The “¿Atypical―
PapanicolaouSmear
Walter B. Jones, M.D.
Patricia E. Saigo, M.D.
Several studies demonstrate the effective
ness of the Papanicolaou smear in screen
ing for cervical cancer. Well-screened
populations show a dramatic reduction in
both the incidence and mortality of clini
cally invasive carcinoma of the cervix.''
In contrast, in areas where intensive
screening has not been practiced, these rates
have not declined.5-7
Along with declining incidence rates
for invasive cervical cancer, there has been
a marked increase in preinvasive disease.
The number of cases of in situ carcinoma,
for example, was thought to be too small
to warrant a separate category in the Sec
ond National Cancer Survey, whereas 23
years later when the time came for the Third
National Cancer Survey, 80 percent of
newly diagnosed carcinoma was discov
ered while still in situ.' According to the
American Cancer Society, an estimated
45,000 new cases of in situ carcinoma of
the cervix will be diagnosed in the United
States in 1986, compared with 14,000 in
vasive cancers.9 In England and Wales, the
number of cases of in situ carcinoma has
been reported to have increased by more
than 100 percent in women aged 15 to 35,
Dr. Jones is Associate Attending Surgeon in the
Gynecology Service, Department of Surgery, of
Memorial Sloan-Kettering Cancer Center in New
York, New York.
Dr. Saigo is Associate Attending Pathologist in
the Department of Pathology of Memorial Sloan
Kettering Cancer Center in New York, New
York.
VOL. 36, NO 4 JULY/AUGUST 1986
whilethenumber of Papanicolaou smears
increased by only 11 percent in the same
population.7 Although the increased inci
dence rates of in situ carcinoma are sink
ing, it is important to note that most patients
with preinvasive disease of the cervix have
a less advanced lesion at the time of di
agnosis. Indeed, in the US, the number of
women who have an early cervical cancer
precursor is estimated to be more than four
times the number of those with in situ car
cinoma.'°
In the asymptomatic patient with a
normal pelvic examination, the earliest
evidence of any precursor lesion of the cer
vix are cytologic abnormalities detected
with a Papanicolaou smear. The clinician,
therefore, must not only determine the re
liability and accuracy of the laboratory in
identifying such abnormalities, but also
understand the implications of the reported
results. When a satisfactory Papanicolaou
smear is reported to contain only normal
cells in a patient with a healthy cervix, the
smear is usually repeated at recommended
intervals; colposcopic examination and bi
opsy are required when the smear contains
cells described as suspicious for malig
nancy.
The dilemma arises when laboratories
utilizing the Papanicolaou classification
group together within the same class a wide
range of cytologic abnormalities that may
signify inflammatory atypia, neoplasia, or,
in some cases, diagnostic uncertainty. Be
cause such findings are often reported as
237
 () H l(i@IN A I
PAP/\N (COt @\OtJ
CLA@S( F (CA T (UN

Class I
Absence of atypical or abnormal cells.

Class II
Atypical cytology, but no evidence of malignancy.

Class III
Cytology suggestive of, but not conclusive for, malignancy.

Class IV
Cytology strongly suggestive of malignancy.

Class V
Cytology conclusive for malignancy.

a Class II (atypical) smear, some patients
with preinvasive disease, or even invasive
cancer of the cervix, may go unrecognized.
This can occur in the patient with a his
tologically early lesion where the associ
ated cytologic abnormality may be mini
mal and difficult to interpret, as well as in
the patient with a more advanced lesion
where the sample contains only a small
number of atypical cells not representa
tive of the significant underlying abnor
mality.
Because the Papanicolaou classifica
tion fails to convey the level of significance
of atypical cells, it is viewed as being
inadequate for reporting such findings.
Instead, when atypical cells are the
distinguishing feature of the smear, the re
port should alert the clinician to the pres
ence of a possibly significant cytologic
abnormality. This can be accomplished by
the use of a system of classification that is
narrative, similar to the histologic classi
fication, and one that employs diagnostic
terms whenever possible.―.'2
The original Papanicolaou classifica
tion divided both positive and negative re
sults into subgroups to take into account
the relatively large number of questionable
or inconclusive smear findings (Table).
While itwas convenient forearlyprac
titioners to use the Papanicolaou classifi
cation, the evolution of knowledge about
the natural history of squamous cancer of
the cervix requires that a method exist for
the reporting of abnormalities classified as
borderline, dysplastic, or premalignant.
Some modifications of the original clas
sification system have included the bor
derline or dysplastic lesions in Class II,
while others have placed them in Class
III.More recently, the term cervicalin
traepithelial neoplasia (CIN) has been used
to describe preinvasive lesions of the cer
vix with the degree of cytologic abnor
mality expressed by increasing Grades
from I to 111.13The use of terms in the
cytologic diagnosis that specify the mag
nitude of change can make the report more
meaningful.
Of particular concern are women whose
smearscontaincellsshowinga significant

238 CA-A CANCER JOURNAL FOR CLINICIANS

 ! :.“@.
•¿â€˜
i.'' •¿
¶
@ @, .@ b
..“@ ‘¿.
@ •¿ .d@ •¿@
@ 1P18.
Fig. 1. Metaplastic squamous cells are smaller
than the mature squamous cells. The cyto
plasm is denser and often bichromatic (Pa
panicolaou stain, x 570).
abnormality but not at a diagnostic level.
This group contains a small number of
women who have a definite premalignant
or malignant lesion. Another subgroup,
however, have disease that may not yet
have developed into a recognizable lesion.
In a follow-up study that extended to six
years, Melamed and Flehinger found that
the likelihood of demonstrating a well
defined lesion on repeat examinations in
these patients was about five to 10 times
greater than for women who did not
show this minimal abnormality.'4 At the
time the smear is performed, there
fore, these women should be identified
as those who require continued follow-up
and investigation.
The term “¿squamous atypia―embraces
a wide range of cytologic deviations. Some
atypical squamous cells are readily rec
ognizable as the result of benign processes
such as squamous metaplasia (Fig. 1) or
as a reaction to inflammatory conditions
or infections or infestations (Fig. 2), oc
casionally with the formation of a benign
pearl (Fig. 3). These benign conditions
produceatypical squamous cellsin many
women.
Some cellular abnormalities, however,
cannot be attributed to physiologic or in
flammatory conditions. An example of this
is the presence of keratinized squamous
cells that could either represent the kera
tinized surface cells of an underlying neo
plastic lesion or be nothing more than an
VOL 36, NO 4 JULY/AUGUST 1986
Fig. 2. In inflammatory conditions, less mature
cells are present at the surface and sampled
for the smear (Papanicolaou stain, x 570).
‘¿@.‘@-
.1_I
“¿@
•¿,@
‘¿
I.,,
Fig. 3. A squamous pearl is occasionally
formed from benign squamous cells in inflam
matory states (Papanicolaou stain, x 570).
exaggerated response to inflammation or
infection (Fig. 4). In still other cases, a
significant abnormality may be represented
by only a few atypical cells, and the pau
city of diagnostic cells negates the possi
bility of a definite diagnosis (Fig. 5).
On the other hand, the squamous atypia
seen in cases of human papillomavirus
(HPV) infection isknown tobe associated
with an underlying dysplasia or carcinoma
in a significant number of patients (Fig.
6).'@-'@Therefore, the identification of
squamous cells showing a significant atypia
below a diagnostic level that cannot be at
tributed to an identifiable benign process
shouldbe reportedin termsthatindicate
follow-up is necessary. Ideally, the termi
nology used for the diagnosis should take
into account the clinician's potential re
239

@ S@@L'J
@ 0
,@ ‘¿I
‘¿I
Fig. 4. There are many parakeratotic cells,
some with hyperchromatic, rather pyknotic
nuclei; note the parasite, Trichomonas vagin
alis, present as a pale blue-gray structure in
the center of the field. (Papanicolaou stain,
x 570).
•¿
I.'-,
Fig. 5. These multinucleated squamous cells
have nuclei that are about the same size as
those of the intermediate cell and are only
slightly darker (Papanicolaou stain, x 570).
sponses in the management of the patient.2°
Recommendations
In the patient with an identifiable cervical
lesion, a biopsy should be performed no
matter what the cytologic findings. Col
poscopy is indicated for a woman with a
grossly healthy cervix with a satisfactory
smear containing atypical cells not clearly
attributed to inflammation or other non
neoplastic conditions but that are below the
diagnostic level of a precancerous lesion.
This recommendation is based in part
on the knowledge that repeat smears after
an initial abnormal smear are notoriously
240
%•
•¿ .@
...,u@ •¿ •¿
S, I
Fig. 6. The koilocytes in this group have slightly
irregular nuclei surrounded by a large pen
nuclear clear area. The nuclei containing the
antigen appear brown when antiserum is used
directed against human papilloma virus. (Im
munoperoxidase stain, x 570).
unreliable. Several studies have shown that
marked discrepancies in cytologic diag
nosis including detection failures may oc
cur between two simultaneously obtained
cervical smears.2'23 The importance of
evaluating the patient after a single abnor
mal smear is supported by the report of
Drescher et al, who found a false-negative
rate of 43.4 percent in CIN I, 22 percent
in CIN II, and 13.7 percent in CIN III,
with an overall rate of 26.4 percent when
smears were repeated prior to biopsy.24
Based on such studies, investigators
have advised against the practice of ob
taining repeat smears for confirmation of
abnormal cytologic findings.25 Koss, for
example, warned that a repeat negative
smear in no way indicates that the lesion
has improved, let alone disappeared.26 In
his view, colposcopic evaluation should be
mandatory after the first abnormal smear,
regardless of the degree of cytologic ab
normality.27
While the incidence of false negative
smears appears to be highest in the patient
with a small early lesion, an atypical or
Class II smear may be the only evidence
of a more advanced precursor. Nyirjesy
found that of his patients who underwent
biopsy because of persistently atypical
smears,more than75 percenthad signif
icant disease, including two patients with
invasive squamous cell carcinoma.28 Sim
ilarly, Figge et al reported that six percent
CA-A CANCERJOURNALFORCLINICIANS
of invasive cancers and 18.9 percent of
cases of carcinoma in situ were suspected
because of atypical smears and that these
smears never progressed to a higher class
before diagnosis.29 In a report by Sandmire
et al, more cases of carcinoma were found
in patients with atypical smears than in
patients with suspicious, probably malig
nant smears or malignant smears.3°
Finally, recent reports have called at
tention to the significant number of women
found to have advanced disease at the time
of diagnosis,3@' despite evidence of a re
cent negative Pap smear or smears showing
only atypia.35-3' The apparently rapid tran
sition from negative cytology to invasive
disease suggests that there may be a bi
modal distribution of cervical cancer pre
cursors in which some women, especially
younger women, do not seem to have a
prolonged preinvasive phase.39-4' Because
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VOL 36, NO 4 JULY/AUGUST 1986
the early stages of this process may be
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In Summary
Optimal management of the patient with
the atypical smear requires a narrative de
scriptionof the findingsas well as frequent
personal communication with the cyto
pathologist. When the cytologic abnor
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underlying early or poorly formed neo
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CA-A CANCER JOURNAL FOR CLINICIANS