Precursor Lesions Research Articles

Spatial transcriptomics characterizes high-grade serous ovarian cancer and its precursor lesions

Spatial transcriptomics characterizes high-grade serous ovarian cancer and its precursor lesions

Multimodal Optical Imaging of Ex Vivo Fallopian Tubes to Distinguish Early and Occult Tubo-Ovarian Cancers

Background: There are currently no effective screening measures to detect early or occult tubo-ovarian cancers, resulting in late-stage detection and high mortality. This work explores whether an optical imaging catheter can detect early-stage tubo-ovarian cancers or precursor lesions where they originate in the fallopian tubes. Methods: This device collects co-registered optical coherence tomography (OCT) and autofluorescence imaging (AFI). OCT provides three-dimensional assessment of underlying tissue structures; autofluorescence imaging provides functional contrast of endogenous fluorophores. Ex vivo fallopian tubes (n = 28; n = 7 cancer patients) are imaged; we present methods for the calculation of and analyze eleven imaging biomarkers related to fluorescence, optical attenuation, and OCT texture for their potential to detect tubo-ovarian cancers and other lesions of interest. Results: We visualize folded plicae, vessel-like structures, tissue layering, hemosiderin deposits, and regions of fibrotic change. High-grade serous ovarian carcinoma appears as reduced autofluorescence paired with homogenous OCT and reduced mean optical attenuation. Specimens containing cancerous lesions demonstrate a significant increase in median autofluorescence intensity and decrease in Shannon entropy compared to specimens with no lesion. Non-cancerous specimens demonstrate an increase in optical attenuation in the fimbriae when compared to the isthmus or the ampulla. Conclusions: We conclude that this approach shows promise and merits further investigation of its diagnostic potential.

Proteomic and serological markers for diagnosing cardia gastric cancer and precursor lesions in a Chinese population

Cardia gastric cancer (CGC) is prevalent in East Asia, and noninvasive, cost-effective screening methods are needed. This study investigated the diagnostic value of serum pepsinogen (PG), gastrin-17 (G-17), Helicobacter pylori (H. pylori) antibodies, and proteomic profiling for CGC and precancerous lesions. We conducted a case-control study involving biopsy-confirmed patients with CGC (n = 60), low-grade intraepithelial neoplasia (CLGD, n = 60), high-grade intraepithelial neoplasia (CHGD, n = 64), and healthy controls (n = 120) matched for age and sex from high-incidence areas in China. Serological markers including PGI, PGII, G-17, and H. pylori were measured using ELISA and Western blot, while plasma protein markers were assessed using Olink® technology. The VSOLassoBag algorithm and nine machine learning (ML) algorithms were employed to identify crucial features and construct predictive models. Various evaluation metrics, including the area under the receiver-operating-characteristic curve (AUC), were utilized to compare predictive performance. Elevated PGII levels, decreased PGR, and H. pylori infection were significantly associated with an increased risk of CGC and precancerous lesions (P for trend < 0.05). The eXtreme Gradient Boosting (XGBoost) model performed best in discriminative ability among the 9 ML models. Following feature reduction based on predictive performance, a final explainable XGBoost model was developed, incorporating five protein biomarkers (CDHR2, ICAM4, PTPRM, CDC27, and FLT1). This model exhibited excellent performance in distinguishing individuals with CGC and precancerous lesions from healthy controls (AUC = 0.931 for CGC, 0.867 for CHGD, and 0.763 for CLGD), surpassing the traditional serological marker-based model. This study underscores the diagnostic potential of serological markers and proteomic profiling in the detection of CGC. Further validation and exploration of combined biomarker approaches are warranted to enhance early diagnosis and improve outcomes in high-risk populations.

Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases

Background: Oncogenic mutations in the KRAS gene are detected in &gt;90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic KRAS drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC. In Ras-driven tumors, YAP can also substitute for oncogenic KRAS to drive tumor survival after the repression of the oncogene. Ras oncoproteins exert their transforming properties through their downstream effectors, including the PI3K kinase, Rac1 GTPase, and MAPK pathways. Methods: To identify Ras effectors that regulate YAP, YAP levels were measured in PC cells exposed to inhibitors of oncogenic K-Ras and its effectors. Results: In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132. This YAP degradation after Rac1 inhibition was observed in a range of cell lines using different Rac1 inhibitors, Rac1 siRNA, or expression of dominant negative Rac1T17N mutant. Several E3 ubiquitin ligases, including SCFβTrCP, regulate YAP protein stability. To be recognized by this ligase, the βTrCP degron of YAP (amino acid 383–388) requires its phosphorylation by casein kinase 1 at Ser384 and Ser387, but these events must first be primed by the phosphorylation of Ser381 by LATS1/2. Using Flag-tagged mutants of YAP, we show that YAP degradation after Rac1 inhibition requires the integrity of this degron and is blocked by the silencing of βTrCP1/2 and by the inhibition of casein kinase 1. Unexpectedly, YAP degradation after Rac1 inhibition was still observed after the silencing of LATS1/2 or in cells carrying a LATS1/2 double knockout. Conclusions: These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCFβTrCP ligase but occurs independently of the LATS1/2 kinases.

Knockout of the Carbohydrate Responsive Element Binding Protein Enhances Proliferation and Tumorigenesis in Renal Tubules of Mice

Glycogen-storing so-called clear cell kidney tubules (CCTs), precursor lesions of renal cell carcinoma, have been described in diabetic rats and in humans. The lesions show upregulation of the Akt/mTOR-pathway and the related transcription factor carbohydrate responsive element binding protein (ChREBP), which is supposedly pro-oncogenic. We investigated the effect of ChREBP-knockout on nephrocarcinogenesis in streptozotocin-induced diabetic and normoglycemic mice. Diabetic, but not non-diabetic mice, showed CCTs at 3, 6 and 12 months of age. Glycogenosis was confirmed by periodic acid schiff reaction and transmission electron microscopy. CCTs in ChREBP-knockout mice consisted of larger cells and occurred more frequently compared to wildtype mice. Progression towards kidney tumors was observed in both diabetic groups but occurred earlier in ChREBP-knockout mice. Proliferative activity assessed by BrdU-labeling was lower in 1-week-old but higher in 12-month-old diabetic ChREBP-knockout mice. Surprisingly, renal neoplasms occurred spontaneously in non-diabetic ChREBP-knockout, but not non-diabetic wildtype mice, indicating an unexpected tumor-suppressive function of ChREBP. Immunohistochemistry showed upregulated glycolysis and lipogenesis, along with activated Akt/mTOR-signaling in tumors of ChREBP-knockout groups. Immunohistochemistry of human clear cell renal cell carcinomas revealed reduced ChREBP expression compared to normal kidney tissue. However, the molecular mechanisms by which loss of ChREBP might facilitate tumorigenesis require further investigation.

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Oncogenic mutations in KRAS are present in ~95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation and low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and phosphorylation of the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

Assessing the impact of deep-learning assistance on the histopathological diagnosis of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes.

In recent years, it has become clear that artificial intelligence (AI) models can achieve high accuracy in specific pathology-related tasks. An example is our deep-learning model, designed to automatically detect serous tubal intraepithelial carcinoma (STIC), the precursor lesion to high-grade serous ovarian carcinoma, found in the fallopian tube. However, the standalone performance of a model is insufficient to determine its value in the diagnostic setting. To evaluate the impact of the use of this model on pathologists' performance, we set up a fully crossed multireader, multicase study, in which 26 participants, from 11 countries, reviewed 100 digitalized H&E-stained slides of fallopian tubes (30 cases/70 controls) with and without AI assistance, with a washout period between the sessions. We evaluated the effect of the deep-learning model on accuracy, slide review time and (subjectively perceived) diagnostic certainty, using mixed-models analysis. With AI assistance, we found a significant increase in accuracy (p < 0.01) whereby the average sensitivity increased from 82% to 93%. Further, there was a significant 44 s (32%) reduction in slide review time (p < 0.01). The level of certainty that the participants felt versus their own assessment also significantly increased, by 0.24 on a 10-point scale (p < 0.01). In conclusion, we found that, in a diverse group of pathologists and pathology residents, AI support resulted in a significant improvement in the accuracy of STIC diagnosis and was coupled with a substantial reduction in slide review time. This model has the potential to provide meaningful support to pathologists in the diagnosis of STIC, ultimately streamlining and optimizing the overall diagnostic process.

Functionalized Nanomaterials In Pancreatic Cancer Theranostics And Molecular Imaging.

Pancreatic cancer (PC) is one of the most fatal malignancies in the world. This lethality persists due to lack of effective and efficient treatment strategies. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive epithelial malignancy which has a high incidence rate and contributes to overall cancer fatalities. As of 2022, pancreatic cancer contributes to about 3 % of all cancers globally. Over the years, research has characterised germline predisposition, the origin cell, precursor lesions, genetic alterations, structural alterations, transcriptional changes, tumour heterogeneity, metastatic progression, and the tumour microenvironment, which has improved the understanding of PDAC carcinogenesis. By using molecular-based target therapies, these fundamental advancements support primary prevention, screening, early detection, and treatment. The focus of this review is the use of targeted nanoparticles as an alternative to conventional pancreatic cancer treatment due to the various side effects of the latter. The principles of nanoparticle based cancer therapy is efficient targeting of tumour cells via enhanced permeability and retention (EPR) effects and decrease the chemotherapy side effects due to their non-specificity. To increase the efficiency of existing therapies and modify target nanoparticles, several molecular markers of pancreatic cancer cells have been identified. Thus pancreatic cancer cells can be detected using appropriately functionalized nanoparticles with specific signalling molecules. Once cancer has been identified, these nanoparticles can kill the tumour by inducing hyperthermia, medication delivery, immunotherapy or gene therapy. As potent co-delivery methods for adjuvants and tumor-associated antigens; nanoparticles (NPs) have demonstrated significant promise as delivery vehicles in cancer therapy. This ensures the precise internalization of the functionalized nanoparticle and thus also activates the immune system effectively against tumor cells. This review also discusses the immunological factors behind the uptake of functionalized nanoparticles in cancer therapies. Theranostics, which combine imaging and therapeutic chemicals in a single nanocarrier, are the next generation of medicines. Pancreatic cancer treatment may be revolutionised by the development of a tailored nanocarrier with diagnostic, therapeutic, and imaging capabilities. It is extremely difficult to incorporate various therapeutic modalities into a single nanocarrier without compromising the individual functionalities. Surface modification of nanocarriers with antibodies or proteins will enable to attain multifunctionality which increases the efficiency of pancreatic cancer therapy.

Ductal pancreatic cancer interception by FGFR2 abrogation.

Mutant KRAS-expressing pancreatic intraepithelial neoplasias (PanINs), the precursor lesions of PDA, are prevalent in the average healthy adult but rarely advance to invasive carcinoma. Here, we discovered that FGFR2 promoted PDA progression by amplifying mutant KRAS signaling and that inactivation of FGFR2 intercepted disease progression.

Complete retinal pigment epithelium and outer retinal atrophy: Is it really an end-stage atrophy?

Geographic atrophy (GA), a late manifestation of age-related macular degeneration (AMD), leads to irreversible vision loss. Early identification of precursor lesions, such as incomplete and complete retinal pigment epithelium and outer retinal atrophy (iRORA and cRORA), is crucial for predicting GA formation. The latter stage has been associated with irreversible and progressive changes, and the eventual development of a dense scotoma on the compromised area. We present an 80-year-old woman with AMD in both eyes, demonstrating progressive changes over a 2-year follow-up. While the right eye developed cRORA with vision decline, the left eye exhibited unexpected restoration of the outer retinal layers within the cRORA lesion. This finding challenges the notion of "end-stage atrophy" in GA development and highlights the potential reversibility of early atrophic lesions. Recognizing these dynamics has implications for the development of targeted therapies aimed at preserving vision in AMD's early stages.

Altering Trends in Pathological Spectrum of Cholecystectomy Specimen: Time to be More Vigilant

Abstract Background: Gall bladder cancer is a rare, most common and aggressive malignancy of the biliary tree, accounting for 80%–90% of biliary tract cancers. Gallstones are one of the major causes of the development of cholecystitis and long-term malignancy in developing countries. Cholecystectomy specimens have a great value in documenting various entities with clinical significance. Early detection is the most important step in improving the prognosis of gall bladder carcinoma (GBC) screening. Aim: Clinico- pathological spectrum of cholecystectomy specimen and Incidence of malignancy and its precursor lesion with gallstones. Patient and Methods: We conducted a retrospective analysis of all gall bladder specimens (cholecystectomy, laparoscopic, open or radical) from the period of January 2019–January 2022, including demographic data of the patients such as age and sex. Additional findings, such as the presence of gallstones, cholesterolosis, gastric or intestinal metaplasia, dysplasia and histopathological type of GBC, were documented. Results: A total of 1221 gall bladder specimens were received, with a higher female preponderance and a female-to-male ratio of 2.6:1. The mean age of presentation was 45 years. The most common histopathological diagnosis made was chronic cholecystitis (97%), and malignant cases accounted for 3% of the total cases. Conclusions: The high propensity of GBC with non-cholelithiasis cases, more than half of cases with metaplasia and increased incidence of adenosquamous carcinoma indicate a high burden of tumours, alerting the clinician as well as the pathologist.

An Adjustable Positivity Threshold for Non-invasive Screening Tests for Colorectal Neoplasms Can Improve Screening Program Effectiveness and Feasibility.

In two-step population screening for colorectal cancer (CRC), a simple non-invasive test, commonly a fecal immunochemical test for hemoglobin (FIT), is first undertaken to predict, based on the fecal hemoglobin concentration (f-Hb), who is more likely to have colorectal neoplasia and needs colonoscopy. To evaluate the importance of being able to adjust the f-Hb threshold that triggers follow-up colonoscopy (the "positivity threshold"), we evaluated the predictive value of f-Hb for colorectal neoplasia and its implications for the configuration of new non-invasive tests. A literature review was conducted on the use of quantitative FIT to select the positivity threshold, followed by using f-Hb from a large population to model how adjusting the positivity threshold enabled achievement of the desired program outcomes in a feasible manner. The literature review and the modeling found that while the f-Hb positivity threshold is predictive for colorectal neoplasia across a wide range of f-Hb, there is a complex relationship between program outcomes and f-Hb. The threshold determines not just clinical accuracy (including true- and false-positive results for CRC and/or advanced precursor lesions), but also the colonoscopy workload. A lower f-Hb threshold is associated with a higher sensitivity for neoplasia but a lower specificity and a heavier load of follow-up colonoscopies. Consequently, the threshold determines a program's impact on population CRC mortality and incidence, but also its feasibility and cost-effectiveness within a health-care system. We are entering a new era of non-invasive screening tests, where multiple biomarkers found in biological samples such as blood as well as feces, are being developed and evaluated. These typically specify a non-transparent algorithm, developed with machine learning, to provide a predictive dichotomous positive/negative result with a fixed associated clinical accuracy and colonoscopy workload. This will restrict use of new tests in jurisdictions where the accuracy and workload implications do not match the desired screening program outcomes. However, similar to flexible FIT positivity thresholds, it would be ideal if new tests also provide capacity for screening program providers to select the positivity threshold that delivers their desired screening outcomes in a feasible manner. How marketing, distribution and reimbursement of non-invasive tests are approved, funded and implemented varies widely across jurisdictions and must be taken into account.

Retraction Note: Nanofabrication in polymeric materials with Raman scattering techniques based on noninvasive imaging for tumor precursor lesions

Retraction Note: Nanofabrication in polymeric materials with Raman scattering techniques based on noninvasive imaging for tumor precursor lesions

Prevalence of Trichomonas vaginalis Infection in Women Screened for Precursor Lesions of Cervical Cancer in a Brazilian Population

Trichomonas vaginalis infection is one of the most prevalent curable STIs. Although treatments are available, T. vaginalis infections pose a significant challenge, especially in resource-limited regions, as the prevalence of this STI is often unknown. We aimed to determine the prevalence of Trichomonas vaginalis infection in women screened for cervical cancer precursor lesions in Botucatu in São Paulo, Brazil. We conducted a descriptive and retrospective study that included 23,735 women who attended the cervical cancer screening program at health units in 2019 and 2022. Clinical and sociodemographic data were collected from the cancer information system (SISCAN) and test requisition forms. Descriptive analysis was conducted, and comparisons were performed using the X2 Test and Student’s t-test (SigmaPlot version 13.0). The prevalence of T. vaginalis infection was 0.84% in 2019 and 0.57% in 2022. The mean age of patients with trichomoniasis was 42 (±11.2) years; 75% self-reported as white, 43% were married or in a stable relationship, and 40% had not completed primary education. Regarding the vaginal microbiota, only 15.3% of the cytology exams with infection by T. vaginalis showed a predominance of lactobacilli species, while inflammation was present in 82% of the smears. Cytological analysis revealed precursor lesions of cervical cancer in 0.05% of patients with trichomoniasis, including ASC, LSIL, and HSIL. The study showed a low prevalence of infection with T. vaginalis in low-risk women screened for precursor lesions of cervical cancer in Botucatu in São Paulo, Brazil.

Clinical application of photoacoustic imaging for cervical precursor lesion detection.

Early diagnosis of a precursor lesion in the uterine cervix is an essential factor in uterine cervical cancer prevention. Although colposcopy is an established procedure for detecting high-risk patients, its accuracy and reproducibility are relatively low. Some supportive or alternative techniques to improve the early diagnosis of a precursor lesion have been studied, and correct diagnosis with high reliability using a minimally invasive, cost-effective technique has been pursued. This study aimed to examine the possibility of using photoacoustic (PA) imaging as a supportive technique to improve the accuracy of early diagnosis of cervical precursor lesions. A PA imaging system for microvessels was used to detect angiogenesis in severe lesions. A total of 21 patients who underwent surgical treatment and 114 outpatients who visited our colposcopy clinic were examined. A retrospective evaluation of PA images was performed as follows: (i) pathological assessment of the specific PA findings and (ii) retrospective evaluation of the severe lesion detection rate through PA. PA image evaluation and pathological findings showed dense angiogenesis in a severe precursor lesion appearing as a "hot spot" in the PA image. A comparison with colposcopy findings was performed for accuracy evaluation, and the detection rate of severe lesions using PA was relatively high (positive predictive value, 84.5%; negative predictive value, 82.1%). Our results indicate the possibility of using PA imaging for early diagnosis of severe cervical precursor lesions. With its ability to yield quantitative information, PA imaging can improve ultrasound diagnosis.

PATHWAYS TO GEOGRAPHIC ATROPHY IN NONNEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

To characterize and quantify the precursor lesions of geographic atrophy in eyes with age-related macular degeneration. A retrospective study of eyes with a minimum of 6-month follow-up before developing geographic atrophy. Evaluations included color and autofluorescence imaging, along with spectral-domain optical coherence tomography, employing definitions from the Consensus of Atrophy Meeting Group and Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group. There were 55 eyes of 44 patients, who had a mean age of 81.3 years at onset of atrophy; 35 (63.6%) were female. The mean duration of follow-up before and after the advent of geographic atrophy was 4.9 years and 1.2 years, respectively. Geographic atrophy was preceded by collapse of a druse in 41 eyes (74.5%). Of these, 29 (70.7%) were drusenoid pigment epithelial detachments. Among the eyes with regressing drusen, there were 9 with overlying vitelliform deposit, and all had concurrent subretinal drusenoid deposit; however, 19 of 30 eyes with no vitelliform deposit overlying the druse had concurrent subretinal drusenoid deposit, a difference that was significant ( P < 0.001). Regression of subretinal drusenoid deposit was found in 4 eyes (7.3%), regression of vitelliform deposit associated with subretinal drusenoid deposit in 5 (9.1%), and regression of vitelliform deposit in eyes concurrently harboring drusen was found in 3 (5.4%) and regression of vitelliform deposit alone in 2 (3.6%) at the site of eventual development of geographic atrophy. Geographic atrophy appears to develop from multiple pathways as manifested by the many precursor lesions, all various forms of extracellular deposit, that upon regression, result in a common end-stage appearance.

A complete benchmark for polyp detection, segmentation and classification in colonoscopy images.

Colorectal cancer (CRC) is one of the main causes of deaths worldwide. Early detection and diagnosis of its precursor lesion, the polyp, is key to reduce its mortality and to improve procedure efficiency. During the last two decades, several computational methods have been proposed to assist clinicians in detection, segmentation and classification tasks but the lack of a common public validation framework makes it difficult to determine which of them is ready to be deployed in the exploration room. This study presents a complete validation framework and we compare several methodologies for each of the polyp characterization tasks. Results show that the majority of the approaches are able to provide good performance for the detection and segmentation task, but that there is room for improvement regarding polyp classification. While studied show promising results in the assistance of polyp detection and segmentation tasks, further research should be done in classification task to obtain reliable results to assist the clinicians during the procedure. The presented framework provides a standarized method for evaluating and comparing different approaches, which could facilitate the identification of clinically prepared assisting methods.

Cell representation in cytopathological examinations of the cervix

The objective of this study was to analyze the relationship between the representation of JEC/ZT in cervical cytopathological tests with the age and clinical variables of women. A retrospective study was carried out, with data collected from the Cancer Information System, referring to cytopathological tests collected in public health services. Most of the tests (60%) showed representation of JEC/ZT cells. It was observed that the younger the woman, the higher the proportion of tests with JEC/ZT cells, and as age advanced, the representation decreased. Most women using oral contraceptives or hormone replacement therapy, as well as most pregnant women, also had JEC/ZT cells in the test. All examinations with the result of squamous intraepithelial lesion or with atypical squamous cells, not excluding lesions of the present grade, showed JEC/ZT cells. The results found corroborate the importance of sample quality in the identification of precursor lesions of cervical cancer, and it is evident that more attention should be paid to collections carried out in older women in order to be successful in representing JEC/ZT.

How to "pick up" colorectal serrated lesions and polyps in daily histopathology practice: From terminologies to diagnostic pitfalls.

Over the last decade, our knowledge of colorectal serrated polyps and lesions has significantly improved due to numerous studies on this group of precursor lesions. Serrated lesions were misleading as benign before 2010, but they are currently reclassified as precancerous lesions that contribute to 30% of colorectal cancer through the serrated neoplasia pathway. The World Health Organization updated the classification for serrated lesions and polyps of the colon and rectum in 2019, which is more concise and applicable in daily practice. The responsible authors prescribe that "colorectal serrated lesions and polyps are characterized by a serrated (sawtooth or stellate) architecture of the epithelium." From a clinical standpoint, sessile serrated lesion (SSL) and SSL with dysplasia (SSLD) are the two most significant entities. Despite these advancements, the precise diagnosis of SSL and SSLD based mainly on histopathology remains challenging due to various difficulties. This review describes the nomenclature and the terminology of colorectal serrated polyps and lesions and highlights the diagnostic criteria and obstacles encountered in the histopathological diagnosis of SSL and SSLD.

Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma.

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.