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Adenocarcinoma and Precursors, Pathology of the Cervix 15
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(Figs. 23 and 24). However, their morphologic
appearance is quite variable and includes various
architectural patterns (glandular, tubular, cystic,
papillary, micropapillary, solid, signet, or single
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 25 Gastric-type adenocarcinoma with dif-
fuse destructive growth
cells), variable cytologic atypia (low to highgrade), stromal desmoplasia, densely eosinophilic
cytoplasm, microcystic elongated and fragmented
(MELF) patterns of invasion, and mucin extravasation (Figs. 25, 26, 27, and 28) (Pirog et al.
2000). Intestinal differentiation in the form of
goblet cells and neuroendocrine-like cells can be
seen. The precursor lesions such as lobular endocervical glandular hyperplasia (LEGH), atypical
lobular endocervical glandular hyperplasia
(ALEGH), and gastric-type adenocarcinoma in
situ can be seen.
The term s adenoma malignum and minimal
deviation adenocarcinoma are no longer considered distinct entities and are captured under the
umbrella term gastric-type adenocarcinoma of the
cervix. They are thought to represent the morphologically well-differentiated end of the spectrum
of gastric-type adenocarcinoma (Karamurzin et al.
2015; Nishio et al. 2019). There is no accepted
grading system for gastric-type adenocarcinomas,
and these tumors can behave aggressive even if
they are of entirely glandular architecture, which
would be considered low-grade by most grading
systems. For this reason, some advocate that
gastric-type adenocarcinomas be automatically
graded as high-grade, regardless of the histologic
pattern (McCluggage et al. 2018).
A
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 26 Gastric-type adenocarcinoma showing
micropapillary growth pattern
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 27 Gastric-type adenocarcinoma with signet
ring cells
Immunophenotype
This is not related to HPV infection, and thus most
cases are negative for p16. Care should be taken
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 28 Gastric-type adenocarcinoma mimicking
the appearance of serous carcinoma
16 Adenocarcinoma and Precursors, Pathology of the Cervix
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however, as some series report p16 positivity in up
to one-third of cases.
These tumors exhibit neutral (gastric/pyloric)
type mucin which stains magenta/red using a
combined Alcian Blue/PAS stain. In contrast, normal endocervical glands, which contain acidic
mucin, stain purple/blue.
MUC6, an epithelial mucin found in colorectal, Goblet, and airway mucin, has variable sensitivity (31–80%) but is not entirely specific, as it
will also stain gastric metaplasia, tunnel clusters
type A, and lobular endocervical glandular
hyperplasia (LEGH). HIK1083, a mucin found
in gastric and Brunner gland cells, has good
sensitivity ( 75%) but is not widely available
(Carleton et al. 2016;Mikamietal.2004).
TFF2 (a secretory protein coexpressed with
MUC6) has recently been described as having
better specificity than MUC6 as it does not stain
normal endocervical glands (Asaka et al. 2019;
Tak a k o et al . 2021).
The majority are positive for CK7, CEA,
CA-IX, and PAX8. Half of cases will be positive
for CDX2 and CK20. Most are negative for ER
and PR. Approximately 50–90%willshow
abnormal staining for p53 (Carleton et al.
2016; Hodgson et al. 2020). HER2 over-
expression is seen in 4% of cases (Hodgson
et al. 2020).
Molecular Features
Gastric-type adenocarcinomas show some molecular overlap with adenocarcinomas of the stomach, pancreas, and biliary tree but do not show
complete overlap (Park et al. 2020). The most
frequently mutated gene is TP53, occurring in
52–90% of cases. Sporadic and germline mutations in STK11 can occur. Additional mutations
have been reported in MSH2/6, POLE, CDKN2A/
B, SLX4, ARID1A, PIK3 CA, PTPRS, FGFR4,
KRAS, GNAS, BRCA2, ATM, NTRK3, and other
genes (Garg et al. 2019; Hodgson et al. 2020; Park
et al. 2020).
Differential Diagnosis
Both gastric-type adenocarcinoma and usualtype adenocarcinoma can show intestinal differ-
entiationintheformofGoblet cells, argentaffin
cells, and signet ring cells. In addition, approximately one-third of gastric-type adenocarcinoma will show block-like p16 staining,
despite its negativity for high-risk HPV infection. Gastric-type adenocarcinoma will be associated with pyloric metaplasia, LEGH, and
ALEGH,whileusual-typewillbeassociated
with HPV-associated precursor lesions, adenocarcinoma in situ (AIS), and high-grade squamous intraepithelial lesion (HSIL). Conspicuous
floating mitoses and apoptotic debris are seen in
usual-type adenocarcinoma; this is much more
subtle in gastric-type adenocarcinomas. Gastrictype adenocarcinomas are more likely to be positive for HIK1083, MUC6, and TFF2. HPV testing may be needed to distinguish the two in
difficult cases.
The papillary architecture seen in gastric-type
adenocarcinoma and aberrant expression of p53
can cause confusion with serous adenocarcinoma.
Careful examination of the uterine corpus and
adnexa are needed to rule out extension of serous
carcinoma from these sites. The finding of mucinous or foamy cytoplasm and precursor lesions
(LEGH, ALEGH) will support a gastric-type
adenocarcinoma.
Clear Cell Carcinoma of the Cervix
Definition
A human papillomavirus (HPV)-independent adenocarcinoma of the uterine cervix exhibiting classic features of clear cell carcinoma as elsewhere in
the gynecologic tract.
Clinical Features
• Incidence
This represents <5% of all cervical adenocar-
cinomas (Stolnicu et al. 2018a).
• Age
The mean age is 50 years for sporadic tumors.
When associated with in utero diethylstilbestrol
(DES) exposure, the age of onset is younger,
20 years.
• Sex
Female.
Adenocarcinoma and Precursors, Pathology of the Cervix 17
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• Site
These tumors more commonly affect the endometrium and ovary. Rarely, clear cell carcinomas occur in the cervix and vagina.
• Treatment
These are aggressive neoplasms that usually
necessitate radical hysterectomy and adjuvant
treatment.
• Outcome
The 5-year survival for patients with prenatal
DES exposure is 86.1% and without documented
DES exposure is 81.2%. This difference was only
statistically significant in the first 5 years, as the
20-year survival of 69% was similar between the
two groups (Huo et al. 2018). Advanced tumor
stage, large tumor size (>4 cm), and pelvic lymph
node metastases were adverse prognosticators
(W ang et al. 2019 ;Yangetal.2017).
Macroscopy
This tumor usually arises in the endocervical
canal. Tumors associated with DES can occur in
the ectocervix. Patients with DES exposure can
also have vaginal adenosis and genital tract abnormalities, such as cervica l stenosis, cockscomb/
collared cervix, uterine hypoplasia, uterine synechiae, T-shaped uterine cavity, abnormal fimbriae, and cornual budding.
Microscopy
These tumors exhibit morphologic features akin
to the endometrium and ovary. The neoplastic
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 29 Clear cell carcinoma of the cervix with
eosinophilic cytoplasm. A tubulocystic pattern is appreciated. There is minimal to no nuclear stratification and
moderate cytologic atypia
cells contain clear (glycogen-rich) or eosinophilic
cytoplasm and form tubulocystic, papillary, or
solid growth patterns (Fig. 29). The cells are
cuboidal or flattened. There is usually minimal
nuclear stratification and moderate nuclear atypia
with scattered high-grade cells. Intranuclear inclusions can be seen, and nucleoli are usually inconspicuous. Hobnail cells, ring formations, hyaline
globules, psammoma bodies, and hyalinization
stroma are also comm on features. Adjacent endometriosis can be found in rare instances.
Immunophenotype
Almost all tumors are negative for ER and positive
for PAX8. These tumors are not related to HPVand
are usually negative for p16; however, p16 positivity has been reported. Napsin-A, AMACR, and
HNF-1β can also be helpful markers, although
both HNF-1β and sometimes Napsin A may be
expressed in gastric-type adenocarcinomas (Talia
et al. 2019). Very rare cases have been associated
with Lynch Syndrome (Nakamura et al. 2018).
Molecular Features
HER2 amplification is seen in 12.5% of cases
(Ueno et al. 2013).
Differential Diagnosis
Arias-Stella reaction can be mistaken for clear cell
carcinoma. Arias-Stella is a benign reactive phenomenon and is usually focal. Mitotic figures will
be absent or rare, and ER is usually positive,
although it can be attenuated in intensity. The
finding of a mass, stromal invasion, tubulocystic
and solid patterns, and stromal hyalinization favor
a diagnosis of clear cell carcinoma. Napsin-A and
AMACR are positive in clear cell carcinoma and
not in ASR. HNF-1β is positive in both entities
and will not be helpful in distinguishing between
the two (Ji et al. 2019).
Clear cell carcinoma with nonclear
(eosinophilic) cytoplasm can be confused with
serous carcinoma. Serous carcinoma will exhibit
diffuse severe cytologic atypia, nuclear stratification, and brisk mitotic activity. p53 shows a mutational pattern staining pattern in >95% of cases,
although 14% of clear cell carcinoma can also
exhibit a mutational p53 pattern (Ju et al. 2018).
A
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Yolk sac tumors are rare malignancies in the
uterine cervix which also contain cubdoidal cells
with clear cytoplasm . They can be distinguished
by clear cell carcinoma by their other morphologic patterns (reticular, Schiller-Duval bodies,
and polyvesicular vitelline) and positivity for
SALL4 and AFP.
Mesonephric Carcinoma
Definition
A tumor affecting the female reproductive tract,
which arises from remnants of the male reproductive tract (vestiges of the mesonephric or
Wolffian duct).
Clinical Features
• Incidence
Rare tumors that account for less than 1% of all
cervical cancers.
• Age
Most women are postmenopausal, but the
reported age range is broad (20–90 years
of age).
• Sex
Female.
• Site
The majority of tumors occur in the uterine
cervix, where mesonephric remnants often per-
sist in the lateral wal ls of the cervix. However,
tumors can arise anywhere along the trajectory
of the embryologic mesonephric/Wolffian
duct. Thus, mesonephric carcinomas have
also been reported in the uterine corpus,
ovary, fallopian tube, and broad ligament.
• Treatment
Most will require radical hysterectomy and
adjuvant therapy.
• Outcome
Approximately half will experience recur-
rences, which include local (pelvic and abdom-
inal) and distant sites (lung, mediastinum).
Most recurrences occur within 5 years, but
long-intervals >10 years have been reported.
In one large multi-institutional study, the
5-year disease-specific survival was 74% for
mesonephric carcinomas of the cervix, 72% for
the uterine corpus, and 71% for the ovary (Pors
et al. 2020c).
Macroscopy
Most tumors occur in the cervix, where a large
mass with involvement of the overlying cervical
mucosa is often seen. Full thickness and circumferential cervical wall invasion, ulceration, and
extension into the lower uterine segment can be
seen. On cut section, tumors are firm, white, gray,
or hemorrhagic.
Microscopy
There are two classic histologic patterns seen in
mesonephric carcinomas: tubular and ductal. In
the tubular (mesonephroid) pattern, back-to-back
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 30 Mesonephric carcinoma of the cervix.
A classic tubular pattern is seen on the left and ductal
(pseudoendometrioid) pattern on the right
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 31 Mesonephric carcinoma of the cervix.
The crowded tubules are lined by cuboidal cells with
papillary-thyroid-carcinoma-like nuclear atypia. The
lumens are filled with dense eosinophilic secretions
Adenocarcinoma and Precursors, Pathology of the Cervix 19
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tubules are lined by cuboidal cells and have
lumens filled with dense eosinophilic secretions
which are PAS and mucicarmine positive. In the
ductal (pseudoendometrioid) pattern, the cells are
columnar and form sharply angulated glands
(Figs. 30 and 31). A variety of other histologic
patterns have also been described, including papillary, retiform, sex cord-like, hobnail,
glomeruloid, sieve-like, spindled, and solid
(Bagué et al. 2004; Clement et al. 1995). Due to
the broad variation in histologic patterns, the
name “the great mimicker” has been given to
mesonephric carcinomas. Nuclear pleomorphism
is usually mild to moderate, with coarse or vesicular chromatin and inconspicuous nuclei. Papillary thyroid-like carcinoma nuclei have also been
used to describe their appearance. Mitotic activity
is variable. By definition, squamous and cytoplasmic mucin are absent, and their finding should
exclude the diagnosis of mesonephric carcinomas.
Spindled and sarcomatous differentiation, in
the form of chondrosarcoma, rhabdomyosarcoma,
and osteosarcoma, lends a diagnosis of mesonephric carcinosarcoma.
No grading system has been applied to mesonephric carcinomas.
Immunophenotype
These neoplasms are not related to human papillomavirus (HPV) infection and thus will be negative for p16. They are negative for ER and positive
for PAX8, GATA3, TTF1, and CD10 (luminal
pattern). Some cases are also positive for TTF1
and calretinin (Pors et al. 2018). p53 is usually
wild-type, even when there is transformation to a
mesonephric carcinosarcoma.
Differential Diagnosis
Mesonephric carcinomas should be distinguished
from benign mesonephric remnants and mesonephric hyperplasia. Helpful features include the
presence of architectural crowding, haphazard
infiltrative growth, elevated mitotic activity,
intraluminal necrotic debris, and nuclear atypia.
KRAS mutations have been found in mesonephric
carcinomas but not in mesonephric hyperplasia
(Mirkovic et al. 2017). Mesonephric hyperplasia
will rarely form a mass lesion, while mesonephric
carcinomas usually do.
The ductal (pseudoendometrioid) pattern of
mesonephric carcinoma can mimic an endometrioid carcinoma. Mesonephric carcinomas
will tend to exhibit a variety of patterns if examined thoroughly, including areas of the more classic tubular pattern. In addition, mesonephric
carcinoma will be negative for ER, while endometrioid carcinoma will be positive.
The papillary and tubular pattern of mesonephric carcinoma can also mimic clear cell carcinoma.
Both tumors will be negative for ER and p16.
Mesonephric carcinomas tend to be negative for
Napsin-A and AMACR, while these markers are
positive in clear cell carcinoma. HNF-1β will not
distinguish between these two entities (Pors
et al. 2020b).
The majority of carcinosarcomas will be
mesonephric-derived as opposed to Mullerian
derived. p53 is usually wild-type in mesonephric
carcinosarcomas, and usually aberrant (mutant) in
Mullerian carcinosarcomas.
Endometrioid Carcinoma of the Cervix
A
Molecular Features
Approximately 75% of tumors harbor KRAS
mutations and gain in chromosome 1q (with a
subset showing concurrent loss of 1p). Two-thirds
have mutations in chromatin remo deling genes
(ARID1A/B or SMARCA4) and one-third in
BCOR/BCORL1 (Mirkovic et al. 2015).
A minority of cases have mutations in TP53,
CTTNB1, and PIK3CA (Pors et al. 2020a). They
have a low mutation burden and absence of microsatellite instability.
Definition
An adenocarcinoma shows classic or confirmatory features of endometrioid carcinoma, occurring in the cervix. These are very rare tumors.
Spread from the endometrium by direct extension
or lymphovascular invasion is far more common,
and thus prudence should be taken to exclude this
first before diagnosing a primary endometrioid
carcinoma in the cervix. To discourage the use of
endometrioid carcinoma of the cervix, it has not
been given a primary heading in the World Health
20 Adenocarcinoma and Precursors, Pathology of the Cervix
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Organization (WHO) and instead falls under the
endocervical adenocarcinoma NOS section.
Clinical Features
• Incidence
These are rare tumors that represent <1% of all
HPV-independent cervical adenocarcinomas. In
the past, the definition of endometrioid carcinoma was somewhat vague, allowing for tumors
which were HPV-associated and had mucin
depletion which mimicked the appearance of
endometrioid adenocarcinoma, as well as true
endometrioid adenocarcinomas which arose
from endometriosis. In the IECC and most recent
edition of the WHO, only the latter definition is
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 32 Endometrioid carcinoma of the cervix
with confirmatory endometrioid features in the form of
neoplastic columnar glands and squamous morular
metaplasia
allowed. This explains the wide ranges of
reported prevalence from 7–50% in the reported
literature previously , to the current reported
prevalence which is close to only 1% (Stolnicu
et al. 2018a; Young and Clement 2002).
• Age
Mostly postmenopausal.
• Sex
Female.
• Site
Uterine cervix.
Immunophenotype
These tumors are not related to HPV and are
negative or show patchy staining for p16. They
are positive for PAX8 and ER. Approximately
half of cases will show loss of ARID1A and/or
PTEN. In high-grade endometrioid carcinomas,
p53 can show mutational pattern of staining in
20–40% of cases. Some cases can show loss of
mismatch repair proteins (MLH1, MSH2, MSH6,
and PMS2).
• Treatment
Most cases requi re hysterectomy. Depending
on the stage and prognostic factors, lymph
Molecular Features
See Endometrioid carcinoma of the endometrium.
node dissection and adjuvant therapy may
also be warranted.
• Outcome
Due to their rarity, their clinical behavior is
largely unknown.
Differential Diagnosis
The major differential diagnosis is between
HPV-associated usual-type adenocarcinoma and
endometrioid carcinoma. Both tumors can have
variable amounts of mucinous cytoplasm and
Macroscopy
There is usually a polypoid or ulcerated mass.
overlapping morphologic patterns (glandular,
villoglandular, and papillary). The former will
exhibit much more conspicuous luminal mitoses,
Microscopy
The tumor should exhibit confirmatory endometrioid features, which include at least focal lowgrade endometrioid glands with columnar cells with
smooth luminal borders and pseudostratified bland
nuclei (Fig. 32) (Stolnicu et al. 2018). The presence
of squamous differentiation and cervical endometriosis are also helpful confirmatory features
(Hirschowitz et al. 2007;Seayetal.2020).
apoptotic debris, and hyperchromasia. Confirmatory endometrioid features, as mentioned above,
will be helpful in the latter diagnosis. A panel of
CEA, p16, ER, and vimentin can be helpful.
HPV-associated usual-type adenocarcinoma
will show block-like positivity for p16 and be
negative for ER a nd vimentin, with th e reverse
pattern in endometrioid adenocarcinom a
(Stewart et al. 2019).
Adenocarcinoma and Precursors, Pathology of the Cervix 21
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Benign Epithelial Tumors and
Tumor-Like Lesions,
Pathology of the Cervix
Simona Stolnicu
University of Medicine, Pharmacy, Sciences and
Technology “George E Palade” of Targu Mures,
Targu Mures, Romania
Arias-Stella Reaction of the Uterine
Cervix
Synonyms
Arias-Stella phenomenon; Change or effect.
Definition
Arias-Stella reaction is a benign glandular change,
due to increased gonadotropin stimulation. It
refers to hypersecretory endocervical glands associated with nuclear atypi a. The nuclear changes
are due to an increase in DNA polyploidy, secondary to pregnancy-related hormonal stimuli in
most cases (Wagner and Richart 1968; AriasStella 2002).
very rare situations in which the lesion devel-
oped at older age (even in postmenopause)
related to hormonal stimulation have been
diagnosed.
• Sex
Female.
• Site
This is a lesion which typically develops in
the endometrium, in association with intra-
uterine or ectopic pregnancy, gestational tro-
phoblastic disease, related to hormonal
treatment or oral contraceptives but can
also develop in the cervix, under similar cir-
cumstances. Occasio nally, no hormonal his-
tory can be elicited. Within the cervix, it is
seen in the upper endocervica l canal but can
also involve glands anywhere in the
endocervix.
• Treatment
No treatment is recommended for Arias-Stella
lesion.
• Outcome
Excellent outcome as this is a benign pseudo-
neoplastic glandular change, with no malig-
nant potential.
Clinical Features
• Incidence
The lesion is identified in 10–50% of hysterectomy specimens from pregnant patients.
• Age
It develops in young fertile women
(19–44 years old) almost all pregnant, although
© 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
Macroscopy
Arias-Stella is usually identified at microscopic
examination and does not form a grossly visible
mass. Rare situations in which Arias-Stella reaction involves an endocervical polyp or polypoid
endometriosis of the uterine cervix have been
described (Felix et al. 2010).
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