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Clinical Features of Human Papillomavirus-Negative Adenocarcinoma: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor: Luca Giannella , Jacopo Di Giuseppe , Giovanni Delli Carpini ,
Camilla Grelloni
, Mariasole Fichera ,
Gianmarco Sartini
,
Serena Caimmi
, Leonardo Natalini , Andrea Ciavattini

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. 

  • adenocarcinoma
  • cervix
  • HPV
  • HPV-negative

1. Gastric-Type Adenocarcinoma (GCA)

HPV. Previous studies using PCR and in situ hybridization demonstrated that GCA is an HPV-negative tumor [1][2].
Epidemiology. GCA, described for the first time in the 1990s, is the most common type of NHPVA [3]. 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 [2][4]. 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) [5].
The mean age of the patients at the time of diagnosis is 52 years (ranging from 23–81), similar to the usual-type-adenocarcinoma [6]. 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 [7].
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 [8].
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 [9][10].
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 [9][11].
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 [9][12].
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 [13]. 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 [3][13]. 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 [10][14][15][16].
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 [17].
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 differentiation [18].
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 [11][19].
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 [9][10][19][20]. 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 [21].
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) [11][19][20].
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 [22].

2. Clear Cell Adenocarcinoma (CCC)

HPV. CCC seems to be associated with HPV infection only in 25–30.4% of cases [23].
Epidemiology. Clear cell carcinoma represents 2–7% of cervical adenocarcinomas [24]. 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 [25]. 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 [26]. In addition, some cases of CCC in non-DES-and-HPV-exposed children and young women have been reported [27][28]. 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 [24][29]. 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 [30].
Symptoms and signs. CCC can present with cervical ulceration that causes abnormal vaginal bleeding (postcoital bleeding, intermenstrual bleeding), usually refractory to hormonal therapy [31]. At the gynecological examination, an abnormality in the consistency of the cervix can sometimes be perceived as “fullness” [32].
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 [33][34].
Radiodiagnostics. CCC at the MRI shows hypointensity on T1-weighted images, hyperintensity on T2-weighted images, and heterogeneous enhancement [32].
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 [35]. Moreover, Talia et al. assumed that even the tubo-endometrial metaplasia adjacent to the cervix could be a precursor of CCC [36].
Prognosis. Previous literature about CCC prognosis is controversial: some authors report the exact outcomes of usual-type adenocarcinoma, whereas others notice more aggressive behavior [32].
Interestingly, Wang et al. reported a better prognosis in DES-exposed CCC patients than those with spontaneous CCC [37]. CCC is more aggressive than squamous cell carcinomas in recurrence and metastasis [38][39]. 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 [40]. Most recurrences of CCC of the uterine cervix get diagnosed within three years after primary tumor treatment, whereas late recurrences are less frequent [28].
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 [33].

3. Mesonephric Adenocarcinoma

HPV. Mesonephric adenocarcinoma seems to be not associated with HPV infection [41].
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 [42].
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 [41].
Pap test. Pap tests performed during routine screening can detect cytological abnormalities, but such detection occurs less frequently than squamous cervical cancer of the cervix. The diagnosis is often obtained through cervical biopsy, curettage, or hysteroscopy [43][44].
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 [42][43].
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 [42][44].

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 [45][46][47]. In contrast, ENACs that develop from the upper endocervix and lower uterine segments are HPV-independent [48][49][50].
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 [45][51].
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 [4].
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 [26].
Precursors. Endometrioid cancer reportedly develops from cervical endometriosis. Some authors suspected ENAC could arise from a malignant transformation of endometriotic areas [52][53].
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% [54].

This entry is adapted from the peer-reviewed paper 10.3390/ijms232315022

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