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Modern Pathology : An Official Journal... Jan 2024Intraductal oncocytic papillary neoplasms (IOPNs) are distinct from intraductal papillary mucinous neoplasms based on characteristic morphologic and genetic features...
Intraductal oncocytic papillary neoplasms (IOPNs) are distinct from intraductal papillary mucinous neoplasms based on characteristic morphologic and genetic features represented by fusion genes involving PRKACA or PRKACB (PRKACA/B). However, pancreatic and biliary tumors with partial oncocytic features are often encountered clinically, and their molecular features are yet to be clarified. This study included 80 intraductal papillary neoplasms: 32 tumors with mature IOPN morphology (typical), 28 with partial or subclonal oncocytic features (atypical), and 20 without oncocytic features (control). We analyzed PRKACA/B fusion genes, including ATP1B1::PRKACA, DNAJB1::PRKACA, and ATP1B1::PRKACB, by reverse-transcription PCR; mRNA expression of fusion genes and nonrearranged PRKACA/B genes by quantitative reverse-transcription PCR; mutations in KRAS, BRAF, and GNAS by targeted sequencing or droplet digital PCR; and the expression of cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunits α (PRKACA) and β (PRKACB), phosphorylated cAMP response element-binding protein, and aberrations of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry. PRKACA/B fusion genes were detected in 100% (32/32) of typical, 46% (13/28) of atypical, and 0% (0/20) of control (P < .05). Expression of PRKACA, PRKACB, and phosphorylated cAMP response element-binding protein was upregulated in neoplasms with PRKACA/B fusion genes (P < .05). mRNA expression of the PRKACA/B fusion genes and protein expression of PRKACA or PRKACB tended to be higher in typical than in atypical cases (mRNA, P = .002; protein expression, P = .054). In some atypical neoplasms with mixed subtypes, PRKACA/B fusion genes were superimposed exclusively on oncocytic components. Typical IOPNs harbored fewer KRAS and GNAS mutations than control samples and fewer alterations in p53 and STK11 than atypical samples (P < .05). In conclusion, PRKACA/B fusion genes not only are the characteristic drivers of IOPNs but also play a crucial role in the development of subclonal oncocytic neoplasms. Moreover, oncocytic morphology is strongly associated with upregulation of PRKACA/B, which may provide clues for potential therapeutic options.
Topics: Humans; Tumor Suppressor Protein p53; Protein Kinases; Catalytic Domain; Cyclic AMP Response Element-Binding Protein; Proto-Oncogene Proteins p21(ras); Pancreatic Neoplasms; Chromosome Aberrations; Adenocarcinoma, Mucinous; Gene Rearrangement; RNA, Messenger; Carcinoma, Pancreatic Ductal; HSP40 Heat-Shock Proteins; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
PubMed: 37871652
DOI: 10.1016/j.modpat.2023.100358 -
Cureus Apr 2024The fifth edition of the World Health Organization (WHO) classification introduces new diagnostic methods based on genetic alterations, providing insight into the... (Review)
Review
The fifth edition of the World Health Organization (WHO) classification introduces new diagnostic methods based on genetic alterations, providing insight into the molecular basis of lesions. As a result, the classification system has evolved, new entities have been introduced, and existing entities have been reclassified. Oncocytic lesions of salivary glands are a group of neoplastic conditions characterized by the presence of oncocytic cells. These lesions present a diagnostic challenge due to their overlapping histological features. Therefore, a comprehensive evaluation, including morphological, immunohistochemical, and molecular analysis, is crucial for accurate diagnosis and appropriate management. Accurate classification of salivary gland pathologies is essential for selecting the appropriate treatment methods and predicting outcomes. The introduction of new therapeutic approaches, such as targeted therapies for malignant salivary gland tumors, has improved patient outcomes. However, to effectively implement these therapies in clinical practice, a clear classification of lesions is necessary.
PubMed: 38817461
DOI: 10.7759/cureus.59328 -
Current Opinion in Oncology Jan 2024The assessment of thyroid nodules is a common clinical problem, linked to the high incidence of thyroid nodules in the population and the low incidence of aggressive... (Review)
Review
PURPOSE OF REVIEW
The assessment of thyroid nodules is a common clinical problem, linked to the high incidence of thyroid nodules in the population and the low incidence of aggressive thyroid carcinoma. The screening is therefore one of the strengths of our patient care. Recently, the 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and 2022 WHO classification of thyroid neoplasms have been released based on the definition of new entities and the growing impact of molecular testing. The aim of this review is to analyze how these upgrades can help us in the daily routine practice diagnosis of thyroid cancer.
RECENT FINDINGS
Our review is focused on the most frequent thyroid tumors derived from thyroid follicular cell. Fine needle aspiration (FNA) is the gold standard for the screening of thyroid nodules with very high levels of sensitivity and specificity. These sensitivity and specificity are improved by molecular testing, which refines the risk of malignancy. The 2023 TBSRTC integrates molecular data and the upgrades integrated in the 2022 WHO classification such as the 'low-risk neoplasms' and the 'high-grade follicular-cells derived carcinoma'. The morphological examination remains crucial since the capsular and/or vascular invasion are key features of malignancy in the follicular thyroid neoplasms. Low-risk neoplasms represent a clinical challenge since no specific guidelines are available. Challenges remain regarding oncocytic thyroid lesions, which are not associated with specific diagnostic molecular biomarkers. Molecular testing can help not only in deciphering the prognosis but also in the targeted therapeutic strategy.
SUMMARY
While molecular testing has succeeded to substantially improve the pre and postoperative diagnosis and risk stratification of thyroid tumors, the morphological examination is still central in the daily routine diagnosis of thyroid pathology. Future is the integrated diagnosis of clinical, morphological, molecular and epigenetic features with the help of artificial intelligence algorithms.
Topics: Humans; Thyroid Nodule; Artificial Intelligence; Adenocarcinoma, Follicular; Thyroid Neoplasms; World Health Organization; Retrospective Studies
PubMed: 37975316
DOI: 10.1097/CCO.0000000000001012 -
Journal of Clinical Oncology : Official... Sep 2023The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant...
PURPOSE
The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points.
METHODS
The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated.
RESULTS
The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial.
CONCLUSION
End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Research Design; Progression-Free Survival
PubMed: 37433103
DOI: 10.1200/JCO.23.00435 -
Virchows Archiv : An International... Sep 2023The sinonasal tract is considered a second hotspot for human papillomavirus (HPV)-related tumors in the head and neck, with HPV being identified in up to 62% of squamous...
The sinonasal tract is considered a second hotspot for human papillomavirus (HPV)-related tumors in the head and neck, with HPV being identified in up to 62% of squamous cell carcinomas (SCCs) and 38% of papillomas. There is limited data from geographical regions with low prevalence of high-risk (HR)-HPV on the association of HR-HPV in sinonasal neoplasms and on utility of p16 as a surrogate marker. p16 immunohistochemistry, HR-HPV mRNA ISH and quantitative real-time PCR (qPCR) were performed on a retrospective cohort of sinonasal papillomas and SCCs. KRAS mutation analysis was done in oncocytic papillomas. p16 positivity was present in 22/142 cases (15.5%) including eight inverted papillomas, one oncocytic papilloma (OP), and 13 SCC. Among these, mRNA ISH showed HR-HPV in the OP and two SCC, while another SCC was found to harbour HPV18 by qPCR. Two HPV-associated SCCs had foci of OP. mRNA ISH was negative in all p16 negative cases. p16 immunohistochemistry showed 68% concordance with mRNA ISH, and had sensitivity and negative predictive value of 100%; specificity was 67%, and positive predictive value was 14.3%. Association with HR-HPV in sinonasal papillomas and SCC is rare, and may be seen in cases demonstrating oncocytic morphology. p16 immunohistochemistry has low specificity and positive predictive value in low-prevalence populations; thus, reflex direct HR-HPV testing should be performed in p16 immunopositive cases. This two-step approach is viable in resource-limited settings, as the proportion of p16 positive cases is small.
Topics: Humans; Human Papillomavirus Viruses; Papillomavirus Infections; Retrospective Studies; In Situ Hybridization; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Papilloma, Inverted; RNA, Messenger; Cyclin-Dependent Kinase Inhibitor p16; Papillomaviridae
PubMed: 37452847
DOI: 10.1007/s00428-023-03601-x -
British Dental Journal Feb 2024
Topics: Humans; Cystadenoma, Papillary
PubMed: 38332080
DOI: 10.1038/s41415-024-7093-5 -
Thyroid : Official Journal of the... Sep 2023Alterations in DNA methylation are stable epigenetic events that can serve as clinical biomarkers. The aim of this study was to analyze methylation patterns among...
Alterations in DNA methylation are stable epigenetic events that can serve as clinical biomarkers. The aim of this study was to analyze methylation patterns among various follicular cell-derived thyroid neoplasms to identify disease subtypes and help understand and classify thyroid tumors. We employed an unsupervised machine learning method for class discovery to search for distinct methylation patterns among various thyroid neoplasms. Our algorithm was not provided with any clinical or pathological information, relying exclusively on DNA methylation data to classify samples. We analyzed 810 thyroid samples ( = 256 for discovery and = 554 for validation), including benign and malignant tumors, as well as normal thyroid tissue. Our unsupervised algorithm identified that samples could be classified into three subtypes based solely on their methylation profile. These methylation subtypes were strongly associated with histological diagnosis ( < 0.001) and were therefore named normal-like, follicular-like, and papillary thyroid carcinoma (PTC)-like. Follicular adenomas, follicular carcinomas, oncocytic adenomas, and oncocytic carcinomas clustered together forming the follicular-like methylation subtype. Conversely, classic papillary thyroid carcinomas (cPTC) and tall cell PTC clustered together forming the PTC-like subtype. These methylation subtypes were also strongly associated with genomic drivers: 98.7% -driven cancers were PTC like, whereas 96.0% -driven cancers had a follicular-like methylation pattern. Interestingly, unlike other diagnoses, follicular variant PTC (FVPTC) samples were split into two methylation clusters (follicular like and PTC like), indicating a heterogeneous group likely to be formed by two distinct diseases. FVPTC samples with a follicular-like methylation pattern were enriched for mutations (36.4% vs. 8.0%; < 0.001), whereas FVPTC- with PTC-like methylation patterns were enriched for mutations (52.0% vs. 0%, Fisher exact = 0.004) and fusions (16.0% vs. 0%, Fisher exact = 0.003). Our data provide novel insights into the epigenetic alterations of thyroid tumors. Since our classification method relies on a fully unsupervised machine learning approach for subtype discovery, our results offer a robust background to support the classification of thyroid neoplasms based on methylation patterns.
Topics: Humans; DNA Methylation; Proto-Oncogene Proteins B-raf; Thyroid Neoplasms; Thyroid Cancer, Papillary; Adenocarcinoma, Follicular; Mutation
PubMed: 37392021
DOI: 10.1089/thy.2023.0074 -
Frontiers in Immunology 2023The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined....
UNLABELLED
The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined. Here, we analyzed plasma samples longitudinally collected at predefined time points and at the time of irAEs from 58 patients with immunotherapy naïve metastatic non-small cell lung cancer treated on clinical protocol with ipilimumab and nivolumab. We used a proteomic microarray system capable of assaying antibody reactivity for IgG and IgM fractions against 120 antigens for systemically evaluating the correlations between auto-reactive antibodies and certain organ-specific irAEs. We found that distinct patterns of auto-reactive antibodies at baseline were associated with the subsequent development of organ-specific irAEs. Notably, ACHRG IgM was associated with pneumonitis, anti-cytokeratin 19 IgM with dermatitis, and anti-thyroglobulin IgG with hepatitis. These antibodies merit further investigation as potential biomarkers for identifying high-risk populations for irAEs and/or monitoring irAEs during immunotherapy treatment.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03391869.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Proteomics; Immune System Diseases; Immunoglobulin G; Immunoglobulin M
PubMed: 38152395
DOI: 10.3389/fimmu.2023.1322818 -
Pancreatology : Official Journal of the... Nov 2023Intraductal papillary mucinous neoplasms (IPMNs) are a cystic precursor to pancreatic cancer. IPMNs deemed clinically to be at high-risk for malignant progression are...
BACKGROUND
Intraductal papillary mucinous neoplasms (IPMNs) are a cystic precursor to pancreatic cancer. IPMNs deemed clinically to be at high-risk for malignant progression are frequently treated with surgical resection, and pathological examination of the pancreatectomy specimen is a key component of the clinical care of IPMN patients.
METHODS
Systematic literature reviews were conducted around eight topics of clinical relevance in the examination of pathological specimens in patients undergoing resection of IPMN.
RESULTS
This review provides updated perspectives on morphological subtyping of IPMNs, classification of intraductal oncocytic papillary neoplasms, nomenclature for high-grade dysplasia, assessment of T stage, distinction of carcinoma associated or concomitant with IPMN, role of molecular assessment of IPMN tissue, role of intraoperative assessment by frozen section, and preoperative evaluation of cyst fluid cytology.
CONCLUSIONS
This analysis provides the foundation for data-driven approaches to several challenging issues in the pathology of IPMNs.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Adenocarcinoma, Mucinous; Retrospective Studies; Pancreatic Neoplasms
PubMed: 37604731
DOI: 10.1016/j.pan.2023.08.002 -
Seminars in Diagnostic Pathology Jan 2024Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomatous tumors involving multiple organs such as the brain, skin, heart,... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomatous tumors involving multiple organs such as the brain, skin, heart, lung and kidney. TSC is caused by inactivating mutations in TSC1/TSC2, which encodes hamartin and tuberin, respectively, and forms a complex that regulates mechanistic target of rapamycin complex 1 (mTORC1), resulting in cell overgrowth and oncogenesis. Since a leading cause of morbidity and mortality in TSC relates to chronic kidney disease and the ability to preserve renal function, this review describes the important pathologic findings in TSC-associated renal neoplasms and their correlating sporadic counterparts. The most common renal tumor in TSC patients are AMLs, followed by a heterogeneous spectrum of renal epithelial tumors, which may provide clues to establishing a diagnosis of TSC.
Topics: Humans; Carcinoma, Renal Cell; Tuberous Sclerosis; Kidney Neoplasms; Kidney; Hamartoma
PubMed: 37993384
DOI: 10.1053/j.semdp.2023.09.001