Is it resectable? A survey regarding tumor classification and vascular involvement.

INTRODUCTION: The anatomic location of the pancreas can result in involvement of major vasculature, which may act as a contraindication to resection. Several classification systems have been developed. We sought to discover the variations in the HPB community determining PDAC resectability. METHODS: The multiple-choice survey was distributed to all full members of the IHPBA. Questions were asked regarding demographics and clinical scenarios regarding tumor resectability. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. Most practiced in either Asia (n = 57,35.9%), North America (n = 52,32.7%), or Europe (n = 32,20.1%). Classification systems used to determine resectability were: NCCN (n = 42,26.3%), JPS (n = 35,21.9%), International consensus (n = 33,20.6%), AHPBA/SSO (n = 23,14.4%), Alliance (n = 3,1.9%), and other/no-classification (n = 23,14.5%). There was significant variation in the frequency of the most common answer within the scenarios (84.7%-33.5%). Participant concordance with their stated classification system found a median rate of 62.5%. Participant decision of tumor resectability was not dependent on their adopted classification system. CONCLUSION: When classifying PDAC resectability, there is significant variation between surgeons as to how they would classify a specific tumour, independent of the classification system they use. In addition, surgeons do not show high concordance with the definitions within that classification system.

Evidence for molecular subtyping in pancreatic ductal adenocarcinoma: a systematic review.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) patients exhibit varied responses to multimodal therapy. RNA gene sequencing has unravelled distinct tumour biology subtypes, forming the focus of this review exploring its impact on survival outcomes. METHODS: A systematic search across PubMed, Medline, Embase, and CINAHL databases targeted studies assessing long-term overall and disease-free survival in PDAC patients with molecular subtyping. RESULTS: Fifteen studies including 2731 patients were identified. Molecular subtyping was performed by RNA sequencing and Immunohistochemistry in 14 studies and by Mass Spectrometry in 1 study. Two main tumour subtypes were identified (classical and basal-like or squamous) with basal like associated with poorer outcomes. Further subtypes were identified in individual studies. Superior survival was seen with classical subtype in all other analyses that compared the classical and basal subtypes. High risk stromal subtypes were identified on further analysis of the stroma and were associated with a worse survival independent of the tumour subtype. CONCLUSION: Molecular subtyping of PDAC specimens can identify patients with high-risk tumour biology and poor survival outcomes. Routine subtyping is limited by the cost of RNA sequencing and the volume of raw data generated which has made its translation into routine clinical practice difficult.

Multi-omics analysis of intra-tumoural and inter-tumoural heterogeneity in pancreatic ductal adenocarcinoma.

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is associated with the tumour heterogeneity. To explore intra- and inter-tumoural heterogeneity in PDAC, we analysed the multi-omics profiles of 61 PDAC lesion samples, along with the matched pancreatic normal tissue samples, from 19 PDAC patients. Haematoxylin and Eosin (H&E) staining revealed that diversely differentiated lesions coexisted both within and across individual tumours. Whole exome sequencing (WES) of samples from multi-region revealed diverse types of mutations in diverse genes between cancer cells within a tumour and between tumours from different individuals. The copy number variation (CNV) analysis also showed that PDAC exhibited intra- and inter-tumoural heterogeneity in CNV and that high average CNV burden was associated poor prognosis of the patients. Phylogenetic tree analysis and clonality/timing analysis of mutations displayed diverse evolutionary pathways and spatiotemporal characteristics of genomic alterations between different lesions from the same or different tumours. Hierarchical clustering analysis illustrated higher inter-tumoural heterogeneity than intra-tumoural heterogeneity of PDAC at the transcriptional levels as lesions from the same patients are grouped into a single cluster. Immune marker genes are differentially expressed in different regions and tumour samples as shown by tumour microenvironment (TME) analysis. TME appeared to be more heterogeneous than tumour cells in the same patient. Lesion-specific differentially methylated regions (DMRs) were identified by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Furthermore, the integration analysis of multi-omics data showed that the mRNA levels of some genes, such as PLCB4, were significantly correlated with the gene copy numbers. The mRNA expressions of potential PDAC biomarkers ZNF521 and KDM6A were correlated with copy number alteration and methylation, respectively. Taken together, our results provide a comprehensive view of molecular heterogeneity and evolutionary trajectories of PDAC and may guide personalised treatment strategies in PDAC therapy.

Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights.

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the "intestinal pathway", to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.

Gene expression profiling of morphologic subtypes of pancreatic ductal adenocarcinoma using surgical and EUS-FNB specimens.

BACKGROUND/OBJECTIVES: Various classifications of pancreatic ductal adenocarcinoma (PDAC) based on RNA profiling resulted in two main subtypes. Kalimuthu and coworkers proposed a morphology-based classification that concurred with these subtypes. Immune therapy approaches in PDAC were so far disappointing. Morphologic PDAC subtypes may differ regarding key immune-oncology pathways. We aimed to examine the reproducibility and prognostic value of Kalimuthu's morphologic classification, and to evaluate differences between subtypes regarding gene expression related to tumor biology and immune-oncology. METHODS: PDAC specimens from 196 patients were included, 108 consecutive chemotherapy-naïve surgical specimens and 88 endoscopic ultrasound-guided fine needle biopsies (EUS-FNBs). The specimens were evaluated as per Kalimuthu by two pancreatic pathologists, resulting in Group A and Group B tumors. Digital mRNA expression profiling was performed, on the surgical specimens using the NanoString IO360 panel of 770 key tumor biology related and 30 custom-genes, and on the EUS-FNBs using a targeted panel of 123 genes. RESULTS: Morphologic subtyping reached substantial interobserver agreement between the two pathologists. In the surgical and EUS-FNB cohorts, 44.4% and 38.6% were Group A tumors, which were associated with improved survival. Group A showed higher expression of immune-related genes and cytokine/chemokine/interleukin signaling and Group B of genes related to cancer cell proliferation and cell cycle regulation. Hierarchical clustering based on significant differences in gene expression levels between Groups A and B revealed clusters with prognostic value. CONCLUSIONS: Morphologic subtyping according to Kalimuthu is reproducible and holds prognostic value, in surgical as well as EUS-FNB specimens. As upregulation of immune-related genes was found in Group A, future studies should evaluate the potential of immune therapy approaches with special emphasis on this subtype of PDAC.

Relationship between the tumor location and clinicopathological features in left-sided pancreatic ductal adenocarcinoma.

PURPOSE: Although the same distal pancreatectomy (DP) is performed regardless of the location of left-sided pancreatic ductal adenocarcinoma (PDAC), the clinicopathological features may differ depending on the tumor location. The present study investigated the relationship between the tumor location and clinicopathological features in patients with left-sided PDAC. METHODS: The records of 59 patients who underwent DP for PDAC were enrolled. The relationship between the tumor location and clinicopathological features was investigated. The tumor location was classified into three groups according to the 7th AJCC/UICC TNM classification: body (Pb), body and tail (Pbt), and tail (Pt). RESULTS: Tumors were located at the Pb in 26 patients, Pbt in 15, and Pt in 18. There was no metastasis to the lymph nodes around the common hepatic artery in Pt. The rate of peritoneal dissemination in the Pt was higher than that in the Pb (P = 0.034) or Pbt (P = 0.002). There were no significant differences in the overall survival among the three groups. CONCLUSION: There was no metastasis to the lymph nodes around the common hepatic artery, and peritoneal dissemination was the most common site of recurrence in Pt tumors.

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology.

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a relative paucity of cancer cells that are surrounded by an abundance of nontumor cells and extracellular matrix, known as stroma. The interaction between stroma and cancer cells contributes to poor outcome, but how proteins from these individual compartments drive aggressive tumor behavior is not known. Here, we report the proteomic analysis of laser-capture microdissected (LCM) PDAC samples. We isolated stroma, tumor, and bulk samples from a cohort with long- and short-term survivors. Compartment-specific proteins were measured by mass spectrometry, yielding what we believe to be the largest PDAC proteome landscape to date. These analyses revealed that, in bulk analysis, tumor-derived proteins were typically masked and that LCM was required to reveal biology and prognostic markers. We validated tumor CALB2 and stromal COL11A1 expression as compartment-specific prognostic markers. We identified and functionally addressed the contributions of the tumor cell receptor EPHA2 to tumor cell viability and motility, underscoring the value of compartment-specific protein analysis in PDAC.

Recent advances in understanding cancer-associated fibroblasts in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a poor survival rate. It is resistant to therapy in part due to its unique tumor microenvironment, characterized by a desmoplastic reaction resulting in a dense stroma that constitutes a large fraction of the tumor volume. A major contributor to the desmoplastic reaction are cancer-associated fibroblasts (CAFs). CAFs actively interact with cancer cells and promote tumor progression by different mechanisms, including extracellular matrix deposition, remodeling, and secretion of tumor promoting factors, making CAFs an attractive target for PDA. However, emerging evidences indicate significant tumor-suppressive functions of CAFs, highlighting the complexity of CAF biology. CAFs were once considered as a uniform cell type within the cancer stroma. Recently, the existence of CAF heterogeneity in PDA has become appreciated. Due to advances in single cell technology, distinct subtypes of CAFs have been identified in PDA. Here we review recent updates in CAF biology in PDA, which may help develop effective CAF-targeted therapies in the future.

Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.

The Eighth Edition of the American Joint Committee on Cancer Distant Metastases Stage Classification for Metastatic Pancreatic Neuroendocrine Tumors Might Be Feasible for Metastatic Pancreatic Ductal Adenocarcinomas.

BACKGROUND: Significant modifications have been made to the 8th edition of the American Joint Committee on Cancer (AJCC) distant metastases (M) stage classification for metastatic pancreatic neuroendocrine tumors (PanNETs). We aimed to validate this revised classification among metastatic PanNET patients using the Surveillance, Epidemiology, and End Results database. We further sought to evaluate the feasibility of applying this classification to metastatic pancreatic neuroendocrine carcinoma (PanNEC) and pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: Stage IV pancreatic neuroendocrine neoplasm (PanNEN, including G1/G2 PanNET and G3 PanNEC classified according to the World Health Organization [WHO] 2010 grading scheme) and PDAC patients with metastatic disease diagnosed between 2010 and 2015 were identified and restaged according to the revised M stage classification for PanNET. Overall survival (OS) was compared using Kaplan-Meier analysis and log-rank test. Uni- and multivariate Cox regression models were utilized to identify prognostic factors. RESULTS: A total of 1,371 stage IV PanNEN and 634 PDAC patients were included. Among PanNEN patients, liver (75.0%) was the most common metastatic site, followed by distant lymph nodes (8.5%), lung (8.4%), bone (7.3%), and brain (1.0%). The 5-year OS for PanNET patients with M1a, M1b, and M1c stage was 44.15, 53.32, and 19.70%, respectively. However, survival comparison showed no significant difference between M1a and M1b stages among PanNET patients. Similar findings were noted after applying this classification to PanNEC patients. Multivariate analysis showed that the age at diagnosis and the number of distant metastatic sites were independent prognostic factors for metastatic PanNEN patients. Interestingly, excellent survival discrimination by M stage among stage IV PDAC patients was noted (M1a vs. M1b vs. M1c, 5-year OS: 5.42, 2.46, and 0%, respectively). CONCLUSION: Our study is the first large sample-based validation of the AJCC 8th M stage classification for PanNET. The revised classification did not effectively stratify metastatic PanNEN patients. However, further study is warranted to validate this classification for PanNET patients according to the WHO 2017 classification. Interestingly, the revised M stage classification might be feasible for PDAC patients with metastatic disease.

Pancreatic Intraepithelial Neoplasia (PanIN) as a Morphologic Marker of Pancreatobiliary Type of Ampullary Carcinoma.

The classification of ampullary adenocarcinoma into intestinal and pancreatobiliary sub-types has been found to be important in predicting prognosis and determining therapeutic strategy. Due to considerable inter-observer variability in sub-typing based solely on morphology, higher frequency of poorly differentiated cancers and low incidence of the disease, the histomorphologic classification of ampullary adenocarcinoma remains one of the grey zones in surgical pathology. Pan-IN is a well recognized precursor to pancreatic adenocarcinoma. Three studies have shown concurrent Pan-IN in patients with ampullary carcinoma, but their association with the two sub-types has not yet been reported. Fourteen cases of surgical resection for ampullary adenocarcinoma were retrieved from the archives. The cases were classified into two groups based on the presence or absence of concomitant Pan-IN. All the cases were stained for CK7, CK 20, Villin and CDX 2 and were classified as intestinal or pancreatobiliary types based on the staining pattern. All the 10 cases with Pan-IN stained negative for CDX2 and were classified as pancreatobiliary type (p = 0.01). Of the cases without Pan-IN, 3 were classified as intestinal sub-type based on morphology and CDX2 positivity and 1 was classified as pancreatobiliary type. Concomitant Pan-IN was present in 91% of pancreatobiliary type of ampullary adenocarcinoma. The grade of Pan-IN did not influence the grade or stage of the adenocarcinoma (p > 0.05). The co-occurrence of Pan-IN in a high percentage of the pancreatobiliary sub-type and its complete absence in the intestinal sub-type may serve as a strong differentiator between the two sub-types.

The diversity between curatively resected pancreatic head and body-tail cancers based on the 8th edition of AJCC staging system: a multicenter cohort study.

BACKGROUND: To our knowledge, there are no studies to systematically compare the detailed clinical significance between curatively resected pancreatic head (ph) and body-tail (pbt) ductal adenocarcinoma based on the new 8th edition of AJCC staging system (8th AJCC stage) that was just applied in clinical practice in 2018. METHODS: Three hundred fifty-one patients with curatively resected pancreatic adenocarcinoma (PC) from three center hospitals were entered into this multicenter cohort study. RESULTS: Increasing tumor size (P < 0.001), T stage (T1 + T2 vs T3 + T4, P = 0.003), frequent postoperative liver metastasis (PLM) (P = 0.002) and 8th AJCC stage (IA to VI, P < 0.001; I + II vs III + IV, P = 0.002) were closely associated with the progression of pbt cancers compared with that in ph cancer patients. Moreover, tumor size≥3 cm (P = 0.012), 8th AJCC stage (III + IV) (P = 0.025) and PLM (P = 0.010) were identified as independent risk factors in pbt cancers in logistic analysis. Patients with pbt cancers had a significantly worse overall survival compared with ph cancer patients (P = 0.003). Moreover, pbt was an independent unfavorable factor in multivariate analysis (P = 0.011). In addition to lymph nodes metastasis, 8th AJCC stage, vascular invasion and PLM, increasing tumor size and advanced T stage were also closely associated with the poor prognosis in 131 cases of pbt cancer patients compared with Ph cancer patients. CONCLUSION: Pbt, as an independent unfavorable factor for the prognosis of PC patients, are much more aggressive than that in ph cancers according to 8th AJCC staging system. 8th AJCC staging system are more comprehensive and sensitive to reflect the malignant biology of pbt cancers.

A machine learning model for the prediction of survival and tumor subtype in pancreatic ductal adenocarcinoma from preoperative diffusion-weighted imaging.

BACKGROUND: To develop a supervised machine learning (ML) algorithm predicting above- versus below-median overall survival (OS) from diffusion-weighted imaging-derived radiomic features in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: One hundred two patients with histopathologically proven PDAC were retrospectively assessed as training cohort, and 30 prospectively accrued and retrospectively enrolled patients served as independent validation cohort (IVC). Tumors were segmented on preoperative apparent diffusion coefficient (ADC) maps, and radiomic features were extracted. A random forest ML algorithm was fit to the training cohort and tested in the IVC. Histopathological subtype of tumor samples was assessed by immunohistochemistry in 21 IVC patients. Individual radiomic feature importance was evaluated by assessment of tree node Gini impurity decrease and recursive feature elimination. Fisher's exact test, 95% confidence intervals (CI), and receiver operating characteristic area under the curve (ROC-AUC) were used. RESULTS: The ML algorithm achieved 87% sensitivity (95% IC 67.3-92.7), 80% specificity (95% CI 74.0-86.7), and ROC-AUC 90% for the prediction of above- versus below-median OS in the IVC. Heterogeneity-related features were highly ranked by the model. Of the 21 patients with determined histopathological subtype, 8/9 patients predicted to experience below-median OS exhibited the quasi-mesenchymal subtype, whilst 11/12 patients predicted to experience above-median OS exhibited a non-quasi-mesenchymal subtype (p < 0.001). CONCLUSION: ML application to ADC radiomics allowed OS prediction with a high diagnostic accuracy in an IVC. The high overlap of clinically relevant histopathological subtypes with model predictions underlines the potential of quantitative imaging in PDAC pre-operative subtyping and prognosis.

AJCC 7th edition staging classification is more applicable than AJCC 8th edition staging classification for invasive IPMN.

BACKGROUND: Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. METHODS: Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973-2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. RESULTS: In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P < 0.001) was higher than that of stage IB disease (HR = 1.48, P = 0.087) by the 7th edition classification, whereas the HR of stage IIA disease (HR = 1.26, P = 0.232) was even lower than that of stage IB disease (HR = 1.48, P = 0.040) by the 8th edition classification. In addition, for the 8th edition staging system, tumor size was not a predictor of survival in patients with resectable tumor > 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). CONCLUSIONS: The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

Imaging of glucose metabolism by 13C-MRI distinguishes pancreatic cancer subtypes in mice.

Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from 13C-glucose imaging localized lactate production and overall glucose metabolism to different regions of some tumors. Such tumor heterogeneity would not be not detectable in FDG-PET.

Differentiation of atypical non-functional pancreatic neuroendocrine tumor and pancreatic ductal adenocarcinoma using CT based radiomics.

PURPOSE: To develop and validate an effective model to differentiate NF-pNET from PDAC. MATERIALS AND METHODS: Between July 2014 and December 2017, 147 patients (80 patients with PDAC and 67 patients with atypical NF-pNET) with pathology results and enhanced CT were consecutively enrolled and chronologically divided into primary and validation cohorts. Three models were built to differentiate atypical NF-pNET from PDAC, including a model based on radiomic signature alone, one based on clinicoradiological features alone and one that integrated the two. The diagnostic performance of the three models was estimated and compared with the area under the receiver operating characteristic curve (AUC) in the validation cohort. A nomogram was used to represent the model with the best performance, and the associated calibration was also assessed. RESULTS: In the validation cohort, the AUC for differential diagnosis was 0.884 with the integrated model, which was significantly improved over that of the model based on clinicoradiological features (AUC = 0.775, p value = 0.004) and was comparable to that of the model based on the radiomic signature (AUC = 0.873, p value = 0.512). The nomogram representing the integrated model achieved good discrimination performances in both the primary and validation cohorts, with C-indices of 0.960 and 0.884, respectively. CONCLUSION: The integrated model outperformed the model based on clinicoradiological features alone and was comparable to the model based on the radiomic signature alone with respect to the differential diagnosis of atypical NF-pNET and PDAC. The nomogram achieved an optimal preoperative, noninvasive differential diagnosis between atypical pNET and PDAC, which can better inform therapeutic choice in clinical practice.

Different shades of pancreatic ductal adenocarcinoma, different paths towards precision therapeutic applications.

BACKGROUND: Different histological and molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different molecular composition and survival statistics, have recently been recognised. MATERIALS AND METHODS: This review describes the currently available studies regarding molecular and histological subtypes in PDAC. Studies from major cohorts such as International Cancer Genome Consortium as well as smaller cohorts are reviewed. We discuss where the described subtypes overlap, where the discrepancies are and which paths forward could be taken regarding diagnosis, ontogeny and therapy. RESULTS: Four molecular subtypes with strong overlap among the different studies can be found, next to a list of mixed findings. Two of the four subtypes (epithelial classical and mesenchymal basal-like) were represented in every study and were often discriminated in other solid tumours as well. These two subtypes differ substantially in prognosis. One biomarker has been discovered, only discriminating these two subtypes, and insights into subtype-specific therapeutic vulnerabilities are scarce. CONCLUSION: Subtypes can be reproducibly detected in cohorts of PDAC patients and two of them directly relate with prognosis. A consensus on the subtypes is warranted. Further discovery and validation studies are needed to identify strong biomarkers, to comprehend subtype ontogeny and to define strategies for precision medicine.

Pancreatobiliary-type intraductal papillary mucinous neoplasm of the pancreas may have 2 subtypes with distinct clinicopathologic and genetic features.

We recently experienced cases of pancreatobiliary-type intraductal papillary mucinous neoplasms (PB-IPMNs) with imaging features resembling pancreatic ductal adenocarcinomas (PDACs), and histologic appearance of purely pancreatobiliary morphology and highly distorted papillary growth, which led to the present study aiming to systematically investigate PB-IPMNs in comparison with PDACs. Surgical cases of PB-IPMNs (n = 31) and PDACs (n = 24) were examined. PB-IPMNs were classified into monotypic tumors (n = 12; 39%) consisting of entirely high-grade pancreatobiliary-type neoplastic cells and polytypic cases (n = 19; 61%) associated with components of low-grade dysplasia and/or other histologic types (eg, gastric, intestinal, or oncocytic types). Clinically, monotypic PB-IPMNs less commonly had dilatation of the ampullary orifice (0% versus 74%) and mucin hypersecretion (17% versus 89%) than did polytypic cases. In most cases of monotypic PB-IPMNs, cystic dilatation of the lesional ducts was less obvious on imaging; therefore, 33% were radiologically diagnosed as PDACs. Histologically, intraductal tumors in monotypic cases showed a highly complex papillary architecture with tubular/cribriform glands and irregular branching, and all these cases were associated with invasive malignancy. GNAS mutations were detected in polytypic PB-IPMNs (6/19; 32%), but there were no GNAS mutations in monotypic cases. The recurrence-free survival of patients with monotypic PB-IPMN or PDAC was similar and significantly worse than that of patients with polytypic PB-IPMN. In conclusion, some cases of monotypic PB-IPMNs lacked the classic characteristics of IPMNs and shared features with PDACs, raising the possibility that these cases may be better classified as a papillary variant of PDACs rather than IPMNs.

A Single-Institution Validation Study of Lymph Node Staging By the AJCC 8th Edition for Patients with Pancreatic Head Cancer: A Proposal to Subdivide the N2 Category.

BACKGROUND: According to the revised staging of the American Joint Committee on Cancer, 8th edition (AJCC8), the N category in pancreatic ductal adenocarcinoma is classified as N0 (0), N1 (1-3), and N2 (≥ 4) based on the number of metastatic lymph nodes (LNs). This study aimed to validate this classification and analyze cutoff values of metastatic LN numbers. METHODS: Patients with pancreatic head ductal adenocarcinoma who underwent pancreaticoduodenectomy at our institution between 2005 and 2016 without preoperative therapy were retrospectively analyzed. The patients were staged by AJCC8, and prognostic analyses were performed. The best cutoff value for the metastatic LN number was determined by the minimum P value approach. RESULTS: In 228 of 309 patients, LN metastases were found (median number of examined LNs, 41). The median survival time (MST) was 56 months in the N0 group, 34 months in the N1 group, and 20 months in the N2 group (N0 vs N1: P = 0.023; N1 vs N2: P < 0.001). The best cutoff number of metastatic LNs was 4 for patients with LN metastases and 7 for patients with N2 disease. The MST for patients with four to six positive nodes (N2a) was significantly longer than for those with seven or more positive nodes (N2b) (24.0 vs 19.1 months: P = 0.012). For N2b patients, conventional adjuvant chemotherapy did not show survival benefits (P = 0.133), and overall survival did not differ significantly from that for patients with para-aortic LN metastasis (P = 0.562). CONCLUSION: The N staging of AJCC8 was valid. Clinicians should regard N2b as similar to distant LN metastasis, and more intensive adjuvant therapy may be indicated for this group.