Adenocarcinoma In Situ Research Articles

Plasma extracellular vesicle long RNA profiling identifies a diagnostic signature for stage I lung adenocarcinoma.

BackgroundThe early diagnosis of lung adenocarcinoma (LUAD) is particularly challenging. Recent studies have reported that extracellular vesicles (EVs) include both small and long RNA. However, the profile and diagnosis-related significance of EV long RNA (exLR) profiles for early LUAD remain unclear.MethodsA case-control analysis was carried out involving 110 participants, including 64 stage I LUAD cases, 24 benign pulmonary nodule (BPN) cases, and 22 healthy controls (HCs). The analysis was performed on the plasma samples’ exLR profile based on exLR sequencing. The d-signature was identified using the least absolute shrinkage and selection operator (LASSO) method and a training set (n=48), and validation was completed through use of an internal validation set (n=32) and an external validation set (n=30).ResultsA diagnostic signature (d-signature) encompassing 8 exLR markers (NFKBIA, NDUFB10, SLC7A7, ARPC5, SEPTIN9, HMGN1, H4C2, and lnc-PLA2G1B-2:3) was identified for the detection of LUAD. This d-signature exhibited a high level of accuracy, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.991 in the training group, 0.921 in the internal validation group, and 0.9 in the external validation group. Moreover, the d-signature could distinguish adenocarcinomas in situ (AIS) and minimally invasive adenocarcinomas (MIA) from the noncancerous controls (NCs), with AUCs of 0.934 and 0.909, respectively, in the combined cohorts.ConclusionsThis study initially characterized the plasma exLR profile of early LUAD and reported on an exLR-based diagnostic signature for the detection of LUAD. This d-signature could be a promising noninvasive biomarker for the early detection and routine screening of LUAD.

Adenocarcinoma in situ or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study

Objective Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. Methods We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). Results Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p = .014) was higher and a history of preterm delivery (p = .0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p = .0099 and .0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26–13.68, p = .019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88–46.42, p < .0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55–34.86, p = .012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24–20.73, p = .024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11–16.62, p = .035) increased the risk of preterm delivery in the multiple regression models in primiparous women. Conclusion Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGES Prior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization. The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

Radiomics for differentiating minimally invasive adenocarcinoma from precursor lesions in pure ground-glass opacities on chest computed tomography.

To explore the correlation between radiomic features and the pathology of pure ground-glass opacities (pGGOs), we established a radiomics model for predicting the pathological subtypes of minimally invasive adenocarcinoma (MIA) and precursor lesions. CT images of 1521 patients with lung adenocarcinoma or precursor lesions appearing as pGGOs on CT in our hospital (The Third Affiliated Hospital of Sun Yat-sen University) from January 2015 to March 2021 were analyzed retrospectively and selected based on inclusion and exclusion criteria. pGGOs were divided into an atypical adenomatous hyperplasia (AAH)/adenocarcinoma in situ (AIS) group and an MIA group. Radiomic features were extracted from the original and preprocessed images of the region of interest. ANOVA and least absolute shrinkage and selection operator feature selection algorithm were used for feature selection. Logistic regression algorithm was used to construct radiomics prediction model. Receiver operating characteristic curves were used to evaluate the classification efficiency. 129 pGGOs were included. 2107 radiomic features were extracted from each region of interest. 18 radiomic features were eventually selected for model construction. The area under the curve of the radiomics model was 0.884 [95% confidence interval (CI), 0.818-0.949] in the training set and 0.872 (95% CI, 0.756-0.988) in the test set, with a sensitivity of 72.73%, specificity of 88.24% and accuracy of 79.47%. The decision curve indicated that the model had a high net benefit rate. The prediction model for pathological subtypes of MIA and precursor lesions in pGGOs demonstrated a high diagnostic accuracy. We focused on lesions appearing as pGGOs on CT and revealed the differences in radiomic features between MIA and precursor lesions. We constructed a radiomics prediction model and improved the diagnostic accuracy for the pathology of MIA and precursor lesions.

Serum Extracellular Nano-Vesicles miR-153-3p to Identify Micronodular Lung Cancer from Sub-Centimeter Lung Nodules.

Identification of malignancy from sub-centimeter lung nodules (LNs, <1 cm) is core for prevention and treatment of primary phases of lung cancer (LC). The study's purpose was to predict micro-nodular lung cancer (mnLC), such as adenocarcinoma in situ (AIS), micro-invasive adenocarcinoma (MIA), and invasive adenocarcinoma stage 1 (IA1) based on serum extracellular nano-vesicles (sEVs) miR-153-3p. sEVs-miR-153-3p was selected in this study and then used to investigate the expression and efficacy by RT-qPCR in the validation phase, followed by sEVs derived from patients of mnLC, benign lung nodule (BLN), and healthy people groups comprised of 135 recruiters. Further, the study established the prediction model which combined sEVs-miR-153-3p expression with multiple clinical-radiomics features by Logistic algorithms and was authenticated by the area under curve (AUC) phenomenon. Then, a simple-to-use nomogram was developed by Cox proportional-hazards regression modeling for predicting mnLC. Besides, in vitro analyses were performed to demonstrate miR-153-3p/ROCK1 axis in regulating biological mechanisms using LC cell lines. Results demonstrated that sEVs-miR-153-5p's expression values were higher in mnLC patients compared to BLN and healthy people. The prediction model for mnLC was successfully established, utilizing sEVs-miR-153-5p biomarker with significant clinical-radiomics features and yielding an AUC = 0.943 (95%CI: 0.898~0.989, P <0.0001). Moreover, the miR-153-3p and its targeted gene ROCK1 were confirmed as down-regulated in NSCLC cell lines and up-regulated expression respectively. Moreover, the miR-153-3p/ROCK1 axis took part in promoting the epithelial-mesenchymal transition (EMT) signaling pathway and regulated certain biological functions, such as proliferation, migration and invasion of LC cells. Therefore, the sEVs-miR-153-3p associated with radiomics-clinical features showed enormous potential to non-invasively identify malignancy from subcentimeter LNs. miR-153-3p could promote the genesis and progress of LC via EMT signaling pathway, which may serve as a therapeutic target.

Endocervical Cytology: Inter- and Intra-Observer Variability in Conventional Pap Smears

Introduction: Although the cytological diagnostic criteria for cervical squamous and glandular lesions are established by the Bethesda System for Reporting Cervical Cytology, the reproducibility of the diagnosis of these lesions has been shown to be variable in previous studies. At best, occasional good kappa (κ) values were reached both inter- and intra-observerly. Generally, consensus on high-grade lesions has been better compared to milder changes. Methods: Altogether, 167 conventional Pap smears from 50 patients with histologically confirmed endocervical adenocarcinomas (EAC) and adenocarcinomas in situ (AIS) and from 28 patients with histologically proven high-grade intraepithelial lesions were analyzed by four cytopathologists. Twenty of the smears were later re-evaluated by the same cytopathologists. κ-values between cytopathologists in the categories of squamous versus glandular, negative for intraepithelial lesion or malignancy (NILM), atypical, and preneoplastic/neoplastic were calculated. The diagnostic Pap smears of EAC and AIS with best and worst consensus between observers were then morphologically analyzed. Results: The reproducibility ranged from poor to substantial. The overall κ-values between the four cytopathologists were 0.412, 0.314, 0.272, and 0.082, respectively, in the categories of preneoplastic/neoplastic, squamous versus glandular, NILM, and atypical. Overall intra-observer κ-values were correspondingly 0.491, 0.616, 0.345, and 0.241. In the diagnostic smears of AIS and EAC, the nuclear size >2 times the normal and nuclear pleomorphism were the commonest features associated with good diagnostic consensus and the lack of nuclear enlargement and degenerative changes were associated with poor consensus. Conclusions: The reproducibility of preneoplasia/neoplasia diagnoses was better than that of atypia and NILM both in the inter- and intra-observer part in this study. In the smears from AIS and EAC patients, general neoplasia-associated features were more common in samples with good agreement by the four cytopathologists of the neoplastic nature and the endocervical origin of the lesion.

Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women.

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12‐16 years, and catch‐up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2‐3 (CIN2‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine‐targeted types HPV16 or HPV18 to CIN2‐3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12‐15 years (n = 36), 16‐18 years (n = 23), 19–22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P < .001). This finding was supported by age at first sexual intercourse; among women with CIN2‐3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2‐3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12‐14 years and catch‐up vaccination for adolescents aged 18 years and younger in Japan.

Changes in HPV16/18 Prevalence among Unvaccinated Women with Cervical Intraepithelial Neoplasia in Japan: Assessment of Herd Effects following the HPV Vaccination Program.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12–16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994–1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1–3 (CIN1–3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among “unvaccinated” cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged <40 years, newly diagnosed with CIN/AIS during 2012–2021 for time trends. Declining trends in HPV16/18 prevalence over 9 years were observed in CIN1 (36.0–10.0%, Ptrend = 0.03) and CIN2–3/AIS (62.5–36.4%, Ptrend = 0.07) among women aged <25 years. HPV16/18 prevalence in CIN1 and CIN2–3/AIS diagnosed at age 20–24 years was lower in 1994–1999 birth cohorts compared with 1988–1993 birth cohorts (4.5% vs. 25.7% for CIN1 and 40.0% vs. 58.1% for CIN2–3/AIS, both p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2–3/AIS suggests herd effects of HPV vaccination in Japan.

Identification of pathological subtypes of early lung adenocarcinoma based on artificial intelligence parameters and CT signs.

Objective: To explore the value of quantitative parameters of artificial intelligence (AI) and computed tomography (CT) signs in identifying pathological subtypes of lung adenocarcinoma appearing as ground-glass nodules (GGNs). Methods: CT images of 224 GGNs from 210 individuals were collected retrospectively and classified into atypical adenomatous hyperplasia (AAH)/adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) groups. AI was used to identify GGNs and to obtain quantitative parameters, and CT signs were recognized manually. The mixed predictive model based on logistic multivariate regression was built and evaluated. Results: Of the 224 GGNs, 55, 93, and 76 were AAH/AIS, MIA, and IAC, respectively. In terms of AI parameters, from AAH/AIS to MIA, and IAC, there was a gradual increase in two-dimensional mean diameter, three-dimensional mean diameter, mean CT value, maximum CT value, and volume of GGNs (all P<0.0001). Except for the CT signs of the location, and the tumor–lung interface, there were significant differences among the three groups in the density, shape, vacuolar signs, air bronchogram, lobulation, spiculation, pleural indentation, and vascular convergence signs (all P<0.05). The areas under the curve (AUC) of predictive model 1 for identifying the AAH/AIS and MIA and model 2 for identifying MIA and IAC were 0.779 and 0.918, respectively, which were greater than the quantitative parameters independently (all P<0.05). Conclusion: AI parameters are valuable for identifying subtypes of early lung adenocarcinoma and have improved diagnostic efficacy when combined with CT signs.

CT-Assisted Improvements in the Accuracy of the Intraoperative Frozen Section Examination of Ground-Glass Density Nodules.

Objectives The intraoperative frozen section examination (IFSE) of pulmonary ground-glass density nodules (GGNs) is a great challenge. In the present study, through comparing the correlation between the computed tomography (CT) findings and pathological diagnosis of GGNs, the CT features as independent risk factors affecting the examination were defined, and their value in the rapid intraoperative examination of GGNs was explored. Methods The relevant clinical data of 90 patients with GGNs on CT were collected, and all CT findings of GGNs, including the maximum transverse diameter, average CT value, spiculation, solid component, vascular sign, air sign, bronchus sign, lobulation, and pleural indentation, were recorded. All the cases received thoracoscopic surgery, and final pathological results were obtained. The cases were divided into three groups on the basis of pathological diagnosis: benign/atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS)/microinvasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). The CT findings were analyzed statistically, the independent risk factors were identified through the intergroup bivariate logistic regression analysis on variables with statistically significant differences, and a receiver operating curve (ROC) was plotted to establish a logistic regression model for diagnosing GGNs. A retrospective analysis was conducted on the coincidence rate of the rapid intraoperative and routine postoperative pathological examinations of the 90 cases with GGNs. The relevant clinical data of 49 cases with GGNs were collected. Conventional rapid intraoperative examination and CT-assisted rapid intraoperative examination were performed, and their coincidence rates with routine postoperative pathological examinations were compared. Results No statistical differences in the onset age, gender, smoking history, and family history of malignant tumors were found among cases with GGNs in the identification of benign/AAH, AIS/MIA, and IAC (P = 0.158, P = 0.947, P = 0.746, P = 0.566). No statistically significant difference was found among the three groups in terms of CT findings, such as lobulation, bronchus sign, pleural indentation, spiculation, vascular sign, and solid component (P > 0.05). The air sign, the maximum transverse diameter of GGNs, and average CT value showed statistically significant differences among the groups (P < 0.001, P < 0.05, P < 0.001). Bivariate logistic regression analysis was performed on three risk factors, and the predicted probability value was obtained. A ROC curve was plotted by using the maximum transverse diameter as a predictor for analysis between the groups with benign/AAH and AIS/MIA, and the results demonstrated that the area under the curve (AUC) was 0.692. A ROC curve was plotted by using the predicted probability value, maximum transverse diameter, and average CT value as predictors for distinguishing between the groups with AIS/MIA and IAC, and the results showed that the AUC values of the predicted probability value, maximum transverse diameter, and CT value were 0.920, 0.816, and 0.772, respectively. A regression model [Logit (P) = 2.304 − 2.689X1 + 0.302X2 + 0.011X3] was established to identify GGNs as IAC, obtaining AUC values of up to 0.920 for the groups with AIS/MIA and IAC, the sensitivity of 0.821, and the specificity of 0.894. The coincidence rate of rapid intraoperative and routine postoperative pathological examinations taken for modeling was 79.3%, that of conventional IFSE and postoperative pathological examination in prospective studies was 83.7%, and that of CT-assisted rapid intraoperative and postoperative pathological examinations was 98.0%. The former two were statistically different from the last one (P = 0.003 and P = 0.031, respectively). Conclusion The air sign, maximum transverse diameter, and average CT value of the CT findings of GGNs had superior capabilities to enhance the pathologic classification of GGNs. The auxiliary function of the comprehensive multifactor analysis of GGNs was better than that of single-factor analysis. CT-assisted diagnosis can improve the accuracy of rapid intraoperative examination, thereby increasing the accuracy of the selection of operative approaches in clinical practice.

Endocervical adenocarcinoma in situ-from Papanicolaou test to hysterectomy: a series of 74 cases.

Endocervical adenocarcinoma in situ (AIS) is not always identified on cervical Papanicolaou (Pap) test cytology because the Pap test has relatively low sensitivity for the diagnosis endocervical glandular lesions. We performed a retrospective study to determine the relative sensitivity of different diagnostic approaches, including Pap tests, cervical biopsy and/or endocervical curettage, loop electrosurgical excision procedure (LEEP), and hysterectomy specimens. Cases of endocervical AIS diagnosed from August 2005 to January 2019 were retrieved from our institution's pathology databases, and their clinicopathologic features were reviewed. A total of 74 patients with endocervical AIS with or without concurrent squamous intraepithelial lesions or cervical neoplasms were identified. Their mean age at diagnosis was 39.9 years. More than one half of the cases of AIS were not detected from screening Pap tests but were diagnosed during histologic examination of cervical biopsy or endocervical curettage, LEEP, or cone biopsy specimens (~66%). Only a few patients had had a definitive diagnosis of AIS from the Pap tests (10.8%). Other abnormal glandular cytology included atypical glandular cells, not otherwise specified (16.2%), atypical glandular cells favoring neoplasia (5.4%), and atypical glandular cells suspicious for malignancy (1.3%). Abnormal squamous cytology was common in the study population (54%), with high-grade squamous intraepithelial lesion the most common finding (30%). AIS was diagnosed in 31 of 42 cervical biopsies or curettages, with 16 cases an incidental finding and 15 cases confirming previous abnormal glandular cytology. In addition, AIS was identified in 51 of 53 LEEPs. Approximately 41.5% of those undergoing LEEP had a previous diagnosis of AIS, and 54.7% of the cases were incidental findings. More than one half of the AIS cases harbored significant concurrent cervical lesions, including 26.7% with high-grade squamous intraepithelial lesion, 5.7% with low-grade squamous intraepithelial lesion, 1.9% with invasive squamous cell carcinoma, 20.9% with invasive adenocarcinoma, and 6.7% with microinvasive adenocarcinoma. Our results have demonstrated that the ability to detect AIS with routine screening Pap testing or biopsy/curettage has variable efficacy depending on the screening methods. Given the relatively low combined sensitivity of Pap testing and biopsy/endocervical curettage in the diagnosis of AIS, all LEEPs and cervical cone biopsies performed for squamous cell abnormalities should be thoroughly evaluated for glandular lesions.

Comparison of the safety between cervical conization and hysterectomy for patients with cervical adenocarcinoma in situ.

To compare the safety between cervical conization (CC) alone and hysterectomy for patients with adenocarcinoma in situ (AIS) of the cervix. Patients diagnosed with AIS after CC during 2007-2021 were identified by computerized databases at Women's Hospital of Zhejiang University School of Medicine. A total of 453 AIS patients were divided into 2 groups according to uterus preservation: hysterectomy group (n=300) and CC(s) alone group (n=153). The prevalence of residual disease and disease recurrence was compared between patients treated by CC(s) alone and hysterectomy. The prevalence of residual disease in specimens from women who had a hysterectomy and repeat CC were compared between positive and negative margins of CC. The factors influencing residual disease and disease recurrence were assessed. Among 310 specimens from women who had a hysterectomy or repeat CC, the prevalence of residual disease was 50.6% (45/89) for a positive margin and 2.3% (5/221) for a negative margin (p=0.000). Four patients had recurrence of vaginal intraepithelial neoplasia in those treated by hysterectomy and one had recurrence of cervical squamous intraepithelial neoplasia in those treated by CC(s) alone. The prevalence of recurrence was 0.7% (1/153) for CC(s) alone and 1.3% (4/300) for hysterectomy (p=0.431). Hysterectomy did not influence residual disease or disease recurrence. CC is an efficacious and safe option for patients with AIS of the cervix provided the margin is negative.

Relationship between 18F-FDG PET/CT Semi-Quantitative Parameters and International Association for the Study of Lung Cancer, American Thoracic Society/European Respiratory Society Classification in Lung Adenocarcinomas

ObjectiveTo investigate the relationship between 18F-FDG PET/CT semi-quantitative parameters and the International Association for the Study of Lung Cancer, American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) histopathologic classification, including histological subtypes, proliferation activity, and somatic mutations.Materials and MethodsThis retrospective study included 419 patients (150 males, 269 females; median age, 59.0 years; age range, 23.0–84.0 years) who had undergone surgical removal of stage IA–IIIA lung adenocarcinoma and had preoperative PET/CT data of lung tumors. The maximum standardized uptake values (SUVmax), background-subtracted volume (BSV), and background-subtracted lesion activity (BSL) derived from PET/CT were measured. The IASLC/ATS/ERS subtypes, Ki67 score, and epidermal growth factor/anaplastic lymphoma kinase (EGFR/ALK) mutation status were evaluated. The PET/CT semi-quantitative parameters were compared between the tumor subtypes using the Mann–Whitney U test or the Kruskal–Wallis test. The optimum cutoff values of the PET/CT semi-quantitative parameters for distinguishing the IASLC/ATS/ERS subtypes were calculated using receiver operating characteristic curve analysis. The correlation between the PET/CT semi-quantitative parameters and pathological parameters was analyzed using Spearman’s correlation. Statistical significance was set at p < 0.05.ResultsSUVmax, BSV, and BSL values were significantly higher in invasive adenocarcinoma (IA) than in minimally IA (MIA), and the values were higher in MIA than in adenocarcinoma in situ (AIS) (all p < 0.05). Remarkably, an SUVmax of 0.90 and a BSL of 3.62 were shown to be the optimal cutoff values for differentiating MIA from AIS, manifesting as pure ground-glass nodules with 100% sensitivity and specificity. Metabolic-volumetric parameters (BSV and BSL) were better potential independent factors than metabolic parameters (SUVmax) in differentiating growth patterns. SUVmax and BSL, rather than BSV, were strongly or moderately correlated with Ki67 in most subtypes, except for the micropapillary and solid predominant groups. PET/CT parameters were not correlated with EGFR/ALK mutation status.ConclusionAs noninvasive surrogates, preoperative PET/CT semi-quantitative parameters could imply IASLC/ATS/ERS subtypes and Ki67 index and thus may contribute to improved management of precise surgery and postoperative adjuvant therapy.

False-negative Papanicolaou tests in women with biopsy-proven invasive endocervical adenocarcinoma/adenocarcinoma in situ: a retrospective analysis with assessment of interobserver agreement.

The objectives of our study were to identify factors contributing to false-negative Papanicolaou (Pap) tests in patients with endocervical adenocarcinoma (EA) or adenocarcinoma in situ (AIS), and to analyze the impact of educational instruction on interobserver agreement in these cases. False-negative Pap tests from patients with EA/AIS were reviewed by a consensus group and by 12 individual reviewers in 2 rounds, with an educational session on glandular neoplasia in Pap tests conducted between the 2 rounds. Of 79 Pap tests from patients with EA/AIS, 57 (72.2%) were diagnosed as abnormal and 22 (27.8%) as negative. Of the 22 false-negative cases, 10 remained negative on consensus review, with false-negative diagnoses attributed to sampling variance. The other 12 cases were upgraded to epithelial abnormalities (including 8 to glandular lesions). The false-negative diagnoses were attributed to screening variance in 2 cases and interpretive variance in 10 cases. On individual review, abnormal cells were misinterpreted as reactive glandular cells or endometrial cells in 7 of 8 and 5 of 8 cases upgraded to glandular abnormalities, respectively. With education, the proportion of individual reviewers demonstrating at least moderate agreement with the consensus diagnosis (Cohen's kappa >0.4) increased from 33% (4 of 12) to 75% (9 of 12). Sampling and interpretive variance each accounted for nearly one-half of the false-negative Pap tests, with underclassification as reactive glandular or endometrial cells the main source of the interpretive variances. Educational instruction significantly decreased the interpretive variance and interobserver variability in the diagnosis of glandular abnormalities.

High-Grade Cervical Intraepithelial Neoplasia (CIN) Associates with Increased Proliferation and Attenuated Immune Signaling.

Implementation of high-risk human papilloma virus (HPV) screening and the increasing proportion of HPV vaccinated women in the screening program will reduce the percentage of HPV positive women with oncogenic potential. In search of more specific markers to identify women with high risk of cancer development, we used RNA sequencing to compare the transcriptomic immune-profile of 13 lesions with cervical intraepithelial neoplasia grade 3 (CIN3) or adenocarcinoma in situ (AIS) and 14 normal biopsies from women with detected HPV infections. In CIN3/AIS lesions as compared to normal tissue, 27 differential expressed genes were identified. Transcriptomic analysis revealed significantly higher expression of a number of genes related to proliferation, (CDKN2A, MELK, CDK1, MKI67, CCNB2, BUB1, FOXM1, CDKN3), but significantly lower expression of genes related to a favorable immune response (NCAM1, ARG1, CD160, IL18, CX3CL1). Compared to the RNA sequencing results, good correlation was achieved with relative quantitative PCR analysis for NCAM1 and CDKN2A. Quantification of NCAM1 positive cells with immunohistochemistry showed epithelial reduction of NCAM1 in CIN3/AIS lesions. In conclusion, NCAM1 and CDKN2A are two promising candidates to distinguish whether women are at high risk of developing cervical cancer and in need of frequent follow-up.

Detection and Outcome of Endocervical Atypia in Cytology in Primary HPV Screening Programme

Most endocervical adenocarcinomas (EAC) are associated with high-risk HPV (hrHPV) infection, with HPV genotypes 16, 18 and 45 accounting for >90% of the cases. Among endocervical glandular lesions, screening with hrHPV test has previously shown to predict the outcome better than cytology, although around one-fifth of the EAC remain negative both in hrHPV testing and cytology. The study consists of two consecutive HPV-primary screening rounds, conducted in 2012–2015 and 2017–2020. Of the 87 women aged 35 to 60 years of age diagnosed with Atypical endocervical cells, NOS or Atypical endocervical cells, favor neoplastic cytology during the first screening round, 63 (72.4%) were hrHPV positive and 24 (27.6%) were hrHPV negative. Among hrHPV positive patients, three EAC, two adenocarcinomas in situ (AIS), one AIS + high-grade intraepithelial lesion (HSIL) and 13 HSIL were found. Of the histologically verified lesions, 68.4% (13/19) were purely of squamous origin. All the EAC and AIS were HPV16 or HPV 18 positive. No high-grade histological lesions were found among the hrHPV negative patients with cytological glandular atypia. A later database search revealed one HPV-negative, gastric-type mucinous EAC that was missed by the HPV primary screening.

Plasma extracellular vesicle microRNA profiling and the identification of a diagnostic signature for stage I lung adenocarcinoma.

At present, there is no effective noninvasive method for the accurate diagnosis of early‐stage lung adenocarcinoma (LUAD). This study examined the profile of plasma extracellular vesicle (EV)‐delivered microRNAs (miRNAs) in patients with invasive stage I LUAD. In this study, a total of 460 participants were enrolled, including 254 patients with LUAD, 76 patients with benign pulmonary nodules (BPNs), and 130 healthy control patients (HCs). miRNA sequencing was used to analyze the EV miRNA profile of the patient plasma samples (n = 150). A diagnostic signature (d‐signature) was identified by applying a stepwise logistic regression algorithm, and a single‐center training cohort (n = 150) was tested, followed by a multicenter validation cohort (n = 100). A d‐signature comprising four EV‐derived miRNAs (hsa‐miR‐106b‐3p, hsa‐miR‐125a‐5p, hsa‐miR‐3615, and hsa‐miR‐450b‐5p) was developed for the early detection of LUAD. The d‐signature had high precision with area under the curve (AUC) values of 0.917 and 0.902 in the training and test cohorts, respectively. Moreover, the d‐signature could recognize patients with adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) with AUC values of 0.846 and 0.92, respectively. To sum up, our study detailed the plasma EV–derived miRNA profile in early LUAD patients and developed an EV‐derived miRNA d‐signature to detect early LUAD.

Adenocarcinoma in situ and minimally invasive adenocarcinoma in lungs of smokers: image feature differences from those in lungs of non-smokers

PurposeWe aimed to examine the characteristics of imaging findings of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in the lungs of smokers compared with those of non-smokers.Materials and methodsWe included seven cases of AIS and 20 cases of MIA in lungs of smokers (pack-years ≥ 20) and the same number of cases of AIS and MIA in lungs of non-smokers (pack-years = 0). We compared the diameter of the entire lesion and solid component measured on computed tomography (CT) images, pathological size and invasive component diameter measured from pathological specimens, and CT values of the entire lesion and ground-glass opacity (GGO) portions between the smoker and non-smoker groups.ResultsThe diameters of AIS and MIA on CT images and pathological specimens of the smoker group were significantly larger than those of the non-smoker group (p = 0.036 and 0.008, respectively), whereas there was no significant difference in the diameter of the solid component on CT images or invasive component of pathological specimens between the two groups. Additionally, mean CT values of the entire lesion and GGO component of the lesions in the smoker group were significantly lower than those in the non-smoker group (p = 0.036 and 0.040, respectively).ConclusionAIS and MIA in smoker’s lung tended to have larger lesion diameter and lower internal CT values compared with lesions in non-smoker’s lung. This study calls an attention on smoking status in CT-based diagnosis for early stage adenocarcinoma.

Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma

Metabolic reprogramming evolves during cancer initiation and progression. However, thorough understanding of metabolic evolution from preneoplasia to lung adenocarcinoma (LUAD) is still limited. Here, we perform large-scale targeted metabolomics on resected lesions and plasma obtained from invasive LUAD and its precursors, and decipher the metabolic trajectories from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC), revealing that perturbed metabolic pathways emerge early in premalignant lesions. Furthermore, three panels of plasma metabolites are identified as non-invasive predictive biomarkers to distinguish IAC and its precursors with benign diseases. Strikingly, metabolomics clustering defines three metabolic subtypes of IAC patients with distinct clinical characteristics. We identify correlation between aberrant bile acid metabolism in subtype III with poor clinical features and demonstrate dysregulated bile acid metabolism promotes migration of LUAD, which could be exploited as potential targetable vulnerability and for stratifying patients. Collectively, the comprehensive landscape of the metabolic evolution along the development of LUAD will improve early detection and provide impactful therapeutic strategies.

Performance of three colposcopic images for the identification of squamous and glandular cervical precursor neoplasias

PurposeTo evaluate prevalence and diagnostic performance of three colposcopic images to diagnose squamous and glandular cervical precursor neoplasias.MethodsCross-sectional study, conducted through analysis of stored digital colposcopic images. To evaluate the diagnostic performance of three images, herein named grouped glands, aceto-white villi, and atypical vessels, for detection of adenocarcinoma in situ (AIS) and cervical squamous intraepithelial neoplasias (CIN) grades 2 and 3, calculations of sensitivity, specificity, accuracy, positive likelihood ratio, receiver operating characteristic (ROC) curve, and area under the curve (AUC) were made, with their respective 95% confidence intervals.ResultsGrouped glands, aceto-white villi, and atypical vessels images had: prevalence of 21.3, 53.8, and 33.8% in patients with AIS, and 16.2, 19.5, and 9.3% in those with CIN 2 and 3; for the diagnosis of AIS, sensitivity of 21.3, 53.8, and 33.8%, specificity of 89.8, 95.2, and 94.9%, accuracy of 76.6, 87.2, and 83.1%, positive likelihood ratio of 2.1, 11.2, and 6.6, and AUC of 0.55, 0.74, and 0.64; for the diagnosis of CIN 2 and 3, sensitivity of 16.2, 19.5, and 9.3%, specificity of 89.8, 95.2, and 94.9%, accuracy of 39.4, 43.4, and 36.3%, positive likelihood ratio of 1.6, 4.1, and 1, 8, and AUC of 0.53, 0.57, and 0.52, respectively.ConclusionPrevalence and accuracy of the three images were higher for the diagnosis of glandular than squamous cervical precursor neoplasias. Sensitivity, specificity, positive likelihood, and AUC of aceto-white villi and atypical vessels images were higher for the diagnosis of glandular than squamous cervical precursor neoplasias.

Quantitative CT imaging analysis to predict pathology features in patients with a congenital pulmonary airway malformation

BackgroundRisk for infection and potential malignant degeneration are the most common arguments for resecting asymptomatic Congenital Pulmonary Airway Malformations (CPAM). We aimed to investigate if CT- imaging characteristics can be used to predict histopathological features, by using an objective quantitative CT scoring method. MethodsArchival CPAM tissue samples were histologically re-assessed and patients who had a pre-operative volumetric CT-scan were included. Lung disease was quantified using the newly-developed congenital lung abnormality quantification(CLAQ) scoring method and obtained percentages were used to predict histopathological signs of inflammation and presence of mucinous proliferation (MP). Because MP is presumed a precursor for mucinous adenocarcinoma in situ (AIS) this method was also used to compare CT-scans of patients with AIS to those with only CPAM. ResultsThirty-three CPAM patients were included of which 13(39%) had histological signs of inflammation and 8(24%) had a MP. Patients with inflammation had a significantly smaller lesion (14% vs 38%) while those with MP had more extensive disease (54%vs17%). Patients with AIS had a significantly smaller lesion compared to CPAM patients (5%vs29%). Significant predictors for inflammation were smaller lesion size and percentage hypodensity within lesions while a larger lesion size and percentage parenchymal hyperdensity (solid lung tissue components) were predictors for MP as well as AIS. ConclusionsSmaller CPAM lesions may be more susceptible to inflammation while larger lesions may be associated with the presence of MP. Parenchymal hyperdensity is found as a predictor for MP as well as AIS and should therefore elicit more extensive gross sampling. Level of evidenceLevel III.