Histopathology 2020, 76, 112–127. DOI: 10.1111/his.
13995
REVIEW
Cervical adenocarcinoma: integration of HPV status, pattern
of invasion, morphology and molecular markers into
classification
Kay J Park
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Park K J
(2020) Histopathology 76, 112–127. https://doi.org/10.1111/his.13995
Cervical adenocarcinoma: integration of HPV status, pattern of invasion, morphology and
molecular markers into classification
Cervical adenocarcinoma is a heterogenous group of
tumours with various aetiologies, molecular drivers,
morphologies, response to treatment and prognosis. It
has become evident that human papillomavirus
(HPV) infection does not drive all adenocarcinomas,
and appropriate classification is critical for patient
management, especially in the era of the HPV vaccine
and HPV-only screening. Identified as one of the most
important developments in gynaecological pathology
during the past 50 years, the separation of cervical
adenocarcinomas into HPV-associated (HPVA) and
HPV-independent has resulted in a transformation of
the classification system for cervical adenocarcino-
mas. HPVA has been traditionally subclassified by
morphology, such as usual type (UEA), mucinous
and villoglandular, etc. However, it has become evi-
dent that cell type-based histomorphological classifi-
cation is not clinically meaningful, and the newly
Keywords: adenocarcinoma, cervix, classification, HPV, pattern
Introduction
Cervical cancer is the fourth most frequent cancer in
women, with an estimated 570 000 new cases in
2018 representing 6.6% of all female cancers world-
wide [World Health Organisation (WHO)].1 The vast
majority of cervical cancers are aetiologically linked
to high-risk human papillomavirus (HPV) infection,
Address for correspondence: K J Park, Memorial Sloan Kettering
Cancer Center, New York, NY 10065, USA. e-mail: parkk@
mskcc.org
© 2019 John Wiley & Sons Ltd.
proposed International Endocervical Adenocarcinoma
Criteria and Classification (IECC) is a necessary and
relevant break from this prior system. Non-HPV-asso-
ciated adenocarcinomas can be divided by their dis-
tinct morphology and molecular genomics with very
different responses to standard therapies and potential
for future targeted therapies. These include gastric-
type, clear-cell, mesonephric and endometrioid adeno-
carcinomas. So-called ‘serous’ carcinomas of the cer-
vix probably represent morphological variants of UEA
or drop metastases from uterine or adnexal serous
carcinomas, and the existence of true cervical serous
carcinomas is in question. This review will discuss
the advances since WHO 2014, and how HPV status,
pattern of invasion as described by Silva and col-
leagues, histological features and molecular markers
can be used to refine diagnosis and prognostication
for patients with cervical adenocarcinoma.
with squamous cell carcinoma (SCC) being by far the
most common histological subtype. Adenocarcinomas
comprise approximately 25% of cervical cancers and,
unlike cervical SCC, which with rare exception is
caused by HPV, adenocarcinomas of the cervix are a
much more heterogeneous group of tumours, with
approximately 15% being unrelated to HPV infec-
tion.2 As has been shown in other organs, it is now
becoming increasingly apparent that HPV status sig-
nificantly affects prognosis and that the different his-
tological subtypes of endocervical adenocarcinoma
(ECA) have different molecular underpinnings that
 Cervical adenocarcinoma: a new paradigm 113

could have important clinical consequences for future Table 1. Endocervical adenocarcinoma classification by
targeted therapies. World Health Organisation 2014 compared to International
Usual HPV-associated ECA still comprises the Endocervical Criteria and Classification (IECC)
majority of glandular neoplasia in the cervix. The
WHO 2014 IECC 2018
International Federation of Gynecology and Obstetrics
(FIGO) stage is the most important parameter for HPV-associated Non-HPV-associated
determining treatment and prognosis; however, in Usual type (HPVA) (NHPVA)
early-stage tumours, there is less granularity and Mucinous Usual type Gastric type
refinement regarding which patients benefit from rad- carcinoma, NOS
ical versus conservative therapy (e.g. pelvic lymph
Gastric type Villoglandular Clear cell
node dissection).
In this review, the recently proposed International Intestinal type Mucinous, NOS Mesonephric
Endocervical Adenocarcinoma Criteria and Classifica-
Signet ring cell Mucinous, intestinal Endometrioid
tion (IECC) that stratifies ECA by HPV status, the var-
ious subtypes of non-HPV-associated ECA, and the Villoglandular Invasive stratified
Pattern Classification System as proposed by Silva mucin-producing
and colleagues as novel methods to substratify ECA Endometrioid Micropapillary
into clinically relevant groups will be discussed.
Clear cell ‘Serous’-like

Classification of endocervical
adenocarcinoma
The 2014 World Health Organisation (WHO) Classifi-
cation of cervical tumours categorises ECA based on
morphological, predominantly cytoplasmic, features.3
This system does not distinguish the tumours based
on any clinically relevant features, but rather on tra-
ditional histomorphology such that mucinous adeno-
carcinoma is one category, subdivided into
endocervical/intestinal type mucinous (HPV-positive)
and gastric-type mucinous (HPV-negative). In con-
trast, the IECC system proposed in 2018 attempts to
categorise ECA by aetiology (HPV status) and mor-
phology with molecular and outcomes evidence to
further support the classification as being more clini-
cally relevant2 (Table 1).
INTERNATIONAL ENDOCERVICAL
ADENOCARCINOMA CRITERIA AND
CLASSIFICATION (IECC)
The IECC was a multinational study comprised of
409 cases of ECA from various countries, including
the United States, Romania, Japan, Mexico and
Israel. The aim of the study was to differentiate HPV-
associated (HPVA) and non-HPV-associated adeno-
carcinomas by morphology alone, correlate with
ancillary studies to confirm HPV status, and deter-
mine outcomes based on these features. Tumours
were first stratified based on the presence of HPV-as-
sociated features – easily identifiable luminal or
‘floating’ mitoses and/or apoptotic bodies at scanning
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
Serous
Mesonephric
HPV, Human papillomavirus; NOS, Not otherwise specified.
magnification (920 or 940). If these were not easily
identifiable, visible only on high power or not visible
at all (no or limited HPV-associated features), this
was taken to indicate a tumour unrelated to HPV
infection (Figure 1). Then the tumours were further
classified based on cytoplasmic features to keep in
continuity with traditional classifications as delin-
eated by the WHO. Immunohistochemistry (IHC)
[p16, p53, vimentin and progesterone receptor (PR)]
and ribonucleic acid (RNA) in-situ hybridisation
(RISH) for HPV were used to validate this classifica-
tion scheme. This simple histology-based method was
highly concordant with IHC and RISH results, p16
and HPV RISH being positive in 90% and 95% of
usual ECA, respectively. In contrast, only 3% of
tumours classified as non-HPV-associated by mor-
phology were positive for HPV RISH. Interestingly,
37% of non-HPV-associated adenocarcinomas
expressed diffuse p16, which highlights the fact that
p16 is only a surrogate marker for high-risk HPV
and that other non-HPV-related molecular alterations
cause p16 overexpression in tumours. There were
also significant clinical differences between HPVA
and non-HPV-associated adenocarcinomas. Non-
HPV-associated adenocarcinomas were larger,
occurred in older patients and presented at a higher
stage than HPVA ECAs. Subsequent studies have
114 K J Park

HPVA NHPVA
(HPV Associated) (Non-HPV Associated)

No easily identifiable mitotic

Apical mitotic figures and apoptotic
bodies at scanning magnification
If features not seen at scanning,
cursory exam at 200x to detect
additional cases
activity and apoptotic bodies at
Figure 1. International
scanning mag
Endocervical Adenocarcinoma
Criteria and Classification
Focal or equivocal HPVA features at (IECC) algorithm for
200x – limited HPVA, tentatively determining human
classified as NHPVA papillomavirus association
based on morphology alone.

borne out the original findings, confirming that IECC
is simple, practical and reproducible with improved
interobserver agreement compared to WHO in classi-
fying ECAs, and that this has important clinical
applications with non-HPV-associated adenocarcino-
mas having significantly worse overall and disease-
free survival when compared to HPVA ECAs.4–6
HPV-ASSOCIATED ENDOCERVICAL
ADENOCARCINOMA
According to the IECC, the defining characteristic of
HPV-associated adenocarcinoma is the presence of
easily identifiable luminal mitoses and apoptotic
bodies at scanning magnification (Figure 2). While
several morphological variants have been described
(see Table 1), separating HPVA by morphology
alone has no real practical importance. There have
been early reports of certain variants being more
aggressive; in particular, invasive stratified mucin-
producing carcinoma (ISMC) and micropapillary
adenocarcinoma.4,7 ISMC is a recently described
morphological variant of HPVA ECA, associated
with stratified mucin-producing intraepithelial
lesion (SMILE), an in-situ glandular lesion charac-
terised by intracytoplasmic mucin involving the full
thickness of the epithelium without the typical
columnar appearance and apical mucin of conven-
tional endocervical adenocarcinoma.8 Micropapillary
pattern endocervical adenocarcinoma is also a newly
described histological pattern most commonly associated
with HPV infection, and is composed of small, tightly
cohesive papillary groups of tumour cells, usually
within a clear space mimicking lymphovascular chan-
nels.7 While these patterns may indeed eventually prove
to be aggressive variants, more studies are needed to
validate these initial findings. It should be noted that
HPVA ECAs may have more than one pattern present
within a single tumour. This is particularly true of
ISMC, which have phenotypical variability that
may reflect the reserve cell nature of the HPV-infected
cells.
NON-HPV-SSSOCIATED SUBTYPES OF
ENDOCERVICAL ADENOCARCINOMA
Once the HPV status of a tumour is established using
the IECC, the HPV-negative subtypes can be cate-
gorised further based on previously existing morpho-
logical (cytoplasmic and architectural) criteria, as
follows:
• Gastric type (previously known as minimal devia-
tion adenocarcinoma or adenoma malignum)
• Clear-cell carcinoma
• Mesonephric carcinoma
• Endometrioid adenocarcinoma
Important points to be noted include the fact that
according to the IECC, primary cervical endometrioid
adenocarcinomas are exceedingly rare and probably
arise in the setting of cervical endometriosis, and that
serous carcinomas of the cervix probably do not exist.
Previous reports of ‘endometrioid’ ECA are, by and
large, UEA with mucin depletion which imparts an
appearance of tall columnar cells with elongated
pseudostratified nuclei, resembling endometrioid mor-
phology; however, true endometrioid adenocarcino-
mas of the cervix akin to uterine corpus and ovarian
counterparts most probably arise in the setting of
endometriosis and are not related to HPV infection.
GASTRIC-TYPE ENDOCERVICAL
ADENOCARCINOMA
First coined in 2007 by Kojima et al., gastric-type
endocervical adenocarcinoma (GEA) is a non-HPV-as-
sociated mucinous adenocarcinoma that is the second
most common subtype of cervical adenocarcinoma
and most common non-HPV-associated adenocarci-
noma subtype, comprising approximately 10% of all
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
 Cervical adenocarcinoma: a new paradigm 115

A B

C D

E F

Figure 2. Human papillomavirus (HPV)-associated endocervical adenocarcinoma, morphological variants. A, Usual type (UEA) with tall
columnar cells, minimal mucin, numerous apoptotic bodies and luminal mitotic figures visible at low to intermediate power [haematoxylin
and eosin (H&E)]; B, villoglandular type with long, slender villi, exophytic and minimal destructive stromal invasion; C, mucinous not other-
wise specified (NOS) type with abundant endocervical-type mucin; D, mucinous intestinal type with abundant goblet cells reminiscent of
intestinal glands; E, invasive stratified mucin producing carcinoma (iSMC) with nests of mucinous cells stratified throughout the entire thick-
ness of the tumour and peripheral palisading of nuclei; F, micropapillary type with tumour papillae within spaces with retraction and associ-
ated lymphovascular invasion; G, whole slide showing diffuse strong block-like p16 reactivity in HPV-associated adenocarcinoma H&E.

© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.

116 K J Park
cervical adenocarcinomas.2,9 Perhaps better known
as minimal deviation adenocarcinoma (MDA) or ade-
noma malignum, it is now recognised that GEA
demonstrates a range of morphological differentiation,
from extremely well-differentiated (MDA) to poorly
differentiated with mucin poor glands, single cells
and clusters.10,11 Regardless of architectural differen-
tiation, these tumours are extremely aggressive with
significantly worse overall and disease-specific sur-
vival compared to UEA, when matched for stage.12
GEA also more frequently presents at a higher stage
and can metastasise to sites not typical for UEA, such
as brain, liver and omentum.12 In Kojima’s paper,
gastric morphology was defined as tumour cells with
distinct cell borders containing voluminous clear to
pale eosinophilic cytoplasm.9,13 Subsequently, Stewart
et al. described the cytoplasm of these tumours as
being more foamy than clear, similar to adenocarci-
nomas of the prostate and pancreas.14 Not infre-
quently, intestinal type goblet cells and
neurosecretory granules can also be present, impart-
ing a truly gastrointestinal morphology and pheno-
type.15 GEA lacks the numerous floating mitoses and
apoptotic bodies of HPVA adenocarcinomas, although
mitotic figures can be seen at high magnification in
small numbers. Overall, GEA morphologically resem-
ble pancreatobiliary adenocarcinomas, and should be
considered in the differential diagnosis when such a
tumour is encountered in the cervix (Figure 3).
Because these tumours are not HPV-driven, gener-
ally they are negative or only patchily positive for
p16 immunohistochemistry, with rare exceptions.16
While p16 should be able to distinguish HPVA from
non-HPV-associated adenocarcinomas most of the
time, it is not entirely sensitive or specific for HPV
infection. In addition, there have been reports of
tumours with mixed UEA/GEA morphology which, by
immunohistochemistry, declare themselves as GEA-
like or UEA-like17 (Figure 4). HPV RISH is the most
sensitive methodology to detect and visualise HPV in
tumour cells and should be utilised if available.2
Other immunohistochemical markers to note include
PAX8 positivity in approximately 68% of GEA (useful
to distinguish from pancreatobiliary adenocarci-
noma), aberrant p53 in 40–50% (null or diffuse
strong expression) suggesting underlying TP53 muta-
tions, hepatocyte nuclear factor 1 beta (HNF1-b) posi-
tivity in the majority of tumours [not helpful in
distinguishing from clear-cell carcinoma (CCC)] and
positive HIK1083 (a marker of gastric mucin). A use-
ful stain for detecting gastric mucin is the periodic
acid phosphatase/Alcian blue (PAS/AB)-combined
histochemical stain. In lesions with predominant
gastric neutral mucin the PAS will predominate,
imparting a magenta/pink heavy staining pattern. In
normal endocervical glands with acidic mucin, the
dark navy-blue Alcian blue stain will dominate. It
should be noted that any intestinal goblet cells will
be Alcian-blue dominant, even in the setting of a gas-
tric lesion (Figure 5).
The molecular underpinnings of GEA are only begin-
ning to be elucidated with the widespread application
of next-generation sequencing (NGS). The association
of Peutz–Jeghers syndrome (PJS) with MDA has been
well established, caused by a germline mutation of the
serine/threonine kinase 11/liver kinase B1 (STK11/
LKB1) tumour suppressor gene that has an autosomal
dominant inheritance pattern.18–20 Sporadic cases of
MDA have also been shown to harbour STK11 muta-
tions.21 Now that it is understood that MDA is within
the morphological spectrum of GEA, it has become evi-
dent that STK11 mutations, germline and sporadic,
are associated with gastric-type adenocarcinoma.22
Other molecular alterations that have been reported
include somatic mutations in TP53, KRAS, CDKN2A,
ERBB2/ERBB3, GNAS, DPC4, ARID1A, BRCA2 and
PIK3CA, among others.23–25 This mutation profile is
not dissimilar to pancreatic adenocarcinoma, and the
morphological similarities to pancreatic tumours may
not be entirely coincidental.
The precursor lesion of GEA is thought to encom-
pass a range of metaplastic/proliferative mucinous
glands with gastric-type mucin and a spectrum of
cytological atypia, including simple gastric/pyloric
metaplasia of endocervical glands, lobular endocervi-
cal glandular hyperplasia (LEGH)/pyloric gland meta-
plasia (PGM), with or without atypia and
adenocarcinoma in-situ of gastric type (gAIS). gAIS
shows cytological features similar to atypical LEGH
without the typical architectural configuration of
LEGH, but rather affecting pre-existing endocervical
glands. For a more detailed discussion on this topic,
please see the paper in this issue: ‘Gastric-type muci-
nous carcinoma of the cervix and its precursors – his-
torical overview’, by Y. Mikami.
CLEAR-CELL CARCINOMA
Clear-cell carcinoma of the cervix comprises approxi-
mately 3% of all cervical adenocarcinomas and is
aetiologically unrelated to HPV infection. Morphologi-
cally, it is similar to CCC of the endometrium or
ovary, with characteristic architectural and cytologi-
cal features. These tumours typically present with
tubulocystic, papillary or solid growth (often in com-
bination) composed of cells that have clear, glycogen-
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
 Cervical adenocarcinoma: a new paradigm 117

A B

C D

Figure 3. Non-human papillomavirus (HPV)-associated endocervical adenocarcinoma, gastric type (GEA). A, Diffuse and deep invasion of
cervical wall by well-formed glands with various shapes and sizes [haematoxylin and eosin (H&E)]; B, mixture of simple glands and small
irregular clusters and single cells in stroma; C, perineural invasion by well-differentiated glands, with apical mucin and no stromal reaction
adjacent, to irregular mucin poor glands with stromal reaction would fall into the category of minimal deviation pattern; D, abundant foamy
cytoplasm with small pyknotic nuclei and no mitoses or apoptotic bodies; E, intestinal goblet cells can be seen in GEA, similar to HPV-associ-
ated adenocarcinoma H&E.

filled cytoplasm (in contrast to the foamy mucinous
cytoplasm of gastric type) and a large round nucleus
with a single prominent nucleolus. The cells line the
tubules, cysts and papillae in a single layer with min-
imal overlapping or tufting, and often protrude above
the basement membrane, imparting the appearance
of a hobnail. Dense eosinophilic stromal hyaline depo-
sition can be seen, which may be exuberant. The cells
may have minimal or eosinophilic cytoplasm, making
the diagnosis of CCC less obvious (Figure 6).
Aetiologically, CCCs of the cervix and vagina have
been linked to in-utero exposure to diethylstilboestrol
(DES), an oral synthetic oestrogen given to pregnant
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
women between 1947 and the early 1970s to prevent
miscarriage. An estimated 2–4 million women were
treated with DES or a similar agent (dienestrol) in the
United States during this time.26 The association of
vaginal CCC and in-utero DES exposure was first
described by Herbst and Scully in 1970.27 Vaginal
cancers were extremely rare, usually of squamous his-
tology, and occurred in older postmenopausal women.
In the report of Herbst and Scully, there were six CCCs
of the vagina in young women aged 15–22 years.
The definitive association was reported by Herbst in
1971, where a 40-fold increased risk of developing
cervical or vaginal CCC was noted in exposed patients.
118 K J Park

A B

Figure 4. Mixed features of usual type and gastric type can be seen within the same tumour. A, Gastric type with portions showing features
of usual type, including numerous mitotic figures and apoptotic bodies (lower half). The tumour was p16-negative and human papillo-
mavirus (HPV)-negative by RNA in-situ hybridisation (not shown) [haematoxylin and eosin (H&E)]; B, usual type with portions resembling
gastric type (voluminous clear cytoplasm), although all components showed easily identifiable mitoses and apoptotic bodies H&E; C, positive
HPV RNA in situ hybridisation seen as punctate dots in the nuclei and cytoplasm in both components.

A B

Figure 5. Histochemical staining in gastric type adenocarcinoma (GEA). A, GEA with intestinal goblet cells showing mucosal infiltration in
small bowel, difficult to recognise on haematoxylin and eosin (H&E) alone; B, periodic acid Schiff-Alcian Blue (PAS-AB)-combined histochem-
ical stain shows magenta pink neutral mucin of GEA in part of the intestinal gland, which shows dark blue acidic mucin of native small
bowel.

In the pre-DES era, CCC were frequently diagnosed in
patients over the age of 50, but in the DES era the
patients were typically aged <30 years. There seems
to be a bimodal peak in age distribution, with a large
peak at age 19 and a smaller but real peak at age
42.28 However, CCC is rare even among DES-exposed
women, suggesting that DES is an incomplete
carcinogen, and other genetic or environmental fac-
tors may be important in its pathogenesis.
Clinically, CCC of the cervix seems to have the
same prognosis as usual-type adenocarcinoma when
controlled for stage. Interestingly, in DES-exposed
patients the peak age is 19 years, with the tumour
tending to occur in the upper third of the vagina
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
 Cervical adenocarcinoma: a new paradigm 119

A B

C D

Figure 6. Clear-cell carcinoma. A, Tubulocystic pattern with single layer of hobnail cells with clear cytoplasm protruding into lumen
[haematoxylin and eosin (H&E)]; B, papillary (top half) and solid (bottom half) growth patterns within same tumour H&E; C, solid growth
pattern with clear to eosinophilic cytoplasm (H&E); D, dense, eosinophilic hyaline deposition in tumour stroma, a finding that can be diffuse
or focal (H&E).

and/or ectocervix, while in non-DES-exposed patients
there is a wide age range (paediatric to post-
menopausal) with the tumours predominantly arising
in the endocervix.28 It should be noted that, like CCC
involving other extra-uterine sites, cervical CCC can
arise in the setting of endometriosis, although only a
single case has been reported.29
There is very limited data on the molecular alter-
ations that drive cervical CCC. One study from 1996
found no mutations in KRAS, HRAS, WT1, TP53 or
ER, although p53 immunohistochemistry showed
aberrant staining in some cases.30 The study found
microsatellite instability in all DES exposed and 50%
of non-DES exposed cases, although it should be
noted that the investigators assessed genetic instabil-
ity of microsatellite repeat sequences using a panel of
15 microsatellite markers, and MSI was quantified by
polymerase chain reaction (PCR) amplification of
paired tumour-normal DNA from the same patient.
While this supports evidence of defective DNA mis-
match repair and suggests that altered DNA repair
may be a critical molecular feature in the develop-
ment of these tumours, there was no mutational
analysis of the mismatch repair genes. Alternatively,
MSI may reflect an indirect effect of oestrogenic stim-
ulation, with DNA replication errors accumulating as
a result of inappropriate cell division.
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
Although it seems logical to consider DNA mis-
match repair defect and the possible association of
Lynch syndrome in cervical CCC, there has been no
definitive evidence to support this. The one case
report of cervical CCC in a Lynch patient is not
convincing for a cervical origin, given that the
tumour measured 4.2 cm and obliterated the entire
cervix with involvement of the lower uterine seg-
ment.31
Immunohistochemical staining patterns for cervical
CCC are no different from that of CCC of the endome-
trium or ovary. Cervical CCC is usually (although not
always) negative for oestrogen receptor (ER) and PR,
and positive for PAX8, HNF1-beta and Napsin-A,
with p16 and p53 ranging from negative to diffuse
and strong.32 CEA is negative in CCC, which may be
useful in differentiating from GEA, which can have
abundant clear/foamy cytoplasm mimicking CCC.
Another possible utility for histochemical stains may
be the use of PAS with diastase in differentiating CCC
from GEA, as the glycogen of CCC should disappear
with diastase while the mucin of GEA should not.
Another potential differential diagnosis is mesoneph-
ric carcinoma, which can mimic CCC (see section on
mesonephric carcinomas below). The immunohisto-
chemical overlap between these two tumours is
nearly complete, with the exception of Napsin-A and
120 K J Park
racemase, which would be positive in CCC but nega-
tive in mesonephric tumours.33
MESONEPHRIC CARCINOMA
Mesonephric carcinoma of the cervix comprises less
than 1% of all cervical adenocarcinomas, and is
derived from persistent mesonephric/Wolffian rem-
nants that involute in females during embryogenesis.
The Wolffian duct is named for Caspar Friedrich
Wolff, a physiologist and founder of embryology
who first described the embryology of the mesoneph-
ric system that connects the kidney to the cloaca.
Early in embryogenesis, the mesonephric (Wolffian)
ducts are present adjacent to Mullerian (parameso-
nephric) ducts and, in the absence of anti-Mullerian
hormone secreted by Sertoli cells in the developing
testis, the mesonephric ducts regress while the Mul-
lerian ducts fuse to form the fallopian tubes, uterus,
cervix and upper portion of the vagina. In males,
the Wolffian ducts give rise to the seminal vesicles,
epididymis, vas deferens and efferent ducts of the
testis.
Mesonephric remnants in the cervix may occur in
up to one-third of normal cervices, usually in the
deep lateral wall (at 3 and 9 o’clock positions).34,35
Carcinomas that arise from these remnants, therefore,
tend also to be located deep in the cervical wall and
may not necessarily involve the mucosal surface.
They can extend into parametria or cause a diffuse
thickening of the cervical wall forming a barrel-
shaped cervix. Mesonephric carcinomas can be focal,
arising in a background of mesonephric hyperplasia,
or diffusely infiltrative with obliteration of normal
anatomical structures. The morphology can be widely
variable, ranging from tubular, ductal, solid, papillary
and retiform (branching, slit-like spaces with intralu-
minal fibrous papillae), all of which can be associated
with a spindle cell component and heterologous ele-
ments imparting the appearance of carcinosar-
coma.36,37 The tubular pattern is composed of
densely packed tubules lined by cuboidal cells with
minimal cytoplasm and can show eosinophilic col-
loid-like intraluminal secretions. The nuclei are ovoid
with regular to irregular nuclear membranes, often
grooved with pseudoinclusions, reminiscent of papil-
lary thyroid carcinoma. Differentiation from meso-
nephric hyperplasia can be made based on the degree
of gland crowding, infiltrative growth, increased mito-
tic activity, intraluminal cellular debris and nuclear
atypia. There is no established grading scheme for
mesonephric carcinomas (Figure 7). Depending on
the dominant architectural pattern, tumours in the
differential diagnosis can include CCC and endome-
trial endometrioid adenocarcinoma that infiltrates the
cervical wall.38 A mixed mesonephric–high-grade
neuroendocrine carcinoma has also been described
that shared mutations and MYCN amplification in
both components, unassociated with HPV.39
The immunohistochemical profile of cervical meso-
nephric carcinoma is characterised by positive PAX8,
GATA3, HNF1b, calretinin and CD10 (apical) and
negative ER, PR, CEA with variable p16; p53 is wild-
type (WT). Thyroid transcription factor-1 (TTF-1),
while reported to be positive in mesonephric-like car-
cinomas in the upper tract, tends to be negative in
the cervix.40
Molecular alterations that drive cervical mesoneph-
ric carcinomas include canonical KRAS mutations in
most with a smaller number harbouring NRAS muta-
tions. ARID1A/B are also commonly mutated. Chro-
mosomal abnormalities, including gain of 1q, loss of
1p and gain of chromosomes 10 and 12 are com-
mon.41 HPV is not a causative agent of mesonephric
carcinoma.32,42
These tumours can have aggressive behaviour,
with late recurrences and metastases to distant sites,
especially lung, even when presenting at a low
stage.43
ENDOMETRIOID ADENOCARCINOMA
The terminology ‘endometrioid adenocarcinoma’ of
the cervix has traditionally been used to denote usual
HPV-associated endocervical adenocarcinoma with
mucin depletion. It is now recognised that true
endometrioid adenocarcinomas of the cervix are
exceedingly rare, comprising 1% of all cervical adeno-
carcinomas, and are not aetiologically related to HPV
infection.2 Using IECC criteria, these tumours have
no or limited HPVA features and have confirmatory
endometrioid features consisting of at least focally
identified low-grade endometrioid glands lined by
columnar cells with pseudostratified nuclei demon-
strating no more than moderate atypia, with or with-
out squamous differentiation and/or endometriosis.
Overall, they resemble endometrial endometrioid ade-
nocarcinomas and must be differentiated from direct
extension of tumour from the uterine corpus (Fig-
ure 8).
Due to their rarity, the molecular alterations and
prognosis of these tumours are unknown. The three
cases in the IECC study were HPV-negative. It is
likely that true cervical endometrioid adenocarcinoma
arises in a setting of endometriosis, like other extra-
uterine endometrioid adenocarcinomas.
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
 Cervical adenocarcinoma: a new paradigm 121

A B

C D

Figure 7. Mesonephric carcinoma. A, Diffuse involvement of cervical wall by a glandular, papillary and solid adenocarcinoma [haematoxylin
and eosin (H&E)]; B, tumour cells have uniform nuclei with open chromatin that resemble papillary thyroid carcinoma cells H&E; C, the cells
can become more spindled and compressed, but still maintain nuclear uniformity with minimal mitoses or apoptotic bodies H&E; D, small
tubular glands diffusely infiltrating cervical wall eliciting minimal stromal reaction H&E; E, nuclei are round, uniform, with open chromatin
and occasional pinpoint nucleoli, and there is a focus of eosinophilic intraluminal secretion (top right) most commonly seen with this archi-
tectural pattern H&E.

negative, WT1-positive with poor outcomes, while

HPV-ASSOCIATED SEROUS-LIKE CARCINOMA
The existence of cervical serous carcinoma is debat-
able. Using IECC criteria, these tumours show papil-
lary and/or micropapillary architecture lined by cells
with diffuse highly atypical nuclei in stratified and
pseudostratified cells. If analogous to high-grade ser-
ous carcinomas of the adnexa or endometrium, these
tumours should be driven by TP53 mutations and
not be associated with concurrent serous carcinomas
at those other sites. Studies of so-called serous carci-
nomas of the cervix have shown a bimodal age distri-
bution (pre- and postmenopausal), and in the era of
serial sectioning and extensively examining the fim-
briated end (SEE-FIM) of the fallopian tube, it has
become evident that some of these tumours are in
fact drop metastases from occult tumours in the
adnexa.44 The postmenopausal cases were HPV-
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
the premenopausal cases were HPV-positive, WT1-
negative with good overall outcomes. These findings
suggest that true serous carcinomas of the cervix do
not exist, and in the premenopausal setting these
may represent high-grade papillary morphological
variants of usual HPV-associated endocervical adeno-
carcinoma (Figure 9).
SILVA PATTERN-BASED CLASSIFICATION OF
ENDOCERVICAL ADENOCARCINOMAS
The treatment of cervical adenocarcinomas is largely
based on stage at the time of presentation, and in early
stages this is based on pathological parameters as
determined by microscopic examination of the tumour,
in particular the depth of stromal invasion. However,
the current FIGO and AJCC staging systems for cervical
122 K J Park

A B

Figure 8. Endometrioid adenocarcinoma. A, Deeply placed tumour without mucosal involvement based in the outer cervical wall [haema-
toxylin and eosin (H&E)]; B, high power shows columnar cells with open chromatin, eosinophilic cytoplasm and abundant tumour-infiltrat-
ing lymphocytes, resembling endometrial endometrioid adenocarcinoma H&E. There was no evidence of carcinoma in the endometrium.
This probably arose in a setting of endometriosis.

A B

C D

Figure 9. Human papillomavirus (HPV)-associated adenocarcinoma with serous-like morphology. A, Usual endocervical adenocarcinoma
can have a predominantly papillary growth pattern, and coupled with high mitotic count, apoptosis and occasional high-grade nuclear aty-
pia – this can mimic serous carcinoma of endometrium or adnexa [haematoxylin and eosin (H&E)]; B, on closer examination, focal intracy-
toplasmic mucin can be seen with rigid luminal borders H&E; C, human papillomavirus (HPV) RNA in-situ hybridisation is positive; D, p53
immunohistochemistry shows a heterogeneous wild-type pattern.

carcinoma do not provide specific guidelines on exactly
how to measure the invasive component. This can be
problematic, especially in endocervical adenocarcino-
mas, as normal endocervical glands lack a well-defined
basement membrane, making it difficult to determine
the exact point of tumour origin. In addition,
adenocarcinoma in situ (AIS) can be quite florid,
obscuring the border between invasion and in-situ
lesions, while predominantly exophytic tumours can be
challenging to measure (thickness versus true inva-
sion). Given that radical surgeries, including lymph
node dissections, are being performed on early-stage,
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
 Cervical adenocarcinoma: a new paradigm 123

Table 2. Silva pattern classification of HPV-associated endocervical adenocarcinoma

Pattern A Pattern B Pattern C

• Well-demarcated glands with rounded
contours, frequently forming groups
• No destructive stromal invasion
• No single cells or cell detachment
• Complex intraglandular growth
acceptable (cribriform or papillae)
• Lack of solid growth
• Depth of tumour or relationship to
large vessels not relevant
• No lymphovascular invasion
• Localised (limited, early) destructive
stromal invasion arising from pattern A
glands
• Individual or small groups of tumour
cells, separated from the rounded
gland, often in focally desmoplastic or
inflamed stroma
• Foci may be single, multiple or linear at
base of tumour
• Lymphovascular invasion +/
• Diffuse destructive stromal invasion, characterised
by diffusely infiltrative glands with extensive
desmoplastic response
• Confluent growth filling a 940 field (5 mm):
glands, papillae (stroma only within papillae) or
mucin lakes
• Glands often angulated or with canalicular
pattern with interspersed open glands
• Solid, poorly differentiated component
(architecturally high grade); nuclear grade is
disregarded
• Lymphovascular invasion +/

minimally invasive tumours with little potential for
metastasis and often in young patients, a risk stratifi-
cation system based on the morphology of tumour
stromal invasion was developed to determine more
effectively which tumours could potentially be treated
more conservatively.45 The Silva Pattern Classification
system was developed by a multi-institutional interna-
tional panel of gynaecological pathologists evaluating
hundreds of cases. This system is applicable only to
HPV-associated endocervical adenocarcinomas, and in
most cases the entire tumour must be examined
microscopically to assign the appropriate group. The
patterns are categorised as follows: pattern A is archi-
tecturally well- to moderately differentiated and lacks
destructive stromal invasion and lymphovascular
invasion; pattern B shows focal destructive invasion
arising in a background of pattern A and may be
accompanied by LVI; pattern C tumours show diffuse
destructive invasion with marked desmoplastic stro-
mal reaction (Table 2; Figure 10).
The initial studies showed that pattern-based classi-
fication correlated with the risk of lymph node metas-
tasis and clinical outcome. Pattern A tumours were
limited to Stage I with no evidence of lymph node
metastasis or tumour recurrence, whereas pattern C
tumours frequently presented at Stage II or higher,
had positive lymph nodes in 22.5% and recurred in
19.7%; pattern B tumours also presented at Stage I,
and the few lymph node-positive cases also showed
LVI.45–48 Similar results were reported by multiple
subsequent independent studies.49–52 One useful out-
come of this classification is obviating the need to dif-
ferentiate AIS from pattern A invasion, which has
poor reproducibility, as both diseases can be treated
with simple excision (cone) with negative margins
and no further therapy.49,50
While pattern C tumours had the worst outcomes
of all three patterns, not all pattern C tumours
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
performed poorly. Additional studies have shown that
positive lymph node status is a significantly poor prog-
nostic factor in pattern C tumours, and stratifying
these tumours based on the presence of LVI and
lymph node involvement could guide treatment.53,54
In a study looking only at pattern C tumours, various
patterns of destructive invasion also appeared to have
different prognostic associations.55 For example, pat-
tern C tumours with bandlike lymphocytic infiltrate
had no recurrences compared to those with diffuse
destructive invasion, and those with linear destructive
invasion were not associated with lymph node
involvement compared to those with a micropapillary
pattern. In fact, micropapillary pattern in cervical ade-
nocarcinoma is a particularly aggressive phenotype.
The largest study of cervical adenocarcinomas with
micropapillary growth showed that all 44 (100%)
cases were positive for LVI and 41 (93%) had lymph
node metastases, and there was no difference when
comparing tumours with >50% or 10–50% micropap-
illary component.7 Therefore, it is most likely that not
all pattern C tumours are created equal.
A cornerstone of successful application of the pat-
tern classification is reproducibility. Several studies
have demonstrated this 3-tiered system to be repro-
ducible among pathologists, with the reported kappa
values ranging from fair to almost perfect (k = 0.24–
0.84)51 and moderate (k = 0.65).49 Another study
showed an overall concordance of 74% with kappa
values of 0.54, 0.32 and 0.59 for patterns A, B and
C, respectively.56 Kappa values improved when com-
paring binarised patterns (A versus B and C).49,51
This system is applicable to all resections, as inva-
sion pattern on cones and loop electrosurgical exci-
sion procedures (LEEPs) can predict invasion pattern
on a subsequent hysterectomy, particularly in pat-
terns B and C tumours.57 Unfortunately, application
in biopsies is suboptimal, particularly in pattern A
124 K J Park

A B

C D

E F

Figure 10. Silva pattern classification. A, Pattern A is characterised by neoplastic cervical glands that are well-demarcated with rounded con-
tours that invade the stroma without eliciting a desmoplastic response [haematoxylin and eosin (H&E)]; B, the glands can reach deep into the cer-
vical wall with a wide horizontal spread and have intraglandular complexity, such as cribriforming or papillary projections H&E; C, pattern B is
similar to pattern A but with small foci of destructive stromal invasion not measuring greater than 4 mm contiguously arising from glands with-
out destructive invasion H&E; D, the invasive cells can be irregular, fragmented, single cells and clusters. Lymphovascular invasion can be seen
in pattern B but not in pattern A H&E; E, pattern C with diffuse, destructive stromal invasion, whole slide image H&E; F, the glands are angulated,
fragmented [resembling microcystic, elongated and fragmented (MELF)] pattern of invasion with exuberant stromal desmoplasia H&E.

tumours. Based on the presence or absence of
destructive invasion in biopsy material, patients could
undergo standard treatment or cone/LEEP procedure,
respectively. Destructive invasion in a cone or LEEP
would trigger additional surgery.48
One important caveat to assessing pattern A
tumours is the possibility of mucosal extension into
the uterine corpus with or without ovarian/tubal
metastases. It is well recognised that tumours that
have been classified as AIS or AIS with focal superficial
invasion can involve the endometrium and/or adnexa,
even without definitive evidence of stromal invasion in
the primary tumour.49,58,59 In reviewing the images
from Ronnett et al., in particular, it is evident that
some of the cases of extensive AIS would now be
classified as pattern A tumours.59 In most of the cases
of adenocarcinoma that involved adnexa in Reyes
et al., the endomyometrium was also usually involved.
Therefore, one must be cautious in taking a conserva-
tive approach with pattern A endocervical adenocarci-
noma and ensure that the endometrium is also well
sampled at the time of surgery/biopsy to confirm that
the tumour has not spread superficially into the cor-
pus. For a more detailed discussion on this topic, please
refer to the article in this issue: ‘Metastases to the
ovary arising from endometrial, cervical and fallopian
tube cancer: recent advances’, by Casey and Singh.
It should be emphasised that pattern classification
applies only to HPV-associated adenocarcinoma and
not any of the non-HPV subtypes. Two independent
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.

studies have shown that all non-HPV-associated ade-
nocarcinomas were categorised as pattern C.4,60
MOLECULAR ALTERATION IN HPV-ASSOCIATED
ADENOCARCINOMA AND ASSOCIATION TO
PATTERN OF INVASION
Several studies of UEA have identified prevalent
mutations in members of the PI3K/Akt/mTOR sig-
nalling pathway regulating cell cycle, including
PIK3CA (11–25%), KRAS (18%) and PTEN (4%)
genes.61–64 These mutations are promising, because
they may be amenable to targeted therapy.65,66 An
integrated analysis of 178 samples based on copy
number, methylation, mRNA and microRNA profiling
by The Cancer Genome Atlas (TCGA) Research Net-
work demonstrated a unique set of endometrial-like,
predominantly HPV-negative, adenocarcinoma-rich
subgroup of cervical cancers with high frequencies of
KRAS, ARID1A and PTEN mutations.67 It is likely
that these HPV-negative endometrial-like tumours
were in fact endometrioid adenocarcinomas of the
corpus/lower-uterine segment extending to the cervix
erroneously included in the analysis.
Two recent studies correlating pattern of invasion
with genetic alterations have given molecular support
to this morphological classification.52,54 Both studies
showed that pattern A tumours had fewer significant
tumour suppressor and oncogene abnormalities than
patterns B or C. In one study by Hodgson et al., inter-
rogating hotspot regions of 50 oncogenes using tar-
geted sequencing of 20 UEAs, prevalent mutations
involving PIK3CA (30%), KRAS (30%), MET (15%)
and RB1 (10%) were detected. PIK3CA, KRAS and
RB1 mutations were seen only in patterns B or C,
and KRAS mutations correlated with advanced stage
(at least FIGO Stage II).54 In the second study, by
Spaans et al., 52 cases were evaluated for hot-spot
mutations in 13 genes and showed mutations in sim-
ilar genes. Unlike the first study, two (20%) pattern A
tumours harboured KRAS mutations, as well as five
(29%) pattern B and five (20%) pattern C tumours.
The remaining pattern A tumours (eight) showed no
other mutations, whereas patterns B and C showed
additional mutations in PIK3CA, PTEN, CDKN2A,
PPP2R1A and FBXW7.52 The data suggest that pat-
tern A tumours are indeed biologically distinct from
patterns B and C with a possible tumour progression
model in which mutations accumulate as the tumour
invades the surrounding stroma. Of note, one case
from the Spaans study showed loss of PMS2 by
immunohistochemistry. Upon careful review of that
case, the investigators concluded that this was
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 112–127.
Cervical adenocarcinoma: a new paradigm 125
misclassification of a lower uterine segment endome-
trial endometrioid adenocarcinoma (HPV-negative),
as UEA in a patient who had undergone supracervi-
cal hysterectomy 20 years prior.
The pattern-based classification has been advocated
to be incorporated into the current FIGO staging sys-
tem.46 However, staging systems typically relate to
tumour size and extent of involvement. The pattern
classification is more analogous to a grading scheme
which denotes risk associated with histological fea-
tures. The combination of IECC and pattern classifica-
tion could create a system analogous to endometrial
carcinoma, wherein all non-endometrioid types are
high-grade by definition, with morphological criteria
reliably separating endometrioid carcinoma into clini-
cally relevant grades. The reproducibility and prog-
nostic relevance of both these systems have been
tested and, moving forward, international collabora-
tive studies are needed to develop and test a risk algo-
rithm similar to that used in endometrial carcinoma.
Under this proposed algorithm, FIGO Stage I, pattern
A cases could be assigned to a low-risk category,
regardless of size/substage, with a recommendation
for conservative, node-sparing surgical treatment,
and patterns B and C cases (the latter including all
HPV-independent histotypes) would be managed
using protocols based on size, stage and vascular
invasion, as well as age and fertility preference.
Summary
Endocervical adenocarcinoma classification has
recently undergone a major update from the days of
morphology only based stratification. Not all cervical
tumours are driven by high-risk HPV infection, and
each subtype has distinct morphology, pathogenesis
and outcomes. Understanding the molecular drivers,
association with HPV, tumour behaviour and epi-
demiological implications are critical for appropriate
treatment and prognostication. Pattern classification
of HPV-associated adenocarcinomas is a novel, mor-
phology-based risk assessment tool that can poten-
tially be used, in addition to existing metrics, to
assign risk of recurrence/metastasis and help to strat-
ify patients to various therapeutic modalities,
although more work needs to be done on a wider
scale with validation of large cohorts.
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