diagnosis? One complicating factor is that agreement is not uniform among cytopathologists as to what criteria should be used to make this diagnosis. Our designation of atypical squamous cells of undetermined significance refers to the presence of abnormalappearing squamous cells that do not meet criteria for defined epithelial abnormalities. There are several reasons for reporting a smear with this designation. In most instances the abnormal cells in the smear are degenerat-
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Fig. 1. Atypical squamous cells of undetermined significance. Degenerating atypical squamous cells. It is not possible to determine whether these represent degenerating normal or neoplastic cells.
Fig. 2. Atypical squamous cells of undetermined significance. Cells demonstrate nuclei that are enlarged and slightly hyperchromatic. These changes could represent metaplasia associated with repair or low-grade squamous intraepithelial lesion. ing a n d it is often difficult to d e t e r m i n e whether these represent d e g e n e r a t i n g n o r m a l or neoplastic cells (Fig. 1). Thus the cytopathologist is u n a b l e to fit the cellular abnormality into any specific epithelial disorder. A n o t h e r circumstance when it is difficult to evaluate cellular changes occurs in the presence of severe inflammation a n d repair. Although the changes associated with repair are easily identified in most instances, this is n o t always the case. Third, poor fixation or poor stains may also lead to cellular changes that the cytopathologist finds difficult to accurately interpret, thus leading to a designation of atypical squamous cells of u n d e t e r m i n e d significance. Finally, when the cytopathologist is n o t quite sure how to interpret the cellular changes noted, this cellular classification leaves a way out. The cytopathologist is aware of the penalty paid when cells difficult to interpret are classified as negative a n d the patient subsequently is f o u n d to have invasive carcinoma of the cervix. Unfortunately, there is n o uniformity of a g r e e m e n t a m o n g pathologists as to what constitutes atypical squa-
mous cells of u n d e t e r m i n e d significance. The College of American Pathologists Cytopathology Committee reviewed 13 cases of cerx~cal a n d vaginal smears that had b e e n designated as atypical squamous cells of undeterm i n e d significance. ~ An i n d e p e n d e n t diagnosis was rendered on each case by each committee member. The lack of uniformity a m o n g these pathologists was readily apparent, with only 62% interpreting the smears as atypical squamous cells of u n d e t e r m i n e d significance on review, whereas 8% felt the smears were n o r m a l a n d 20% felt they demonstrated reactive changes only, The College of American Pathologists Cytopathology Committee reviewed an additional 31 cases diagnosed as atypical squamous cells of u n d e t e r m i n e d significance in 1994. ~ Seventeen cytopathologists took part in this study. In only 7 of 31 cases (23%) was a review diagnosis of atypical squamous cells of u n d e t e r m i n e d significance obtained from >70% of the participants a n d in only 5 of 31 cases (16%) was a diagnosis of atypical squamous cells of u n d e t e r m i n e d significance made by >80% of the experts. No
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Table I. Frequency of atypical squamous cells of u n d e t e r m i n e d significance a n d low-grade squamous intraepithelial lesions (52,167 smears) Age 0-14 15-19 20-24 25-29 30-34 35+ All
No. of smea~
512 1,363 4,431 7,535 9,379 28,947 52,167
ASCUS and HPV
ASCUS
t2 32 128 139 179 453 943
(2.34) (2.35) (2.89) (1.84) (1.91) (1.56) (1.8)
1 2 10 14 20 36 83
(0-20) (0.15) (0.23) (0.19) (0.21) (0.12) (0.16)
HPV
8 57 143 161 166 318 853
(1-56) (4.18) (3.23) (2.14) (1.77) (1.10) (1.6)
Cervicalinlraepithegalneoplasia grade l and HPV
4 34 99 90 93 152 463
(0.78) (2.49) (2.03) (1.20) (1.0) (0.52) (0.89)
Invasive HGSIL
3 8 33 48 43 69 204
(0.59) (0.59) (0.74) (0.64) (0.45) (0.24) (0.39)
canc~
12 (0.023)
Values m parentheses are percents. ASCUS, Atypical squamous cells of undetermined significance; HGSIL, high-grade squamous intraepithelial lesions. Table II. Follow-up data on 118 patients whose smears were designated as atypical squamous cells of u n d e t e r m i n e d significance Diagnosis
Normal Cervical polyp Squamous metaplasia HPV LGSIL HGSIL CIN grade 2 CIN grade 3 Squamous cell cancer ?dS Adenocarcinoma
No.
17 8 40 31 9 11 0 1 1
%
14 7 34 26 8 9
0.85 0.85
LGSIL, Low-grade squamous intraepithelial lesions; HGSIL, high-grade squamous intraepithelial lesions; C/N, cervical intraepithelial neoplasia; AIS, adenocarcinoma in situ.
single case received this diagnosis by all the reviewing cytopathologists. 5 Thus, it is obvious that opinions a m o n g cytopathologists are highly variable as to what constitutes atypical squamous cells of u n d e t e r m i n e d significance. Following are some of the criteria utilized in our laboratory in making this diagnosis. There may very well be disagreem e n t with these criteria. The relatively low percentage of smears signed out by us as atypical squamous cells of u n d e t e r m i n e d significance may account for the finding of significant pathology, in a relatively high percentage of these individuals.
Cytologic criteria associated with the diagnosis of atypical squamous cells of undetermined significance T h e cellular changes most often observed in smears classified as atypical squamous cells of u n d e t e r m i n e d significance include a loss of tile n o r m a l nuclear/cytoplasm ratio, associated ~dth n u c l e a r enlargement. Nuclear detail is often poorly defined, a n d the nuclei may appear hyperchromatic. The cells may appear in clusters; however, single a b n o r m a l - a p p e a r i n g cells may also be observed (Figs. 2 to 5). Occasionally, cells with slight perinuclear clearing a n d slightly enlarged nuclei
may suggest the presence of koilocytes b u t are n o t diagnostic. During 1993, 52,162 smears were reviewed in our cytopathology laboratory at Baylor College of Medicine. Of these, 943 (1.8%) were designated as atypical squamous cells of u n d e t e r m i n e d significance a n d 83 (0.16%) as atypical squamous cells of u n d e t e r m i n e d significance associated with HPV changes. Thus slightly <2% of smears were given this diagnosis (Table I). What is the significance of a smear reported as atypical squamous cells of u n d e t e r m i n e d significance, and how should such a patient be followed up? We attempted to obtain follow-up data o n 146 patients whose smears were designated as atypical squamous cells of u n d e t e r m i n e d significance. Follow-up was successful in 118 (81%) of these individuals. Table II presents the follow-up data on these women. Of significance is the fact that 9% of these w o m e n (11 individuals) were f o u n d to have either cervical intraepithelial neoplasia grade 2 or 3 on follow-up biopsy. O n e patient (0.85%) was f o u n d to have a d e n o c a r c i n o m a in situ and one (0.85%) had invasive a d e n o c a r c i n o m a of the cervix. Thus almost 11% of these w o m e n were f o u n d to have significant disease in the cervix. O f additional interest is that 8% of the group (nine patients) were f o u n d on follow-up biopsy to have cervical intraepithelial neoplasia grade 1 a n d 26% to have changes compatible with HPV infection. These findings are similar to those reported by SidawT and Tabbara. 6 According to data acquired by the College of American Pathologist Interlaboratory PAP Program, the m e d i a n rate of atypical squamous cells of u n d e t e r m i n e d significance in 1992 in the laboratories surveyed was 2.9%, with 10% of these laboratories reporting rates >9.0%. 4 Follow-up of patients with atypical squamous cells of u n d e t e r m i n e d significance by these laboratories revealed a range of 10.3% to 43% with tile diagnosis of squamous intraepithelial lesion. Fewer than 6% of the cases, however, had a high-grade squamous intraepithelial lesion. In this study Davey et al. 4 c o m m e n t e d o n the different applications of criteria for atypical squamous cells of u n d e t e r m i n e d significance in different laboratories. The authors suggest that one m e t h o d of m o n i t o r i n g laboratories
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Fig. 3. Atypical squamous cells of undetermined significance. These cells with large, slightly hyperchromatic nuclei demonstrate some perinuclear clearing, yet they are degenerating. These changes suggest, but are not diagnostic of, HPV infection.
Fig. 4. Atypical squamous cells of undetermined significance. This cluster of degenerating cells is difficult to interpret. However, they cannot be ignored. is to compare the atypical squamous cells of undetermined significance/squamous intraepithelial lesion ratio. When a laboratory reports a high percentage of smears as atypical squamous cells of undetermined significance compared x~qth squamous intraepithelial lesion (high ratio), it can be anticipated that a relatively small proportion of these patients will actually exhibit a squamous intraepithelial lesion on f011ow-up. Conversely, a laboratory with a lower ratio would be expected to have more patients with squamous intraepithelial lesion on follow-up. Davey et alJ r e c o m m e n d that clinicians using a specific laboratory have this information because it may guide them regarding the management of patients with smears designated as atypical squamous cells of undetermined significance. Thus it may be reasonable to follow up some patients with repeat cytologic studies rather than move directly to colposcopy and biopsy. It is vitally important that clinicians communicate closely with the pathologist interpreting their cytologic smears so that they can gain insight as to the significance of a report of atypical squamous cells of u n d e t e r m i n e d
significance. As already discussed, criteria used to make this diagnosis vary significantly from laboratory to laboratory. The clinician should request that the pathologist qualify, a diagnosis of atypical squamous cells of undetermined significance and indicate whether the changes observed are believed to be "reactive" or "degenerative" or may represent a squamous intraepithelial lesion. Most pathologists do, in fact, currently follow this practice. However, many cytopathologists prefer not to because they feel that the diagnosis of atypical squamous ceils of undetermined significance should only be used for socalled "gray zone" lesions.
Cytologic changes associated with low-grade squamous intraepithelial lesion The cellular findings associated with HPV infection and cervical intraepithelial neoplasia grade 1 are closely related, with considerable overlap of the morphologic changes seen in each. It is for this reason that the two conditions are grouped together as low-grade squamous intraepithelial lesion in the Bethesda system. However,
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Fig. 5. Atypical squamons cells of undetermined significance. Atypical degenerating (glandular?) cells are noted. Nuclei are hyperchromatic and enlarged.
Fig. 6. Low-grade squamous intraepithelial lesion. A, Koilocyte is identified in this cluster of cells. Nucleus is enlarged and hyperchromatic, and there is distinct perinuclear clearing. Several other cells in the cluster also demonstrate enlarged hyperchromatic nuclei. B, Koilocytes are seen. Two cells with enlarged hyperchromatic nuclei with perinuctear clearing are seen.
there are those 2' ~ who feel that the biologic behavior of HPV infection differs f r o m that of cervical intraepithelial neoplasia of a low-grade type (grade 1). Lonky et a l ) r e c o m m e n d e d that " a l t h o u g h difficult and subjective, the descriptive demarkation between mild dysplasia and HPV cytopathologic changes has predictive significance
and should be preserved in reports to the clinician." Further long-term studies will be r e q u i r e d to see whether this is the case; however, what does r e m a i n true is that most cytopathologists are not able to clearly distinguish the two cytologically. 6 For the put-poses of this discussion, HPV changes and cervical intraepithelial neoplasia will
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Fig. 7. Low-grade squamous intraepithelial lesion. Dyskeratocytes are seen. These cells are mature squamous cells and have orangophylic cytoplasm. Nuclei are enlarged mad hyperchromatic. Several cells have more than one nucleus.
Fig. 8. HPV changes on cervical biopsy. Koilocytes are evident. Nuclei are enlarged and hyperchromatic.
be described separately a n d some of the subtle differences between them will be emphasized although this distinction may be of little practical value when it comes to patient m a n a g e m e n t . The cytologic criteria for the diagnosis of HPV changes include the presence of koilocytosis, dyskeratocytosis, parakeratotic cells, a n d binucleation. Properly defined, the koilocyte is a cell c o n t a i n i n g a large, hyperchromatic, flat nucleus with indistinct c h r o m a t i n structure. Perin u c l e a r clearing is p r o m i n e n t in a cell with a b u n d a n t cytoplasm (Fig. 6, A a n d B). The dyskeratocyte is a mature squamous cell with uniformly dense orangophylic cytoplasm (Fig. 7). Its nucleus is similar to that of the koilocyte. Often these cells are seen in clusters with overlapping. Schneider et al. 7 evaluated the sensitivity of using "classic" koilocytosis a n d dyskeratocytosis to identify the presence of HPV infection. With these criteria, the authors identified only 15 % of HPV deoxyribonucleic acidpositive cases ( d e t e r m i n e d by deoxyribonucleic acid-filter hybridization in situ). They observed that five " n o n classic" cytologic criteria for diagnosing the presence of
HPV infection were significantly more sensitive in correctly identifying 84% of the HPV-positive group. These criteria included "mild koilocytosis," mild dyskeratocytosis, hyperchromatic nuclei, binucleation a n d multinucleation, a n d cleared cytoplasm. The morphologic evidence of HPV infection as seen on biopsy is the koilocyte. These cells are m o s t c o m m o n l y seen n e a r the surface of the squamous epithelium in the more mature squamous epithelial cells (Fig. 8). The basal and parabasal cells appear relatively n o r m a l in most instances. The criteria c o m m o n l y used for a cytologic diagnosis of cervical intraepithelial neoplasia grade 1 include the presence of enlarged, irregular nuclei in mature squamous epithelial cells (Fig. 9). The nucleus has a regular, granular, or reticular appearance a n d the nuclear memb r a n e is uniform. There is an increased nuclear/cytoplasm ratio. These are all changes that may be seen in association with HPV infection a n d thus distinguishing between the two disorders is of n o practical value. Morphologically, the distinction between cervical intraepithelial neoplasia grade 1 a n d pure HPV changes can be
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Fig. 9. Low-grade squamous intraepithelial lesion. These changes suggest cervical intraepithelial neoplasia grade 1 in association with HPV changes. Nuclei are enlarged, hyperchromatic, and varied. Several cells with faint perinuclear clearing are also noted.
presence of a b n o r m a l mitotic figures in the biopsy specim e n (Fig. 10).
Management of atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion
Fig, 10. Cervical intraepithelial neoplasia grade 1 in cervical biopsy specimen. Abnormal cell proliferation begins deep in epithelium, and scattered abnormal mitoses are noted. Cells mature as they move toward surface, and koilocytes are seen in more superficial epithelial cells.
m a d e m o r e easily. In the presence of cervical intraepithelial neoplasia grade 1, the a b n o r m a l cellular changes begin in the d e e p e r layers of the epithelium, with maturation o f the a b n o r m a l cells o c c u r r i n g as they move to the surface. Koilocytes are often seen in the m o r e superficial epithelium. In contrast to the " p u r e " HPV infection, cervical intraepithelial neoplasia is associated with the
T h e r e c o m m e n d a t i o n s p r o p o s e d h e r e are similar to those r e c o m m e n d e d by K u r m a n et al. s as interim guidelines for m a n a g e m e n t of a b n o r m a l cytologic results. As discussed above, there is considerable interlaboratory variation in r e p o r t i n g smears as atypical squamous cells of u n d e t e r m i n e d significance. For this reason, which cann o t be emphasized enough, the clinician and the cytopathologist must c o m m u n i c a t e with one a n o t h e r clearly and frequently. W h e n possible, the cytopathologist should c o m m u n i c a t e to the clinician any suspicions regarding the changes o c c u r r i n g in the cervix w h e n a smear has b e e n r e p o r t e d as atypical squamous cells of u n d e t e r m i n e d significance. Does the cytopathologist believe that the smear represents d e g e n e r a t i o n of cells, repair, possible HPV infection, or even cervical intraepithelial neoptasia? T h e cytopathologist's view often will act as a guide for the clinician in the m a n a g e m e n t of the patient. Unless the cytopathologist indicates that the changes seen could r e p r e s e n t the presence of a significant abnormality (cervical intraepithelial neoplasia, invasive carcinoma), a satisfactory a p p r o a c h to m a n a g e m e n t is to have the patient return for a follow-up Papanicolaou smear in 3 to 4 months. If a second smear is designated as atypical squamous ceils of u n d e t e r m i n e d significance, the patient should then be seen for colposcopy and directed biopsies as indicated. In the presence of a r e p e a t negative smear, the patient should be seen at 6-month intervals until three consecutive negative smears have b e e n obtained. After this the patient can be seen on an annual basis. T h e r e are certain modifications to the above. In the pa-
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CIN I/HPV Changes on Pap Smear
,1 Repeat Smear in 3 Months
,l I f CIN I/HPV Changes Present
I f Negative
!
Colposcopy with biopsy
If Negative~
Y
S
j
/
i I f C1N I/HPV Changes Only
Follow with Smear Every 6 Months
Repeat Smear in 6 Months
IfHGSIL I f Negative x 3 Biopsies and Treat Annual Smear Fig. 11. Management of low-grade squamous intraepithelial lesion. C/N, Cervical intraepithelial neoplasia; HG:SIL, high-grade squamous intraepithelial lesion.
dent with diagnosed acute vaginitis, the infection should be adequately treated and the smear repeated in 3 months. The postmenopausal woman with severe atrophic vaginitis should be instructed to use systemic or topical estrogen until the vaginal mucosa is estrogenized, at which time the smear should be repeated. Occasionally women receiving chemotherapy may demonstrate cytologic changes that appear abnormal. Invariably these changes will regress after cessation of treatment. Further follow-up in the above instances will d e p e n d on the findings noted in the repeat smear. It is our policy to follow up patients with smears designated as low-grade squamous intraepithelial lesion (either HPV changes alone or in association with cervical intraepithelial neoplasia grade 1 in a conservative manner (Fig. 11). The patient is seen again in 3 months, and the smear is repeated. If similar changes are noted on the
repeat smear, the patient is seen for colposcopic examination and directed biopsies as indicated. If changes indicative of HPV or low-grade squamous intraepithelial lesion alone are found, the patient is then seen at 6-month intervals for follow-up smears. If there is a persistence of cytologic evidence of low-grade squamous intraepithelial lesion, when, if ever, should such a patient be treated? In our own experience 15% of women whose smears and biopsies demonstrate a low-grade squamous intraepithelial lesion will in fact have a high-grade lesion present in the cervix. However, it is reasonable to assume that if such a patient is followed up at regular intervals after the diagnosis of a low-grade lesion cytologic or colposcopic evidence will eventually demonstrate the presence of a high-grade lesion. Thus it is our policy to continue to follow up such patients with cytologic study until a high-grade lesion is found on the Papanicolaou
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smear or until three consecutive smears have b e e n reported as negative. The use of HPV screening has b e e n advocated to help select those patients demonstrating atypical squamous cells of u n d e t e r m i n e d significance or low-grade squamous intraepithelial lesions o n a Papanicolaou smear who may n e e d colposcopy2' 10 The theory has b e e n proposed that those individuals d e m o n s t r a t i n g a low-risk HPV type do n o t n e e d immediate colposcopy a n d biopsy a n d can be followed up conservatively. However, for those individuals with a high-risk HPV type, immediate colposcopy a n d biopsy should be performed. To date, however, there are n o data to suggest that this course of action has validity. O u r own findings n a n d those of Downey et al. 12 would suggest that using currently available HPV testing techniques is of little practical value as a means of patient triage. It is possible that new, more sensitive HPV screening tests may serve this purpose. Comment
Some researchers have opposed the Bethesda system because of its allegedly associated potential for overrep o r t i n g a n d overtreatment in cases of atypical squamous cells of u n d e t e r m i n e d significance a n d low-grade squamous intraepithelial lesion. Indeed, the p r o p o r t i o n of smears with the designation of atypical squamous cells of u n d e t e r m i n e d significance has increased since the adoption of the Bethesda system. Several reasons exist for reporting smears with this designation, i n c l u d i n g the presence of d e g e n e r a t i n g cells, the presence of severe i n f l a m m a t i o n a n d repair, a n d suboptimal fixation a n d staining. Pathologists do n o t agree o n what constitutes atypical squamous cells of u n d e t e r m i n e d significance. In our laboratory slightly <2% of smears in 1993 were given this designation. I n f o r m a t i o n regarding a particular laboratory's atypical squamous cells of u n d e t e r m i n e d signific a n c e / s q u a m o u s intraepithelial lesion ratio should be provided to the clinician for guidance in patient management. C o m m u n i c a t i o n between the cytopathologist a n d clinician is essential for d e t e r m i n i n g the significance of a report of atypical squamous cells of u n d e t e r m i n e d significance. T h e cellular changes associated with HPV a n d cervical intraepithelial neoplasia can be hard to distinguish from one another. O u r treatment guidelines in cases of atypical squamous cells of u n d e t e r m i n e d significance a n d low-grade squamous intraepithelial lesion closely parallel those set forth by K u r m a n et al. 8 Unless "high-grade" cervical intraepithelial neoplasia or invasive carcinoma is suspected, the patient with a r e p o r t of atypical squamous cells of u n d e t e r m i n e d significance can be asked to r e t u r n within 3 to 4 m o n t h s for a repeat
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Papanicolaou smear. If this second smear is r e t u r n e d as atypical squamous cells of u n d e t e r m i n e d significance, colposcopy and directed biopsy should be performed. If the second smear is negative, smears should be taken at 6-month intervals until three negative smears have b e e n obtained, after which a n n u a l visits suffice. Patients with vaginitis or who are postmenopausal with severe atrophic vaginitis require special treatment. Patients whose smears are reported as low-grade squamous intraepithelial lesion because HPV changes alone or in the presence of cervical intraepithelial neoplasia grade 1 should be treated conservatively, with repeat smears a n d colposcopy with directed biopsy if the second repeat smear contains the same abnormality. Patients with high-grade lesions should be treated immediately. REFERENCES
1. National Cancer Institute Workshop. The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262:931-4. 2. Syrjanen K, Kataja V, Liskoski M, et al. Natural history of cervical human papillomavirus lesions does not substantiate the biologic relevance of the Bethesda system. Obstet Gynecol 1992;79:675-82. 3. Lonky NM, Navarre GL, Saunders S, et al. Low-grade Papanicolaou smears and the Bethesda system: a prospective cytohistopathologic analysis. Obstet Gynecol 1995;85:71620. 4. Davey DD, Naryshkin S, Nielsen ML, Klein TS. Atypical squamous cells of undetermined significance: interlaboratory comparison and quality assurance monitors. Diagn Cytopathol 1994;11:390-6. 5. RobbJA. The "ASCUS" swamp. Diagn Cytopathol 1994;11: 319-20. 6. 8idauT MK, Tabbara SO. Reactive change and atypical squamous cells of undetermined significance in Papanicolaou smears: a cytohistologic correlation. Diagn Cytopathol 1993; 9:423-9. 7. Schneider A, Meinhardt G, De-Villiers EM, Gissmann L. Sensitivity of the cytologic diagnosis of cervical condyloma in comparison with HPV-DNA hybridization studies. Diagn Cytopathol 1987;3:250-5. 8. Kurman RJ, Henson DE, HerbstAL, et al. Interim guidelines for management of abnormal cervical cytology. JAMA 1994; 271:18660. 9. CoxJT, Lorincz AT, Shiffman MH, et al. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet G)mecol 1995;172:946-54. 10. Wright TC, Sun TW, KorelosJ. Comparison of management algorithms for the evaluation of women with low grade cytologic abnormalities. Obstet Gynecol 1995;85:202-10. 11. Kaufman RH, lcenogle J, Adam E, et al. The relevance of HPV screening in the management of cervical intraepithelial neoplasia. In: Proceedings of the Thirteenth International Papillomavirus Conference, Amsterdam, The Netherlands, October 8-12, 1994. Amsterdam: International Papillomavirus Conference, 1994. 12. Downey GP, Bovin PJ, Deery ARS, et al. Relation between human papillomavirus type 16 and potential for progression of minor-grade cervical disease. Lancet 1994;344:432-5.