VPH Negativo
VPH Negativo
VPH Negativo
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 *
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.
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
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].
Table 3. Cont.
Abbreviations
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