Search Results (10)

Cervical cancer remains a global health burden, with persistent infection by high-risk human papillomaviruses (HR-HPVs) being the primary etiological factor. HR-HPVs target stem-like cells of the cervical epithelium to establish chronic infections. Upon infection of the cervical transformation zone (TZ)—a region adjacent to the squamocolumnar junction (SCJ)—these viruses drive neoplastic transformation, which is due in part to the unique cellular composition and hormonal responsiveness of the TZ. Reserve cells, which can accumulate at the cervical crypt entrances of the TZ, are thought to be highly susceptible to HR-HPV infection because of their location beneath a single layer of columnar cells. Infection of the stratified ectocervical epithelium, in contrast, requires a wound to allow basal cell infection, replication, and the expression of early genes to adjust epithelial homeostasis while facilitating immune evasion. Persistent infection by HR-HPV types, particularly HPV16 and HPV18, can result in the deregulated expression of viral genes E6 and E7, driving cell cycle disruption, genomic instability, and subsequent viral genome integration. Differences in the microenvironment and transcriptional environment of the ectocervix compared with the TZ could explain the frequent deregulation of E6 and E7 at the latter site, which can drive disease progression towards cancer. Full article

Cervical cancer ranks third among malignant diseases of the female reproductive system and progressively develops through a series of pathological changes known as cervical intraepithelial neoplasia (CIN). Despite being extremely aggressive and causing increased mortality, the main treatment options include surgery or a combination of chemotherapy and radiotherapy, often based on cisplatin-based chemotherapy and external beam radiotherapy or brachytherapy. Cervical dysplasia is an abnormal growth of cells on the surface of the cervix that could lead to cervical cancer. CIN most commonly occurs at the squamocolumnar junction of the cervix, a transitional zone between the squamous epithelium of the vagina and the columnar epithelium of the endocervix. The primary cause of CIN is chronic infection of the cervix with Human Papillomavirus (HPV). Oxidative stress (OS) and chronic inflammation are associated with HPV-induced cervical dysplasia. Reactive oxygen species (ROS) facilitate the progression of CIN through DNA damage, immune evasion, and cellular mutations. Thus, the inflammatory environment, characterized by increased expression of proinflammatory cytokines, contributes to epithelial transformation. Given these mechanisms, antioxidants, including vitamins A, C, D, E, polyphenols, and carotenoids, are being investigated for their potential as adjunctive therapies in CIN management. This review aims to provide a comprehensive analysis of the influence of oxidative stress, antioxidants, and inflammation on cervical cancer. Full article

Background/Objectives: To investigate the risk factors for CIN2+ lesions (cervical intraepithelial neoplasia 3 or worse) in endocervical curettage (ECC) and to evaluate the relationship between the addition of ECC to punch biopsy in terms of the yield of CIN2+ lesions. Methods: Between February 2018 and 2019, data on colposcopy results from 11,944 patients were gathered from the Cancer Department of the Turkish Ministry of Health across the country. A total of 6370 women whom were referred to colposcopy were included in this study. Risk factors were identified using both univariate and multivariate logistic analyses. Results: The median age was 42 years old (range, 30–65). ASC-H (atypical squamous cells-suggestive of high-grade squamous intraepithelial lesion)/HSIL (high-grade intraepithelial lesion) cytology (OR 7.648 95% CI (3.933–14.871)) and HPV (human papillomavirus)-16/18 infection (OR 2.541 95% CI (1.788–3.611)) were identified as risk factors for having CIN2+ lesions. CIN2+ diagnostic yield by ECC is only 1.2% all patients. CIN2+ diagnostic yield by punch biopsy and ECC are 9.7% and 6% of patients, respectively. A higher CIN2+ yield by ECC was observed with increasing age. Among cytology groups, ASC-H/HSIL has highest CIN2+ yield by ECC. Finally, in patients with incomplete visualization of the squamocolumnar junction (SCJ), ECC yields approximately twice as many CIN2+ lesions. Conclusions: ECC should be considered in cases of advanced patient age and in situations where the SCJ is not routinely visualized. In addition, evaluation of the endocervical canal is necessary in HPV-positive cases infected with HPV-16/18 types and in cases infected with HPV of any type but with cytological abnormalities. Full article

The aim of this study was to evaluate the endocervical margin status according to transformation zone (TZ) and high-risk HPV (hr-HPV) subtype in specimens with cone length ≤ 10 mm versus > 10 mm to provide data for informed decision making and patients counseling especially for women wishing to conceive. In this retrospective cohort study, 854 patients who underwent large loop excision of the transformation zone during a nine-year period (2013–2021) for cervical disease were analyzed. The main outcome parameters were excision length, histological result, TZ type, HPV subtype and endocervical margin status. A subgroup analysis was performed according to excision length, with a cut-off value of 10 mm. A two-step surgical procedure was performed in case of an excision length of > 10 mm. The overall rate of positive endocervical margins irrespective of excision length was 17.2%, with 19.3% in specimens with ≤ 10 mm and 15.0% with > 10 mm excision length. Overall, 41.2% of women with a visible TZ and HPV 16/hr infection and 27.0% of women with HPV 18 received an excisional treatment of > 10 mm length without further oncological benefit, respectively. In contrast, assuming that only an excision of ≤ 10 mm length had been performed in women with visible TZ, the rate of clear endocervical margins would have been 63.7% for HPV 16/hr infections and 49.3% for HPV 18 infections. In conclusion, the decision about excision length should be discussed with the patient in terms of oncological safety and the risk of adverse pregnancy events. An excision length > 10 mm increases the number of cases with cervical tissue removed without further oncological benefit, which needs to be taken into account in order to provide an individual therapeutic approach. Furthermore, HPV 18 positivity is related to a higher rate of positive endocervical margins irrespective of TZ. Full article

Junctional epithelia are common sites for pathological transformations. In mice, the stratified epithelium of the forestomach joins the simple glandular epithelium of the cardia at the limiting ridge. We previously demonstrated the expression of vitamin A receptors in the gastric stem/progenitor cells and their progeny and found that excess retinoic acid enhances cellular dynamics of gastric epithelium. This study examines how deficiency of vitamin A would alter gastric epithelial stem cell lineages. Three-week-old mice of both genders were weaned and fed with a vitamin A deficient (VAD) diet for 4 or 8 months. Sex- and weight-matched littermate mice received a standard (control) diet. To label S-phase cells, all mice received a single intraperitoneal injection of 5-bromo-2-deoxyuridine before being euthanized. Stomach tissues were processed for microscopic examination and protein analysis to investigate stem cell lineages using different stains, lectins, or antibodies. The Student’s t-test was used to compare quantified data showing differences between control and VAD groups. Eight-month-vitamin-A deficiency caused enlarged forestomach and overgrowth of the squamocolumnar junction with metaplastic and dysplastic cardiac glands, formation of intramucosal cysts, loss of surface mucosal integrity, increased amount of luminal surface mucus, and upregulation of trefoil factor 1 and H⁺,K⁺-ATPase. These changes were associated with decreased cell proliferation and upregulation of p63. In conclusion, vitamin A is necessary for maintaining gastric epithelial integrity and its deficiency predisposes the mouse stomach to precancerous lesions. Full article

Precancerous screening using visual inspection with acetic acid (VIA) is suggested by the World Health Organization (WHO) for low–middle-income countries (LMICs). However, because of the limited number of gynecological oncologist clinicians in LMICs, VIA screening is primarily performed by general clinicians, nurses, or midwives (called medical workers). However, not being able to recognize the significant pathophysiology of human papilloma virus (HPV) infection in terms of the columnar epithelial-cell, squamous epithelial-cell, and white-spot regions with abnormal blood vessels may be further aggravated by VIA screening, which achieves a wide range of sensitivity (49–98%) and specificity (75–91%); this might lead to a false result and high interobserver variances. Hence, the automated detection of the columnar area (CA), subepithelial region of the squamocolumnar junction (SCJ), and acetowhite (AW) lesions is needed to support an accurate diagnosis. This study proposes a mask-RCNN architecture to simultaneously segment, classify, and detect CA and AW lesions. We conducted several experiments using 262 images of VIA+ cervicograms, and 222 images of VIA−cervicograms. The proposed model provided a satisfactory intersection over union performance for the CA of about 63.60%, and AW lesions of about 73.98%. The dice similarity coefficient performance was about 75.67% for the CA and about 80.49% for the AW lesion. It also performed well in cervical-cancer precursor-lesion detection, with a mean average precision of about 86.90% for the CA and of about 100% for the AW lesion, while also achieving 100% sensitivity and 92% specificity. Our proposed model with the instance segmentation approach can segment, detect, and classify cervical-cancer precursor lesions with satisfying performance only from a VIA cervicogram. Full article

Despite therapeutical advancements, and in contrast to other malignancies, esophageal adenocarcinoma (EAC) prognosis remains dismal while the incidence has markedly increased worldwide over the past decades. EAC is a malignancy of the distal esophageal squamous epithelium at the squamocolumnar junction with gastric cells expanding into the esophagus. Most EAC patients have a history of Barret’s esophagus (BE), a metaplastic adaption to chronic reflux, initially causing an inflammatory microenvironment. Thus, the immune system is highly involved early on in disease development and progression. Normally, anti-tumor immunity could prevent carcinogenesis but in rare cases BE still progresses over a dysplastic intermediate state to EAC. The inflammatory milieu during the initial esophagitis phase changes to a tolerogenic immune environment in BE, and back to pro-inflammatory conditions in dysplasia and finally to an immune-suppressive tumor microenvironment in EAC. Consequently, there is a huge interest in understanding the underpinnings that lead to the inflammation driven stepwise progression of the disease. Since knowledge about the constellations of the various involved cells and signaling molecules is currently fragmentary, a comprehensive description of these changes is needed, allowing better preventative measures, diagnosis, and novel therapeutic targets. Full article

The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated. Full article

The treatment of cervical intraepithelial neoplasia aims at removing the squamocolumnar junction area, including abnormal tissues, up to the healthy tissue. Old postpartum perineal tears associated with cystorectocele, hypertrophic cervical elongation, and first and second degree uterine prolapse are pelvic static disorders. Particular aspects of pelvic-genital static disorder are related to the vulnerability of the pelvic-perineal floor during birth. On the occasion of birth, especially when there are different forms of dystocia during labor, the degradation of soft pelvic, genital, and vaginal-perineal tissues can occur. The objective of this study was to re-evaluate the conservative treatment of cervical dysplasia, depending on the degree of cervical lesions, the surface extension, the age of the patients, and the pathology associated with cervical lesions – colpocele, cystorectocele, and urinary incontinence in the old postpartum perineal tears. In order to solve the three types of concomitant lesions, we used the Manchester operation: the anterior colporrhaphy with the recalibration of the urethra and the suspension of the cystocele, the minimal colpectomy, the lesional cervical amputation with the anterior fixation of the parameters, and the posterior colpoperineorrhaphy with high myorrhaphy of the levator ani muscles. The decision on the management of cervical dysplasia has taken into account the degree of cervical lesions, the extension on the surface, the patients’ age and the pregnancy planning, and the pathology associated with cervical lesions. The Manchester operation is a conservative surgical procedure, effective in women under 45 years old, multiparous, with present genital activity, with dysplastic cervical lesions and cystorectocele. It also solves cystorectocele, cervical dysplasia, hypertrophic cervical elongation, and first and second degree uterine prolapse. Full article

Human papillomavirus (HPV)-induced neoplasms have long been considered to originate from viral infection of the basal cell layer of the squamous mucosa. However, this paradigm has been recently undermined by accumulating data supporting the critical role of a discrete population of squamo-columnar (SC) junction cells in the pathogenesis of cervical (pre)cancers. The present review summarizes the current knowledge on junctional cells, discusses their high vulnerability to HPV infection, and stresses the potential clinical/translational value of the novel dualistic model of HPV-related carcinogenesis. Full article