International Journal of

Molecular Sciences

Review
HPV-Negative Adenocarcinomas of the Uterine Cervix: From
Molecular Characterization to Clinical Implications
Luca Giannella , Jacopo Di Giuseppe , Giovanni Delli Carpini, Camilla Grelloni, Mariasole Fichera,
Gianmarco Sartini, Serena Caimmi, Leonardo Natalini and Andrea Ciavattini *

Woman’s Health Sciences Department, Gynecologic Section, Polytechnic University of Marche,

60123 Ancona, Italy
* Correspondence: [email protected]; Tel.: +39-0715962172; Fax: +39-07136576

Abstract: Cervical cancer is the fourth most common cancer in women. It is the leading cause of
female deaths in developing countries. Most of these cervical neoplasms are represented by squamous
lesions. Cervical adenocarcinoma causes about a quarter of cervical cancers. In contrast to squamous
lesions, cervical glandular disease is HPV-negative in about 15–20% of cases. HPV-negative cervical
adenocarcinomas typically present in advanced stages at clinical evaluation, resulting in a poorer
prognosis. The overall and disease-free survival of glandular lesions is lower than that of squamous
lesions. Treatment options require definitive treatments, as fertility-sparing is not recommended.
Moreover, the impact of HPV vaccination and primary HPV screening is likely to affect these lesions
less; hence, the interest in this challenging topic for clinical practice. An updated review focusing on
clinical and molecular characterization, prognostic factors, and therapeutic options may be helpful
for properly managing such cervical lesions.

Citation: Giannella, L.; Di Giuseppe,

Keywords: adenocarcinoma; cervix; HPV; HPV-negative; therapy; molecular basis; gene mutations
J.; Delli Carpini, G.; Grelloni, C.;
Fichera, M.; Sartini, G.; Caimmi, S.;
Natalini, L.; Ciavattini, A.
HPV-Negative Adenocarcinomas of
1. Introduction
the Uterine Cervix: From Molecular
Characterization to Clinical The WHO estimates cervical cancer is the fourth most frequent cancer in women. The
Implications. Int. J. Mol. Sci. 2022, 23, incidence was 570,000 cases in 2018, representing 6.6% of all female cancers worldwide [1–3].
15022. https://doi.org/10.3390/ SCC is the most common subtype of cervical cancer, and most histological groups are
ijms232315022 linked to HPV infection [4–6]. Adenocarcinomas comprise approximately 25% of cervical
Academic Editor: Marcus Vetter
cancers, and they are much more heterogeneous than SCC, with 15% of them approximately
unrelated to HPV infection [7,8]. Therefore, it has become evident that HPV does not drive
Received: 27 October 2022 all ECA. Furthermore, while there is a reduction in cervical squamous lesions, glandular
Accepted: 28 November 2022 lesions appear to increase [2]. In North America, cervical squamous carcinomas decreased
Published: 30 November 2022 from 95% to 67–84% over the past 20 years. In contrast, cervical adenocarcinomas increased
Publisher’s Note: MDPI stays neutral from 5% to 8–27% [9].
with regard to jurisdictional claims in As demonstrated for other organs, HPV status can significantly affect prognosis, and
published maps and institutional affil- the different subtypes of ECA have different molecular patterns that could have significant
iations. clinical consequences for the survival of women [4,5,10]. In the era of HPV-vaccine and
HP-only screening, it seems critical for clinical practice to distinguish ECA related to HPV
infection from those not [2,3,11]. Currently, the study of NHPVAs represents a trending
topic, given their different clinical course with worse outcomes in the face of guidelines that
Copyright: © 2022 by the authors. do not differentiate the management of these lesions from their squamous counterpart [2,3].
Licensee MDPI, Basel, Switzerland. Therefore, a comprehensive review of this topic, including clinical, molecular, and
This article is an open access article
prognostic characterization, may interest clinicians who deal with this pathology in their
distributed under the terms and
clinical practice.
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Int. J. Mol. Sci. 2022, 23, 15022. https://doi.org/10.3390/ijms232315022 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 15022 2 of 20

2. Critical Issues in Diagnosing Non-HPV-Related Cervical Lesions

HPV-Negative Cervical Cancer
There is no clear definition of HPV-negative cervical cancer. Yoshida et al. defined
an HPV-negative cervical cancer as primary cancer diagnosed through its histological
features, with a negative HPV test without a possible justification [4]. When dealing with
HPV-test-negative cervical cancer, the clinician must consider three plausible reasons for
the negative HPV result:
1. Real HPV-negative cervical cancer;
2. False HPV-negative case;
3. Incorrect classification of a non-cervical cancer.
a. Real HPV-negative cervical cancer
A meta-analysis investigating 30,848 invasive cervical cancers between 1990 and
2010 found a gradual decrease in HPV negativity. The increasing trend of HPV-positive
diagnoses (from 85.9% in 1990 to 92.9% in 2010) seems to correlate with an improvement in
the sensitivity of HPV tests and a more accurate classification of histotypes [12].
Patients’ age influence the HPV infection rate in cervical carcinomas, material storage
time, geographic factors, and, more than anything else, the histological subtype [13].
In 2017, a clinical study of the Cancer Genome Atlas estimated the prevalence of
HPV in cervical carcinoma specimens collected in the United States: 5% resulted negative
for HPV infection [14]. The overall incidence of HPV-negative cancer, reported by recent
literature, fluctuates between 7 and 11% [4,14–18].
Several studies detected the presence of HPV in nearly 100% of cervical squamous
cell carcinoma, confirming that HPV acts as an oncogenic driver for this tumor [7]. Unlike
this, the existence of HPV-negative cervical adenocarcinomas is accepted by most authors,
estimated at approximately 15 to 38% [1,7,19].
Table 1 summarizes the prevalence rates of HPV-positivity in the various subtypes of
cervical adenocarcinoma, classified according to the WHO (2020)/IECC (2018) [7,13,20,21].

Table 1. HPV-positivity rate according to histologic subtypes.

HPVA NHPVA Ref.

Adenocarcinoma Histology HPV Positivity Rate (%)
Usual type 72–100 - [7,13,20]
Mucinous 83–100 - [7]
Gastric type - 0 [20]
Clear cells type - 0–28 [13,20,21]
Mesonephric type - 0 [7]
Endometrioid type - 0–27 [7,13,20]

b. False HPV-negative case

Only some rare histotypes of cervical cancers are truly HPV negative, and a specific
rate of false negative results at the HPV test must be considered. Thus, this may lead to an
overestimation of the incidence of HPV-negative cancer in the literature [13,22,23].
Possible causes of false negative HPV tests are:
- Loss of targeted HPV DNA fragment
The HPV L1 fragment is usually well-conserved in most HPV genotypes and therefore
is used as a target in many HPV tests. Integrating the viral DNA within the DNA host can
destroy L1, L2, E1, and E2 fragments, resulting in a false negative HPV test. On the contrary,
the expression of the oncogenes E6 and E7 is always present [5]. Tjalma et al. found that
the HPV L1 test can miss 8.3% of HPV16 and 27.9% of HPV18 infections, compared with
the HPV test covering E6 and E7 regions [24].
Int. J. Mol. Sci. 2022, 23, 15022 3 of 20

Another study showed that during the development of cervical cancer, there might be
an inactivation of HPV, which no longer expresses the oncogenes E6 and E7 [25]. Therefore,
it is desirable that cervical cancer screening should be based on tests targeting both the
early (E) and the late (L) genes [24].
- Low viral load in latent HPV infection
Natural HPV infection has a latent period, during which the immune system fights
viral replication and silences oncogenes. Latent infections have a low incidence of tumori-
genesis. However, nearly 0.05% of HPV-negative cases can evolve into CIN 3 or cervical
cancer in 3–5 years [26]. In these patients, the viral load is too low to be detected by the
HPV test, with a higher risk of false negativity. Moreover, it must be considered that the
glandular type epithelium does not support HPV viral infection. Therefore, in adenocar-
cinomas, HPV-DNA is often detected in the form of genomic integration. Summarizing,
especially in adenocarcinomas, the use of sensitive HPV DNA detection tests is particularly
essential [27].
- Cervical cancer caused by low-risk HPV-genotype
Most of the HPV tests currently in use target high oncogenic risk genotypes of HPV
(HPV16 and HPV18), while they cannot reveal the presence of a low-risk HPV infection [27].
However, low oncogenic risk HPV (6, 11, 42, 44, 70) can cause cervical cancer [28,29].
According to Petry et al., these genotypes are detected in approximately 1–2% of primary
cervical cancers [15]. It is still unclear whether their presence within malignant tumors
represents the oncogenic driver or whether it is multiple accidental infections. In cervical
adenocarcinomas, multiple HPV infections are present in approximately 8% of cases. In
most cases, co-infections are represented by HPV genotypes 16 and 18 [30]. Multiple HPV
infections in adenocarcinomas appear slightly lower than in the squamous counterpart.
However, multiple HPV infections do not seem to influence the cancer process [31].
- False negative HPV-test (incorrect sampling/pre-analytical errors)
There are several HPV tests available in the market, each with different sensitivities
and specificities. Nucleic acid signal amplification methods include polymerase chain
reaction (PCR; e.g., CobasTM HPV and BD’s OnclarityTM HPV) and transcription-mediated
amplification (e.g., APTIMATM HPV).
Non-nucleic acid amplification methods are: hybridization capture (e.g., HC2TM ) and
invader chemistry (e.g., CervistaTM HPV). Moreover, pathologists can use HPV hybridiza-
tion in situ in formalin-fixed paraffin-embedded sections. HPV-tests currently validated by
the Food and Drug Administration (FDA) for cervical cancer screening are: Hybrid Capture
2TM (hybridization capture), CervistaTM (invader chemistry), CobasTM (PCR), OnclarityTM
(PCR), APTIMATM (TMA) [5].
The most widespread cause of false negative HPV tests is the significant difference
in the sampling procedures used by clinicians. Factors that can lead to false negatives
are the following: sampling scanty cellular material from necrotic or inflamed areas, the
presence of blood or lubricant in the sample, the time elapsed between excision and fixation,
and degradation of viral DNA/RNA, especially in formalin-fixed and paraffin-embedded
specimens [4,5].
A retrospective study showed that specimens from older patients and longer stored
had a lower HPV positivity rate. In particular, storage time significantly influences the
HPV positivity of adenocarcinomas more than squamous carcinomas [13].
c. Incorrect classification of a non-cervical cancer
Histotypes of non-primary cervical cancers that may be misinterpreted are endome-
trial cancer extending to the cervix and metastases of HPV-negative tumors from other
sites. A 2017 retrospective study reviewed cases of HPV-negative cervical cancer and found
that more than two-thirds did not originate primarily from the cervix [15]. Therefore,
endometrial carcinoma and HPV-negative cervical adenocarcinomas share a similar mor-
phology, and tumor/stroma immunostaining is often required for differential diagnosis.
Int. J. Mol. Sci. 2022, 23, 15022 4 of 20

Diagnosis of HPV-negative cervical adenocarcinoma is based on a combination of histology

characteristics (for example, CD10 and CEA negativity) of the tumor and on the patient’s
age (patients are usually younger than those with endometrial cancer) [7].
The tumors most frequently metastasize here are, in order of frequency: ovaries,
colorectal, stomach, breast, kidney, and lungs [32]. Although it is not usually a site of metas-
tasis, some studies indicate that 3.7% of female genital tract cancers extend to the cervix.

3. Classification of Endocervical Adenocarcinoma

The 2014 WHO Classification of cervical tumors distinguished ECA based exclu-
sively on morphological and architectural features and the presence of intracytoplasmatic
mucin [33]. This system did not account for clinical characteristics and was found to be
poorly reproducible [34].
The newest IECC of 2018 attempted to categorize ECA by etiology (HPV status) and
morphology with molecular and outcome evidence to give practitioners a more relevant
clinical categorization [33–36].
The IECC was the result of a multi-institutional study that examined 409 cases of ECA
from various countries (USA, Mexico, Romania, Japan, and Israel): it aimed to classify ECA
based on HPV association. Then, their morphology was described and correlated with
patients’ outcomes [33].
The first stratification of tumors was done by searching HPV-associated features:
easily identifiable luminal or “floating” mitoses and/or apoptotic bodies and scanning
magnification [33]. If they were not easily recognizable, visible only on high power, or not
visible at all (no or limited HPV-associated features), the tumor has been considered non-
HPV-related [33]. After this first subdivision, the ECA was further classified, considering
the cytoplasmatic features to keep continuity with traditional classifications as delineated
by 2014 WHO [33,36].
The last process includes IHC—p16, p53, vimentin, progesterone receptor PR- and
RISH for HPV to validate this classification scheme. The method was concordant with IHC
and RISH results: usual ECA shows 90% of p16 positivity and 95% of HPV-RISH; only 3%
of NHPVA tumors showed HPV-RISH expression [33,36].
Other differences between HPVA and NHPVA were found in clinical aspects: NHPVA
tumors were more extensive, occurred in older patients, and presented at a higher stage
than HPV ECAs [4,5,33]. Subsequent studies have confirmed that IECC, compared with
the WHO 2014 system, is more straightforward, practical, and reproducible, with a higher
inter-observer agreement among pathologists [33,34]. Moreover, this new classification
system is easy to perform in any laboratory since it only needs H&E (hematoxylin-eosin)
staining without sophisticated additional tests [37].
The IECC 2018 created the basis for the latest WHO 2020 classification, which, for
the first time, divides cervical epithelial tumors (including ECAs) and their precursor
into different types based on HPV association. A recent workshop dedicated to ECAs,
organized by the ISGyP in 2020, recommended categorizing ECAs according to the WHO
2020 classification system, which incorporates the IECC system [37].
The tumor types classified by the WHO 2014 and IECC 2018/WHO 2020 systems are
reported in Table 2 [36,38,39].
Int. J. Mol. Sci. 2022, 23, 15022 5 of 20

Table 2. Classifications of adenocarcinoma of the uterine cervix.

WHO 2014 IECC 2018/WHO 2020

HPV-Associated (HPVA) Non-HPV-Associated (NHPVA)
Usual type Usual type Gastric type
Mucinous carcinoma, NOS Villoglandular Clear cells
Gastric type Mucinous, NOS Mesonephric
Intestinal type Mucinous, intestinal Endometrioid
Invasive stratified
Signet ring cell
mucin-producing
Villoglandular Micropapillary
Endometrioid Serous’-like
Clear cells
Serous
Mesonephric

4. Clinical Features of Human Papillomavirus-Negative Adenocarcinoma

4.1. Gastric-Type Adenocarcinoma (GCA)
HPV. Previous studies using PCR and in situ hybridization demonstrated that GCA is
an HPV-negative tumor [40,41].
Epidemiology. GCA, described for the first time in the 1990s, is the most common type
of NHPVA [42]. It is also the second most frequent histotype of cervical adenocarcinoma,
accounting for approximately 10% of all ECA worldwide. It is frequent in Japan and reaches
over 20% of all cervical adenocarcinomas [36,41]. The true incidence is still unknown
because before the WHO 2020 classification, it was part of a spectrum of lesions ranging
from MDA to undifferentiated adenocarcinoma, or it was confused with other histotypes
(usual type, intestinal or clear cells) [43].
The mean age of the patients at the time of diagnosis is 52 years (ranging from 23–81),
similar to the usual-type-adenocarcinoma [44]. GCA and its well-differentiated form of
MDA often develop in patients with Peutz-Jeghers disease, a rare autosomal dominant
syndrome associated with multiple gastrointestinal hamartomatous and mucocutaneous
pigmentations [45].
Symptoms and signs. In contrast to usual-type ECA, GCA develops mainly in the
upper part of the endocervix. The most reported symptoms are blood loss and intense
watery discharge. Because of the highly infiltrative growth pattern, the most distinctive
sign is an enlarged cervix without a well-defined mass [46].
Pap test. Pap-test can result as normal in 30–50% of cases, while other 50–70% of
patients receive an abnormal cytology result not specific to mucinous adenocarcinoma [47,48].
Colposcopy. The most frequent localization of the GCA is the upper part of the cervix,
so during colposcopy, the transformation zone can appear normal. However, the cervix has
an enlarged appearance, with a stiffer consistency, without a well-defined mass [47,49].
Radiodiagnostics. At the ultrasound exam, GCA appears as a multilocular cystic
mass and can present hypervascularization with Power Doppler. On MRI, the cervix seems
enlarged and has a heterogeneous pattern, with T2 hyperintensity and enhancement [47,50].
Precursors. Several cases of GCA appear to originate from precursor lesions, such as
simple gastric hyperplasia and LEGH, a benign form occasionally associated with Peutz-
Jeghers syndrome [51]. LEGH is often found in the upper cervix in the context of GCA,
and histological examination shows a gastric-markers lobular architecture. Moreover,
the average age of patients with LEGH is 45–49 years, similar to GCA [42,51]. These
characteristics and the fact that it shares the same genetic mutations of the GCA (KRAS,
STK11, TP53, and others) make it a probable benign precursor of GCA [48,52–54].
Int. J. Mol. Sci. 2022, 23, 15022 6 of 20

There are also atypical forms of LEGH, variants of the GAIS, which show an atypical
histological architecture (loss of polarity, papillary arrangements, enlargement of cell nuclei,
evident nucleoli, etc.,) without invasion of the stroma [55].
GAIS and GCA frequently occur together and share the same genetic profile (e.g.,
acquisition of chromosome 3p and loss of 1p), indicating that LEGH, GAIS, and GCA are
different shades of HPV-independent cervical adenocarcinoma with gastric differentia-
tion [56].
Prognosis. GCA shows aggressive behavior and is associated with a lower survival
rate than the usual-type adenocarcinoma, even in stage I, because of its higher probability
of invasion, metastasis, and chemoresistance. The 5-year overall survival rate reported in
the literature is 30% to 43% for gastric-type NHPVA, compared to 74–91% for usual-type
adenocarcinoma [49,57].
GCA shows higher rates of lymphovascular invasion, depth and horizontal invasion,
parametrial and vaginal extension, regional and distant lymph node metastasis, and ascitic
fluid than the usual endocervical type adenocarcinoma [47,48,57,58]. Moreover, it usually
presents in an advanced stage of the disease, probably because of its negativity to HPV-test
and because the cytology has a low sensibility for MDA since cytologic aspects of GCA are
a recent acquisition [59].
At the time of diagnosis, 40–100% of patients are stages II-IV, while 75% can present
metastasis to distant organs (especially lung, ovary, liver, colon, and bone) [49,57,58].
As the new guidelines indicate the HPV test is the best screening test for cervical
cancer, Omori et al. proposed adding a further molecular test for gastric mucin to the HPV
test. Using a monoclonal antibody against gastric mucin showed an excellent positive
predictive value for gastric-type benign and malignant lesions [60].

4.2. Clear Cell Adenocarcinoma (CCC)

HPV. CCC seems to be associated with HPV infection only in 25–30.4% of cases [5].
Epidemiology. Clear cell carcinoma represents 2–7% of cervical adenocarcinomas [7].
Although its etiology is unknown, CCC has been linked to in-utero exposure to synthetic
oral estrogen, DES, widely used in several countries between 1948 and 1970 to prevent
miscarriage and preterm birth [61]. In the DES-exposed group, the peak incidence is
reached at 19 years and remains high throughout life. The non-DES-exposed group has no
peak age because the incidence ranges from pediatric to postmenopausal [4]. In addition,
some cases of CCC in non-DES-and-HPV-exposed children and young women have been
reported [62,63]. In DES-exposed patients, the most frequently involved zones are the
ectocervix and the anterior upper part of the vagina. Instead, in women with non in
utero-DES-exposure, CCC mainly develops in the endocervix [7,33]. In utero exposure to
DES can cause both CCC and genito-urinary malformations. Several cases of CCC arise
in women with double uteri and vagina with unilateral renal agenesis, atresic hemicervix,
and ipsilateral renal agenesis or bicornuate uterus [64].
Symptoms and signs. CCC can present with cervical ulceration that causes abnormal
vaginal bleeding (postcoital bleeding, intermenstrual bleeding), usually refractory to hor-
monal therapy [65]. At the gynecological examination, an abnormality in the consistency
of the cervix can sometimes be perceived as “fullness” [66].
Pap test. Cytology is poorly sensitive in diagnosing CCC, and previous clinical
research reported that only 18% of patients with CCC had an abnormal Pap test [67,68].
Radiodiagnostics. CCC at the MRI shows hypointensity on T1-weighted images,
hyperintensity on T2-weighted images, and heterogeneous enhancement [66].
Precursors. Although the pathogenesis of CCC is not still understood, its genetic
profile suggests that, in non-DES-exposed cases, CCC can arise from areas of ectocervical
adenosis or cervical endometriosis [69]. Moreover, Talia et al. assumed that even the
tubo-endometrial metaplasia adjacent to the cervix could be a precursor of CCC [70].
Int. J. Mol. Sci. 2022, 23, 15022 7 of 20

Prognosis. Previous literature about CCC prognosis is controversial: some authors

report the exact outcomes of usual-type adenocarcinoma, whereas others notice more
aggressive behavior [66].
Interestingly, Wang et al. reported a better prognosis in DES-exposed CCC patients
than those with spontaneous CCC [71]. CCC is more aggressive than squamous cell carcino-
mas in recurrence and metastasis [72,73]. Local recurrence may occur more frequently than
disease dissemination to other organs. Metastasis occurs in about 18% of I-stage diseases
and nearly 50% of II-stage tumors. The lungs, liver, and bones are the most common
extra-pelvic sites [74]. Most recurrences of CCC of the uterine cervix get diagnosed within
three years after primary tumor treatment, whereas late recurrences are less frequent [63].
The survival rate of patients with FIGO stages I/II ranges from 81.5% to 91%, and 57%
of patients are still alive after a 10-year follow-up [67].

4.3. Mesonephric Adenocarcinoma

HPV. Mesonephric adenocarcinoma seems to be not associated with HPV infec-
tion [75].
Epidemiology. The average age of patients is 52, ranging from 35 to 72 years. Its
prevalence has a homogeneous distribution in the various periods from the 3rd to the 6th
decade, and there is no age in which it has a peak incidence [76].
Symptoms and signs. It usually develops in the lateral-to-posterior part of the cervix.
It can rarely involve the entire cervix without forming a well-defined mass. Its growth
pattern can be invasive, bulky, or exophytic [75].
Pap test. Pap tests performed during routine screening can detect cytological ab-
normalities, but such detection occurs less frequently than squamous cervical cancer of
the cervix. The diagnosis is often obtained through cervical biopsy, curettage, or hys-
teroscopy [77,78].
Precursors. Mesonephric adenocarcinoma is presumed to originate from normal or
hyperplastic mesonephric duct remnants located in 22% of adult women in the lateral part
of the cervix [76,77].
Prognosis. About 70% of the patients are diagnosed at stage IB. The recurrence rate
is 32%, with a mean recurrence interval of 24 months. This tumor has an aggressive
behavior and can metastasize early to distant organs, so the overall prognosis remains less
favorable compared to other cervical adenocarcinomas. The average survival time is about
50 months [76,78].

4.4. Endometrioid Adenocarcinoma (ENAC)

HPV. HPV is identified in 0–27% of cases of ENAC. In particular, HPV is detected in 100%
of ENAC arising from the squamocolumnar junction [79–81]. In contrast, ENACs that develop
from the upper endocervix and lower uterine segments are HPV-independent [1,13,82].
Epidemiology. This tumor is sporadic and accounts for less than 5% of cases of cervical
adenocarcinoma. The mean age of incidence of ENAC ranges from 43 to 50 years [79,83].
It is estimated that using the new WHO 2020 guidelines for diagnosis, only 1.1% of
endometrioid adenocarcinomas previously identified using the WHO 2014 classification
would be confirmed [36].
Given its low incidence, more common pictures such as endometrioid adenocarcinoma
of the endometrium extending into the cervix or unusual presentations of usual-type
adenocarcinoma should be suspected before diagnosing ENAC [4].
Precursors. Endometrioid cancer reportedly develops from cervical endometriosis.
Some authors suspected ENAC could arise from a malignant transformation of endometri-
otic areas [84,85].
Prognosis. Because of its rarity, data about ENAC prognosis are still limited. A recent
study compared usual-type adenocarcinoma with endometrioid adenocarcinoma in terms
of overall and disease-specific survival and found no statistically significant difference
between them. The 5-years overall survival for ECA was 75.6% [86].
Int. J. Mol. Sci. 2022, 23, 15022 8 of 20

5. Molecular Characterization of Non-HPV Associated Adenocarcinoma

5.1. Gastric-Type Adenocarcinoma
The most common gastric-type NHPVA genetic alterations reported in the literature
are TP53, STK11, KRAS, ARID1A, BRCA2, CDKN2A, and others (Table 3) [8,44,48,54,87,88].

Table 3. Genetic mutations and gene amplification in gastric-type adenocarcinoma.

Sample Size Cases with Genetic

Genetic Mutation Ref.
(Number of Patients) Mutation (%)
AKT1 11 33 [54]
ARID1A 14 29 [48]
ARID1A 15 20 [87]
ATM 11 18 [54]
BRCA2 14 21 [48]
BRCA2 21 10 [88]
CDKN2A 3 67 [8]
CDKN2A 14 36 [48]
CDKN2A 15 27 [87]
CDKN2A 68 18 [44]
ELF 11 18 [54]
ERBB2 68 9 [44]
ERBB3 21 10 [88]
ERBB3 68 10 [44]
FGFR4 21 14 [88]
GNAS 21 10 [88]
GNAS 68 9 [44]
HLA-B 21 19 [88]
KMT2D 11 18 [54]
KRAS 3 33 [8]
KRAS 11 36 [54]
KRAS 68 17 [44]
MSH2 14 21 [48]
MSH6 14 43 [48]
NTRK3 11 18 [54]
PIK3CA 11 18 [54]
PIK3CA 68 7 [44]
POLE 14 36 [48]
PTEN 15 20 [87]
PTPRS 21 19 [88]
SLX4 14 36 [48]
SLX4 14 36 [48]
SLX4 21 10 [88]
SMAD4 68 9 [44]
STK11 3 33 [8]
Int. J. Mol. Sci. 2022, 23, 15022 9 of 20

Table 3. Cont.

Sample Size Cases with Genetic

Genetic Mutation Ref.
(Number of Patients) Mutation (%)
STK11 14 29 [48]
STK11 15 33 [88]
STK11 19 21 [88]
STK11 68 10 [44]
TP53 3 67 [8]
TP53 11 46 [54]
TP53 14 50 [48]
TP53 15 53 [87]
TP53 21 52,4 [88]
TP53 68 41 [44]
CDK12 15 7 [87]
ERBB2 15 13 [87]
MDM2 14 14 [48]
MECOM 15 7 [87]

This package of mutations is similar to the genomic profile of pancreaticobiliary

adenocarcinoma, which resembles endocervical adenocarcinoma from a morphological
and molecular point of view [33].
Garg et al. using NGS, investigated 161 cancer-driver genes and copy-number varia-
tions, gene fusions, and insertions/deletions in 14 gastric-type endocervical adenocarcino-
mas. They detected a group of mutations involved in DNA repair mechanisms, cell cycle,
Fanconi anemia, and PI3K-AKT signaling [48].
Other studies assessed that TP53, STK11, CDKN2A, ATM, and NTRK3 mutations are
more frequent in gastric-type endocervical adenocarcinoma than the usual type adenocarci-
noma, while PIK3CA seems to be less frequent [44,54].
In addition to detecting mutations of TP53 (53%), STK11 (33%), and CDKN2A (27%),
Lu et al. showed amplification of the ERBB2 gene in 13% of patients [87].
TP53: TP53 is a gene activated in response to several forms of cellular stress (i.e.,
DNA damage, oncogene expression, and hypoxia) and exerts multiple antiproliferative
functions. Its transcription factor p53 stimulates the expression of p21, an inhibitor of
mitosis transitions. In some cases, the activation of p53 leads to apoptosis by activating the
Bax protein and stimulates the expression of genes that prevent blood vessel formation, a
fundamental process in tumor growth [89].
Loss of p53 occurs due to E6 protein in usual-type HPV-related adenocarcinomas,
while in GCA, which are entirely HPV-independent, it occurs due to somatic mutation of
the TP53 gene.
An ever-increasing body of literature demonstrated that TP53 is the most frequently
mutated gene in GCA (see Table 3) [48]. Interestingly, the frequency of TP53 mutation
seems to be higher in patients with HPV-independent cervical adenocarcinoma than in
HPV-positive patients [90].
Some authors demonstrated that p53 overexpression is more frequent in GCA than
in other cervical histotypes and represents an independent prognostic factor for poor
disease-specific survival and risk of tumor recurrence [91].
STK11: the serine/threonine kinase 11 (STK11), also known as liver kinase B1 (LKB1),
is a tumor suppressor gene. Its mutation in the inactivating sense was found in Peutz-
Jeghers syndrome and several sporadic tumors [92]. In particular, Peutz-Jeghers syndrome
is caused by a germline mutation of STK11, with autosomal dominant inheritance, and it is
Int. J. Mol. Sci. 2022, 23, 15022 10 of 20

associated with the development of MDA, a well-differentiated form of cervical adenocarci-

noma. Moreover, Kuragaki et al. found sporadic STK11 mutations in 55% of 11 MDA [45,93].
Now that it is accepted that MDA is part of the morphological spectrum of gastric-type
ECA, it has been understood that the STK11 mutation, both sporadic and germline, belongs
to gastric-type adenocarcinoma [94].
Understanding the mechanism of action of STK11 is crucial since it seems to be an
independent adverse prognostic factor associated with increased mortality [90]. In HPV-
associated cervical cancer, Zeng et al. demonstrated that the loss of copies of STK11
amplifies the HPV16 E6/E7 oncogenic potential and leads to increased cell growth and
metastatic invasion [92].
In gastric-type adenocarcinoma, STK11 mutation is associated with significantly lower
survival and more extensive lymphovascular invasion regardless of the FIGO stage [87].
While its involvement in HPV-associated cancer is partially elucidated, the significance
of the STK11 mutation in NHPVA adenocarcinoma has yet to be investigated. Its role in
HPV-independent oncogenesis must be further understood for target therapies to be used
in the future.
APOBEC3. APOBEC3 is associated with some drivers mutation and is thought to
play an important role in cervical cancer pathogenesis.
A recent study among the Chinese population found a gain of somatic copy number
of APOBEC3B in 20% of 25 GCA cases, while it was absent in usual-type adenocarcinoma.
Interestingly, a high positivity to APOBEC3B was associated with a favorable prognosis.
Thus, in the future APOBEC3B could become a potential prognostic value of lower relapse
risk of GCA, independently from the tumor stage [95].
ERBB2. The ERBB2 gene encodes the HER2 protein, the human epidermal growth
factor receptor 2. Amplification of the ERBB2 gene is associated with breast, ovary, gastric,
colorectal, and uterus carcinoma.
A recent study analyzed 209 cases of adenocarcinoma, including 159 HPV-related
and 50 instances of NHPVA. While in 10% of mucinous-type adenocarcinoma, HER2
amplification was detected, in the GCA patients, the frequency of HER2 amplification was
14.7%, and it was the highest value of all histotypes. Moreover, HER2 was associated with
increased tumor stage (FIGO III/IV), perineural involvement, lymphovascular invasion,
and ovarian spread.
If, on the one hand finding HER2 amplification in a patient with adenocarcinoma worsens
the prognosis, from another point of view, it makes her susceptible to Trastuzumab therapy.
Gene amplification’s predictive value needs further investigation. Other studies are
necessary to decide the best technique (immunohistochemistry or fluorescence in situ
hybridization) to search for HER amplification on histological examination [91].

5.2. Clear Cell Adenocarcinoma (CCC)

CCC is a rare variant of cervical adenocarcinoma. Thus, data about its molecular profile
remain limited. Microsatellite instability was found in 100% of DES-exposed women, but it
was present in only 50% of non-DES-exposed cases [96].
Recently, Lee et al. found in CCC DES-exposed women the POLE gene mutation
associated with increased tumor-infiltrating lymphocytes and high PD-L1 expression [97].
The involvement of mismatch repair genes is unclear: Mills et al. found a case of
CCC with MMR deficiency but without MMR proteins. At the same time, Nakamura et al.
reported a patient with Lynch Syndrome who developed a synchronous CCC with loss of
MSH2 and MSH6 [98,99].
It is also hypothesized that the PI3K-AKT pathway is involved in the pathogenesis of
CCC. Ueno et al. found p-AKT and p-mTOR positivity in 50% of cases; elderly patients
had a loss of PTEN in 50% of cases, an increase in EGFR in 75%, and an amplification of
HER2 in 50% of cases [21].
Int. J. Mol. Sci. 2022, 23, 15022 11 of 20

5.3. Mesonephric Adenocarcinoma

Previous studies suggest that the molecular profile of mesonephric carcinoma is
characterized by the KRAS mutation, which, unlike other cervical carcinomas, is present in
81% of cases, often associated with the activating mutation of NRSA [100].
This histotype also shows mutations of ARID1A/B and SMARCA4 (in 62% of cases)
and BCOR/BCORL1 (in 33% of cases). No alterations in PTEN, ARID1A, TP53, or mi-
crosatellite instabilities were found [100].
Two recent case reports found the FGFR2 mutation in two cases with mesonephric
adenocarcinoma. In particular, Devarashetty et al., after surgical treatment, offered the
patient a targeted therapy of tyrosine kinase inhibitors and immunotherapy, with an
excellent response. Thus, FGFR2 mutation is one of the possible genetic abnormalities in
this histological type and needs to be searched to offer the patient a targeted treatment [77].
At the chromosomal abnormalities analysis, 71% of tumors exhibit 1q gain, often
accompanied by 1p loss. In addition, 57% of these tumors harbor chromosome 10 gain,
frequently associated with chromosome 12 gain [7,101].
Even though mesonephric adenocarcinoma is thought to originate from hyperplastic
mesonephric remnants, the pathogenesis toward malignity is unclear. According to Kim
et al., mesonephric atypical hyperplasia could be a pre-invasive lesion that evolves into
mesonephric carcinoma through the gain of KRAS and chromosome 1 mutation [102].

5.4. Endometrioid Adenocarcinoma

The molecular characteristics of endometrioid carcinoma are still unknown. In 2020,
Jenkins et al. analyzed the genome of eight cases of HPV-negative endometrioid adeno-
carcinoma and detected several somatic genetic mutations: PIK3CA (50%), PTEN (50%),
CTNNB1, FBXW7, KRAS, AKT1, MSI-H. In the future, it will be helpful to identify genetic
similarities with endometriosis-related carcinomas or molecular peculiarities that may help
in the differential diagnosis of endometrial cancer that extends to the cervix [8].

5.5. PD1 and PDL1 Expression in NHPVA

PDL1 and PD1 are proteins expressed by immunity cells (lymphocytes, macrophages,
antigen-presenting cells, APC, and thymic epithelial cells). The interaction between PD1
and PDL1 promotes T-cell apoptosis and functional exhaustion [103]. The interaction
between PD1 and PDL1 also prevents the activation of the cells’ immune response and
their cytotoxic response against tumor cells [104,105].
The block of the PD1-PDL1 axis by anti-PD1 or anti-PDL1 antibodies has been proven
to be a successful strategy for interrupting tumor immune tolerance and enhancing an
antineoplastic immune response in several tumors [106]. Studies about PDL1 expression
in NHPVA are limited. Recently, Song and Chen investigated PDL1 expression among
different histotypes of NHPVA and its correlation with prognosis, progression-free survival,
and overall survival [107,108].
Positivity for PDL1 was evaluated using a combined positive score (CPS) and tumor
proportion score (TPS). CPS is defined as the number of PDL1 stained cells (tumor cells,
lymphocytes, and macrophages) divided by the total number of viable tumor cells and then
multiplied by 100. TPS is the percentage of viable tumor cells showing partial or complete
membrane staining adenocarcinoma positive or PDL1 expression [107,108].
Song et al. observed no statistical difference in PDL1 expression between the different
histological types of adenocarcinomas when evaluating PDL1 positivity through CPS.
However, PDL1 showed high positivity in clear cell carcinomas compared to gastric-type
adenocarcinoma. This study showed a higher association between PDL1 positivity and
CCC when TPS defined PDL1 positivity (58.3% PDL1 positivity vs. 14.3% positivity for
gastric type adenocarcinoma and 40% positivity for endometrioid adenocarcinoma). PDL1
was not expressed in mesonephric carcinoma cases [107].
PDL1 expression was significantly associated with a high tumor-infiltrating lympho-
cyte percentage and with worse progressive free survival and overall survival rate [107].
 gastric type adenocarcinoma and 40% positivity for endometrioid adenocarcinoma).
PDL1 was not expressed in mesonephric carcinoma cases [107].
PDL1 expression was significantly associated with a high tumor-infiltrating
lymphocyte percentage and with worse progressive free survival and overall survival rate
Int. J. Mol. Sci. 2022, 23, 15022
[107]. 12 of 20
Chen et al. studied PDL1 expression in NHPVA, focusing on gastric-type
adenocarcinoma, and compared it with HPVA [108]. They observed no statistically
significant difference
Cheninettheal. expression of PDL1
studied PDL1 between
expression in HPVA
NHPVA, andfocusing
HPV-independent
on gastric-type adeno-
lesions. However, they also observed that PDL1 expression correlates
carcinoma, and compared it with HPVA [108]. They observed withno
progression-
statistically significant
free survival and in
difference survival in patients
the expression with HPV-independent
of PDL1 between gastric-type
HPVA and HPV-independent lesions. How-
adenocarcinoma
ever, [108].
they also observed that PDL1 expression correlates with progression-free survival
A scheme
andof the significant
survival gene
in patients withmutations in HPV-negative
HPV-independent adenocarcinomas
gastric-type adenocarcinoma is [108].
shown in Figure 1.A scheme of the significant gene mutations in HPV-negative adenocarcinomas is
shown in Figure 1.

Figure 1. Main gene mutations in different HPV-negative cervical adenocarcinomas.

6. Treatment of Human Papillomavirus-Negative Cervical Cancer

6.1. Staging
Inmutations
Figure 1. Main gene patients with HPV-unrelated
in different cervical
HPV-negative adenocarcinoma,
cervical treatment planning should
adenocarcinomas.
be established on a multidisciplinary basis (e.g., a tumor board meeting). The choice of
6. Treatmentoptions
of Human mustPapillomavirus-Negative
be based on the accurate knowledge of prognostic and predictive factors for
Cervical Cancer
6.1. Staging an oncological outcome, quality of life, and morbidity [109]. A team of specialists dedicated
to oncological
In patients gynecology
with HPV-unrelated shouldadenocarcinoma,
cervical carry out appropriate counseling.
treatment planning should
According to The European Society of Gynaecological
be established on a multidisciplinary basis (e.g., a tumor board meeting). Oncology (ESGO)/European
The choice of
Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for
options must be based on the accurate knowledge of prognostic and predictive factors for
the Management of Patients with Cervical Cancer [109] and the National Comprehensive
an oncological outcome, quality of life, and morbidity [109]. A team of specialists
Cancer Network (NCCN) guidelines for Cervical Cancer [110], staging should be performed
dedicated to oncological gynecology should carry out appropriate counseling.
according to the TNM classification, and clinical staging (FIGO) should be recorded.
According to The European Society of Gynaecological Oncology (ESGO)/European
It is recommended to record [109]:
Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the
Management1. of Patients
TNM andwith
FIGOCervical
stage, including
Cancermaximum
[109] andtumor
the size and detailed
National description of extracervical
Comprehensive
tumor extension and nodal involvement.
2. Pathological tumor type.
3. Depth of cervical stromal invasion and a minimum thickness of uninvolved cervical stroma.
4. Presence (or absence) of lymphovascular space involvement (LVSI).
5. Presence or absence of distant metastases.
Diagnostic workup includes: (1) pelvic examination and biopsy (with or without
colposcopy) are mandatory; (2) pelvic MRI is necessary to assess pelvic tumor extent;
(3) endovaginal/transrectal ultrasound is an option if performed by an expert sonographer;
(4) cystoscopy or rectoscopy may be considered to provide a biopsy if suspicious lesions in
the urinary bladder or rectum are documented on MRI or ultrasound.
Int. J. Mol. Sci. 2022, 23, 15022 13 of 20

Diagnosis of a T1a tumor must be based on a conization specimen examined by an

expert pathologist. The depth of the cervical conization may be tailored to the lesion’s size,
location, and histotype (if known). In a patient with suspicion of invasive adenocarcinoma
versus adenocarcinoma in situ, the cone biopsy would be designed as a cylindrical cone
extending to the internal os to exclude possible invasion in the endocervical canal. Length
of the cold cone of at least 10 mm is preferred and can be increased to 18–20 mm in patients
who have completed childbearing [111,112].
Distant diagnostic workup, according to ESGO guidelines [109], includes:
1. In the early stage (T1a, T1b1, T2a1), surgical/pathological staging of pelvic lymph
nodes is the gold standard to assess the prognosis and guide treatment (except for
T1a1 and no LVSI).
2. In locally advanced cervical cancer T1b2 and higher (except T2a1) or early stage
disease with suspicious lymph nodes on imaging, positron emission tomography-
computed tomography (PET-CT) or chest/abdomen computed tomography (CT) is
recommended for assessment of nodal and distant disease.
3. Paraaortic lymph node dissection, at least up to the inferior mesenteric artery, may be
considered in locally advanced cervical cancer with negative paraaortic lymph nodes
on imaging for staging purposes.
NCCN guidelines differentiate diagnostic workups based on the desire for fertility-
sparing and the clinical stage of the disease [110].

6.2. Mangement of Stage T1a

Microinvasive disease (stage Ia1) with no LVSI has less than a 1% risk of lymphatic
metastasis. A patient with squamous cell carcinoma or usual-type (HPV-related) carcinoma
may be managed conservatively. This is important for preserving fertility with cone biopsy
with negative margins or with simple extrafascial hysterectomy when fertility preservation
is not required.
In patients with non-HPV associated subtypes of endocervical adenocarcinoma, treat-
ment of stage T1a (T1a1 and T1a2) differ from other histotypes [109,110]: according to the
ESGO guidelines, in a patient with rare histological subtypes of cervical cancer including
non-HPV-related adenocarcinomas (except for adenoid basal carcinoma), and neuroen-
docrine carcinomas, fertility-sparing treatment should not be recommended [109]. NCCN
guidelines do not allow conservative treatment in the event of gastric type adenocarci-
noma, or adenoma malignum (minimal deviation adenocarcinoma), or in case of small cell
neuroendocrine histology because of their high-risk nature and a lack of data [110].

6.3. Management of Other Stages (T1b/TIV)

Surgery is typically reserved for early stage diseases, such as stage Ia, Ib1, Ib2, and
IIa1 [113]. Concurrent chemoradiation is generally the primary treatment for stages
IB3 to IVA disease, based on five randomized clinical trials [114,115] and for patients
who are not candidates for hysterectomy. Although few studies have assessed treat-
ment for cervical adenocarcinomas, they are typically treated similarly to squamous cell
carcinomas [109,110,116–118]. Ovarian preservation cannot be proposed in the case of
HPV-unrelated cervical adenocarcinoma.
Adjuvant treatment is indicated after radical hysterectomy, depending on surgical
findings and disease stage. Adenocarcinoma (in particular, adenocarcinoma non-HPV
related) is considered an additional risk factor [119,120].

Author Contributions: Conceptualization, investigation, writing—original draft preparation, A.C.

and L.G.; investigation, writing—original draft preparation, J.D.G., G.D.C., C.G., M.F., G.S., S.C. and
L.N.; supervision, A.C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Int. J. Mol. Sci. 2022, 23, 15022 14 of 20

Informed Consent Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

AKT1 Serine-threonine protein kinase AKT1

APOBEC3 Apolipoprotein B mRNA editing enzyme, catalytic subunit 3
ARID1A AT-rich interactive domain-containing protein 1A
ATM Ataxia telangiectasia mutated
BCOR BCL6 corepressor
BRCA2 Breast cancer gene 2
CCC Clear cell adenocarcinoma
CDK12 Cyclin dependent kinase 12
CDKN2A Cyclin dependent kinase inhibitor 2
CIN Cervical intraepithelial neoplasia
CTNNB1 Catenin Beta 1
DES Diethylstilbestrol
DNA Deoxyribonucleic acid
ECA endocervical adenocarcinoma
EGFR Epidermal growth factor receptor
ELF Ets domain transcription factor
ENAC Endometrioid adenocarcinoma
ERB2 Erb-B2 receptor tyrosine kinase 2
FBXW7 F-box and WD repeat domain containing 7
FDA Food and Drug Administration
FGFR2 fibroblast growth factor receptor 2
FGFR4 Fibroblast growth factor receptor 4
GAIS Gastric-type adenocarcinoma in situ
GCA Gastric-type adenocarcinoma
GNAS Guanine nucleotide binding protein
H&E hematoxylin eosin
HER2 Human epidermal growth factor receptor 2
HLA-B Human leukocyte antigen-B
HPV Human papillomavirus
IECC International endocervical criteria and classification
IHC immunohistochemistry
ISGyP International Society of Gynecological Pathologists
KMT2D Lysine methyltransferase 2D
KRAS Kirsten rat sarcoma
LEGH Lobular endocervical glandular hyperplasia
MDA Minimal-deviation adenocarcinoma
MDM2 Mouse double minute 2
MECOM MDS1 and EVI1 complex locus
MMA DNA mismatch repair
MRI Magnetic resonance imaging
MSH2 MutS homolog 2
MSH6 MutS homolog 6
MSI-H microsatellite instability-high
NGS Next generation sequencing
NHPVA non-HPV adenocarcinoma
NTRK3 Neurotrophic receptor tyrosine kinase 3
p-mTOR Phosphorylated mammalian target of rapamycin
PCR Polymerase chain reaction
PD-L1 programmed cell death ligand 1
PI3K-AKT Phosphatidylinositol-3-kinase
PIK3CA Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
POLE polymerase epsilon
Int. J. Mol. Sci. 2022, 23, 15022 15 of 20

PTEN Phosphatase and tensin homolog

PTPRS Protein tyrosine phosphatase receptor type S
RISH RNA in-situ hybridization
RNA Ribonucleic acid
SCC Squamous cell carcinoma
SLX4 Structure-specific endonuclease subunit
SMAD4 Mothers against decapentaplegic homolog 4
SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin,
subfamily A, member 4
STK11 Serine/threonine kinase 11
TP53 Tumor protein p53
WHO World Health Organization

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