Noninvasive Precursor Lesions Research Articles

Urinary bladder: tumor precursors and non-invasive carcinoma

In recent years, our understanding of the genesis and development of urothelial carcinomas (UC) has expanded considerably thanks to advancing molecular classifications. These advances have led to significant changes in the 5thedition of the WHO classification of tumors of the urinary tract and male genitalia. The new findings allow both the introduction of modern diagnostic approaches and areturn to proven methods in the evaluation of precursor lesions and non-invasive carcinomas. This article is intended to provide asummarized overview of the various precursor lesions and pathways of urothelial carcinoma. The changes and clarifications in the 5thedition of the WHO classification reflect the progress made in the molecular and morphological characterization of urothelial carcinomas. These adjustments provide an improved basis for diagnosis and treatment and emphasize the importance of differentiated molecular profiles for the classification and treatment of UC. Despite all this, conventional histology remains the gold standard for the diagnosis and classification of non-invasive carcinomas and precursor lesions.

Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project.

Integrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of IPMNs, which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.

Somatic loss of ATM is a late event in pancreatic tumorigenesis.

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Abstract PO-117: The role of Hippo signaling in stromal-epithelial interactions in acinar-to-ductal metaplasia and pancreatic cancer initiation

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths with a 5-year survival rate of approximately 7%. PDAC may originate from acinar cell trans-differentiation into ductal-like cells, termed acinar-to-ductal metaplasia (ADM), triggered by chronic pancreatitis and/or mutations in K-Ras. The progression to PDAC is associated with a dense fibrotic stroma, including cancer-associated fibroblasts (CAFs). YAP is a tension-stimulated CAF activator that promotes ECM stiffening, creating a permissive microenvironment for cancer progression. We hypothesize that the Hippo pathway may coordinate fibroinflammatory signals emanating from the stromal compartment during regenerative responses to acinar cell injury and progression towards PDAC. Methods: To resolve the transcriptional changes occurring during the transition to ADM and PDAC, we mapped the in situ expression of over 1800 RNA targets in patient-derived tissues using NanoString Technologies’ Digital Spatial Profiling (DSP) technology. We also performed immune-profiling and evaluated Yap expression in human ADM by immunohistochemistry. To study the in vivo role of Hippo signaling in stromal cells, we conditionally deleted Yap/Taz in Collagen1a2-producing cells in a murine model of caerulein-induced pancreatitis, which recapitulates many of the features associated with human ADM. I will analyze the resulting phenotype by immunostaining for metaplastic, proliferative, immune and stromal markers. Results: DSP analysis revealed genes implicated in fibroblast activation, epithelial-to-mesenchymal transition (EMT), neutrophil activation and IFNγ signaling as potential key drivers of ADM. I will further evaluate the expression of candidate genes and survey Yap expression at the single cell level in human ADM tissue by multiplexed RNAscope in situ hybridization. We found up-regulation of CD4+ and CD8+ T cells in ADM, and an increasing trend of neutrophil and macrophage accumulation in the progression from normal parenchyma to ADM to PDAC. Conclusions: This work will provide an in-depth understanding of epithelial-stroma crosstalk in ADM and a foundation for the development of new therapeutic strategies for treating non-invasive precursor lesions like ADM, thereby preventing pancreatic cancer progression. Source of Funding: This research is supported by the Fonds de Recherce du Quebec – Santé (FRQS), Canadian Institutes of Health Research (CIHR) and the Research Institute of the McGill University Health Centre (RI-MUHC). Citation Format: Julia Messina-Pacheco, Yasser Riazalhosseini, Zu-hua Gao, Alex Gregorieff. The role of Hippo signaling in stromal-epithelial interactions in acinar-to-ductal metaplasia and pancreatic cancer initiation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-117.

DEVIL, VAAD and vLSC constitute a spectrum of HPV-independent, p53-independent intra-epithelial neoplasia of the vulva.

We aimed to characterise a large cohort of non-invasive, human papillomavirus (HPV) and p53-independent verruciform lesions, such as 'vulvar acanthosis with altered differentiation' (VAAD), 'differentiated exophytic vulvar intra-epithelial lesion' (DEVIL) and 'verruciform lichen simplex chronicus' (vLSC). From January 2008 to December 2020 we retrospectively identified 36 eligible patients with verruciform non-invasive lesions (n = 36) and collected clinical, histological and follow-up parameters. Verruciform non-invasive lesions occurred at a median age of 71 years, with a median follow-up of 33.5 months. Clinically, pruritus was only reported in patients with VAAD (n = 3, 21%). Lesion colour was significantly different across categories (P = 0.028). Apart from the histopathological criteria already known to distinguish these entities (hypogranulosis, epithelial pallor and low-magnification architecture), no other significant criteria were discovered and significant overlap was observed, particularly between VAAD and DEVIL. Patients with vLSC trended towards longer survival without recurrence compared to VAAD and DEVIL (P = 0.082), but showed comparable invasion-free survival interval (P = 0.782). Squamous cell carcinomas (SCC) associated with either VAAD, DEVIL or vLSC displayed similar clinical, histopathological and biological parameters. In non-invasive precursor lesions, stromal oedema was associated with invasion (P = 0.015) and remained so upon Cox regression analysis (P = 0.009). Our study of HPV and p53 independent non-invasive verruciform lesions of the vulva highlights significant clinical, histopathological and biological overlap between VAAD, DEVIL and vLSC, suggesting that these pre-invasive lesions should be viewed as a spectrum. We also show that stromal features such as oedema might play an import role in progression to invasion.

Diagnosis of the pancreatic cancer

Introduction: The pancreatic cancer arises from non-invasive precursor lesions and develops through the accumulation of characteristic gene mutations. The recent scientific reports based on genetic tests state that the approximate time between cancerous initiation and the development of cancer with metastasisis15 years. We candistinguish three main precancerous lesions leading to the pancreatic cancer: pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasms (MCN), and intraductal papillary mucinous neoplasms (IPMN). The imaging tests used for the diagnostics and observation of precancerous pancreas lesions are MR, MRC, CT and EUS. Method: review of the recent literature based on PubMEd, Google scholar research based onthe following key words: pancreatic cancer, precancer of the pancreas, pancreatic cyst, tuber of the pancreas, medical imaging of the pancreasPurpose of the work: systematizing information about precancers of the pancreatic cancer based on the latest research and findings

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions

ObjectiveIntraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic...

MiRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis.

Distal cholangiocarcinoma (dCCA) is a biliary tract cancer with a dismal prognosis and is often preceded by biliary intraepithelial neoplasia (BilIN), representing the most common biliary non-invasive precursor lesion. BilIN are histologically well defined but have not so far been characterised systematically at the molecular level. The aim of this study was to determine miRNA-regulated genes in cholangiocarcinogenesis via BilIN. We used a clinicopathologically well-characterised cohort of 12 dCCA patients. Matched samples of non-neoplastic biliary epithelia, BilIN and invasive tumour epithelia of each patient were isolated from formalin-fixed paraffin-embedded tissue sections by laser microdissection. The resulting 36 samples were subjected to total RNA extraction and the expression of 798 miRNAs was assessed using the Nanostring® technology. Candidate miRNAs were validated by RT-qPCR and functionally investigated following lentiviral overexpression in dCCA-derived cell lines. Potential direct miRNA target genes were identified by microarray and prediction algorithms and were confirmed by luciferase assay. We identified 49 deregulated miRNAs comparing non-neoplastic and tumour tissue. Clustering of these miRNAs corresponded to the three stages of cholangiocarcinogenesis, supporting the concept of BilIN as a tumour precursor. Two downregulated miRNAs, i.e. miR-451a (-10.9-fold down) and miR-144-3p (-6.3-fold down), stood out by relative decrease. Functional analyses of these candidates revealed a migration inhibitory effect in dCCA cell lines. Activating transcription factor 2 (ATF2) and A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) were identified as direct miR-451a target genes. Specific ATF2 inhibition by pooled siRNAs reproduced the inhibitory impact of miR-451a on cancer cell migration. Thus, our data support the concept of BilIN as a direct precursor of invasive dCCA at the molecular level. In addition, we identified miR-451a and miR-144-3p as putative tumour suppressors attenuating cell migration by inhibiting ATF2 in the process of dCCA tumorigenesis. © The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Organoid-Transplant Model Systems to Study the Effects of Obesity on the Pancreatic Carcinogenesis in vivo.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoid models of pancreatic cancer have provided insight into the fundamental pathways driving tumor progression from a normal cell to non-invasive precursor lesion and finally to widely metastatic disease, offering new opportunities for identifying the key driver of cancer evolution. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poorer prognosis and treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose a feasible and manageable organoid-based preclinical tool to study the effects of obesity on pancreatic carcinogenesis. Therefore, we tracked the effects of obesity on the natural evolution of PDAC in a genetically defined transplantable model of the syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived-organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our results suggest that organoid-derived transplant in obese mice represents a suitable system to study early steps of pancreatic carcinogenesis and supports the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.

MMR deficiency in urothelial carcinoma of the bladder presents with temporal and spatial homogeneity throughout the tumor mass

BackgroundMicrosatellite instability (MSI), a hypermutator phenotype described in many cancers, has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in bladder cancer, but data on the possible extent of intratumoral heterogeneity are lacking. MethodsTo study MSI heterogeneity in bladder cancer, a tissue microarray (TMA) comprising 598 muscle-invasive urothelial carcinomas of the bladder was utilized to screen for MSI by immunhistochemistry with antibodies for MLH1, PMS2, MSH2, and MSH6. ResultsIn 9 cases suspicious for MSI, MMR status was further evaluated by large section examination and polymerase chain reaction (PCR)-based analysis of microsatellites (“Bethesda panel”) resulting in the identification of 5 validated MSI cases from 448 interpretable cancers (prevalence 1.1%). MMR deficiency always involved PMS2 loss, in 3 cases with additional loss or reduction of MLH1 expression. Four cancers were MSI-high and 1 was MSI-low in the PCR analysis. Parallel sequencing revealed an inactivating MLH1 mutation in 1 tumor but no further known pathogenic MMR gene mutations were found. Immunostaining of all available 72 cancer-containing tissue blocks of the 5 confirmed bladder cancer with MSI including prior and subsequent biopsies showed complete homogeneity of the MMR protein defects and the status of the 4 MMR proteins did not markedly change in sequential resections. In all 4 cases with noninvasive precursor lesions, MSI was also detectable. ConclusionThese data suggest that MSI occurs early in invasive bladder cancer and immunohistochemical MMR analysis on limited biopsy material is sufficient to estimate MMR status of the entire cancer mass.

Abstract I06: Clonal evolution and progression of pancreatic cancer precursor lesions

Abstract Pancreatic cancer arises from noninvasive precursor lesions that are curable if detected and treated early enough. These precursor lesions include microscopic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). Interrogation of these lesions can provide critical insights into the earliest stages of pancreatic tumorigenesis and provide a rational foundation for early detection approaches. We have performed comprehensive genomic analyses of PanINs, IPMNs, and associated invasive carcinomas, highlighting several unique features of initiation and progression of pancreatic neoplasms. We show that early-stage precursor lesions contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. In addition, we identify convergent evolution of tumor suppressor gene loss at later stages of tumorigenesis, as well as subclonal complexity of driver gene mutations and mutations in specific genes limited to invasive cancers. Taken together, these data challenge the traditional monoclonal origin of pancreatic tumors, highlight distinct evolutionary features of precancerous lesions, and transform our understanding of the clonal evolution of pancreatic neoplasia. Citation Format: Laura D. Wood. Clonal evolution and progression of pancreatic cancer precursor lesions [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I06.

Histomorphology of pancreatic cancer in patients with inherited ATM serine/threonine kinase pathogenic variants

Germline pathogenic variants in the ATM serine/threonine kinase (ATM) gene are associated with an increased risk of pancreatic ductal adenocarcinoma. It is important to identify germline ATM pathogenic variants in pancreatic cancer patients because these alterations are potentially targetable with chemotherapeutic drugs and/or radiation and have implications for other family members. As germline pathogenic variants in other genes have been associated with distinct histologic subtypes of pancreatic cancer, we studied the histomorphology of pancreatic cancer in 23 patients with germline ATM pathogenic variants. The histologic subtype was ductal adenocarcinoma in 19/23 (83%) of the patients, adenosquamous carcinoma in 1/23 (4%), and colloid (mucinous non-cystic) carcinoma in 3/23 (13%). The percentage of colloid (mucinous non-cystic) carcinomas is higher than we have previously observed in patients with familial and sporadic pancreatic cancer (1 and 2% in prior reports, p < 0.01 and p < 0.01, respectively). Three carcinomas (2 colloid carcinomas, 1 ductal adenocarcinoma) arose in association with intraductal papillary mucinous neoplasms. Among the resected pancreata, non-invasive precursor lesions, including pancreatic intraepithelial neoplasia and incipient intraductal papillary mucinous neoplasms, were identified in 83%. We conclude that pancreatic cancers in patients with germline ATM pathogenic variants are more frequently of colloid (mucinous non-cystic) morphology but are overall morphologically diverse supporting the utility of universal germline genetic testing for patients with pancreatic cancer.

Prevalence and Clinical Significance of Biliary Intraepithelial Neoplasia (BilIN) in Cholangiocarcinoma

Biliary intraepithelial neoplasia (BilIN) is a noninvasive precursor lesion which progresses to cholangiocarcinoma (CC). BilIN is often found synchronously adjacent to the tumor or at the surgical resection margin of resection CC. However, irrespective of its location, its prognostic significance on outcome after CC resection is unknown. The aim of this study was to elucidate the prevalence of BilIN in CC and to determine if the presence of BilIN has a prognostic or predictive effect on survival after resection for CC with curative intent. We retrospectively analyzed the database of patients with CC who underwent curative surgery performed at our institution from 2010 to 2017. There were 142 patients who underwent curative surgery for CC. BilIN was detected in 42 patients (29.5%) and showed a significantly higher prevalence in extrahepatic CC (90.5%) than in intrahepatic CC (9.5%; p = 0.003). On univariate analysis, extrahepatic hepatic CC patients with BilIN lesions significantly showed better disease-free survival (p = 0.05). Also, although not statistically significant, extrahepatic CC patients with BilIN lesions revealed better overall survival (p = 0.09). On multivariate analysis, presence of BilIN lesion, irrespective of location, was significantly associated with better disease-free (HR = 1.959, 95% CI 1.026–3.743, p = 0.042) and overall survival (HR = 2.140, 95% CI 1.006–4.552, p = 0.048) in extrahepatic CC patients. In conclusion, the presence of BilIN lesions was not uncommon in CC patients and was significantly associated with better disease-free and overall survival in extrahepatic CC patients. However, larger studies with longer follow-up are needed to accurately determine its clinical significance.

Prevalence and Clinical Significance of Biliary Intraepithelial Neoplasia (BilIN) in Cholangiocarcinoma

Biliary intraepithelial neoplasia (BilIN) is the most common noninvasive precursor lesion which progresses to cholangiocarcinoma (CC) and is often found synchronously adjacent to the tumor or at the surgical resection margin. The aim of this study was to elucidate the prevalence and prognostic effect of BilIN on survival after resection for CC. We retrospectively analyzed the database of patients with CC who underwent surgery performed at our institution from 2010 to 2017. There were 142 patients who underwent surgery for CC. BilIN was detected in 42 patients (29.5%). On univariate analysis, extrahepatic CC (ExtraH CC) patients with BilIN lesions significantly showed better disease-free survival (P = 0.05). Also, although not statistically significant, ExtraH CC patients with BilIN lesions revealed better overall survival (OS) (P = 0.09). On multivariate analysis, presence of BilIN lesion, irrespective of location, was significantly associated with better disease-free survival (HR = 2.059, 95% confidence interval (CI): 1.057-4.432, P = 0.041) and OS (HR = 1.831, 95% CI: 1.149-3.534, P = 0.044) in ExtraH CC patients. The presence of BilIN lesions was not uncommon in CC patients and was significantly associated with better disease-free survival and OS in ExtraH CC patients. However, larger studies with longer follow-up are needed to accurately determine its clinical significance.

From somatic mutation to early detection: insights from molecular characterization of pancreatic cancer precursor lesions.

Pancreatic cancer arises from noninvasive precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), which are curable if detected early enough. Recently, these types of precursor lesions have been extensively characterized at the molecular level, defining the timing of critical genetic alterations in tumorigenesis pathways. The results of these studies deepen our understanding of tumorigenesis in the pancreas, providing novel insights into tumor initiation and progression. Perhaps more importantly, they also provide a rational foundation for early detection approaches that could allow clinical intervention prior to malignant transformation. In this review, we summarize the results of comprehensive molecular characterization of PanINs, IPMNs, and MCNs and discuss the implications for cancer biology as well as early detection. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Precancerous neoplastic cells can move through the pancreatic ductal system.

Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.

The Role of Photodynamic Therapy in the Treatment of Vulvar Intraepithelial Neoplasia.

Background: vulvar intraepithelial neoplasia is a non-invasive precursor lesion found in 50–70% of patients affected by vulvar squamous cell carcinoma. In the past, radical surgery was the standard treatment for vulvar intraepithelial neoplasia, however, considering the psychological and physical morbidities related to extensive surgery, several less aggressive treatment modalities have been proposed since the late 1970s. Photodynamic therapy is an effective and safe treatment for cutaneous non-melanoma skin cancer, with favorable cosmetic outcomes. Methods: in the present paper, the results of selected studies on photodynamic therapy in the treatment of vulvar intraepithelial neoplasia are reported and discussed. Results: Overall, complete histological response rates ranged between 20% and 67% and symptom response rates ranged between 52% and 89% according to different studies and case series. Conclusions: the real benefit of photodynamic therapy in the setting of vulvar intraepithelial neoplasia lies in its ability to treat multi-focal disease with minimal tissue destruction, preservation of vulvar anatomy and excellent cosmetic outcomes. These properties explain why photodynamic therapy is an attractive option for vulvar intraepithelial neoplasia treatment.

Deleted in Malignant Brain Tumor 1 (DMBT1) Expression Pattern in Normal Cervix and at Different Stages of Squamous Intraepithelial Lesions

Background: Cervical cancer is one of the most frequently occurring malignancies in women worldwide, with high mortality rates. Cervical Squamous Cell Carcinoma (SCC) presents previous states of non-invasive precursor lesions, and early stage Low-Grade Squamous Intraepithelial Lesions (LSIL) regress to normal or Atypical Squamous Cells of Undetermined Significance (ASCUS) in approximately 50% of cases. Deleted in Malignant Brain Tumors 1 (DMBT1) is a tumour suppression glycoprotein, which absence is considered a malignancy marker in many epithelial cancers. Objective: To analyse DMBT1’s presence and localization in SCC and precursor lesions. Method: Immunohistochemistry for DMBT1 was performed in cervix biopsies classified as normal, LSIL, HSIL and SCC. Results: DMBT1 was detected at the supranuclear and sometimes infranuclear regions of the endocervix monolayer epithelial cells in normal and HSIL biopsies. In LSIL samples the detection of DMBT1 in endocervix was variable between patients. Also variable was DMBT1 staining in cells of glandular epithelium. The glycoprotein was not detected in the stratified epithelium of the exocervix, regardless of the lesion grade; nor in dysplastic cells. Conclusion: The absence of DMBT1 from endocervix only in some samples of LSIL is promising as a candidate for possible lesion regression potential marker.

Clinical significance of pancreatic intraepithelial neoplasia in resectable pancreatic cancer on survivals.

PurposeNoninvasive precursor lesions for pancreatic adenocarcinoma include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. PanIN is often found synchronously adjacent to resected pancreatic ductal adenocarcinoma (PDAC) tumors. However, its prognostic significance on outcome after PDAC resection is unknown. The purpose of the current study was to determine if the presence of PanIN has a prognostic or predictive effect on survival after resection for PDAC with curative intent.MethodsWe retrospectively reviewed the clinicopathologic data of patients who underwent pancreatectomy for PDAC from January 2002 to January 2013. Intraductal papillary mucinous lesions and mucinous cystic neoplasms were excluded. All available postoperative imaging and clinical follow-up data were reviewed.ResultsThere were 95 patients who underwent pancreatectomy. Tumors were most commonly located in the pancreas head and as such pancreaticoduodenectomy was the most commonly performed operation. The median tumor size was 3.2 cm. An absence of PanIN lesions was identified in 39 patients (41%). Of the patients with PanIN lesions, high-grade PanIN (grade 3) was the most common type (64.3%) followed by grade 2 (28.6%). There was no significant difference in overall survival or disease-free survival between the non-PanIN and PanIN groups.ConclusionThe presence or absence of PanIN lesions did not affect survival in patients undergoing resection for pancreatic cancer. However, patients with high-grade PanINs tended to have better overall survival. Larger studies with longer follow up are needed to accurately determine its clinical significance.

Understanding the Genetics of Pancreatic Adenocarcinoma

The underlying molecular basis of pancreatic ductal adenocarcinoma (PDAC) is complex, with multiple genetic, epigenetic, and transcriptomic changes. Five to 10% of PDAC cases have a hereditary basis, with multiple risk-conferring genetic mutations running in the family. All PDAC tumors develop from noninvasive precursor lesions that reflect the temporal accumulation of mutations. Recent advances in high-throughput sequencing technologies have facilitated a better understanding of the diverse mutational landscape of PDAC, reaffirming the role of genes previously known to be mutated (K-ras, CDKN2A, TP53, SMAD4, SLIT/ROBO, SWI/SNF) and revealing novel insights into the differential gene expression patterns and structural variations involved. K-ras mutation, an early event in disease pathogenesis, plays a pivotal role in the initiation, progression, and maintenance of PDAC, with the mutation type impacting disease pathophysiology and prognosis. The subsequent loss of tumor suppressors (CDKN2A, TP53, SMAD4) promotes genetic instability and uncontrolled cellular proliferation. Molecular subtypes with potential prognostic and therapeutic relevance have been identified. The challenge now is to translate this wealth of knowledge to the clinic. This review contains 3 figures, 3 tables and 50 references Key words: familial pancreatic cancer, heterogeneity, molecular subtypes, pancreatic ductal adenocarcinoma, whole genome/exome sequencing