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480 Other Epithelial Tumors
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Other Epithelial Tumors (Adenosquamous Carcinoma, Mucoepidermoid Carcinoma, Adenoid Basal
Carcinoma, Adenoid Cystic Carcinoma), Pathology of
the Cervix, Fig. 3 Adenoid basal carcinoma of the cer-
vix. Infiltrative nests of basaloid cells are accompanied by
areas of squamous differentiation (low power)
Other Epithelial Tumors (Adenosquamous Carcinoma, Mucoepidermoid Carcinoma, Adenoid Basal
Carcinoma, Adenoid Cystic Carcinoma), Pathology of
the Cervix, Fig. 4 Adenoid basal carcinoma of the cer-
vix. Infiltrative nests of basaloid cells are accompanied by
areas of squamous differentiation (high power)
even carcinosarcoma. Complete removal and
examination of the lesion are needed to rule out
the presence of an adjacent high-grade carcinoma.
Immunophenotype
The tumor cells are positive for p16 (block-like)
and p63. The basaloid cells are positive for
CAM5.2, which is helpful when they become
attenuated or obscured by the central squamous
cells, which will be negative for CAM5.2 (Fig. 7).
Molecular Features
None.
Other Epithelial Tumors (Adenosquamous Carcinoma, Mucoepidermoid Carcinoma, Adenoid Basal
Carcinoma, Adenoid Cystic Carcinoma), Pathology of
the Cervix, Fig. 5 Adenoid basal carcinoma of the cer-
vix. Lobular clusters of basaloid cells separated by
unaltered endocervical stroma
Other Epithelial Tumors (Adenosquamous Carcinoma, Mucoepidermoid Carcinoma, Adenoid Basal
Carcinoma, Adenoid Cystic Carcinoma), Pathology of
the Cervix, Fig. 6 Adenoid basal carcinoma of the cer-
vix. The areas of squamous differentiation can show cytologic atypia
Differential Diagnosis
Adenoid basal carcinoma should be distinguished
from adenoid basal hyperplasia, which is a nonneoplastic proliferation of reserve cell origin. Adenoid basal hyperplasia is a superficial lesion
(<1 mm depth) which retains connection with the
overlying surface epithelium and lacks infiltrative
growth.It isnegative for p16 and HPV (Goyal et al.
2016). Adenoid basal hyperplasia almost never
shows squamous cells, while adenoid basal carcinoma typically does (Kerdraon et al. 2012).
Adenoid cystic carcinoma is another neoplasm
of the cervix which is made of basaloid cells. The
Other Epithelial Tumors 481
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Definition
Adenoid cystic carcinoma is an uncommon malignant neoplasm that arises from secretory glands
and forms a distinct histologic appearance, with
basaloid cells forming cribriform, tubular, and
solid architecture admixed with basement membrane material.
Clinical Features
• Incidence
Other Epithelial Tumors (Adenosquamous Carcinoma, Mucoepidermoid Carcinoma, Adenoid Basal
Carcinoma, Adenoid Cystic Carcinoma), Pathology of
the Cervix, Fig. 7 Adenoid basal carcinoma of the cer-
vix. CAM5.2 stains the basaloid cells diffusely, and in the
areas of squamous differentiation, stains a rim around the
nests
Adenoid cystic carcinoma is rare, constituting
<1% of cervical cancers. Some studies suggest
higher rates in women with high parity and
those of African descent.
• Age
The majority are postmenopausal, but a wide
age range has been reported (30–70 years of
cells in adenoid cystic carcinoma, however, are
higher grade, with enlarged nuclei, conspicuous
mitotic activity, necrosis, desmoplastic stroma,
and lymphovascular and perineural invasion
(Ferry and Scully 1988). They will form cribriform and solid patterns and usually have conspicuous basement membrane deposition, which is
usually negligible in adenoid cystic carcinoma.
Adenoid cystic carcinoma tends to be positive
for CD117, while adenoid basal carcinoma is not
(Chen et al. 2012).
The squamous cells fill the nests of adenoid
basal carcinoma, which can be misinterpreted as
invasive squamous cell carcinoma. The nests in
adenoid basal carcinoma will have smooth contours, be rimmed by CAM5.2 positive basaloid
cells, and lack stromal desmoplasia. Basaloid
squamous cell carcinoma will also show diffuse,
block-like p16 positivity throughout, but will tend
toward high-grade nuclear features and stromal
desmoplasia. Basaloid squamous cell carcinoma
is also more strongly positive for CK7, CK17, and
Ber-EP4 (Shi et al. 2020).
age).
• Sex
Female for the uterine cervix. Both genders are
affected at other sites, such as the salivary
gland.
• Site
The cell of origin has been hypothesized to
be reserve cells of the transformation zone of
the cervix, and most tumors occur in the
cervical transformation zone. These tumors
are more commonly found in the salivary
glands and respiratory tract, but they can
occur in any organ with a secretory gland
component (br east, vulva, prostate, and lacrimal glands).
• Treatment
A complete excision is needed to ensure
removal of the lesion and exclude an adjacent
high-grade carcinoma component.
• Outcome
The prognosis is poor, as approximately 50%
of patients will experience local recurrences or
distant metastases. Metastases to the lung are
the most common site of distant spread (Musa
et al. 1985).
Adenoid Cystic Carcinoma
Synonyms
Adenocystic carcinoma.
Macroscopy
An ill-defined friable mass can be seen in the
uterine cervix.
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and have shown variable expression for
myoepithelial markers S100, HHF35, and MSA.
CD117 (cKIT) is positive like in other sites, but it
can be focal. They are negative for ER and
PR. p16 is variable; some cases associated with
high-risk human papillomavirus infection show
block-like positivity for p16 (Shi et al. 2015).
One study has shown nuclear positivity for
MYB. The basement membrane material is positive for type IV collagen, laminin, and period acid
Schiff stains.
Other Epithelial Tumors (Adenosquamous Carcinoma, Mucoepidermoid Carcinoma, Adenoid Basal
Carcinoma, Adenoid Cystic Carcinoma), Pathology of
the Cervix, Fig. 8 Adenoid cystic carcinoma, comprising
of basaloid cells forming nested and trabecular architecture
Molecular Features
The characteristic NFIB-MYB gene rearrangement
documented in adenoid cystic carcinomas at other
anatomical sites has not yet been documented in
the cervix (Shi et al. 2015).
Microscopy
This tumor has a characteristic histologic appearance encompassing basaloid cells forming cribriform, nested, trabecular, corded, and solid
One case report of mixed adenoid cystic carcinoma and neuroendocrine carcinoma had alterations in FGFR2 and a FGFR2-TACC2 fusion
(Gill et al. 2020, p. 2).
architecture (Fig. 8). Basement membrane material is conspicuous and found in the acini or in
between the tumor cells. In the early descriptions
of these tumors, they were referred to as
cylindromas due to the appearance of cylinders
or bands of hyaline stroma which was separated
by cords of small basaloid cells. In the nested
pattern, there can be palisading of cells at the
periphery. Rarely, focal keratinization can be
seen. Desmoplastic or fibroblastic stromal reaction can be seen and approximately half of tumors
will show perineural invasion.
A subset of tumors are associated with HPV
and have been found to have an associated highgrade squamous intraepithelial lesion (HSIL).
Some tumors can be mixed with a component
of adenoid basal carcinoma, or another highergrade carcinoma, such as squamous cell carcinoma, small cell neuroendocrine carcinoma,
and carcinosarcoma. The most common
admixed h igh-grad e carcinoma is squamous
cell carcinoma.
Differential Diagnosis
Adenoid cystic carcinoma has been found to exist
in association with adenoid basal carcinoma. Due
to their overlapping immunoprofiles, some have
hypothesized that adenoid basal carcinoma may
be the substrate or precursor of adenoid cystic
carcinoma and that both share a common cell of
origin, but this has yet to be subst antiated
(Grayson et al. 1999). Distinction between the
two entities is important, beca use adenoid basal
carcinoma is clinically indolent while adenoid
cystic carcinoma is biologically aggressive. Adenoid cystic carcinoma usually has a grossly visible
mass, nuclear atypia, desmoplastic stromal
response, lymphovascular, and perineural invasion. One paper suggests that CD117 may also
be a helpful marker, being negative in most adenoid basal carcinomas (Chen et al. 2012).
Basaloid squamous cell carcinoma can show
overlapping features, p63 positivity, and association with HSIL. These tumors tend to show areas
of more conventional squamous cell carcinoma
Immunophenotype
They are positive for keratin and MNF116, and
demonstrate variable expression of CK7, CEA,
and EMA. They are positive for p63 and p40
and strong positivity for CK7 and Ber-EP4.
Small cell neuroendocrine carcinoma also
comprises of basaloid-like cells, but it shows conspicuous nuclear atypia, apoptotic debris, and
Other Epithelial Tumors, Pathology of the Vagina 483
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mitotic activity. It will also be positive for neuroendocrine markers, such as synaptophysin and
chromogranin.
References and Further Reading
Brainard, J. A., & Hart, W. R. (1998). Adenoid basal
epitheliomas of the uterine cervix: A reevaluation of
distinctive cervical basaloid lesions currently classified
as adenoid basal carcinoma and adenoid basal hyperplasia. The American Journal of Surgical Pathology,
22, 965–975.
Chen, T.-D., Chuang, H.-C., & Lee, L. (2012). Adenoid
basal carcinoma of the uterine cervix: Clinicopathologic features of 12 cases with reference to CD117
expression. International Journal of Gynecological
Pathology, 31,25–32.
Ferry, J. A., & Scully, R. E. (1988). ‘Adenoid cystic’
carcinoma and adenoid basal carcinoma of the uterine
cervix. A study of 28 cases. The American Journal of
Surgical Pathology, 12, 134–144.
Gill, C. M., et al. (2020). Histology-specific FGFR2 alter-
ations and FGFR2-TACC2 fusion in mixed adenoid
cystic and neuroendocrine small cell carcinoma of the
uterine cervix. Gynecologic Oncology Reports, 34,
100668.
Goyal, A., Wang, Z., Przybycin, C. G., & Yang, B. (2016).
Application of p16 immunohistochemistry and RNA in
situ hybridization in the classification of adenoid basal
tumors of the cervix. International journal of gyneco-
logical pathology, 35 ,82–91.
Grayson, W., Taylor, L. F., & Cooper, K. (1999). Adenoid
cystic and adenoid basal carcinoma of the uterine cervix: Comparative morphologic, mucin, and immunohistochemical profile of two rare neoplasms of putative
‘reserve cell’ origin. The American Journal of Surgical
Pathology, 23, 448–458.
Kerdraon, O., Cornélius, A., Farine, M.-O., Boulanger, L.,
& Wacrenier, A. (2012). Adenoid basal hyperplasia of
the uterine cervix: A lesion of reserve cell type, distinct
from adenoid basal carcinoma. Human Pathology, 43,
2255–2265.
Lennerz, J. K. M., Perry, A., Mills, J. C., Huettner, P. C., &
Pfeifer, J. D. (2009). Mucoepidermoidcarcinoma of the
cervix: Another tumor with the t(11;19)-associated
CRTC1-MAML2 gene fusion. The American Journal
of Surgical Pathology, 33, 835–843.
Longatto-Filho, A., et al. (2009). Molecular characteriza-
tion of EGFR, PDGFRA and VEGFR2 in cervical
adenosquamous carcinoma. BMC Cancer, 9, 212.
Musa, A. G., Hughes, R. R., & Coleman, S. A. (1985).
Adenoid cystic carcinoma of the cervix: A report of
17 cases. Gynecologic Oncology, 22, 167–173.
Shi, X., et al. (2015). Co-existing of adenoid cystic
carcinoma and invasive squamous cell carcinoma
of the uterine cervix: A report of 3 cases with
immunohistochemical study and evaluation of
human papillomavirus status. Diagnostic Pathology,
10, 145.
Shi, H., et al. (2020). A clinicopathological and molecular
analysis of cervical carcinomas with basaloid features.
Histopathology, 76, 283–295.
Stewart, C. J. R., Koay, M. H. E., Leslie, C., Acott, N., &
Leung, Y. C. (2018). Cervical carcinomas with a micro-
papillary component: A clinicopathological study of
eight cases. Histopathology, 72, 626–633.
Stolnicu, S., et al. (2019). Cervical adenosquamous carci-
noma: Detailed analysis of morphology, immunohisto-
chemical profile, and clinical outcomes in 59 cases.
Modern Pathology, 32, 269–279.
Thelmo, W. L., et al. (1990). Mucoepidermoid carcinoma
of uterine cervix stage IB. Long-term follow-up, histo-
chemical and immunohistochemical study. Interna-
tional Journal of Gynecological Pathology, 9,
316–324.
Yordanov, A., et al. (2020). Mucoepidermoid carcinoma of
the uterine cervix-single-center study over a 10-year
period. Medicina (Kaunas, Lithuania), 56, 37.
Other Epithelial Tumors,
Pathology of the Vagina
Raji Ganesan
Birmingham Women’s and Children’s NHS Trust,
Birmingham, UK
O
Tubulosquamous Polyp
Definition
It is a polyp composed of benign squamous and
tubular elements in a collagenous stroma. They are
believed to be derived from misplaced periurethral
Skene glands (Kelly et al., 2011; Roma 2016).
Clinical Features
They present as polyps or cysts and can be found
incidentally (Kelly et al., 2011).
• Incidence
They are rare lesions.
• Age
There is a wide age range; reported between
39 and 78 years (McCluggage & Young 2007).
• Site
Commonly in the upper vagina.
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• Treatment
Local excision.
• Outcome
Likely benign.
Macroscopy
These are small polyps with a solid cut surface.
Microscopy
There are well-circumscribed nests of squamous
cells with small tubules at the periphery. These are
embedded in a hypocellular fibrous stroma. The
tubules are lined by bland cells which are sometimes bilayered.
Immunophenotype
The inner layer of the tubules is variably
stained with prostate-specific immunohistochemical markers (PSA, PAP, NKX3-1). The
squamous cells stain with GATA 3 and p63
(Roma, 2016).
Differential Diagnosis
The morphology and immunohistochemical
results are distinctive (Fig. 1).
Mullerian Papilloma
Definition
It is a papillary, surface or intramural tumor of the
vagina that is lined by Mullerian type epithelium
(McCluggage et al., 1999).
Clinical Features
Commonly presents with vaginal bleeding
(Tumini et al., 2010).
• Incidence
Rare.
• Age
Most cases are seen in prepubertal females
(McQuillan et al., 2016).
• Site
Lower part of the vagina.
• Treatment
Surgical excision.
• Outcome
In most cases, surgical excision is curative.
Recurrences, including multiple recurrences
and malignant transformation, have been
reported (Dudič et al., 2019).
Macroscopy
Surface lesions show a friable polypoid appearance whilst intramural masses have a solid-cystic
appearance.
Microscopy
They are exophytic or intramural lesions with a
papillary architecture composed of slender fibrovascular cores lined by non-atypical, cuboidal, or
columnar epithelium. Mitoses are usually absent.
Differential Diagnosis
Polypoid lesi ons as discussed in the villous adenoma section (Fig. 2).
Other Epithelial Tumors, Pathology of the Vagina,
Fig. 1 (a) Tubulosquamous polyp showing a well-
circumscribed nest of squamous cells. (b) Peripheral
glands are appreciated on deeper levels. On immunohistochemistry, the cells are positive for PSA
Other Epithelial Tumors, Pathology of the Vagina 485
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Other Epithelial Tumors, Pathology of the Vagina,
Fig. 2 (a) A low power view showing an exophytic
vaginal tumor with a villous and glandular architecture.
Villous Adenoma
Synonym
Adenomatous polyp; Intestinal-type adenoma;
Tubulovillous adenoma.
Definition
This is a benign glandular tumor of the villous
and/or tubular structures. These are lined by
pseudostratified, intestinal type, columnar
epithelium.
Clinical Features
The commonest presentation is with vaginal
bleeding or vaginal mass.
• Incidence
These are rare vaginal lesions.
• Age
These lesions have been described in adult
women of all ages.
• Site
These have no predilection for any particular
part of the vagina (Staats et al., 2014).
• Treatment
Surgical removal.
• Outcome
Information is limited. Some cases have been
known to recur (Staats et al., 2014). One adenoma with high grade dysplasia progressed to
adenocarcinoma and another associated with
late development of tubulovillous adenoma of
the vulva (Shuangshoti & Teerapakpinyo 2019).
(b) The villous structures are lined by pseudostratified,
intestinal type, columnar epithelium with mild dysplasia
Macroscopy
They present as polypoid masses ranging from 0.9
to 3 cm in size (Peña-Fernández et al., 2013).
Microscopy
These are polyps that have villous structures at the
surface and tubular structures more often seen at
the base. These are lined by columnar epithelium
with pseudostratified hyperchromatic nuclei,
often containing scattered goblet cells. High
grade nuclear and/or architectural atypia may be
present and such cases should be assessed using
the criteria applicable to colorectal adenomas
(Staats et al., 2014).
Immunophenotype
They show a CK20 positive, CDX2 positive profile. CK7 positivity, if present, is patchy.
Molecular Features
KRAS and APC gene mutations have been
described in one case (Shuangshoti &
Teerapakpinyo 2019).
Differential Diagnosis
Mullerian papillomas, polypoid endometriosis,
and prolapsed fallopian tubes may all present as
polypoid tumors. However, villous adenoma is
lined exclusively by mucinous epithelium in
contrast to the other entities. A diagnosis of a
villous adenoma should not be made in very
superficial biopsies. Making this diagnosis in
the absence of the base may result in missing an
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invasive adenocarcinoma with a superficial villous pattern.
Mixed Tumor
Synonyms
Spindle cell epithelioma (not recommended
by WHO).
Definition
These are benign tumors that contain spindle and
epithelial elements; the latter may be glandular or
squamous in type.
Clinical Features
Most patients are asymptomatic or have mass
related symptoms (Branton & Tavassoli 1993).
• Incidence
Rare.
• Age
Wide age range.
• Site
Distal vagina, near the hymen.
• Treatment
Surgical removal.
• Outcome
Benign.
Macroscopy
They are soft, rubbery, and well-circumscribed
masses.
Microscopy
The tumors are composed of a mixture of spindled
and epithelial cells. The spindle cell component is
arranged in corded, reticular, or nested patterns
and is distinct from the epithelial component that
is usual ly keratinizing squamous or mucinous
glandular in type. The stroma may be loose or
collagenous and may contain eosinophilic hyaline
material (Oliva et al., 2004). Mitotic activity is
generally absent.
Immunophenotype
There is coexpression of epithelial (CK7, EMA,
AE1/AE3) and mesenchymal markers (SMA,
Desmin, H-caldesmon, CD10) as well as WT1,
calretinin, CD34, and BCL2 (Berdugo et al.,
2015). The spindle cells exhibit strong staining
with epithelial markers.
Differential Diagnosis
The presence of spindle cells and positive staining
with mesenchymal markers instigate a differential
diagnosis of smooth muscle and endometrial stromal tumors. The strong diffuse expression of epithelial markers and other markers such as
calretinin and CD34, and the presence of
intermingled epithelial elements argue against
these differentials. The presence of epithelial and
stromal components raises the possibility of carcinosarcoma as a differential diagnosis. However,
mixed tumors of the vagina do not show atypia or
mitotic activity that is consistently seen in carcinosarcomas (Fig. 3).
Other Epithelial Tumors, Pathology of the Vagina,
Fig. 3 (a) Well-circumscribed tumor located beneath the
squamous epithelial lining of the vagina. (b) Higher power
view shows inactive stromal cells with scanty, clear cytoplasm, round to spindled nuclei. (c) In some cases, small
squamous foci maybe seen
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References and Further Reading
Berdugo, J., Gauthier, P., Provencher, D., Matte, C., Piché,
J., & Rahimi, K. (2015).Spindle cellEpithelioma of the
vagina: Report of two cases, literature review, and new
immunohistochemical markers. International Journal
of Surgical Pathology, 23(8), 677–681.
Branton, P. A., & Tavassoli, F. A. (1993). Spindle cell
epithelioma, the so-called mixed tumor of the vagina.
A clinicopathologic, immunohistochemical, and ultrastructural analysis of 28 cases. American Journal of
Surgical Pathology, 17(5), 509–515.
Dudič, R., Dudičová, V., & Urdzík, P. (2019). The rare
cause of childhood bleeding – Recurrent Müllerian
papilloma. Journal of Obstetrics and Gynaecology,
39, 432–433.
Kelly, P., McBride, H. A., Kennedy, K., Connolly, L. E., &
McCluggage, W. G. (2011). Misplaced Skene’s glands:
Glandular elements in the lower female genital tract
that are variably immunoreactive with prostate markers
and that encompass vaginal tubulosquamous polyp and
cervical ectopic prostatic tissue. International Journal
of Gynecologic Pathology, 30(6), 605–612.
McCluggage, W. G., & Young, R. H. (2007). Tubulo-
squamous polyp: A report of ten cases of a distinctive
hitherto uncharacterized vaginal polyp.American Jour-
nal of Surgical Pathology, 31(7), 1013–1019.
McCluggage, W. G., Nirmala, V., & Radhakumari,
K. (1999). Intramural müllerian papilloma of the
vagina. International Journal of Gynecological Pathol-
ogy, 18,94–95.
McQuillan, S. K., Grover, S. R., Pyman, J., & Jayasinghe,
Y. L. (2016). Literature review of benign Müllerian
papilloma contrasted with vaginal rhabdomyosarcoma.
Journal of Pediatric and Adolescent Gynecology, 29,
333–337.
Oliva, E., Gonzalez, L., Dionigi, A., & Young, R. H.
(2004). Mixed tumors of the vagina: An immunohisto-
chemical study of 13 cases with emphasis on the cell of
origin and potential aid in differential diagnosis. Mod-
ern Pathology, 17(10), 1243–1250.
Peña-Fernández, M., Abdulkader-Nallib, I., Novo-
Domínguez, A., Turrado-Sánchez, E. M., Brea-
Fernández, A., Sebio-Lago, L., Ruíz-Ponte, C., &
Cameselle-Teijeiro, J. (2013). Vaginal tubulovillous
adenoma: A clinicopathologic and molecular study
with review of the literature. International Journal of
Gynecological Pathology, 32, 131–136.
Roma, A. A. (2016). Tubulosquamous polyps in the
vagina. Immunohistochemical comparison with
ectopic prostatic tissue and skene glands. Annals of
Diagnostic Pathology, 22,63–66.
Shuangshoti, S., & Teerapakpinyo, C. (2019).
Tubulovillous adenoma of vagina with both KRAS
and APC mutations: Case report. International Journal
of Gynecological Pathology, 38(5), 498–501.
Staats, P. N., McCluggage, W. G., Clement, P. B., &
Young, R. H. (2014). Primary intestinal-type glandular
lesions of the vagina: Clinical, pathologic, and immu-
nohistochemical features of 14 cases ranging from
benign polyp to adenoma to adenocarcinoma. Ameri-
can Journal of Surgical Pathology, 38(5), 593–603.
Tumini, S., Carinci, S., Anzellotti, M. T., Chiesa, P. L. L.,
Rossi, C., Stuppia, L., Bertelloni, S., & Chiarelli,
F.(2010). Genital sanguineousdischarge in prepuberty:
A case of mullerian papilloma of vagina in a nine-year-
old girl. Journal of Pediatric Endocrinology and
Metabolism, 23, 831–832.
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Pap Test, Pathology of the
Cervix
Vaishali Pansare
Department of Pathology, Corewell Health East
Beaumont Troy and Grosse Pointe, Grosse Pointe,
MI, USA
Department of Pathology and Laboratory
Medicine, OUWB School of Medicine,
Rochester, MI, USA
Introduction and Statistics
“The Pap Test,” traditionally known as The Pap
smear, derives its name from its inventor, George
N. Papanicolaou. Papanicolaou, an anatomist,
was studying hormonal maturation of the vaginal
mucosa and accidentally stumbled upon some
malignant cells. He published his work in 1928
describing cancer detection in smears collected
from the vagina. “The first observation of cancer
cells in the smear of the uterine cervix gave me
one of the greatest thrills I ever experienced during my scientific career,” he later recalled (Barter
1992; Vilos 1998). However, this was received
with much skepticism by the medical community
as he presented his findings at a Conference in
Michigan on January 4, 1928, reading a paper
entitled “New cancer diagnosis” (Papanicolaou
1928). Dr. Papanicolaou then collaborated with a
gynecologist, Herbert Traut, and published the
historic paper “The diagnostic value of vaginal
smears in carcinoma of the uterus” in 1941
(Papanicolaou and Traut 1941). This gained
much recognition and Pap Smear was eventually
adopted as a screening test for cervical cancer
detection. A noninvasive and relatively simple
method of cancer detection, Pap Test revolutionized early detection of cervical cancer.
After its adoption for routine screening purposes, incidence of cervical cancer showed a significant decline in late 1940s. Figure 1 shows
steady decline in the incidence of cervical cancer
in the USA from 1975 to 2005. Currently in the
USA, there are approximately 13,000 new cervical cancer cases each year and 4000 deaths (Siegel
et al. 2017) (Fig. 2). Worldwide, cervical cancer
ranks fourth for both incidence and mortality
(>500,000 cases and 300,000 deaths annually);
with an estimated more than 600,000 new cases in
2020 (Bray et al. 2018) (IARC data). The lack of
routine cervical cancer screening due to limited
resources in developing countries is primarily the
cause of this high incidence worldwide.
Screening Guidelines
Pap Test screening is part of the routine physical
examination in the USA (Safaeian et al. 2007).
Prior to HPV DNA testing, Pap Test alone was
done annually for routine screening. The current
screening guidelines include Pap Test alone, high
risk HPV DNA testing (HPV) alone, or a combination of both. Current guidelines are
© Springer Nature Switzerland AG 2023
S. Stolnicu, R. Ali-Fehmi (eds.), Gynecologic Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-030-97378-0
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15
14
13
12
11
10
9
(per 100, 000 women)
8
Cervical Cancer Incidence Rate
7
0
1975 1980 1985 1990 1995 2000 2005
Year
Pap Test, Pathology of the Cervix, Fig. 1 Incidence of cervical cancer in the US from 1975 to 2005. (Adopted from
SEERS Cancer statistics Review)
recommended by the US Preventive Services
Task Force (USPSTF 2018), American College
of Obstetricians and Gynecologists (ACOG)
(ACOG 2012) and a consortium of the American
Cancer Society (ACS), American Society of Cervical Cytology and Colposcopy (ASCCP 2012
with modification added in 2015), and American
Society of Clinical Pathology (ASCP) (Saslow
et al. 2012). The overall guidelines by these different entities are similar and are listed below.
Cervical cancer screening guidelines in the
USA:
Women less than 19 years old:
No screening.
Women aged 21–29 years:
Screening with Cytology (Pap Test) is
recommended. High risk HPV testing (HPV) is
not recommended.
Women aged 30–65 years:
Cotesting (Cytology plus hrHPV testing) every
5 years is preferred.
Alternate approaches would be to do Cytology
every 3 years or primary HPV every 5 years. If
only primary hrHPV is performed, further management is based on HPV 16 and 18 results.
Women over 65 years:
No screening necessary following adequate
prior negative screening history*.
Women after hysterectomy:
No screening is necessary for women who
have undergone complete hysterectomy
(removal of cervix) and adequate prior negative
screening history*.
*Adequate negative screening history refers to
cervical intraepithelial neoplasia 2 (CIN 2) and
higher lesions in past 20 years.
Sampling and Preparation Methods
Prior to 1996, conventional smears (CS) were
made by the physician in his/ her office, where
the cervical scrape was smeared onto the glass
slides and immediately spray fixed. As expect ed,
this heavily operator-dependent technique introduced problems such as clumping of cells due to
inadequate smearing, improper fixation or drying
before fixative spray was applied.
Liquid-based cytology (LBC) was introduced in
1996 with the FDA approval of Thin Prep Hologic
for cervical cytology (https://www.fda.gov/medical-
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