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46 Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix
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(microglandular-like endometrioid adenocarcinoma). However, at microscopic examination,
this tumor displays cytologic atypia (even sometimes mild), m itotic figures, areas of more characteristic endometrioid adenocarcinoma with
stromal foamy macrophages, and areas of squamous metaplasia (which are superficially
located, in contrast to basal location i n microglandular hyperplasia) (Qiu and Mittal 2003).
Patient’s age is also important since microglandular hyperplasia occurs in reproductiveage women, while endometrial endometrioid
adenocarcinoma is often present in pre- and postmenopausal patients. Of i nterest, endometrioid
adenocarcinoma can very rarely occur as a primary cervical tumor, of human papillomavirus
(HPV)-independent subtype. Morphologically
and immunohistochemically, this tumor is similar to the one in the uterine corpus. Variants
presenting with signet-ring cells must be differentiated from signet-ring adenocarcinoma, primary or metastatic to the cervix. Both tumors
are associated with atypia and frequent mitotic
figures and to exclude a primary tumor, p16 and
HPV testing are of great help because this cervical tumor subtype is HPV-associated, while for
excluding the presence of a metastasis, immunohistochemistry together with clinical history of
the patient can be helpful.
• Sex
Female.
• Site
Usually involves the posterior part of the
cervix.
• Treatment
Surgical excision is curative.
• Outcome
Excellent, the lesion is benign. Occasional
recurrences have been reported, possibly due
to incomplete excision (Schmedding
et al. 1997).
Macroscopy
The tumor is unifocal, polypoid, or exophytic,
with friable consistency, usually with a diameter
of less than 2 cm and associated with vaginal
bleeding or discharge.
Microscopy
Delicate fibrovascular branching papillae are
lined by a single layer of benign cuboidal/columnar epithelial cells. The cells have bland nuclei
and no mitotic activity (Fig. 31). Areas of squamous metaplasia can be identified. Edema and
inflammatory cells typically occur in the stroma
of the papillae. Psammoma bodies or osseous
metaplasia have been also reported in several
cases.
Mullerian Papilloma of the Uterine
Cervix
Synonyms
Mullerian papilloma of infancy.
Definition
Benign papillary tumor with papillary
architecture.
Clinical Features
• Incidence
The tumor is a rare finding.
• Age
Mullerian papilloma develops almost exclusively in children (age 2–5 years), but cases
developed in older age have been reported.
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 31 Mullerian papilloma:
delicate fibrovascular branching papillae are lined by a
single layer of benign cuboidal/columnar epithelial cells
without mitotic activity and atypia. (Courtesy of Dr. Raji
Ganesan)
Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix 47
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Immunophenotype
P16 is negative (patchy), PAX8 is positive.
Molecular Features
Not clinically relevant.
Differential Diagnosis
Given its exophytic appearance and age distribution, there is commonly clinical concern
for botryoid rhabdomyosarcoma. However,
the arborizing glandular epithelial morphology
of Mullerian papilloma makes the distinction
straightforward. Also, in older patients,
Mullerian papilloma should be differentiated
from papillary squamous intraepithelial lesions
(SILs) (characterized by p16 block-like positivity in high-grade SIL and negativity, patchy in
low-grade SIL) and from squamous p apilloma
(single papillary frond, with a fibrovascular
core, lined by mature squamous epithelium,
lacking koilocytes). Mullerian papilloma
should also be differentiated from condyloma
acuminatum, the latter being associated with
the presence of koilocytes and low-risk human
papillomavirus (HPV) genotypes. Finally,
villoglandular adenocarcinoma of the cervix
is characterized by prominent exophytic papillary growth in the superficial portion of
the tumor, composed of papillae of variable
thickness and length, containing central fibrous
cores and lined by columnar pseudostratified
epithelial cells that exhibit low- to moderategrade nuclear atypia. Villoglandular adenocarcinoma however occurs in older patients
than Mullerian papilloma and is an HPVassociated tumor, positive f or p16 (block-like)
and HPV testing.
Radiation Atypia of the Uterine Cervix
Synonyms
Radiation-related changes.
Definition
A lesion which may affect both squamous and
glandular epithelium, due to a prior radiation
treatment.
Clinical Features
• Incidence
Frequently found at microscopic examination
of surgical specimens, after irradiation.
• Age
Any age can be affected.
• Sex
Female.
• Site
It may involve both ectocervix and endocervix.
• Treatment
No treatment is recommended.
• Outcome
Excellent.
Macroscopy
The lesion does not usually produce a macroscopic lesion, but sometimes, mucosal irregularity, fibrosis, induration, or stenosis can be
identified.
Microscopy
The changes can be unifocal or multifocal but
usually do not involve the entire epithelium. Epithelial cells are enlarged in size, with bizarre
nuclear shape and enlarged nuclei, with smudged
indistinct chromatin and sometimes with prominent nucleoli. Normal nuclear/cytoplasmic ratio
is however preserved (Lesack et al. 1996). There
is uniform nuclear spacing, with minimal
crowding and a low mitotic index. Eosinophilic
intranuclear inclusions are seen. The cytoplasm
is finely vacuolated or eosinophilic. Apoptotic
bodies and mitotic figures are absent, as well as
nuclear stratification. The stroma presents
changes with hyalinization, ectatic vessels,
inflammatory infiltrate with numerous macrophages, edema, necrosis, myxoid changes, calcifications, multinucleated cells, blood vessels
with sclerosis hyaline thickening, and atypical
endothelial cells seen in acute lesio ns (almost
immediately after irradiation) (Figs. 32, 33, 34,
and 35). Of interest, chronic changes can be
observed weeks, months, or many years after
radiation treatment. These changes include a
decreased number in endocervical glands in
association with cytologic changes described
below.
B
48 Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix
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Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 32 Radiation atypia:
stroma presents changes with numerous macrophages
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 33 Radiation atypia:
epithelial cells lining an endocervical gland are enlarged
in size, with bizarre nuclearshape and enlarged nuclei,with
prominent nucleoli
Immunophenotype
The lesion is negative for p16 (patchy) and Ki-67
index is low.
Molecular Features
No molecular features have been described.
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 34 Radiation atypia:
epithelial cells lining an endocervical gland have clear
cytoplasm and bizarre nuclear shape but with minimal
crowding and a low mitotic index
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 35 Radiation atypia
involving squamous epithelium
the lesion can mimic adenocarcinoma in situ and
clear cell adenocarcinoma. Besides the absence of
mitotic figures and apoptotic bodies, radiation
atypia does not form a mass and does not invade
the cervical stroma, while the glandular architecture of the glands is normal.
Differential Diagnosis
In squamous epithelium, radiation atypia has
to be distinguished from squamous intraepithelial
lesions (SILs) by the absence of mitotic figures and
apoptotic bodies in correlation with clinical history
of the patient and additional immunohistochemical
stains. In the endocervical glandular epithelium,
Reparative Changes of the Uterine
Cervix
Definition
Presence of reactive or reparative changes, due to
mechanical, surgical, or chemical local trauma.
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Clinical Features
• Incidence
This is a frequent lesion.
• Age
It can occur at any age.
• Sex
Female.
• Site
Any area can be invol ved but especially the
ectocervix.
• Treatment
Surgery is not recommended.
• Outcome
Benign.
Macroscopy
Areas of erosion, mucosal irregularities, or induration of the mucosa.
Microscopy
Reparative changes are represented by glandular
or squamous monomorphic epithelial cells, with
flat or micropapillary architecture, well-defined
cellular borders, eosinophilic cytoplasm and loss
of mucin (in columnar cells), minimal nuclear
pleomorphism, and visible nucleo li, with sparse
mitoses (Fig. 36). The stroma presents as an
inflammatory infiltrate.
Immunophenotype
Not clinically relevant.
Molecular Features
Not clinically relevant.
Differential Diagnosis
Presence of atypia, especially in a biopsy material,
must be differentiated from precursor or malignant lesions (including eosinophilic dysplasia)
(Soslow et al. 2021). Lack of cellular atypia and
mitotic figures together with additional immunohistochemical stai ns (p16, Ki-67) and HPV testing
can be of help.
Squamous Metaplasia of the Uterine
Cervix
Synonyms
Epidermalization.
Definition
A process that involves proliferation of endocervical reserve cells and their subsequent differentiation into squamous cells, replacing the
columnar epithelium. The stimulus is thought to
be the increased acidity of the vaginal environment, compared with that of the cervical canal.
B
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 36 Reparative changes:
glandular epithelial cells, with flat architecture, eosinophilic cytoplasm and loss of mucin, minimal nuclear pleomorphism, and visible nucleoli, with sparse mitoses, while
the stroma presents an inflammatory infiltrate
Clinical Features
• Incidence
Squamous metaplasia is a common physiological process that occurs in women.
• Age
Occurs in post-pubertal women.
• Sex
Female.
• Site
Squamo-columnar junction.
• Treatment
No treatment is indicated for this lesion.
• Outcome
Benign process, not associated with a risk for
developing subsequent malignancy.
Macroscopy
This is a lesion identified only at microscopic
examination. However, on colposcopy, there is a
50 Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix
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sharp demarcation between normal squamous epithelium a nd squamous metaplasia, which is of
pale pink or white-pink color.
Microscopy
The rese rve cells first transform into immature
metaplastic epithelium (immature squamous
metaplasia). The cells are crowded, cuboidal,
with uniform oval/round nuclei and scanty
eosinophilic cytoplasm, without glycogen
(higher nuclear-to-cytoplasm ratio) but with
occasional normal mitoses. These cells are
located beneath the columnar epithelial cells.
Nuclei have uniform ch romatin and smooth
nuclear contour. They resemble the basal or
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 37 Immature squamous
metaplasia
parabasal cells of the ectocervical squamo us
epithelium. Immature squamous metaplasia is
only a few cell layers thick, and remnants of
columnar epithelium may overlie metaplastic
epithelium (Fig. 37). Under hormonal stimulation, cells in immature squamous metaplasia get
additional maturation and become glycogenated
and the epithelium becomes thick, with cells
having abundant c lear cytoplasm and a 1:1
nuclear-to-cytoplasmic ratio (mature squamous
metaplasia)(Fig.38). In both immature and
mature squamous metaplasia, atypical cells
and mitotic figures are not present.
Immunophenotype
In both mature and immature squamous metaplasia, Ki-67 index is low (less than 15%) and p16 is
negative (patchy). The cells are cytokeratinpositive (Cytokeratin 17, a marker for reserve
cells as bottom-heavy pattern, and Cytokeratin
7 as top-heavy pattern) and p63-positive, and
some may be positive for mucicarmine, MUC 2,
and MUC 5 (Soslow et al. 2021).
Molecular Features
Not clinically relevant.
Differential Diagnosis
The main differential is with high-grade squamous intraepithelial lesion (HSIL). Although
cells constituting immature squamous metaplasia
have reduced cytoplasm, with an increased
nuclear-to-cytoplasmic ratio and elongated,
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 38 Immature and mature
squamous metaplasia
sometimes hyperchromatic nuclei, the nuclei are
nonetheless uniform, without chromatin changes,
there are few mitoses, and the nucleoli are distinct.
Also, cells in immature squamous metaplasia
maintain cell organization. High-grade SIL
displays greater cellularity and cellular disorganization with lack of polarity. Also, HSIL is positive
block-like for p16 and Ki-67 index is high, while
squamous metaplasia is negative (patchy) for p16
and Ki-67 index is low. Cases previously called
atypical immature metaplasia can be reclassified
as HSIL, based on p16 staining, and this terminology should be avoided. A lesion called papillary
immature squamous metaplasia is associated with
human papillomavirus (HPV) infection, being
Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix 51
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now considered as low-risk HPV-induced SIL
(p16 is patchy) and should be differentiated from
immature squamous metaplasia. Florid squamous
metaplasia involving multiple endocervical
glands can mimic invasive squamous cell carcinoma. The nests in squamous metaplasia have a
rounded and smooth contour, lack atypia and stromal desmoplasia.
Transitional Metaplasia of the Uterine
Cervix
B
Synonyms
Cervical Walthard islands.
Definition
Cervical benign lesion, in which normal epithelium is replaced by a multilayered epithelium,
resembling the mucosa of a normal bladder.
Clinical Features
• Incidence
Incidental finding, occurring in the cervix (and
vagina) in peri- and postmenopausal patients.
It is found not only on biopsy but also on Pap
smears. Rarely, the lesion has been reported in
association with hormonal influence but
mostly occurs in an atrophic epithelium,
under hypoestrogenism. More recently, cases
in genetic females who received androgen therapy for gender reassignment were published.
• Age
Mean age is 62 years, with range 30–87 (Egan
and Russel 1997; Weir et al. 1997; Weir and
Bell 1998).
• Sex
Female.
• Site
It involves transformation zone, ectocervix,
and sometimes also the endocervix.
• Treatment
No treatment is recommended.
• Outcome
Excellent.
Macroscopy
The lesion is not macroscopically evident.
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 39 Numerous glands
are involved by transitional metaplasia in a postmenopausal patient
Microscopy
Transitional metaplasia is confinedtosurfaceepithelium or involves cervical stroma in the form of
isolated nests. It is composed of a multilayered
epithelium of basal and parabasal cells, with absence
of maturation, high nuclear-to-cytoplasmic ratio,
oval or fusiform nuclei, with delicate chromatin
and longitudinal grooves that are oriented vertically
in the deep layers and horizontally in the superficial
ones (suggesting a streaming pattern and resembling
transitional epithelium) (Munsick and Janovski
1961;Weiretal.1997).Thenucleoliaresmallor
indistinct, and mitoses are absent or rare. Frequently,
cells have a clear perinuclear halo (Figs. 39 and 40).
Asuperficial layer of “umbrella” cells is a rare
finding.
Immunophenotype
The cells are positive for p63. Also, transitional
cell metaplasia (like urothelium epithelium)
expresses Cytokeratin 7, 13, 17, and 18, but in
contrast to the urothelium, it is negative for
Cytokeratin 20 (Fig. 41). Ki-67 index is low and
p16 is negative (patchy).
Molecular Features
Not clinically relevant.
Differential Diagnosis
Main differential is with high-grade squamous
intraepithelial lesion (HSIL). The loss of polarity
52 Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix
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and presence of cellular atypia and mitotic figures
together with positivity for p16 (block-like pattern) and human papillomavirus (HPV) are in
favor of HSIL. Also, HSIL is characterized by a
high Ki-67 index, while in transitional metaplasia,
the index is low (less than 10%) and p16 is patchy.
Tubal and Tubo-endometrioid
Metaplasia of the Uterine Cervix
Synonyms
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 40 Transitional metapla-
sia: multilayered epithelium of basal and parabasal cells,
mostly with absence of maturation, high nuclear-tocytoplasmic ratio, oval or fusiform nuclei, with delicate
chromatin and longitudinal grooves and a clear perinuclear
halo; areas of squamous metaplasia are also present; mitoses are absent or rare
Serous metaplasia.
Definition
Replacement of endocervical epithelium by tubal
or tubo-endometrioid epithelium, due to previous
surgery. Rare cases in association with diethylstilbestrol exposure have been reported.
Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix, Fig. 41 Transitional metaplasia: the
cells resembling transitional epithelium (a) are positive for Cytokeratin 7 (b) but negative for Cytokeratin 20 (c)
Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix 53
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Clinical Features
• Incidence
This is a common lesion found in endocervical
glands in two-thirds of surgical specimens
(Jonasson et al. 1992).
• Age
Women of reproductive age.
• Sex
Female.
• Site
Endocervical glands (usually located in the
inner third of cervical wall) and surface endocervical epithelium.
• Treatment
No treatment is recommended.
• Outcome
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 42 Tubal metaplasia: at
low-power examination, normally located endocervical
glands involved by tubal metaplasia look dark-blue
Benign lesion.
Macroscopy
Tubal and tubo-endometrioid metaplasia do not
usually form visible macroscopic lesions and are
incidental findings. Very rare cases of polypoid
lesions have been described. They may be also
identified through Pap smear examination.
B
Microscopy
At low-power examination, the normally located
endocervical glands look dark-blue (in contrast to
pale blue normal glands), while at high power,
glands are lined by a pseudostratified columnar
mucin-depleted epithelium, composed of ciliated
and nonciliated cells, with intercalated or peg
cells, similar to the fallopian tube or with an
overlap of tubal and endometrioid cell types.
One or more glands can be involved and the
shape of glands is round, oval, or branching
(Figs. 42 and 43). No cytologic atypia or mitotic
activity is found. Adjacent stroma can be mildly
hypercellular, with edema, calcifications, and
inflammatory infiltrate.
Immunophenotype
p16 is negative (patchy) and Ki-67 index is low.
Estrogen receptors (ERs) and progesterone receptors (PRs) as well as BCL2 and PAX2 are positive.
Molecular Features
Not clinically relevant.
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 43 Tubal metaplasia:
glands are lined by a pseudostratified columnar mucindepleted epithelium, composed of ciliated and nonciliated
cells
Differential Diagnosis
In contrast to tubal or tubo-endometrioid metaplasia, human papillomavirus (HPV)-associated
in situ adenocarcinoma is characterized by
dark-blue epithelium lining the glands but in
association with elongated and atypical nuclei,
mitotic figures, apoptotic bodies, while p16 is
block-like positive. Of interest, rare cases of
atypical tubo-endometrioid metaplasia have
been reported, and it has been speculated that
this could represent a precursor lesion to invasive
adenocarcinoma of tubal type but more recent
data do not support this view. Typical cervical
54 Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix
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endometriosis presents with endometrial-type periglandular stroma in addition to endometrioid type
of glands, but sometimes the stroma can be scant
and partly obscured by inflammatory cells and
distinction between the two lesions is impossible
(and not clinically relevant). Mesonephric hyperplasia can sometimes present with an endometrioid
morphology but is usually located in the outer third
of the cervical wall. Also, immunohistochemistry
can help distinguish the two lesions.
Tunnel Clusters of the Uterine Cervix
Definition
Benign lobular proliferation of endocervical
glands, related to hormonal stimulation. Two
types have been described: type A (non-cystic)
and type B (cystic).
Clinical Features
• Incidence
It occurs in up to 10% of multiparous women.
• Age
Women in reproductive age are mostly
affected.
• Sex
Female.
• Site
Endocervical canal.
• Treatment
No treatment is recommended for tunnel
clusters.
• Outcome
Excellent.
(Figs. 44 and 45). Type B (cystic) is composed of
cystically dilated glands, lined by cuboidal/flat
mucinous epithelium (Figs. 46 and 47). No cellular atypia and no mitoses are present. Both types
are architecturally characterized by a rounded lobular configuration and are usually located beneath
the surface endocervical epithelium, along the
endocervical canal. The lesion can be multifocal
(in up to 80% of cases) but is never associated
with stromal desmoplasia. Pools of mucin and
inflammatory infiltrate can be occasionally found
within the stroma. Cases of tunnel clusters type
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 44 Tunnel clusters type A
Macroscopy
Type A is an incidental finding (and usually
asymptomatic) and does not form a visible mass
in most of cases. However, type B may be more
extensive and may produce cysts that can be
detected on gross examination.
Microscopy
Type A (non-cystic) is represented by a proliferation of small glands, with round or undulated
contour, lined by a cuboidal/columnar mucinous
epithelium, with small and basally located nuclei
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 45 Tunnel clusters type
A: proliferation of small glands, with round or undulated
contour, lined by a cuboidal/columnar mucinous epithelium, with small and basally located nuclei
Benign Epithelial Tumors and Tumor-Like Lesions, Pathology of the Cervix 55
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gastric morphology and is consequently positive
for gastric type of markers. Lobular endocervical
glandular hyperplasia (LEGH) can mimic tunnel
clusters but has gastric morphology.
References
Abi-Raad, R., Alomari, A., Hui, P., & Buza, N. (2014).
Mitotically active micro- glandular hyperplasia of the
cervix: A case series with implications for the differential diagnosis. International Journal of Gynecological
Pathology, 33, 524–530. https://doi.org/10.1097/PGP.
0000000000000086.
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 46 Tunnel clusters type
B: cystically dilated glands arranged in a rounded lobular
configuration
Benign Epithelial Tumors and Tumor-Like Lesions,
Pathology of the Cervix, Fig. 47 Tun nel clusters type
B: cystically dilated glands, lined by flat mucinous epithelium
A with superimposed gastric metaplasia have also
been described (Kondo et al. 2007).
Immunophenotype
Estrogen receptors (ERs) and progesterone receptors (PRs) are positive in both types.
Molecular Features
Not clinically relevant.
Differential Diagnosis
Minimal deviation adenocarcinoma is usually
deeply infiltrative and presents at least focal cytologic atypia and stromal desmoplasia. It has also a
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B
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