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Received 19 December 2020; received in revised form 20 January 2021; accepted 22 January 2021
KEYWORDS Introduction It is recommended that female-to-male (FTM) transgender patients with a cervix follow the same
Cervical cancer; cervical cancer screening guidelines as cisgender women. This study analyzes Papanicolaou tests, HPV results, and
HPV; follow-up histology in FTM patients, and compares those results to other atrophic populations at our institution.
Papanicolaou; Materials and methods A cohort of FTM patients receiving androgen therapy was identified through our institu-
Transgender; tion’s translational research database. We collected data on Papanicolaou tests, human papillomavirus (HPV) results,
Cytology follow-up surgical procedures, and duration of androgen therapy. ThinPrep slides were reviewed for cellularity and
cytomorphology. The results of these tests were compared with those of an atrophic control group consisting of post-
partum and postmenopausal cisgender women.
Results We identified 71 FTM patients with 77 Papanicolaou tests collected over 6 years. Papanicolaou interpre-
tations included: negative for intraepithelial lesion (69%), atypical cells of undermined significance (5%), low grade
squamous intraepithelial lesion (1%), atypical glandular cells (1%), and unsatisfactory due to inadequate cellularity
(23%). Five of 27 (18.5%) HPV tests were positive. Follow-up surgical specimens did not identify high-grade le-
sions. Unsatisfactory rates among FTM patients differed significantly from the atrophic group (P < 0.05), while
epithelial abnormality rates and HPV positivity did not (P > 0.05). Most FTM Papanicolaou tests reviewed showed
features of atrophy.
Conclusions FTM patients receiving androgen have high Papanicolaou test unsatisfactory rates secondary to at-
rophy. Epithelial abnormality and HPV rates do not differ significantly from atrophic cisgender patients. Lowering
the cellularity threshold for this population to 2000 like that of other atrophic groups should be considered.
Ó 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.
*Corresponding author: Fang Fan, MD, PhD; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow
Boulevard, Kansas City, KS 66160; Tel.: 626-218-4829; Fax: 626-218-8145.
E-mail address: ffan@coh.org (F. Fan).
2213-2945/$36 Ó 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jasc.2021.01.004
256 R.M. Plummer et al.
interpreted as NILM, 83 (4.2%) as ASC-US, 32 (1.6%) as or THBSOdall of which had no histopathologic abnor-
LSIL, 7 (0.4%) as atypical squamous cells cannot exclude a mality on microscopic examination. Of note, however, tubal
high-grade squamous intraepithelial lesion (ASC-H), 7 metaplasia was noted in the cervix of the THBSO specimen
(0.4%) as high-grade squamous intraepithelial lesion (HSIL), that corresponded to the Papanicolaou test diagnosed as
2 (0.1%) as squamous cell carcinoma, 6 (0.3%) as AGC, 2 AGC. HR-HPV results and corresponding cytomorphologic
(0.1%) as adenocarcinoma (ADCA), 1 (0.1%) as small cell diagnoses are summarized in Table 3. Of the remaining
carcinoma, and 60 (3.0%) as Unsat. Of the Unsat samples, 56 FTM transgender patients who had not undergone HR-HPV
were due to inadequate cellularity, 2 were due to obscuring testing, 2 had a Papanicolaou test interpretation other than
inflammation, and 2 were due to a combination of obscuring Unsat or NILM. One patient with ASC-US proceeded to
inflammation and inadequate cellularity. For a comparison of THBSO, which on microscopic examination had no histo-
Papanicolaou test results between groups, see Table 2. pathologic abnormality. One patient with LSIL had no
HR-HPV testing was performed on 27 of 77 (35%) FTM follow-up specimens for review.
transgender Papanicolaou tests. HR-HPV was detected in 5 Of the 18 FTM Papanicolaou tests interpreted as Unsat, 4
(18.5%) cases. Papanicolaou test diagnoses corresponding had follow-up gender-affirming THBSOdall of which had
to these positive HR-HPV tests included ASC-US (1) and no histopathologic abnormality on microscopic examina-
NILM (4). The patient with ASC-US and positive HPV tion. Five had follow-up Papanicolaou tests performed.
proceeded to colposcopy and cervical biopsy, which resul- Results of follow-up Papanicolaou tests are as follows:
ted in a diagnosis of low-grade squamous intraepithelial Unsat (3), NILM (1), and ASC-US (1). As previously
lesion (CIN1). One HPV-positive patient with a Papanico- mentioned, the patient with ASC-US was tested positive for
laou test diagnosis of NILM proceeded to total hysterec- HR-HPV and proceeded to colposcopy.
tomy with bilateral salpingo-oophorectomy (THBSO), By c2 analysis, the proportion of Papanicolaou tests that
which on microscopic examination had no histopathologic were unsatisfactory for evaluation differed significantly
abnormality. There were no follow-up specimens on the between groups (P < 0.05). The proportion of Papanicolaou
other 3 HPV positive cases. tests with associated positive HR-HPV test results and
Papanicolaou test diagnoses corresponding to the nega- Papanicolaou tests that resulted in an epithelial abnormality
tive HR-HPV tests included ASC-US (2), AGC (1), NILM did not differ significantly between groups (P > 0.05).
(15), and Unsat (4). Of the patients who were tested and Of the 18 FTM Papanicolaou tests interpreted as Unsat,
negative for HR-HPV, 12 had follow-up Papanicolaou tests 17 were available for review. Cellular concentrations ranged
Table 2 Distribution of Papanicolaou test results between FTM patients and CGA patients.
UE NILM Other ASC-US/ASC-H LSIL HSIL SCCA AGC ADCA Any epithelial
abnormality
FTM Patients 23.4% 68.8% n/a 5.2% 1.3% n/a n/a 1.3% n/a 7.8%
(n Z 77) (n Z 18) (n Z 53) (n Z 0) (n Z 4) (n Z 1) (n Z 0) (n Z 0) (n Z 1) (n Z 0) (n Z 6)
CGA Patients 3.0% 89.9% 0.1% 4.6% 1.6% 0.4% 0.1% 0.3% 0.1% 7.2%
(n Z 1974) (n Z 60) (n Z 1775) (n Z 1) (n Z 90) (n Z 32) (n Z 7) (n Z 2) (n Z 6) (n Z 2) (n Z 140)
Abbreviations: ADCA, adenocarcinoma; AGC, atypical glandular cells; ASC-H, atypical squamous cells cannot exclude a high-grade squamous intraepithelial
lesion; ASC-US, atypical squamous cells of undermined significance; CGA, cisgender atrophic; FTM, female-to-male; HSIL, high-grade squamous intraepi-
thelial lesion; LSIL low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy; Other, small cell carcinoma; SCCA,
squamous cell carcinoma; UE, unsatisfactory for evaluation.
258 R.M. Plummer et al.
from 628.3 to 4298.9 squamous and metaplastic cells per rates of cervical cancer screening owing at least in part to
slide. Five of the 17 cases had a cellular concentration perceived discrimination and the significant emotional and
>2000 cells. None of the Unsat Papanicolaou tests had an psychological burden that accompanies the procedure. As
identifiable epithelial abnormality. such, these patients are less likely to return for follow-up
Sixty-eight of the 77 FTM cases were available for re- after an unsatisfactory Papanicolaou test result.5,6 Of the
view of cytomorphologic features. Features encompassing FTM patients in this study with an unsatisfactory Papani-
atrophy were identified in 93% of FTM ThinPrep slides colaou test, 9 (50%) did not have a follow-up Papanicolaou
reviewed (Fig. 1). These features included a preponderance test within the 2-4 month interval recommended.4
of parabasal/basal cells (81%), autolysis (26%), decreased Although current Bethesda guidelines recommend that a
cellularity (31%), and transitional cell metaplasia (21%). minimum of 5000 well-visualized squamous or squamous
Inflammation and reactive/reparative changes were noted in metaplastic cells be present on a liquid-based preparation in
41% and 34% of cases reviewed, respectively. All epithelial order to be considered adequate, allowances are given to certain
lesion diagnoses were noted and confirmed. Of note, 1 case patient populations. Papanicolaou tests from patients who have
in which ASCUS was diagnosed featured abundant transi- received chemotherapy or radiation therapy, have a surgically
tional cell metaplasia, a previously documented feature by absent cervix, or have post-menopausaleinduced atrophy are
Williams et al. that can be seen in Papanicolaou test slides often not held to the same strict 5000 cell threshold with lower
from FTM patients and a known cytomorphologic pitfall.9 degrees of cellularity considered acceptable based on the
assumption that low cellularity specimens from these patients is
Discussion relatively unavoidable.14-16 Indeed, studies have shown that
adhering to strict adequacy standards pertaining to specimen
Cervical Papanicolaou tests are a major challenge for FTM cellularity leads to high unsatisfactory rates.15 Moreover, the
transgender patients. Although necessary to detect cervical scientific evidence from which the 5000-cell threshold is based
intraepithelial neoplasia, FTM patients often have lower is relatively limited.17,18
Papanicolaou tests in the female-to-male transgender population 259
Figure 1 Examples of changes associated with atrophy from female-to-male transgender patients. (A) Low power show preponderance of
parabasal/basal cells. (B) High power showing transitional cell metaplasia. (C) High power showing autolysis. (D) High power showing reac-
tive/reparative changes.
As seen in other studies that looked at cytomorphologic designated Unsat in both FTM and CGA patients in our study
findings of Papanicolaou tests in FTM patients receiving were overwhelmingly designated as such due to inadequate
androgen therapy, the patients in our study showed atrophic cellularity, one must ask about the large discrepancy in un-
changes similar to those seen in other atrophic groups.7,9 satisfactory rates between the groups. The requisition forms
However, in our study, compared with CGA patients, that accompany Papanicolaou tests at our institution offer the
FTM patients were 7.8 times more likely to have unsatis- option to select whether a patient is post-therapy (radiation or
factory Papanicolaou tests (3.0% versus 23.4%). Similar chemotherapy), but they do not offer the option to designate
studies that looked at Papanicolaou test results among FTM your patient as receiving androgen therapy. In addition to
patients found unsatisfactory rates that ranged from 5.9% to this, among the 71 FTM patients in this study, 45 (63%) were
13%.5,7,9 These studies attribute such levels of unsatisfac- designated as female within CoPathPlus. Of those with Unsat
tory rates to use of lubricant, physical changes induced by Papanicolaou tests, 11 (61%) were from FTM patients
testosterone therapy, and provider/patient discomfort with designated as a female in CoPathPlus. The cytotechnologists
the exam.5,8 Rates of epithelial abnormality within FTM that screen the Papanicolaou tests account for a patient’s
patients in our study did not differ significantly from those post-therapy status and adjust their threshold for adequate
seen in the CGA patients (7.8% versus 7.2%) and were cellularity accordingly whereas FTM transgender patients are
similar to those detected in other studies that looked at not given the same dispensation. Indeed, if FTM patients in
Papanicolaou test results in FTM transgender patients (7.8% this study were held to the same amended cellularity standard
versus 6%-30%).5,7,9 Additionally, of the 23 patients that as the postmenopausal and postpartum patients (>2000 well-
had follow-up surgical specimens in our study, only 1 had preserved/well-visualized squamous and metaplastic cells per
evidence of intraepithelial neoplasia (CIN1). preparation), 5 additional Papanicolaou tests would have
Cytomorphologic features encompassing atrophy were been considered adequate, which would have reduced the
seen in 93% of FTM cases reviewed. Given similar atrophic unsatisfactory rate from 23.4% to 16.9%.
cytomorphologic findings between FTM patients and other Additionally, this study looked at HPV test results. The
CGA patients,13 and given that those Papanicolaou Tests prevalence of HR-HPV within FTM patients (18.5%) was
260 R.M. Plummer et al.
higher than the prevalence within the CGA patients (8.9%) transgender females: implications for cervical cancer screening. J
and the age matched general non-atrophic population Gen Intern Med. 2014;29:778e784.
6. Peitzmeier SM, Agénor M, Bernstein IM, et al. “It can promote an exis-
(9.3%), but not in a statistically significant manner. The tential crisis”: factors influencing papanicolaou test acceptability and
median age of the patients within the FTM group was 26 utilization among transmasculine individuals. Qual Health Res. 2017;
years of age. Of those tested for HPV, patient age ranged 27:2138e2149.
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However, the prevalence of HR-HPV in FTM patients in DNA testing in female-to-male trans masculine patients. PLoS One.
our study is slightly higher than that detected among FTM 2018;13:1e21.
patients in other studies (18.5% versus 13%-16%).8 9. Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorpho-
logic findings of cervical Papanicolaou smears from female-to-male
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