PAX1 methylation as a robust predictor: developing and validating a nomogram for assessing endocervical curettage (ECC) necessity in human papillomavirus16/18-positive women undergoing colposcopy.

OBJECTIVE: The major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless, current reported models often overestimate the validity and necessity of ECC, making it difficult to improve benefits for patients. This research hypothesized that assessing paired boxed gene 1 methylation levels (PAX1m) and clinical characteristics could enhance the predictive accuracy of detecting additional high-grade squamous intraepithelial lesions or worse (HSIL +) through ECC that were not identified by colposcopy-directed biopsy (CDB). METHODS: Data from 134 women with HPV16/18 positivity undergoing CDB and ECC between April 2018 and April 2022 were collected and analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was utilized to measure PAX1m, expressed as ΔCp. Univariate and multivariate regression analyses were conducted to screen variables and select predictive factors. A nomogram was constructed using multivariate logistic regression to predict additional HSIL + detected by ECC. The discrimination, calibration, and clinical utility of the nomogram were evaluated using receiver operating characteristic curves (ROC) and the calibration plot. RESULTS: Age (odds ratio [OR], 5.654; 95% confidence interval [CI], 1.131-37.700), cytology (OR, 24.978; 95% CI, 3.085-540.236), and PAX1 methylation levels by grade (PAX1m grade) (OR, 7.801; 95% CI, 1.548-44.828) were independent predictive factors for additional detection of HSIL + by ECC. In HPV16/18-positive women, the likelihood of additional detection of HSIL + through ECC increased with the severity of cytological abnormalities, peaking at 43.8% for high-grade cytological lesions. Moreover, when cytological findings indicated low-grade lesions, PAX1 methylation levels were positively correlated with the additional detection of HSIL + by ECC (P value < 0.001). A nomogram prediction model was developed (area under curve (AUC) = 0.946; 95% CI, 0.901-0.991), demonstrating high sensitivity (90.9%) and specificity (90.5%) at the optimal cutoff point of 107. Calibration analysis confirmed the model's strong agreement between predicted and observed probabilities. CONCLUSION: The clinical nomogram presented promising predictive performance for the additional detection of HSIL + through ECC among women with HPV16/18 infection. PAX1 methylation level could serve as a valuable tool in guiding individualized clinical decisions regarding ECC for patients with HPV 16/18 infection, particularly in cases of low-grade cytological findings.

Cytology-histology correlation of atypical glandular cells on cervical Papanicolaou tests: A study of 628 cases.

INTRODUCTION: The finding of atypical glandular cells (AGC) on Papanicolaou test is becoming more important as the incidence of squamous intraepithelial lesions decreases in recent decades. Therefore, the interpretation and follow-up of patients with AGC are particularly important. The aim of our study was to assess the histologic findings and clinical correlations in patients with AGC identified on Papanicolaou test. MATERIALS AND METHODS: A total of 714 patients with AGC identified on cervical Papanicolaou tests were studied for their clinicopathologic features, such as follow-up histology and patient age. We investigated the histologic follow-up results for each individual subcategories of AGC and their correlation with patients' age. RESULTS: Most of the glandular cell abnormalities (80.0%) in the study group were classified as "atypical glandular cells, not otherwise specified (NOS)". About 28.9% of patients' follow-up histology showed malignant or precancerous lesions. The mean age of patients with malignant or precancerous lesions was significantly higher than that of patients with benign or non-precancerous lesions. The malignant histologies included 52 cases of endometrial cancers and 31 cases of cervical carcinomas. The second most common subcategory was "atypical glandular cells, favor neoplastic" (5.0%), while "atypical endocervical cells, favor neoplastic" constituted about 2.7% of cases in our study. The average age of patients with "atypical glandular cells, favor neoplastic" was significantly higher than that of patients with "atypical endocervical cells, favor neoplastic". The follow-up histology of about 82.1% of "atypical glandular cells, favor neoplastic" showed endometrial (73.9%) or cervical malignancies (26.1%). The follow-up histology of about 70.6% of "atypical endocervical cells, favor neoplastic" showed endometrial (50.0%) or cervical cancers (50.0%). Other glandular abnormalities included 25 of 714 cases of "atypical endometrial cells" (3.5%) and 6 of 714 cases of "atypical endocervical cells" (0.8%). CONCLUSION: Based on our data, we have observed significantly more endometrial malignancies in both "atypical glandular cells, NOS" and "atypical glandular cells, favor neoplastic" subcategories and even some in "atypical endocervical cells, favor neoplastic" category. This predominance of endometrial malignancies is also associated with patients' age and tumor types.

Ovarian Metastasis from Human Papillomavirus-associated Usual-type Endocervical Adenocarcinoma: Clinicopathological Characteristics for Distinguishing from Primary Ovarian Mucinous or Endometrioid Tumor.

BACKGROUND/AIM: Distinguishing ovarian metastasis of usual-type endocervical adenocarcinoma (UEA) from primary ovarian tumors is often challenging because of several overlapping features. This study aimed to investigate the clinicopathological characteristics and outcomes of patients with metastatic ovarian UEA. PATIENTS AND METHODS: Clinicopathological information was collected from eight patients with metastatic ovarian UEA. Immunostaining was also performed. RESULTS: Most patients presented with adnexal masses that were suspected to be primary ovarian tumors. All examined cases showed block p16 positivity in paired primary and metastatic tumors. Five patients who completed post-operative chemotherapy or concurrent chemoradiotherapy (CCRT) did not experience recurrence. In contrast, one patient who refused further treatment after the first CCRT cycle experienced ovarian and peritoneal metastases. One patient with isolated ovarian metastasis left untreated and developed peritoneal metastasis during follow-up. CONCLUSION: Patients with UEA who received proper management for ovarian metastases showed favorable outcomes. Given that ovarian metastatic UEA can mimic primary ovarian borderline tumor or carcinoma of the mucinous or endometrioid type, pathologists should be aware of this unusual but distinctive morphology to avoid misdiagnosis and inappropriate treatment.

Cytologic Parameters in Predicting the Outcome of Atypical Glandular Cells on Papanicolaou Smears: A Single-Institutional Experience.

Background: Atypical glandular cells (AGCs) diagnosis on Pap (Papanicolaou) smears are uncommon and may represent various benign and malignant lesions. Objective: This study aims to report the incidence of AGC on Pap smear, to study the relationship of AGC with malignancy, and to determine cytomorphological features that help in predicting malignancy. Materials and Methods: Retrospective analytical study conducted in the Department of Oncopathology at Tertiary Cancer and Research Institute. In this retrospective study, we included cases diagnosed with AGC between July 2017 to July 2022. All slides were reviewed and subclassified according to the Bethesda 2014 classification system (TBS). The predetermined cytomorphological features observed in the smears were recorded. The follow-up histopathological diagnoses of the cases were retrieved. The significant cytomorphological and clinicopathological findings for malignancy were determined. Results: Pearson χ2 test with SPSS software version 22 to compare cytologic features of cases with benign and malignant follow-up. The significant cytomorphological features observed in neoplastic cases were cells in 3-dimensional clusters, nuclear overlapping, reniform nucleus, irregular nuclear membrane, increased nuclear size, single macronucleoli, engulfed neutrophils, and prominently vacuolated cytoplasm. Conclusions: The diagnosis of AGC on cytology is associated with clinically significant lesions, and cytomorphologic parameters can be used to predict the benign and malignant outcome.

Can Mitotic Figures in Hyperchromatic Crowded Groups be Cytodiagnostic Criteria for High-Grade Squamous Intra-epithelial Lesions?

Aims: The present study aimed to investigate whether the presence of mitoses in hyperchromatic crowded groups (HCGs) in cervical cytological specimens can serve as cytological criteria for high-grade squamous intra-epithelial lesions (HSILs). Methods and Material: Various parameters were examined, including the frequency of mitotic figures per high power field (HPF) in Pap, hematoxylin eosin (HE) samples, and PHH3 immunocytochemical (ICC) and immunohistochemical (IHC) analyses. Results: In the Pap and PHH3-ICC samples, the number of mitotic figures observed in HCGs was significantly higher in HSIL (P < 0.001) compared to other groups. Furthermore, the frequency of observing two or more mitoses was significantly higher in HSIL (Pap: P = 0.002, PHH3-ICC: P < 0.001) than in low-grade squamous intra-epithelial lesions (LSILs). Moreover, a comparison between Pap samples and PHH3-ICC showed that the frequency of two or more mitoses was significantly higher in the PHH3-ICC analysis of HSIL (P = 0.042). Regarding HE and PHH3-IHC samples, counting the number of mitoses in the lower and middle/upper layers of the squamous epithelial layer revealed that HSIL had a significantly higher value (HE: P = 0.0089, PHH3-IHC: P = 0.0002) than LSIL in the middle/upper layers. Conclusions: Hence, the presence of two or more mitotic figures in HCGs per HPF in cervical cytology indicates a suspicion of HSIL. The detection of mitoses in PHH3-ICC samples is more sensitive and easier to observe than in Pap samples, making it a valuable mitotic marker.

A case of uterine adenomyoma of endocervical type that was suspected as minimal deviation adenocarcinoma on biopsy, MRI findings, and literature review.

Uterine adenomyomas of endocervical type are rare benign tumors of the uterine cervix commonly presented as cyst-like, dilated glandular structures within polypoid masses. A premenopausal woman in her 50s was referred to our hospital because of an increasing watery vaginal discharge. A multifocal cyst measuring 5 × 4.5 cm in size projecting into the endocervical canal was revealed on a contrast-enhanced MRI. The fluid within the tumor showed a hypointense signal on T1-weighted imaging (T1WI) and a hyperintense signal on T2-weighted imaging (T2WI). On T2WI, most of the septa within the tumor showed a slightly hyperintense to hypointense signal, whereas some areas revealed a strong hypointense signal; the contrast effect on the septum was satisfactory. On the T2WI taken 2 years previously, the tumor was a 4.5 × 3.5 cm polypoid mass protruding from the posterior endocervical wall. Contrastingly, the current T2WI showed that the stem was no longer identifiable because of tumor growth. Because previous imaging showed that the tumor was a stalked tumor protruding from the posterior endocervical wall, the imaging diagnosis was uterine adenomyoma of the endocervical type. A biopsy suggested the possibility of a minimal deviation adenocarcinoma (MDA). Hence, a total hysterectomy was performed. The final diagnosis confirmed the uterine adenomyoma of endocervical type. Uterine adenomyoma of the endocervical type might be difficult to differentiate from MDA in small biopsy specimens; therefore, evaluation of morphology by MRI is considered important in preoperative diagnosis.

SMFM Consult Series #70: Management of short cervix in individuals without a history of spontaneous preterm birth.

Most deliveries before 34 weeks of gestation occur in individuals with no previous history of preterm birth. Midtrimester cervical length assessment using transvaginal ultrasound is one of the best clinical predictors of spontaneous preterm birth. This Consult provides guides for the diagnosis and management of a short cervix in an individual without a history of preterm birth. The following are Society for Maternal-Fetal Medicine recommendations: (1) we recommend that all cervical length measurements used to guide therapeutic recommendations be performed using a transvaginal approach and in accordance with standardized procedures as described by organizations, such as the Perinatal Quality Foundation or the Fetal Medicine Foundation (GRADE 1C); (2) we recommend using a midtrimester cervical length of ≤25 mm to diagnose a short cervix in individuals with a singleton gestation and no previous history of spontaneous preterm birth (GRADE 1C); (3) we recommend that asymptomatic individuals with a singleton gestation and a transvaginal cervical length of ≤20 mm diagnosed before 24 weeks of gestation be prescribed vaginal progesterone to reduce the risk of preterm birth (GRADE 1A); (4) we recommend that treatment with vaginal progesterone be considered at a cervical length of 21 to 25 mm based on shared decision-making (GRADE 1B); (5) we recommend that 17-alpha hydroxyprogesterone caproate, including compounded formulations, not be prescribed for the treatment of a short cervix (GRADE 1B); (6) in individuals without a history of preterm birth who have a sonographic short cervix (10-25 mm), we recommend against cerclage placement in the absence of cervical dilation (GRADE 1B); (7) we recommend that cervical pessary not be placed for the prevention of preterm birth in individuals with a singleton gestation and a short cervix (GRADE 1B); and (8) we recommend against routine use of progesterone, pessary, or cerclage for the treatment of cervical shortening in twin gestations outside the context of a clinical trial (GRADE 1B).

Gastric-type endocervical adenocarcinoma: a case report and literature review.

Gastric-type endocervical adenocarcinoma (G-EAC) represents a rare variant of cervical mucinous adenocarcinoma that is typically unrelated to human papillomavirus (HPV) infection. G-EAC exhibits highly atypical clinical presentations and characteristics, and aggressive biological behavior often leads to challenges in timely diagnosis. Here, we present a case study involving a 74-year-old Chinese woman who experienced urinary incontinence for one month. Biopsy pathology confirmed the diagnosis of G-EAC, revealing stage IVa by imaging examinations. The patient subsequently underwent three cycles of chemotherapy, followed by adjuvant radiotherapy and surgical excision of residual tumor foci. This comprehensive treatment approach yielded a favorable survival outcome. For patients with advanced G-EAC, a multimodal therapeutic approach holds promise and warrants further exploration.

Tall-columnar glandular cells in SurePath™ liquid-based cytology Pap sample: Learning from mimics/pitfalls.

We offer a comprehensive depiction of the cytomorphological characteristics of lobular endocervical glandular hyperplasia (LEGH) as observed in SurePath™ liquid-based cytology (LBC), subsequently confirmed on cone biopsy. Lobular endocervical glandular hyperplasia (LEGH), a precursor to gastric-type adenocarcinoma (GAE) of the endocervix, is rare and reports of it in cervical cytology are scarce. We provide a thorough description of the cytomorphological features of LEGH observed in SurePath™ liquid-based cytology (LBC), later confirmed by cone biopsy. To the best of our knowledge, this is the first report documenting cytology of LEGH in LBC of a Pap sample.

Comparative performance of vulvovaginal swab sampling versus endocervical sampling for the detection of Chlamydia, Gonorrhea, Mycoplasma genitalium, and Trichomoniasis: a cross-sectional study in Spain.

INTRODUCTION: The global increase in sexual transmitted infections (STI) makes it necessary to seek public health strategies that facilitate rapid and minimally invasive diagnosis. The objective was to evaluate the concordance between vaginal and endocervical samples for STI diagnosis. MATERIALS AND METHODS: A retrospective cross-sectional study was carried out on vaginal and endocervical samples from women attended in our reference area with symptoms suggestive of vulvovaginitis or for STI screening during the study period. RESULTS: A total of 130 paired samples were analyzed; fifty-seven and 59 samples were positive for vaginal and endocervical specimens (Kappa index of 0.969 (Standard error = 0.022). The sensitivity of the vaginal samples was 96.5% (IC95%: 87.2-99.4), with a specificity of 100% (IC95%: 93.0-100). DISCUSSION: The introduction of STI screening in vaginal samples in our environment can facilitate rapid and effective diagnosis and allow early treatment of STI. Additionally, it facilitates sample collection and diagnosis in the community setting, essential for optimal screening.

Gastric Type Endocervical Adenocarcinoma With Concurrent High-Grade Squamous Intraepithelial Lesion: A Clinicopathologic Study of Three Patients.

OBJECTIVE: We investigate gastric-type endocervical adenocarcinoma (ECA), a prominent HPV-independent adenocarcinoma, and its coexistence with high-grade squamous intraepithelial lesion (HSIL) through the examination of three such tumors. METHODS: In this study, we conducted an in-depth review of three patients with gastric-type ECA, each associated with high-risk HPV infection as detected on Pap smears. We detailed the clinical and pathological features of each patient and utilized RNAscope for high-risk HPV testing to ascertain HPV status in both gastric-type ECA and HSIL components. Immunohistochemistry with p16, p53, and other biomarkers was also applied. RESULTS: The gastric-type ECA component, characterized by well-differentiated glands with abundant, clear to eosinophilic cytoplasm, distinct cellular borders, and pale nuclei with conspicuous nucleoli, tested negative for both p16 and high-risk HPV, unlike the concurrent HSIL components which were positive. Additionally, two tumors showed aberrant p53 protein expression in the gastric-type ECA areas, and elevated carbohydrate antigen19-9 levels were noted in two patients. Treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy, supplemented by chemotherapy and/or radiation, with disease-free intervals of 24, 12, and 40 months post-treatment, respectively. CONCLUSION: This study highlights the critical need for meticulous diagnostic protocols that combine morphological examination, immunohistochemistry, and HPV RNA in situ hybridization. The rarity of gastric-type ECA coexisting with HPV infection underscores the necessity for continuous research and vigilant monitoring in the field of gynecological oncology.

Comparison of Clinicopathological and Prognostic Characteristics Between Minimal Deviation Adenocarcinoma and Gastric-type Endocervical Adenocarcinoma.

BACKGROUND/AIM: Minimal deviation adenocarcinoma (MDA) is an extremely well-differentiated variant of gastric-type endocervical adenocarcinoma (GEA). This study compared the clinicopathological and prognostic characteristics of MDA to those of GEA. PATIENTS AND METHODS: Nine MDAs and 22 GEAs were included in this study. We reviewed electronic medical records and pathology slides to collect clinicopathological and prognostic information. RESULTS: GEA showed significantly higher stage at presentation, more frequent parametrial extension and lymphovascular space invasion, and recurrence than MDA. Patients with GEA had significantly lower survival rates than those with MDA. None of the cases with MDA exhibited singly dispersed or clustered tumor cells, diffuse stromal desmoplasia, severe nuclear pleomorphism, loss of nuclear polarity, or coarse chromatin, all of which were frequently observed in GEA. CONCLUSION: Significant differences were observed in the clinicopathological characteristics and patient outcomes between MDA and GEA. Further investigations using a larger cohort are warranted to determine the clinical behavior and aggressiveness of MDA.

The Silva pattern-based classification for HPV-associated endocervical adenocarcinoma: A single institution concordance study of trainees and gynecologic pathologists.

The Silva pattern-based classification of HPV-associated endocervical adenocarcinoma has become an integral part of the histologic assessment of these tumors. Unfortunately, the Silva system reproducibility has had mixed results in past studies, and clinical practice still favors the FIGO stage assessment in directing therapeutic interventions for patients. In our study, we aimed to assess our institution's concordance including not only gynecologic pathologists, but also pathology trainees through a series of 69 cases. The grouped total kappa concordance from all participants was 0.439 (Moderate), with an overall trainee kappa of 0.417 (moderate) and an overall pathologist kappa of 0.460 (moderate). Perfect concordance among all 10 study participants was seen in 8/69 cases (11.6 %), corresponding to 5/22 Pattern A cases (22.7 %), 0/16 Pattern B cases (0 %), and 3/31 Pattern C cases (9.7 %), with similar findings between trainees and pathologists when compared within their own cohorts. Recurrence was identified in 2 Pattern A cases, indicating a potential issue with limited excisional specimens which may not fully appreciate the true biologic aggressiveness of the lesions.

Unraveling the role of the circadian clock genes in cervical squamous cell carcinoma and endocervical adenocarcinoma: A prognostic indicator for prognostic, immunotherapy response, and chemotherapy sensitivity.

Background: Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) account for a significant proportion of gynecological malignancies and represent a major global health concern. Globally, CESC is ranked as the fourth most common cancer among women. Conventional treatment of this disease has a less favorable prognosis for most patients. However, the discovery of early molecular biomarkers is therefore important for the diagnosis of CESC, as well as for slowing down their progression process. Methods: To identify differentially expressed genes strongly associated with prognosis, univariate Cox proportional hazard analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were used. Using multiple Cox proportional hazard regression, a multifactorial model for prognostic risk assessment was then created. Results: The expression of biological clock-related genes, which varied considerably among distinct subtypes and were associated with significantly diverse prognoses, was used to categorize CESC patients. These findings demonstrate how the nomogram developed based on the 7-CRGs signature may assist physicians in creating more precise, accurate, and successful treatment plans that can aid CESC patients at 1, 3, and 5 years. Conclusions: By using machine learning techniques, we thoroughly investigated the impact of CRGs on the prognosis of CESC patients in this study. By creating a unique nomogram, we were able to accurately predict patient prognosis. At the same time, we showed new perspectives on the development of CESC and its treatment by analyzing the associations of the prognostic model with immunity, enrichment pathways, chemotherapy sensitivity, and so on. This research provides a new direction for clinical treatment.

Atypical glandular cells and predictive features of malignancy in Pap smears: A retrospective monocentric study.

OBJECTIVE: The introduction of cytological screening with the Papanicolau smear significantly reduced cervical cancer mortality. However, Pap smear examination can be challenging, being based on the observer ability to decode different cytological and architectural features. This study aims to evaluate the malignancy rate of AGC (atypical glandular cells) category, investigating the relationships between cytological and histological diagnosis. METHODS: Eighty-nine patients, diagnosed as AGC at cytological evaluation and followed up with biopsy or surgical procedure at Policlinico Gemelli Hospital, Rome, Italy, were included in the study. The cytopathological architectural (feathering, rosette formation, overlapping, loss of polarity, papillary formation, three-dimensional formation) and nuclear (N/C ratio, nuclear enlargement and hyperchromasia, mitoses, nuclei irregularity, evident nucleoli) features of AGC were evaluated. Statistical analyses were performed to assess cyto-histological correlation and determine the relevance of architectural and nuclear features in the diagnosis of malignancy. RESULTS: Of the 89 AGC patients, 48 cases (53.93%) were diagnosed as AGC-NOS and 41 (46.07%) were diagnosed as AGC-FN, according to the Bethesda classification system. The follow-up biopsies or surgical resections revealed malignancy in 46 patients (51.69%). The rates of malignancy for AGC-NOS and AGC-FN were 35.41% and 70.73% respectively. Furthermore, analysing cytopathological features, we found that both architectural and nuclear criteria were statistically significant (p < 0.05). Only overlapping, nuclear irregularity and increased N/C ratio were not found to be statistically significant for detecting malignancy. CONCLUSIONS: Cytological diagnosis of glandular lesions remains a valid tool, when appropriate clinical correlation and expert evaluation are available.

Immunohistochemical p16 overexpression and Rb loss correlate with high-risk human papillomavirus infection in endocervical adenocarcinomas.

AIMS: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect. METHODS AND RESULTS: We examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR-HPV infection by mRNA in-situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR-HPV was detected in 83 of 108 ECA cases (77%), including five HPV-associated adenocarcinomas in situ and 78 invasive HPV-associated adenocarcinomas. All 83 HPV-positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV-independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV-independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR-HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR-HPV infection correlated with better prognosis among invasive ECAs. CONCLUSIONS: The results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR-HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.

Diagnosis and management of gastric-type endocervical adenocarcinoma: A case report and review of the literature.

Gastric-type endocervical adenocarcinoma (GEA), a rare subtype of cervical cancer, has garnered increasing attention recently for its distinctive histopathological features, unique classification, genetic characteristics, and variable clinical outcomes compared to squamous cell and adenocarcinoma subtypes. Historically, GEA has evolved from a poorly understood entity to a distinct subtype of cervical adenocarcinoma, only recently recognized in the 2020 World Health Organization (WHO) classification. Accordingly, characteristic morphological features define GEA, shedding light on the diagnostic challenges and potential misclassification that can occur in clinical practice. Genetic alterations, including KRAS, ARID1A, and PIK3CA mutations, play a pivotal role in the development and progression of GEA. This article reviews a case of GEA and aims to provide a contemporary overview of the genetic mutations and molecular pathways implicated in GEA pathogenesis, highlighting potential therapeutic targets and the prospects of precision medicine in its management. Patients with GEA have variable clinical outcomes, with some exhibiting aggressive behavior while others follow a more indolent course. This review examines the factors contributing to this heterogeneity, including stage at diagnosis, histological grade, and genetic alterations, and their implications for patient prognoses. Treatment strategies for GEA remain a topic of debate and research. Here, we summarize the current therapeutic options, including surgery, radiation therapy, and chemotherapy, while also exploring emerging approaches, such as targeted therapies and immunotherapy. This article provides a comprehensive overview of GEA, synthesizing current knowledge from historical perspectives to contemporary insights, focusing on its classification, genetics, outcomes, and therapeutic strategies.

ZNF695, A Potential Prognostic Biomarker, Correlates with Immune Infiltrates in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma: Bioinformatic Analysis and Experimental Verification.

BACKGROUND: The role of Zinc Finger Protein 695 (ZNF695) is unclear in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). OBJECTIVE: The objective of this study was to conduct a comprehensive analysis and experimental validation of ZNF695 in CESC. METHODS: The study investigated the expression of ZNF695 in both pan-cancer and CESC, utilizing data from The Cancer Genome Atlas (TCGA) database to assess its diagnostic value. The present study investigated the association between ZNF695 expression levels and clinical characteristics, as well as prognosis, in patients with CESC. The study explored potential regulatory networks involving ZNF695, including its association with immune infiltration, immune score, stemness index based on mRNA expression (mRNAsi), and drug sensitivity in CESC. We explored the expression of ZNF695 in CESC single cells. ZNF695 expression was validated using GSE29570. RESULTS: ZNF695 was found to be aberrantly expressed in pan-cancer and CESC. There was a significant correlation observed between an elevated level of ZNF695 expression in patients with CESC and histological grade (p = 0.017). Furthermore, a strong association was found between high ZNF695 expression in CESC patients and poorer overall survival (OS) (HR: 1.87; 95% CI: 1.17-3.00; p = 0.009), Progression-free Survival (PFS) (HR: 1.86; 95% CI: 1.16-2.98; p = 0.010), and Disease-specific Survival (DSS) (HR: 1.98; 95% CI: 1.15-3.42; p = 0.014). The expression of ZNF695 in CESC patients (p = 0.006) was identified as an independent prognostic determinant. ZNF695 was associated with steroid hormone biosynthesis, oxidative phosphorylation, and so on. ZNF695 expression correlated with immune infiltration, immune score, and mRNAsi in CESC. ZNF695 expression significantly and negatively correlated with AICA ribonucleotide, BIX02189, QL-XI-92, STF-62247, and SNX-2112 in CESC. ZNF695 gene was upregulated in CESC tissues and cell lines. ZNF695 was significantly upregulated in the CESC cell lines. CONCLUSION: ZNF695 may be a potential prognostic biomarker and immunotherapeutic target for CESC patients.

Impact of histological subtypes on clinical outcome of endocervical adenocarcinoma.

OBJECTIVE: This multicenter study aimed to investigate the disparity in clinical features and prognosis among different histopathologic subtypes of endocervical adenocarcinoma (EA) based on the 2014 World Health Organization (WHO) classification. METHODS: We retrieved and analyzed data from the Chinese Four C Database between 2004 and 2018. 672EA patients with radical hysterectomies from 32 institutions were retrospectively reviewed. Clinicopathologic characteristics, five-year overall survival (OS), and disease-free survival (DFS) were compared based on histological subtypes. RESULTS: The 5-year DFS and OS rates for usual, endometrioid, mucinous, gastric, villoglandular, clear cell/serous/mesonephric EAs were as follows: 81.3 %, 89.1 %, 63.0 %, 35.6 %, 88.6 %, 79.9 %, respectively (P < 0.0001); 87.4 %, 96.6 %, 74.7 %, 34.0 %, 96.7 %, 86.3 %, respectively (P < 0.0001). Gastric- and mucinous-type exhibited a higher frequency of lymph node metastasis, deep stromal invasion, uterine corpus invasion, and recurrence than the usual -type (recurrence rate:50.00 % vs 29.90 % vs 15.50 %, P < 0.0001). Multivariate analysis revealed gastric-type was significantly associated with inferior DFS (HR,3.018; 95 % CI, 1.688-5.397; P < 0.0001) and OS(HR, 4.114; 95 % CI, 2.002-8.453; P < 0.0001). Furthermore, compared to the usual -type, mucinous-type demonstrated significantly worse DFS (HR, 1.773; 95 % CI,1.123-2.8; P = 0.014) and OS (HR, 2.168; 95 % CI,1.214-3.873; P = 0.009) whereas endometrioid-type was an identified as independent factor for better DFS (HR, 0.365; 95 % CI,0.143-0.928; P = 0.034). Villoglandular subtype displayed similar features and favorable prognosis as the usual type. CONCLUSIONS: Relevant clinical features and prognosis varied significantly among histological subtypes of EA, thus offering valuable guidance for the development of subtype-specific treatment strategies to optimize EA management.