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CANCER
254
CYTOPATHOLOGY
Adenocarcinoma In Situ with a Small Cell
(Endometrioid) Pattern in Cervical Smears
A Test of the Distinction from Benign Mimics Using Specific Criteria
Kenneth R. Lee,
M.D.
Department of Pathology, Brigham and Women’s
Hospital, Boston, Massachusetts.
BACKGROUND. Papanicolaou smears have been less effective in preventing cervical
adenocarcinoma than in preventing squamous carcinoma. One reason may be a
lack of awareness of certain smear patterns of adenocarcinoma in situ (AIS) such
as those with crowded small cells (endometrioid pattern).
METHODS. A test set of 29 smears (17 AIS with an endometrioid pattern, 12 benign
mimics) was reviewed by 11 cytologists (4 experienced cytotechnologists, 3 cytopathology fellows, and 4 cytopathologists with varying levels of experience). Participants were blinded as to the actual diagnosis and the number of cases in each
category and were instructed to diagnose either AIS or a benign lesion. Results of
this review were not disclosed before a second review conducted after instruction
in specific criteria for “endometrioid” AIS. Results were compiled using kappa
statistics.
RESULTS. In the first round, the ability to distinguish these lesions was poor for 8
of the 11 reviewers, and no reviewer was in excellent agreement with the actual
diagnosis. In the second round, only 1 reviewer had a poor rating, and 4 of 11 were
in the excellent category. Misdiagnoses in both rounds were more commonly the
result of underdiagnosis of AIS than overdiagnosis of benign cases.
CONCLUSIONS. The presentation of AIS in smears as groups of crowded small cells
is prone to underdiagnosis. Awareness of this problem and use of criteria improves
sensitivity. [See editorial on pages 243– 4, this issue.] Cancer (Cancer Cytopathol)
1999;87:254 – 8. © 1999 American Cancer Society.
KEYWORDS: cervix, adenocarcinoma, adenocarcinoma in situ, cytology, Papanicolaou smear, cervicovaginal smears.
n a prior study1 it was found that in cases of adenocarcinoma in situ
(AIS) that were underdiagnosed in cervicovaginal smears, there
were two cytologic patterns. In one, cells resemble reactive endocervical cells; in the other, the cells are small, mimicking endometrial
cells or endocervical cells from high in the canal and/or with tubal
metaplasia. To study the latter problem, a test set of 29 smears
composed of AIS cases containing small (endometrioid) cells and
cases containing their benign mimics was reviewed by three pathologists with the goal of developing criteria to separate benign from
malignant cells in these diagnostically difficult cases.2 In that study
statistically significant criteria selected as favoring AIS were as follows:
I
The author thanks Elizabeth Allred, Ph.D., for statistical assistance.
Address for reprints: Kenneth R. Lee, M.D., Department of Pathology, Brigham and Women’s
Hospital, 75 Francis St., Boston, MA 02115.
Received October 7, 1998; revisions received
March 5, 1999; accepted March 18, 1999.
© 1999 American Cancer Society
1. Absence of endometrial stromal cells and endometrial-like tubules
2. Coarse chromatin
Testing Criteria for “Endometrioid” AIS/Lee
TABLE 1
Criteria Favoring “Endometrioid” AIS vs. Benign Mimics
Absent endometrial stroma
Coarse nuclear chromatin
Extreme nuclear crowding
Mitotic figures
“Feathering”
Absent endometrial tubules
Rosettes
Strips of columnar cells
Modified from Lee KR, Genest DR, Minter LJ, Granter SR, Cibas ES. Adenocarcinoma in situ in cervical
smears with a small cell (endometrioid) pattern: distinction from cells directly sampled from the upper
endocervical canal or lower segment of the endometrium. Am J Clin Pathol 1998;109:738–42.
3. Extreme nuclear crowding (lack of honeycombing)
4. Mitotic figures
5. Feathering.
Rosettes of cells and strips of columnar cells also favored AIS but were not statistically significant (Table
1).2 The current study uses the same 29 cases to test
the ability of cytotechnologists and pathologists to
discriminate among them before and after having
been instructed in the use of the above criteria.
255
TABLE 2
Number of Incorrect Diagnoses of 29 Unknown Cervicovaginal
Smears of Either AIS or Benign Glandular Cells Reviewed
by 11 Study Participants
Mean
Median
Range
First round
Second round
9.4
11
5–14
6.2
6
2–15
TABLE 3
Kappa Statistic for Each Individual Review of 29 Cases
Cytotechnologists
Cytology fellows
Cytopathologists
First round
Second round
0.35
0.19
0.03
0.30
0.66
0.19
0.35
0.30
0.38
0.68
0.65
0.10
0.46
0.58
0.47
0.73
0.56
0.78
0.60
0.53
0.72
0.86
Kappa , 0.4 5 poor, 0.4 to 0.7 5 fair to good, . 0.7 5 excellent.
MATERIALS AND METHODS
Thirty-five smears (20 AIS,; 15 benign) were selected
from a teaching collection accrued from the files of the
Brigham and Women’s Hospital, Boston, Massachusetts, and the Medical Center Hospital of Vermont,
Burlington ,Vermont, during the interval May 1982 to
December 1996. Cases were selected by the author
from a larger group that originally had caused difficulty in the differential diagnosis between AIS and
cells from the upper endocervix, sometimes with tubal
metaplasia, or from the endometrium. These were
reviewed, and cases in which the diagnosis was judged
straightforward and those in which diagnostic cells
were scant or poorly preserved were excluded. The 20
AIS smears were selected from 12 patients. The diagnosis of AIS without a concomitant high-grade squamous lesion was confirmed by cone biopsy, hysterectomy, or both. The 15 smears with benign lesions were
from 15 different patients, 7 of whom had undergone
a previous cone biopsy (high-grade squamous lesion,
5; AIS, 1; tubal metaplasia, 1.). Follow-up in these 15
patients included one to three negative smears in 7
patients (4 with negative results of endocervical curretage as well) and a cone biopsy or hysterectomy with
negative results in 6 (4 with tubal metaplasia of the
cervix). Two smears were recent examples of direct
endometrial sampling that had caused difficulty in the
distinction from AIS.
Three smears from each of the two categories
were selected as teaching slides to be used after all
participants had reviewed the remaining 29 cases for
the first time. The 29 smears were reviewed independently by 11 individuals (4 experienced cytotechnologists, 3 cytopathology fellows, and 4 cytopathologists
of varying levels of experience). Participants were not
informed of the number of cases in each category and
were instructed to record their diagnosis as either
benign or AIS. After the first review, participants were
instructed in the differential diagnosis, first by a lecture format in which the criteria found to be most
useful in the prior study (Table 1.) were illustrated and
discussed and then by small group instruction using a
multiheaded microscope with the teaching set of six
cases. Several months later participants re-examined
the 29 smears without knowledge of how they had
performed in the original review.
Incorrect diagnoses for each individual for the
first and second review were recorded and analyzed
by kappa statistics, which account for the skewed
probability for an incorrect diagnosis resulting from
the imbalance of cases with AIS and benign changes
(kappa , 0.4 5 poor, 0.4 to 0.7 5 fair to good, . 0.7 5
excellent). After results were tallied, smears from individual cases that were particularly problematic (6 or
more of the 11 participants with an incorrect diagnosis
256
CANCER (CANCER CYTOPATHOLOGY) October 25, 1999 / Volume 87 / Number 5
FIGURE 1. Representative groups from four difficult AIS cases. (A) Small cells with extreme crowding, nuclear coarseness. Wispy cytoplasmic “tails” are seen
at the bottom of the group. (B) Two groups with extreme nuclear crowding. The group on the left is a strip of columnar cells. Nuclear coarseness is less evident
in these groups. (C) AIS group with feathering, extreme nuclear crowding, and chromatin coarseness. (D) A small rosette is present at bottom right of a group
containing crowded, hyperchromatic, small nuclei.
in either round) were reviewed by the author to assess
possible reasons for the difficulties.
RESULTS
The number of incorrect diagnoses for the entire
group in each of the two rounds is given in Table 2. In
Table 3 the diagnoses for each individual relative to
the expected diagnosis is given in terms of kappa
values and stratified by cytotechnologists, fellows and
cytopathologists. These data may be summarized as
follows: the ability to separate AIS with small (endometrioid) cells from benign lesions in the first round
was poor for 8 of the 11 reviewers, whereas in the
second round, it remained poor for only 1 of the 11.
Conversely, no reviewer had an excellent rating in the
first round, whereas, in the second round 4 of 11 were
in the excellent category.
There was a tendency towards underdiagnosis of
AIS rather than overdiagnosis of benign lesions. In the
first round, considering all diagnoses from the 11 observers, 40% of AIS cases were misdiagnosed versus
21% of the benign cases. In the second round, these
values were 26% and 14%, respectively. In the first
round all six cases in which there were six or more
incorrect diagnoses were AIS. In the second round
there was only one case, also AIS, with six incorrect
diagnoses.
Upon review of the six AIS cases that were particularly prone to underdiagnosis, the common theme
appeared to be the mistaken identification of small
groups of crowded cells as either benign endometrial
or endocervical cells. In some of these cases, the abnormal cells were confined to small areas of the slide.
However, in no case were they extremely scant or
poorly preserved. Representative cell groups from four
of these difficult AIS cases are illustrated in Figure 1.
From this figure, the difficulties in suspecting AIS may
be appreciated. Some of the cell groups are quite
small, and there is a lack of significant nuclear pleomorphism and obviously malignant nuclear features.
However, the cells are generally well preserved, and
most groups demonstrate some of the findings that
Testing Criteria for “Endometrioid” AIS/Lee
257
FIGURE 2. Two benign cases demonstrate findings that discriminate them from AIS. (A) An endometrial tubule is seen at the top, and a sheet of evenly spaced
endocervical cells is present at the bottom. The nuclear chromatin is fine and evenly dispersed. (B) A folded sheet of cells containing evenly spaced small nuclei
with fine, evenly dispersed chromatin.
help distinguish AIS from benign endometrial and
endocervical cells (illustrated in Fig. 2), such as extreme nuclear crowding, nuclear hyperchromasia, and
slight coarsening of the chromatin in conjunction with
subtle endocervical cell differentiation (feathering, columnar cells, rosettes).
DISCUSSION
Invasive endocervical adenocarcinoma is increasing
in proportion to squamous carcinoma.3,4Evidence
exists that Papanicolaou smears do not afford the
same degree of protection from the development of
adenocarcinoma as they do for squamous carcinoma.5–7 To increase the effectiveness of the Papanicolaou smear in the prevention of adenocarcinoma,
it is critical that cytotechnologists and cytopathologists are able to recognize the patterns of presentation of the precursor lesion, adenocarcinoma in situ.
It has been shown that AIS smears with groups of
small (endometrioid) cells are particularly prone to
underdiagnosis.1 The results in the first round of the
current study reinforce that observation, while at
the same time the round two results demonstrate
that instruction in the recognition of this pattern
can improve diagnostic accuracy. The principal differential diagnosis is with small glandular cells,
which may be derived either from the upper endocervix, sometimes with tubal or tuboendometrial
metaplasia,8,9 or from the endometrium.10,11 Smears
with such benign cells are more commonly encountered than those with AIS, and it is crucial that
cytologists recognize this distinction in attempting
to increase sensitivity for AIS without a large increase in falsely positive smears. The value of the
criteria previously developed2 and education in the
use of these criteria has been demonstrated in this
study. However, the differential diagnosis remains a
difficult one. It is hoped that through the educational function of exercises such as this one and the
dissemination of information relative to the less well
known features of adenocarcinoma in situ, awareness will improve and the Papanicolaou smear will
become a more powerful tool in the prevention of
cervical adenocarcinoma.
REFERENCES
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Lee KR, Minter LJ, Granter SR. Papanicolaou smear sensitivity for adenocarcinoma in situ of the cervix: a study of 34
cases. Am J Clin Pathol 1997;107:30 –5.
Lee KR, Genest DR, Minter LJ, Granter SR, Cibas ES.
Adenocarcinoma in situ in cervical smears with a small
cell (endometrioid) pattern: distinction from cells directly
sampled from the upper endocervical canal or lower segment of the endometrium. Am J Clin Pathol 1998;109:
738 – 42.
Hopkins MP, Morley GW. A comparison of adenocarcinoma
and squamous carcinoma of the cervix. Obstet Gynecol 1997;
77:912– 7.
Peters RK, Chow A, Mack TM, Bernstein TD, Henderson BE.
Increased frequency of adenocarcinoma of the uterine cervix in young women in Los Angeles County. J Natl Cancer
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Nieminen F, Kallio M, Hajama M. The effect of mass
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Boon ME, Guilloud JCD, Kok LT, Olthof AM, van Erp EJM.
Efficacy of screening for cervical squamous and adenocarcinoma: the Dutch experience. Cancer 1987;59:862– 6.
Mitchell H, Medley G, Gordon I, Giles G. Cervical cytology
reported as negative and risk of adenocarcinoma of the
cervix: no strong evidence of benefit. Br J Cancer 1995;71:
894 –7.
258
8.
CANCER (CANCER CYTOPATHOLOGY) October 25, 1999 / Volume 87 / Number 5
Novotny DB, Maygarden SJ, Johnson DE, Frable WJ. Tubal
metaplasia: a frequent potential pitfall in the cytologic diagnosis of endocervical glandular dysplasia on cervical
smears. Acta Cytol 1992;36:1–10.
9. Ducatman BS, Wang HH, Jonasson JG, Hogan CL, Antonioli
DA. Tubal metaplasia: a cytologic study with comparison to
other neoplastic and non-neoplastic conditions of the endocervix. Diagn Cytopathol 1993;9:98 –105.
10. Babkowski RC, Wilbur DC, Rutkowski MA, Facik MS, Bon-
figlio TA. The effects of endocervical canal topography, tubal
metaplasia, and high canal sampling on the cytologic presentation of non-neoplastic endocervical cells. Am J Clin
Pathol 1996;105:403–10.
11. dePeralta-Venturino MN, Purslow MJ, Kini SR. Endometrial cells of the “lower uterine segment” (LUS) in cervical
smears obtained by endocervical brushings: a source
of potential diagnostic pitfall. Diagn Cytopathol 1995;
12:263–71.
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