PART TWO
Diagnostic Cytology
Negative for intraepithelial Lesion or Malignancy
(NiLM)
The Bethesda 2001 category of NILM is used to report non-
neoplastic findings in the absence of an intraepithelial lesion
or malignancy. This term is used both as a general categoriza-
tion and as an interpretation and incorporates the reporting
of
organisms
and other non-neoplastic findings such as
reactive
cellular changes
(Table 6.1). The NILM category replaces the two
prior Bethesda categories of "within normal limits" (WNL) and
"benign cellular changes" (BCC). The basis of this change was
to clearly communicate to the physician that despite any other
"benign" changes reported, the Pap test is "negative" or without
evidence of cervical intraepithelial neoplasia or malignancy.
Clearly, the main purpose of cervical cytology screening is the
detection of cervical squamous cell carcinoma and its precur-
sors; however, reporting the findings of organisms or reactive
conditions can make an important contribution to patient care.
This documentation can facilitate patient triage, provide clinical-
cytologic correlation, and focus attention on cytomorphologic
criteria during microscopic screening and interpretation of
cervical cytology.
The category of "infections" was changed to "organisms"
in TBS 2001 since the presence of some organisms represents
colonization rather than a clinically significant infection. Excel-
lent specificity and reproducibility can be achieved for the
cytopathologic interpretation of fungal elements,
Trichomonas
vaginalis, Actinomyces,
and herpes simplex virus, by application
of reproducible morphologic criteria. The interpretation of
Chlamydia
spp. is not listed in TBS because of the acknowledged
low diagnostic accuracy of routine cytology for this organism
and because of the availability of other, more accurate detec-
tion methods. TBS lists the organisms that should be reported;
however, the laboratory is advised to discuss the relevance of
reporting organisms and other non-neoplastic findings with
their clinicians and come to a decision about what to report
under the NILM category.
Cells manifest reactive morphologic changes in response to
a variety of traumatic insults such as infection, inflammation,
and radiation. Reparative processes, radiation, atrophy, and intra-
uterine contraceptive devices are examples of entities that induce
cellular changes that may mimic intraepithelial lesions or even
cancer. Severe reactive/reparative changes are difficult to dis-
tinguish from neoplastic changes and such interpretations are
well known to have lower reproducibility than classic repair.35
It is, however, important to recognize benign reactive features
in order to avoid overinterpretation and resulting false-positive
interpretations. A CAP report indicates that reparative changes
tend to be easier to recognize on LBP, yielding less false positives
than on conventional smears.36
Keratotic
cellular changes—hyperkeratosis,
parakeratosis,
and dyskeratosis—are descriptive terms that do not clearly
communicate a diagnostic interpretation and are not included
in TBS. The classification of such changes as benign/reactive
or dysplastic should be based on the cytoplasmic and nuclear
alterations present and reported under the appropriate general
category/interpretation.
Occasionally, benign-appearing glandular cells may be seen
in post-hysterectomy patients that can have a wide variety of
sources, including adenosis, metaplasia, and prolapse of the
remaining fallopian tube after a simple hysterectomy.37,38 This
finding can be communicated to the clinician under the NILM
category and per current ASCCP guidelines does not require
further follow-up.9 Other non-neoplastic changes that may be
reported under NILM include atrophy and tubal metaplasia.
Details regarding the morphology of these entities are dis-
cussed elsewhere in this book.
Endometrial cells
TBS 1991 recommended that benign-appearing endometrial
cells in postmenopausal women be reported as an "epithelial
cell abnormality" based on the increased risk for endometrial
adenocarcinoma (6%) and endometrial hyperplasia (12%) on
a meta-analysis.3,39,40
In TBS 2001, a new category was included to report the pres-
ence of benign-appearing endometrial cells in women aged 40
years or older.7,10 The basis for including this new category in TBS
2001 was twofold: (a) review of the published literature showed
an exceedingly low rate of significant lesions in anyone less than
40 years of age, and (b) pathologists may lack clinical informa-
tion on menstrual dates/menopausal status, hormone therapy/
tamoxifen, abnormal bleeding, and other endometrial carcinoma
risk factors. It is important to include in the interpretation whether
the cytology is "negative for squamous intraepithelial lesion."
Only exfoliated, intact endometrial cells should be reported
under the "other" category. As described in Bethesda 2001, the
exfoliated groups of endometrial cells may be of epithelial and/
or stromal origin; morphological distinction of these two cell
types is usually not possible. Directly sampled lower uterine seg-
ment or abraded stromal cells/histiocytes, when present alone,
should not be reported under this category. Atypical endome-
trial cells should be reported as an epithelial glandular cell
abnormality.1,10
The prevalence of benign-appearing endometrial cells cervi-
cal in Pap tests from women aged 40 years or older is difficult
to assess due to differences in study designs, but has been esti-
mated to range from 1-3/100 to 1/1600 or less.39 After adoption
of TBS 2001, there have been many reports in the cytology litera-
ture that have shown minimal risk associated with this interpre-
tation, especially in premenopausal women.40 This TBS category
has been controversial for clinicians and initially resulted in an
increase in endometrial biopsies.
It may be useful to add an educational note to this interpre-
tation in order to clearly communicate to clinicians that this
interpretation has an increased risk of neoplasia, but the risk
is low, especially in premenopausal women and those without
endometrial carcinoma risk factors, and that clinical correlation
with other risk factors and symptoms is necessary. Examples
of educational notes for this interpretation can be found in the
second edition of the Bethesda atlas.10
The 2006 ASCCP guidelines provide additional guidance and
suggest that for asymptomatic women who are documented by
clinical history to be premenopausal, with benign appearing
endometrial cells, endometrial stromal cells, or histiocytes; no
further evaluation is required. For documented postmenopausal
women with endometrial cells, on the other hand, endometrial
assessment is suggested, regardless of symptoms.9
epithelial cell Abnormalities: Squamous cell
Squamous intraepithelial lesion (SIL) encompasses the morpho-
logic spectrum of noninvasive squamous epithelial abnormali-
ties associated with HPV infection. Since the Bethesda System
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