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Adenocarcinoma and Precursors, Pathology of the Cervix 5
https://t.me/med1917
cervical specimens, after review of archival
material from two institutions (Boyle and
McCluggage 2015; Onishi et al. 2016).
• Age
The mean age of patients is around 35 years
(range: 20–58 years) (Boyle and McCluggage
2015; Park et al. 2000; Lastra et al. 2016), on
average 15 years younger than patients who
have SMILE with associated invasive
carcinoma.
• Sex
Female.
• Site
Cervical transformation zone.
• Treatment
Complete excision with negative margins is
recommended to ensure removal and exclude
an invasive carcinoma component.
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 5 Stratified mucin-producing intraepithelial
lesion (SMILE), overlying invasive stratified mucinproducing carcinoma. The SMILE can look like highgrade squamous intraepithelial carcinoma on low-power,
but on high-power examination there are mucin vacuoles
within the preneoplastic cells, throughout the epithelial
thickness. The nuclei are disorganized, enlarged, and
there are scattered mitoses
• Outcome
Due to the rarity of isolated SMILE, the natural
history is unclear. In one study, patients were
followed over 29 months (range
3–105 months), and all fertility sparing
patients with negative margins experienced
no recurrences (Kahn et al. 2020).
[ISMC]) (Boyle and McCluggage 2015; Park
et al. 2000; Lastra et al. 2016).
A single ultrastructural story of SMILE
showed surface microvilli and vacuolar structures, suggesting it has more similarity to adenocarcinoma in situ than a squamous intraepithelial
lesion (Onishi et al. 2016).
Macroscopy
Unknown.
Immunophenotype
p16 shows diffuse block-like positivity. p63 is
Microscopy
SMILE has an architecture similar to high-grade
squamous intraepithelial lesion (HSIL). The difference is that SMILE has intracellular mucin
confined to the basal layers of SMILE and lost in
areas of mucicarmine positivity. The cells are
negative for keratin-14 and IMP3 (a marker of
AIS). Ki67 is present strongly in all cell layers.
within the cells, which causes conspicuous sparing of nuclei in the lower to middle epithelial
layers. Discrete mucin vacuoles can be seen
Molecular Features
Unknown.
(Fig. 5). Mucicarmine shows diffuse staining in
all layers of the epithelium. The epithelial-stromal
junction can have a rounded contour, similar to
HPV-associated adenocarcinoma in situ (AIS).
SMILE is often found with conventional HSIL
and AIS. Various invasive carcinomas can be
found in association with SMILE, including
HPV-associated usual-type adenocarcinoma,
adenosquamous carcinoma, squamous cell
carcinoma, and invasive SMILE (also known as
invasive stratified mucin-producing carcinoma
Differential Diagnosis
At first glance, SMILE can be mistaken for HSIL.
In SMILE however, there is mucin present within
the preneoplastic cells, which stain positive for
mucicarmine. p63 and CK14 only stain focally,
usually in the lower epithelial layers, of SMILE
while in HSIL these stains are positive throughout
the epithelial thickness.
SMILE can also be mistaken for reactive colum-
nar epithelium. In benign reactive squamous
A
6 Adenocarcinoma and Precursors, Pathology of the Cervix
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metaplasia, the columnar cells with mucin are concentrated in the upper and middle layers, while in
SMILE the mucin is seen throughout the epithelial
layers. Multinucleated cells, uniform nuclei, and
opaque chromatin are features of reactive change
rather than SMILE. In rare cases, SMILE can undermine the normal columnar epithelium identical to
subcolumnar reserve cells (Park et al. 2000).
AIS is another preneoplastic lesion with
intracytoplasmic mucin, but this will form readily
appreciable columnar cells. IMP3 is negative in
SMILE and positive in AIS (Boyle and
McCluggage 2015; Onishi et al. 2016).
Gastric Type Adenocarcinoma In Situ
Definition
Human papillomavirus (HPV)-independent in situ
dysplasia of the endocervical glands which
exhibit a gastric/pyloric phenotype.
Clinical Features
• Incidence
Rare. The incidence is unknown.
• Age
There is a wide age range from 25 to 73 years,
with a mean age of 51 years.
• Sex
Female.
• Site
This lesion occurs at or proximal to
the transformation zone. It can extend into the
lower uterine segment and even colonize the
endometrium and fallopian tubes (Ura et al. 2018).
• Treatment
Complete excision is recommended.
• Outcome
Due the rarity of finding gastric-type
adenocarcinom in situ as an isolated lesion,
the natural history remains largely unknown.
There is a report of a patient who was diag-
nosed with gastric-type adenocarcinoma in situ
in a cervical polyp on retrospective review,
after the patient was diagnosed with invasive
gastric type adenocarcinoma 6 years later
(Talia et al. 2017).
Macroscopy
These are not usually grossly visible and do not
produce acetowhite lesions (Yuan et al. 2016).
Microscopy
Approximately 19% of gastric-type adenocarcinomas will have adjacent gastric-type adenocarcinoma in situ (Stolnicu et al. 2018a). They are
only rarely found in isolation (Talia et al. 2017).
The abnormal endocervical cells exhibit voluminous eosinophilic, pale pink, foamy, or clear
cytoplasm. They tend to have a more eosinophilic
appearance compared to the more basophilic
appearance of the normal endocervical glands
(Fig. 6). Most lesions show a sharp demarcation
with the background normal endocervical cells.
Goblet cells are seen in half of cases. The nuclei
are basally located with nuclear stratification limited to the lower one-half of the epithelium. The
normal endocervical glandular architecture is
largely preserved. There can be some mild
increase in intraglandular complexity, such as
small papillary infoldings or cribriform areas.
The lesion can colonize the endocervical
mucosa and rarely colonize the endometrium
and fallopian tubes, in either a continuous or
skip fashion (Ura et al. 2018; Talia et al. 2017).
Some cases are found in association with lobular endocervicalglandular hyperplasia (LEGH) and
pyloric metaplasia (Okuyama et al. 2017). The
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 6 Gastric type adenocarcinoma in situ of the
cervix. The atypical columnar cells are partially involving
a native endocervical gland, without distorting its architecture. The cells exhibit eosinophilic cytoplasm, enlarged
nuclei, vesicular chromatin, and scattered mitoses
Adenocarcinoma and Precursors, Pathology of the Cervix 7
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most recent edition of the World Health
Organization proposes that atypical LEGH and
gastric-type adenocarcinoma in situ all represent a
morphologic spectrum of the same HPVindependent precursor lesion family and allow capture of these precursor lesions under the umbrella
term HPV-independent adenocarcinoma in situ.
Immunophenotype
Similar to its invasive counterpart, these lesions
are positive for CK7, MUC6, and HIK1083.
Approximately half of cases will be positive for
PAX8, CK20, CDX2, and CEA. One-third of
cases are positive for ER and PR and show an
aberrant p53 pattern (overexpression or null). p16
is usually negative or patchy (nonblock staining)
(Talia et al. 2017).
Differential Diagnosis
The only difference between atypical LEGH and
gastric-type adenocarcinoma in situ is that the latter
does not distort the normal endocervical glandular
architecture. Atypical LEGH forms lobulated clusters of glands surrounding a dilated duct.
Gastric-type adenocarcinoma in situ will also
exhibit mitotic activity and apoptotic bodies, but
they are much less conspicuous than in HPVassociated adenocarcinoma in situ. The latter is
also positive for p16 and HPV, while gastric-type
adenocarcinoma in situ shows variable staining
for p16 and is negative for HPV.
Invasive gastric-type adenocarcinoma can be
difficult to distinguish between gastric-type adenocarcinoma in situ in early stage lesions. The
former tends to exhibit stromal desmoplasia and
a highly destructive growth pattern.
Lobular Endocervical Glandular
Hyperplasia (LEGH) and Atypical Lobular
Endocervical Glandular Hyperplasia
(ALEGH)
Synonyms
Atypical lobular endocervical glandular hyperplasia also falls under the umbrella term HPVindependent adenocarcinoma in situ.
Definition
A lobular proliferation of endocervical glands,
characterized by a central cleft-like space
surrounded by a lobular arrangement of glands.
The glands often exhibit pyloric/gastric
differentiation.
Clinical Features
• Incidence
Rare.
• Age
This lesion is most often seen in women of
reproductive age, but a wide range has been
reported (range: 47–71 years).
• Sex
Female.
• Site
The upper endocervix is confined to the inner
half of the cervical wall. It can be associated
with multifocal mucinous metaplasia/lesions
elsewhere in the gynecologic tract, such as
the endometrium and fallopian tubes (Mikami
et al. 2009).
• Treatment
Atypical LEGH is associated with adenoma
malignum (gastric type adenocarcinoma) in
one-third of cases, and thus complete excision
is recommended to rule out an undersampled
adjacent malignancy.
• Outcome
LEGH is itself considered benign. A small proportion of cases have been associated with
Peutz-Jegher’s syndrome. Atypical LEGH
may be associated with adenoma malignum
(gastric-type adenocarcinoma).
Macroscopy
Sometimes a mass can be visible, but more often
these lesions are discovered incidentally.
Microscopy
The lesion consists of an exuberant proliferation
of endocervical glands with distinct lobular architecture, confined to the inner half of the cervical
wall (Fig. 7). In many cases, the lobular proliferations contain a central dilated duct or cleft-like
space. The glands are lined by tall columnar cells
A
8 Adenocarcinoma and Precursors, Pathology of the Cervix
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Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 7 Lobular endocervical glandular hyperpla-
sia, where a dilated central space is surrounded by a lobular
proliferation of glands
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 8 Lobular endocervical glandular hyperpla-
sia, where a cleft-like space is lined by tall columnar cells
exhibiting pyloric differentiation. The nuclei are bland
with pale to eosinophilic cytoplasm and basally
located nuclei. The nuclei are bland (Fig. 8). There
is no stromal desmoplasia, mitotic figures, or
squamous differentiation (Mikami 2020).
Atypical LEGH, on the other hand, does
exhibit nuclear atypia in the form of nuclear
enlargement, irregular nuclear contours, prominent nucleoli, coarse chromatin, loss of polarity,
scant apoptotic bodies, and mitotic figures
(Fig. 9). This can be accompanied by architectural
infoldings, tufts, and papillae.
Immunophenotype
LEGH/ALEGH contain neutral mucin, similar to
gastric foveolar epithelium. This neutral mucin
will stain red with an Alcian blue/PAS combination stain. They are also both positive for
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 9 Atypical lobular endocervical glandular
hyperplasia (on the right) shows nuclear atypia, while
there is an absence ofnuclear atypia in lobular endocervical
glandular hyperplasia (on the left)
HIK1083 and MUC6, and usually negative for
ER and PR (Mikami et al. 2004).
Molecular Features
Approximately half of LEGH have been found to
harbor mutations (GNAS, KRAS,andSTK11)
which suggests they are preneoplastic, rather than
a mere metaplastic lesion (Matsubara et al. 2014).
Gains in chromosome 3q and loss of 1p have been
reported in LEGH and adenoma malignum,
supporting LEGH as a preneoplastic lesion to adenoma malignum (Kawauchi et al. 2008).
Differential Diagnosis
Diffuse laminar endocervical glandular hyperplasisa (DEGH) is another benign glandular proliferation in the cervix. It involves the inner third of
the cervix and demonstrates a sharp demarcation
with the underlying cervical stroma. The glands
tend to be irregular, angulated, or star-shaped.
Atypical LEGH should be distinguished from
adenoma malignum (gastric-type adenocarcinoma) by the lack of destructive stromal invasion
and desmoplasia.
HPV-Associated Adenocarcinoma, Usual
and Mucinous-Types
Synonyms
Mucinous-type endocervical adenocarcinoma;
Usual-type endocervical adenocarcinoma.
Adenocarcinoma and Precursors, Pathology of the Cervix 9
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Definition
A human papillomavirus (HPV)-driven adenocarcinoma that exhibits invasion in the form of either
destructive stromal invasion or exophytic/
expansile-type invasion. HPV 18 and 16 account
for >90% of infections. They account for 15–25%
of all cervical cancers.
Clinical Features
• Incidence
The incidence varies between 1 and 6/100,000
women worldwide, affected by the implementation of nationwide vaccination programs.
The incidence of cervical adenocarcinomas
has increased relative to squamous cell carcinoma, due to increased detection and management of early squamous lesions on PAP smear.
• Age
The average age is 40 years and is younger
than that seen in HPV-independent invasive
endocervical adenocarcinomas.
• Sex
Female.
• Site
The majority originate from the cervical
transformation zone.
• Treatment
In general, early-stage lesions (stage IA1 and
IA2) without lymphovascular invasion and
Silva Pattern A (lack of destructive growth)
can be managed conservatively, such as
through cold knife cone, without the need for
lymph node dissection. Lesions of higher stage
or which exhibit lymphovascular invasion will
generally require a trachelectomy or radical
hysterectomy, lymph node sampling, and consideration of chemoradiation.
• Outcome
5-year survival for localized disease is 92–100%,
regional disease is 56%, and distant disease is
3–17%. The risk of lymph node spread and
recurrence is affected by the Silva Pattern,
where patterns A, B, and C correlate with a 0%,
4%, and 20–25% of risk of lymph node metastasis (Diaz De Vivar et al. 2013;Romaetal.
2015). Within pattern C tumors, those with dif-
fuse destructive and confluent growth had higher
rates of recurrent disease (Alvarado-Cabrero
et al. 2017). Tumors with micropapillary growth
had higher risk of lymph node metastases than
tumors without micropapillary growth
(Alvarado-Cabrero et al. 2019). Survival for
HPV - associated tumors is more favorable com-
pared to HPV-independent endocervical adeno-
carcinomas (Stolnicu et al. 2018a).
Macroscopy
Most often, these tumors are exophytic/polypoid.
Rarely, they can be indurated, nodular for diffuse/
barrel-shaped.
Microscopy
HPV-associated adenocarcinomas are typified by
conspicuous apical mitoses and karyorrhect ic
debris (Fig. 10). Luminal borders are smooth,
and nuclei are hyperchromatic, enlarged, have
coarse chromatin, and show loss of polarity. Various archiectural patterns such as cribriform, papillary/villoglandular, solid, and micropapillary
can be seen (Figs. 11 and 12).
HPV-associated adenocarcinoam of usual type
denotes a tumor where intracyotplasmic mucin is
seen in 0–50% of the tumor. Villoglandular architecture is captured under
usual-type and is no
longer considered a separate diagnostic entity.
HPV-associated adenocarcinoma of mucinous
type denotes a tumor where intracytoplasmic
mucin is seen in 50% of the cells. Mucinous
type can be further divided into: Mucinous NOS:
cells resemble normal endocervix with pale-
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 10 HPV-associated adenocarcionma of usual
type. Columnar cells with mucin depletion show conspicuous apical mitoses and apoptotic debris. There is nuclear
atypia, hyperchromasia, and loss of polarity
A
10 Adenocarcinoma and Precursors, Pathology of the Cervix
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Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 11 HPV-associated adenocarcinoma of
usual-type, cribriform growth pattern with destructive
growth
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 12 HPV-associated adenocarcinoma of
usual-type, papillary growth pattern
purple cytoplasm; Intestinal-type: containing
Goblet cell, enteroendocrine cell differentiation,
representing 50% of the tumor; Signet ring type:
signet ring cells are seen in 50% of the tumor;
and Stratified mucin-producing intraepithelial
carcinoma (ISMC) (covered separately)
(Stolnicu et al. 2018a).
HPV-associated adenocarcinomas are also
stratified by the three patterns of stromal invasion,
using the Silva classification system (Diaz De
Vivar et al. 2013). This pattern-based classification correlates pattern with risk of nodal metastases and survival. Pattern A: nondestructive
stromal invasion; well demarcated glands with
rounded contours, no destructive growth; and no
lymphovascular invasion (Fig. 13); Pattern B:
focal destruction by irregular glands, cell clusters,
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 13 HPV-associated adenocarcinoma of
usual-type, Silva pattern A growth pattern. Complex confluent glands about the underlying cervical stroma, with a
smooth interface
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 14 HPV-associated adenocarcinoma of
usual-type, Silva pattern B growth pattern. Small infiltrative nests and single cells are seen emanating from a Silva
pattern A tumor
or individual cells arising from a pattern A tumor
(Fig. 14); and Pattern C: Diffuse destructive invasion or confluent glands filling a 5 mm field
(Fig. 15).
Immunophenotype
p16 (a surrogate marker for high-risk HPV) is
positive in 95% of tumors (Fig. 16). There can be
rare p16 negative tumors that are due to
methylation-induced inactivation of p16 or loss
of heterozygosity. HPV in situ hybridization or
polymerase chain reaction is positive. The
tumors are negative for ER and vimentin and
show cytoplasmic staining for mCEA (Figs. 17
and 18).
Adenocarcinoma and Precursors, Pathology of the Cervix 11
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Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 15 HPV-associated adenocarcinoma of
usual-type, Silva pattern C growth pattern. Diffuse destructive growth with stromal desmoplasia
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 18 HPV-associated adenocarcinoma of
usual-type is negative for vimentin
The micropapillary pattern shows an inside-out
(reverse polarity) staining pattern with MUC1
(Stewart et al. 2018).
Molecular Features
KRAS and PIK3CA are frequently mutated.
A
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 16 HPV-associated adenocarcinoma of
usual-type shows block-like positivity for p16
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 17 HPV-associated adenocarcinoma of
usual-type is negative for ER
Differential Diagnosis
The major differential diagnostic consideration is
low-grade endometrioid carcinoma. A classic
panel of ER, vimentin, p16, and mCEA can be
helpful. End ometrioid adenocarcinoma will be
positive for ER and vimentin and negative for
p16 and mCEA, with the reverse profile in HPVassociated adenocarcinoma.
Drop metastases of serous carcinoma from
the endometrium and adnexa can also be positive for p16. Extensive gross examination and
sampling can help rule out spread of tumor from
elsewhere.
Usual-type adenocarcinoma with benignappearing squamous differentiation should not
be mistaken for adenosquamous carcinoma
(Stolnicu et al. 2022).
Invasive Stratified Mucin-Producing
Carcinoma
Synonyms
Invasive stratified mucin-producing intraepithelial
lesion (iSMILE).
12 Adenocarcinoma and Precursors, Pathology of the Cervix
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Definition
A human papillomavirus (HPV)-associated invasive
carcinoma that arises from reserve cells in the cervical transformation zone that retain their pluripotent
ability. In the World Health Organization (WHO)
5th edition classification, this is considered under the
umbrella of HPV-associated, mucinous adenocarcinoma. It has been formerly abbreviated as invasive
stratified mucin-producing intraep ithelial lesion
(iSMILE) and more currently as invasive stratified
mucin-producing carcinoma (ISMC).
Adenocarcinoma and Precursors, Pathology of the
Clinical Features
Cervix, Fig. 19 Invasive stratified mucin-producing car-
cinoma, showing invasive nests of neoplastic cells
• Incidence
ISMC constitutes 2–9% of cervical adenocarcinomas and 9–11% of HPV-associated adenocarcinomas (Hodgson et al. 2019).
• Age
The mean age of patients is around 45 years
(range: 34–64) (Lastra et al. 2016), on average
15 years older than patients who have isolated
SMILE.
• Sex
Female.
• Site
Cervical transformation zone.
• Treatment
Surgical resection with consideration of lymph
node sampling/dissection and adjuvant
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 20 Invasive stratified mucin-producing car-
cinoma, showing invasive nests where the cells contain
intracytoplasmic mucin throughout
therapy.
• Outcome
ISMC is considered an aggressive subtype of
HPV-associated adenocarcinoma. One-third of
cases present with lymph node metastases, and
half develop distant metastases, to the lung,
liver, and skin (Stolnicu et al. 2020; Horn
et al. 2019).
intraepithelial mucin can be subtle or conspicuous.
The nuclei are round/ovoid and irregular. There can
be peripheral palisading. Apoptotic bodies and
mitotic figures, typical of HPV-associated tumors,
are readily visible. Peritumoral and intratumoral
neutrophilic infiltratesareacommonfeature.The
majority show a destructive growth pattern (Silva
Macroscopy
Most tumors are polypoid-exophytic and > 2cm
in size.
pattern C) (Stolnicu et al. 2020).
The morphologic appearance can be quite varied. Architectural patterns of insular, glandular,
solid, papillary, trabecular, micropapillary, and sin-
Microscopy
Typically, ISMC comprises of invasive solid nests
of neoplastic cells, similar to squamous cell carcinoma (Fig. 19). It differs from squamous cell carcinoma by the presence of intraepithelial mucin,
stratified throughout the nests (Fig. 20). The
gle cell can be seen. Cytologic variability in the
form of delicate eosinophilic cytoplasm and clear
cytoplasm are possible, as well as histiocytoid,
glassy cell-like, and signet ring-like cells. Mucin
extravasation, bizarre nuclear atypia, and squamous
differentiation in the form of cells with dense
Adenocarcinoma and Precursors, Pathology of the Cervix 13
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eosinophilic cytoplasm lacking intercellular bridges
and keratinization are rare (Stolnicu et al. 2020).
ISMC can arise from SMILE, or from highgrade squamous intraepithelial lesion (HSIL),
adenocarcinoma in situ (AIS), or a combination
thereof. ISMC can be found in pure form, or
mixed with other carcino ma types
(HPV-associated usual-ty pe or mucinous-type
adenocarcinoma, adenosquamous carcinoma,
and high-grade neuroendocrine carcinoma)
(Stolnicu et al. 2020).
A single ultrastructural story of ISMC showed
mucous-like vacuoles, abundant mitochondria,
and intracytoplasmic lumen, without
tonofilaments, suggesting it has more similarity
to adenocarcinoma than a squamous cell carcinoma (Onishi et al. 2016).
Immunophenotype
PAS and mucicarmine will stain the intracytoplasmic mucin in the neoplastic cells (Fig. 21).
p16 shows diffuse block-like positivity. p40
and p63 are expressed in the peripheral cells of
the tumor cell nests, independent of the presence
of peripheral palisading (Fig. 22). CK7 is positive
in almost all cases. Less than 25% of cases are
positive for PAX8, ER/PR, and vimentin
(Stolnicu et al. 2018b). Approximately half stain
positive for MUC6 but are negative for HIK1083
(Stolnicu et al. 2018b).
Molecular Features
In a small series of five ISMC, two harbored
mutations in STK11 (Hodgson et al. 2020).
Differential Diagnosis
In adenosquamous carcinoma, there are distinct
components of glandular and squamous
neoplasia.
Both ISMC and squamous cell carcinomas can
comprise of infiltrative solid nests. Squamo us cell
carcinomas will have intercellular bridges, keratinization, and diffuse expression of p63 and p40.
Squamous cell carcinoma will not contain intracellular mucin.
Mucoepidermoid carcinoma is not formally
recognized by the WHO 5th edition, but it is
identical to that seen in the salivary gland and
can look similar to ISMC. It is characterized by
the presence of 3 cell types: (1) epidermoid/
squamoid cells, (2) mucous cells, and (3) intermediate cells and lacks overt glandular differentiation. Mucoepidermoid carcinomas tend to have a
more squamoid appearance and lack an associated
intraepithelial lesion, intralesional neutrophilic
infiltrates, and conspicuous apoptotic debris.
Molecular analysis has shown CRTC1-MAML2
fusion, rearrangements of CRTC1, and aberrations of MAML2 (Lennerz et al. 2009).
The micropapillary pattern in ISMC can mimic
serous carcinoma. Serous carcinoma will lack
mucin and have diffuse high-grade nuclear atypia.
A search for an in situ lesion (SMILE, AIS, and
A
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 21 Invasive stratified mucin-producing car-
cinoma. PASD stains intracytoplasmic mucin within the
neoplastic cells
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 22 Invasive stratified mucin-producing car-
cinoma. p40 stains the periphery of the invasive nests
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HSIL) will also be helpful for a diagnosis
of ISMC.
ISMC can have cytoplasmic clearing and
hyaline-like globules, mimicking the appearance
of solid-pattern clear cell carcinoma. Again, a
search for an in situ lesion is informative for
ISMC. More prototypical architectural patterns,
such as tubulocystic and papillary, favor clear
cell carcinoma. Care should be taken with
HNF-1β and Napsin-A, as they stain 15% of
ISMC as well (Stolnicu et al. 2020).
Gastric-Type Adenocarcinoma
Synonyms
Adenoma malignum; Minimal deviation
adenocarcinoma.
Definition
An human papillomavirus (HPV)-independent
adenocarcinoma of the uterine cervix exhibiting
gastric or pyloric type differentiation.
• Outcome
Half of patients will present with advanced
stage disease (FIGO stage II), lymph node
metastases, and one-third of patients with have
distant disease (abdominal, omentum, brain,
and bone). The 5-year overall survival is 42%
(Karamurzin et al. 2015).
Macroscopy
They form large polypoid or indurated masses.
Circumferential cervical infiltration can cause a
classic “barrel-shaped” cervix on imaging.
Microscopy
Microscopically, these tumors have 3 classic features: 1) voluminous cytoplasm; 2) pale, clear, or
foamy cytoplasm; and 3) distinct cell borders
Clinical Features
• Incidence
The incidence is less than for HPV-associated
endocervical adenocarcinoma. It constitutes
10–15% of all cervical adenocarcinomas
(Stolnicu et al. 2018a), with slightly higher
proportions in Japan (Karamurzin et al.
2015). A proportion of cases are associated
with Peutz-Jeghers Syndrome (germline muta-
tions in STK11).
• Age
The mean age is 50 years, but a wide range has
been described. The age is slightly older than
for HPV-associated adenocarcinomas
(Stolnicu et al. 2019b).
• Sex
Female.
• Site
This tumor usually arises in the endocervical
canal but can extend into the uterine corpus.
• Treatment
These are aggressive neoplasms that usually
necessitate radical hysterectomy and adjuvant
treatment.
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 23 Gastric-type adenocarcinoma showing
foamy cytoplasm with distinct cell borders and nuclear
atypia
Adenocarcinoma and Precursors, Pathology of the
Cervix, Fig. 24 Gastric-type adenocarcinoma showing
eosinophilic cytoplasm
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