criterios citomorfológicos de esfregaços cervicais após uso de testosterona

1. Cancer Cytopathology July 2020 491
Original Article
Cytomorphologic Findings of Cervical Pap Smears From
Female-to-Male Transgender Patients on Testosterone
Therapy
Michael P.A. Williams, MD, MSc; Vinita Kukkar, MD; Melissa N. Stemmer, MBA, CT (ASCP);
and Kamal K. Khurana, MD
BACKGROUND: The cervical cancer screening recommendation for transgender female-to-male (FTM) patients is the same
as that for cisgender females. A lack of literature on testosterone-induced changes in cervical cytology in these patients
may result in interpretation errors, especially without a proper clinical history. The aim of this study was to delineate the
Papanicolaou (Pap) test findings in this patient population. METHODS: A pathology laboratory information system was used
to obtain a cohort of FTM transgender patients on testosterone therapy (2009-2019). A cohort of age-matched, atrophic,
control cisgender female patients (postpartum or menopausal) was selected. A retrospective review of the cytomorphologic
findings on cervical Pap smears, pertinent follow-up, and human papillomavirus (HPV) test results was performed. RESULTS:
Fourteen transgender patients (age range, 21-64 years; mean age, 42.5 years) receiving testosterone therapy with 17 Pap
smears were identified. One of the 5 available HPV tests was positive for HPV, and 4 were negative. A Pap smear review
revealed the following: negative for intraepithelial lesion (NILM; 82.4%), unsatisfactory (5.9%), atypical squamous cells of
undetermined significance (ASCUS; 5.9%), and low-grade squamous intraepithelial lesion (5.9%). The Pap smears of the
atrophic cisgender cohort (102 patients) revealed the following: NILM (92.5%), unsatisfactory (0.9%), ASCUS (5.6%), and
high-grade squamous intraepithelial lesion (0.9%). The difference between the rates of epithelial cell abnormality in the 2
cohorts was not statistically significant. Although atrophy was noted in both groups, cytomorphologic findings of transi-
tional cell metaplasia (TCM; 88.2%) and “small cells” (82.4%) were characteristic of the testosterone-treated transgender
cohort. Histologic correlates of TCM and small cells were noted in hysterectomy specimens from 6 patients. CONCLUSIONS:
Small cells and TCM are common cytomorphologic findings in Pap smears of testosterone-treated transgender (FTM)
patients. On the basis of histologic follow-up, small cells most likely represent atrophic parabasal cells of cervical-vaginal
epithelium. Cancer Cytopathol 2020;128:491-498. © 2020 American Cancer Society.
KEY WORDS: Papanicolaou smears; small cells; transgender female-to-male; transitional cell metaplasia.
INTRODUCTION
Transgender individuals represent a diverse population whose assigned sex at birth differs from their current
gender identity or expression. Approximately 0.6% of the US population identifies as transgender or gen-
der-nonconforming.1
Female-to-male (FTM) transgender individuals are anatomically normal females who
identify as male. The goal of the administration of testosterone therapy in these individuals is to induce viriliza-
tion and to stop menses.2
They also have the option of undergoing complete sex reassignment surgery, which
includes hysterectomy, bilateral salpingo-oophorectomy, and mastectomy. However, the majority of FTMs may
not choose to complete sex reassignment surgery or undergo total hysterectomy later in life.3
Corresponding Author: Kamal K. Khurana, MD, Department of Pathology, Upstate Medical University, State University of New York, 750 E Adams St,
Syracuse New York 13210 (khuranak@upstate.edu).
Department of Pathology, Upstate Medical University, State University of New York, Syracuse, New York
This study was presented in part at the 67th Annual Meeting of the American Society of Cytopathology (November 14-17, 2019; Salt Lake City, Utah) and
received the Warren R. Lang, MD, Resident Physician Award for best resident platform presentation.
Received: December 6, 2019; Revised: January 23, 2020; Accepted: February 10, 2020
Published online March 3, 2020 in Wiley Online Library ­
(wileyonlinelibrary.com)
DOI: 10.1002/cncy.22259, wileyonlinelibrary.com
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2. Original Article
492 Cancer Cytopathology July 2020
Data on the prevalence of cervical cancer and cervi-
cal cancer screening in the FTM transgender population
are lacking. However, an FTM transgender with retained
natal reproductive organs, including the cervix, for a con-
siderable period in their lifetime can develop cancer in
these organs. The occurrence of cervical carcinoma in
FTM transgenders has been documented.4,5
Although
the American College of Obstetricians and Gynecologists
recommends following the same screening guidelines for
cisgender females and transgender men with a cervix,
Papanicolaou (Pap) test use in the latter continues to
be lower.6
Psychological issues related to the disconnect
between sex and gender identity, increased anxiety about
undergoing genital examinations, and discomfort asso-
ciated with painful speculum insertion into an atrophic
vagina after long-term androgen administration have
been implicated as barriers to cervical screening in the
FTM transgender population.7,8
There is a lack of literature on Pap test evaluation in
FTM transgender patients and its correlation with histo-
logic findings from hysterectomy specimens. Peitzmeier
et al9
reported a higher rate of unsatisfactory Pap tests in
FTM transgender patients on androgen therapy in com-
parison with cisgender females. A recent study discussed
challenges in detecting dysplasia in the Pap tests of 11
transgender patients.10
Cervical squamous epithelial atrophy and transi-
tional cell metaplasia (TCM) are well-documented his-
topathologic findings in hysterectomy specimens from
FTM transgender patients on testosterone therapy.11,12
Atrophic cervical epithelium composed of “small ba-
sophilic cells” lacking normal maturation has also been
described in this population.12
However, none of these
studies performed a correlation with Pap tests.
This report describes cytologic findings with a spe-
cial emphasis on TCM and “small cells” in cervical smears
from FTM transgender patients on testosterone therapy
at our institution. We also attempted to correlate our
cytologic findings with any available surgical pathology
follow-up to better understand the Pap test findings in
this population.
MATERIALS AND METHODS
The CoPath pathology laboratory information system
was searched for all Pap smear reports for patients on tes-
tosterone therapy or Pap smears for male or transgender
patients between 2009 and 2019. Pap smear slides and
any available surgical pathology follow-up along with
human papillomavirus (HPV) test results on identified
patients were reviewed. The duration of testosterone ther-
apy was obtained from clinical charts. An atrophic control
group composed of menopausal or postpartum cisgender
patients with atrophic changes from 2015 to 2019 was
also selected. Pap smears as well as any surgical pathol-
ogy follow-up on the atrophic control patients were also
reviewed. All Pap smears were evaluated with ThinPrep
Pap tests and were specifically rescreened and reviewed
for the presence or absence of cytologic findings that in-
cluded any specific epithelial cell abnormality, TCM, or
small cells (with scant to absent cytoplasm) that might
correlate with previously described small round cells lack-
ing normal maturation in the atrophic cervical epithelium
of FTM transgender patients.12
The criteria for TCM in
Pap smears has been well described by Weir and Bell,13
and it is characterized by the presence of cohesive sheets
of cells with spindled nuclei that have grooves, tapered
ends, and wrinkled nuclear contours and a perinuclear
halo.13
All Pap smears were rescreened by a cytotechnolo-
gist with 20 years of experience (M.S.), and Pap tests with
cytologic findings (as described previously) were reviewed
by 2 pathologists with 25 years of experience (K.K.K.)
and 7 years of experience (V.K.) and a third-year pathol-
ogy resident (M.W.). Unsatisfactory rates for Pap smears
were also determined on the basis of the total number of
unsatisfactory Pap smears reviewed in each group.
A 2-proportion z test was used to determine whether
there was any significant difference in the cytologic find-
ings as well as unsatisfactory rates in the 2 groups. A sig-
nificance level was established at P < .05. The Spearman
rank correlation coefficient (rs) was calculated to deter-
mine any relationship between the duration of testoster-
one treatment and the presence of any TCM or small cells
in Pap smears of FTM patients. rs can vary from −1 to
+1: +1 indicates perfect agreement on ranks, 0 indicates
no relationship, and −1 indicates a perfect inverse rela-
tionship. A significance level was established at P < .05.
VassarStats software was used for statistical computation.
This study was exempted from institutional board review.
RESULTS
Fourteen FTM transgender patients (age range,
21-64 years; mean age, 42.5 years) with 17 Pap smears
were identified on the basis of our search criteria. All
of these patients were on testosterone treatment, which
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3. 493
Cancer Cytopathology July 2020
Findings of Pap Smears From FTM Patients/Williams et al
ranged from 1 to 13 years in duration (mean, 6.5 years).
The control group was composed of 102 cisgender
patients ranging in age from 22 to 88 years (mean age,
48 years) with 107 Pap smears.
Table 1 compares the Pap test results for the FTM
transgender patients on testosterone therapy with the
atrophic cisgender group. Epithelial cell abnormality rates
(11.8% vs 6.5%) and unsatisfactory rates (5.9% vs 0.9%)
in the 2 groups were not statistically significant.
HPV test results were available for 5 FTM transgen-
der patients. High-risk HPV was detected in 1 patient,
and the results were negative in the remaining 4 patients.
Table 2 reveals the HPV test results and corresponding
cytologic diagnoses for the FTM transgender patients.
Additional Cytologic Findings
In addition to atrophy, 2 characteristic cytologic find-
ings that were frequently encountered in FTM transgen-
der patients on testosterone therapy were small cells and
sheets of cells characteristic of TCM.
Small cells occurred as groups of cells with scant to
absent cytoplasm and a small, grapelike cluster arrange-
ment. The nuclei of these cells exhibited fine, hyperchro-
matic nuclear chromatin, occasional indistinct nucleoli,
and smooth nuclear membranes (Fig. 1A,B). The nu-
clei of these cells were similar to those of surrounding
parabasal cells. These cell were reminiscent of the small
cells that have been described in Pap smears of patients
on tamoxifen therapy14,15
Figure 2A,B shows the mor-
phology of small cells in 2 cisgender patients on tamox-
ifen therapy (a patient from the control group who was
also on tamoxifen therapy and another patient from our
archival files).
Flat sheets of exfoliated cells with oval to spin-
dle-shaped nuclei, powdery chromatin, tapered ends,
small nucleoli, and prominent nuclear grooves (“coffee
bean nuclei”) characterized TCM in Pap smears. The
nuclear size ranged from 1.5 to 3 times the size of an
intermediate nucleus. The cells demonstrated less cyto-
plasm than the squamous metaplastic cells. (Fig. 3A,B).
Table 3 compares the presence of small cells and
TCM in the FTM transgender cohort on testosterone
therapy and the atrophic cohort. Small cells and TCM
were noted in 82.4% and 88.2% of the Pap smears
of FTM transgender patients on testosterone therapy,
respectively. In contrast, the cisgender controls demon-
strated small cells and TCM in 3.7% and 14% of Pap
smears, respectively. These differences were statistically
significant (P < .001). Of the 4 patients in the cis-
gender group with small cells in Pap smears, 1 was on
tamoxifen therapy. Spearman rank correlation did not
show any statistically significant relationship between
the duration of testosterone treatment and the occur-
rence of small cells and TCM in Pap smears of FTM
patients (rs for TCM = −0.02, P > .05; rs for small
cells = 0.1, P > .05).
Histologic Correlation
Hysterectomy with bilateral salpingo-oophorectomy was
available for a retrospective review for 6 cases in the FTM
transgender group. Small cell correlates were seen in the
sections of exocervix. These were composed of groups
and clusters of small basophilic cells with hyperchromatic
round nuclei clinging to the surface of atrophic cervical
epithelium or areas of TCM (Fig. 4A,B).
TABLE 1. Comparison of Papanicolaou Test Results for an FTM Transgender Cohort on Testosterone Therapy
(2009-2019) and an Atrophic Cohort (2018-2019)
Patient Population NILM, % (n/N) Unsatisfactory, % (n/N) ASCUS, % (n/N) LGSIL, % (n/N) HGSIL, % (n/N)
Transgender (FTM) patients 82 (14/17) 5.9 (1/17) 5.9 (1/17) 5.9 (1/17) 0
Cisgender patients 92.5 (99/107) 0.9 (1/107) 5.6 (6/107) 0 0.9 (1/107)
Abbreviations: ASCUS, atypical squamous cells of undetermined significance; FTM, female-to-male; HGSIL, high-grade squamous intraepithelial lesion; LGSIL,
low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion.
The epithelial cell abnormality rates in the 2 groups were not statistically significant (11.8% vs 6.5%). The P value was>.05 for the test for the difference in propor-
tions using the z value.
TABLE 2. HPV Test and Cytomorphologic Diagnoses
in an FTM Transgender Cohort on Testosterone
Therapy
No. HPV Result Pap Test Result
1 Positive NILM
2 Negative NILM
3 Negative NILM
4 Negative ASCUS
5 Negative NILM
Abbreviations: ASCUS, atypical squamous cells of undetermined signifi-
cance; FTM, female-to-male; HPV, human papillomavirus; NILM, negative for
intraepithelial lesion; Pap, Papanicolaou.
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4. Original Article
494 Cancer Cytopathology July 2020
Figure 1. (A,B) Small cells in two different transgender female-to-male patients on testosterone therapy. Small cells have fine,
hyperchromatic nuclear chromatin, occasional indistinct nucleoli, and smooth nuclear membranes. Cytoplasm is scant to minimal
(Papanicolaou stain, ×40).
Figure 2. Small cells in patients who were treated with tamoxifen: (A) a patient from the control group who was also on tamoxifen
therapy and (B) another patient from archival files (Papanicolaou stain, ×40).
Figure 3. (A,B) Transitional cell metaplasia in cervical smears of two different female-to-male patients on testosterone therapy. Note
the longitudinal grooves, elongated oval nuclei, and fine chromatin (Papanicolaou stain, ×40).
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5. 495
Cancer Cytopathology July 2020
Findings of Pap Smears From FTM Patients/Williams et al
Areas of TCM were characterized by hyperplastic
­
epithelium lacking maturation with vertically oriented
nuclei in deeper layers and horizontally oriented nuclei in
a streaming pattern located superficially (Figs. 4B and 5).
The nuclei were spindled with tapered ends and frequently
showed longitudinal nuclear grooves. The nuclear-to-­
cytoplasmic ratio was low. These were seen in the trans-
formation zone. Endometrium was atrophic in all cases.
Table 4 summarizes the correlation of Pap smear
findings with histologic findings from the hysterectomy
specimens. All 6 cases showing TCM and 5 cases with
small cells in Pap smears correlated with histologic find-
ings from the hysterectomy specimens.
In the atrophic control group, histologic follow-up
was available for 5 patients and included 3 cervical biopsies
and 2 endometrial curettage specimens. Corresponding
Pap smears for these cases showed atypical squamous cells
of undetermined significance (3 cases) and atrophy with
reactive changes (2 cases) without any cytologic findings
of TCM or small cells. Cervical biopsies revealed a low-
grade squamous intraepithelial lesion (1 case), a high-
grade squamous intraepithelial lesion (1 case), and no
significant pathology (1 case). An endometrial curettage
specimen revealed a few fragments of histologically unre-
markable endometrial tissue. No areas of TCM or small
blue cells were identified in these cases.
DISCUSSION
In 1939, an isolated case report described atrophic
changes in Pap smears of patients treated with testoster-
one for dysmenorrhea and menorrhagia.16
The literature
on Pap test findings in FTM transgender patients is very
limited. In the current study, we identified small cells
and TCM in 82.4% and 88.2%, respectively, of the Pap
smears from FTM transgender patients on testosterone
therapy. The incidence of small cells (3.7%) and TCM
(14%) was significantly lower in our atrophic control
group. To the best of our knowledge, none of the prior
studies have reported the presence of small cells or TCM
in Pap smears of FTM transgender patients.
TCM is a distinctive benign metaplastic change of
cervical and vaginal epithelium that has the potential for
being misdiagnosed as a high-grade squamous intraepi-
thelial lesion.17,18
A cytologic correlate of TCM has been
previously reported in postmenopausal women who
were not on any exogenous hormone replacement ther-
apy.16
The detection rate of TCM on cervical smears in
this patient population with histologically proven TCM
was 5.5%. In contrast, we found TCM in 88.2% of Pap
smears from the FTM transgender group on testosterone
therapy. Although TCM has been well documented in 2
histopathologic studies of 28 and 32 FTM patients who
underwent hysterectomy after testosterone treatment,
the cytologic correlate of this entity has not been stud-
ied in this population.11,12
In our study, we were able to
demonstrate a cytohistologic correlation of TCM in 6 of
our cases on the basis of a review of sections from hyster-
ectomy specimens.
Cytologically, TCM occurs as cohesive sheets of cells
with spindled nuclei with prominent grooves, tapered
ends, and wrinkled contours, as previously described by
Weir et al.13
Coarse, hyperchromatic chromatin, irregular
nuclear contours, and high nuclear-to-cytoplasmic ratios
are characteristic atypical cytologic features of a high-
grade squamous intraepithelial lesion that allow its dis-
tinction from TCM. These atypical cytologic features are
not identified in TCM.
Ng et al19
reported that TCM was related to HPV in
all 7 cases in their study. Although in 1 of our cases with
HPV-positive results we were able to identify TCM, no
correlation could be established between HPV positivity
and the occurrence of TCM. The role of TCM as a pre-
cursor lesion to a transitional cell neoplasm is not clear.
Whether the FTM transgender population is at increased
risk for transitional cell neoplasms because of an increased
incidence of TCM, as noted in our study, is unknown.
Small cells reported in prior studies of cervical-
vaginal smears of patients treated with tamoxifen have
been considered similar to the reserve cells in atrophic
smears.14,15
However, none of these studies showed a his-
tologic correlate. Opjorden et al15
described small cells in
19% of cervical-vaginal smears of patients treated with
tamoxifen and found no difference in their incidence
TABLE 3. Presence of Small Cells and Transitional
Cell Metaplasia in an FTM Transgender Cohort on
Testosterone Therapy Versus an Atrophic Cohort
Patient Population
Small Cells, %
(n/N)
Transitional Cell
Metaplasia, % (n/N)
Transgender (FTM)
patients
82.4 (14/17) 88.2 (15/17)
Cisgender patients 3.7 (4/107) 14 (15/107)
Abbreviation: FTM, female-to-male.
The rates for small cells and transitional cell metaplasia in the 2 groups were
statistically significant. The P value was <.001 for the test for the difference in
proportions using the z value.
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6. Original Article
496 Cancer Cytopathology July 2020
from patients without tamoxifen. In contrast, in our study
of FTM patients on testosterone, 82.4% of Pap smears
showed these small cells, and this was significantly differ-
ent from the incidence of 3.7% in the atrophic control
group. Furthermore, we were able to show with histologic
correlation of hysterectomy specimens in 5 cases that these
cells represented severely atrophic parabasal cells cling-
ing to areas of TCM or atrophic epithelium in exocervix
sections. Miller et al12
reported similar “small basophilic
cells” lacking maturation and involving atrophic ectocer-
vical mucosa in sections of cervix of FTM patients on
androgen therapy. The presence of endometrial atrophy in
hysterectomy specimens of FTM patients on testosterone
therapy in our study further supports the idea that these
small cells do not represent endometrial cells.
The distinction of small cells from endometrial cells
is of the utmost importance for preventing unnecessary
endometrial biopsies or curettage procedures, especially
in FTM patients who are on testosterone therapy and are
Figure 4. (A) Small basophilic cells with hyperchromatic nuclei clinging to the surface of atrophic cervical epithelium and (B) areas
of transitional cell metaplasia (H & E, ×20).
Figure 5. Transitional cell metaplasia characterized by
hyperplastic epithelium lacking maturation with vertically
oriented nuclei in deeper layers and horizontally oriented
nuclei in a streaming pattern located superficially (H & E, ×20).
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Cancer Cytopathology July 2020
Findings of Pap Smears From FTM Patients/Williams et al
older than 45 years. Compared with cohesive, tridimen-
sional endometrial cells (Fig. 6), small cells have regular
and smooth nuclear contours, lack nuclear grooves, and
usually occur as cellular, loosely arranged aggregates.20
A
history of testosterone therapy is useful clinical informa-
tion for FTM transgender patients that may further aid
in the consideration of small cells instead of endometrial
cells in this population. All FTM patients in our study
had testosterone-induced amenorrhea and did not have
any history of vaginal bleeding.
The duration of testosterone therapy in our study
ranged from 1 to 13 years (mean, 6.5 years).We did not
find any significant relationship between the duration
of testosterone therapy and the presence of TCM and
small cells in Pap smears from FTM patients. One of
the limitations of our study was the lack of hysterectomy
specimens, endometrial biopsies, or cervical biopsies for
patients in the atrophic control group that had TCM and
small cells. The available cervical biopsies in this group
did not show any histologic evidence of TCM or small
round cells. However, prior studies have shown a histo-
logic correlate of TCM in Pap smears from patients who
have not been treated with exogenous hormones.13,17
In summary, we are reporting an increased in-
cidence of small cells and TCM in FTM transgender
patients on testosterone therapy. Because TCM can
be mistaken for a high-grade squamous intraepithelial
lesion, recognition of its characteristic cytologic features
is important, especially in this population, in which the
incidence of TCM is high. On the basis of histologic
follow-up, we have also shown that the small cells repre-
sent severely atrophic parabasal cells. The distinction of
small cells from endometrial cells in FTM patients on
testosterone therapy is important for preventing unnec-
essary invasive procedures, especially in patients older
than 45 years.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
AUTHOR CONTRIBUTIONS
Michael P.A. Williams: Data curation, formal analysis, investiga-
tion, methodology, validation, supervision, resources, software,
visualization, and writing–review and editing. Vinita Kukkar:
Data curation, formal analysis, investigation, methodology, visu-
alization, and writing–review and editing. Melissa N. Stemmer:
Data curation, investigation, resources, and writing–review and
editing. Kamal K. Khurana: Conceptualization, data curation,
formal analysis, investigation, methodology, validation, project
administration, supervision, resources, software, visualization,
writing–original draft, and writing–review and editing.
TABLE 4. Summary of the Correlation of Pap Smear Findings With Histologic Findings From Hysterectomy
Specimens for FTM Patients on Testosterone
No.
Pap Smear Findings for FTM Patients on Testosterone Histologic Findings From Hysterectomy Specimens
Small Cells Transitional Cell Metaplasia Small Cells Transitional Cell Metaplasia Endometrial Pathology
1 — + — + Atrophy
2 + + + + Atrophy
3 + + + + Atrophy
4 + + + + Atrophy
5 + + + + Atrophy
6 + + + + Atrophy
Abbreviations: FTM, female-to-male; Pap, Papanicolaou.
Plus signs indicate present, and minus signs indicate absent.
Figure 6. Endometrial cells characterized by a 3-dimensional
cohesive cluster of cells that tend to be degenerated and often
exhibit nuclear grooves (Papanicolaou stain, ×40).
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8. Original Article
498 Cancer Cytopathology July 2020
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