Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct expression patterns and potential markers of progression.

In order to advance our understanding of precancers in the pancreas, 69 pancreatic intraductal papillary neoplasms (IPNs), including 64 intraductal papillary mucinous neoplasms (IPMNs) and 5 intraductal oncocytic papillary neoplasms (IOPNs), 32 pancreatic cyst fluid samples, 104 invasive pancreatic ductal adenocarcinomas (PDACs), 43 normal adjacent tissues (NATs), and 76 macro-dissected normal pancreatic ducts (NDs) were analyzed by mass spectrometry. A total of 10,246 proteins and 22,284 glycopeptides were identified in all tissue samples, and 756 proteins with more than 1.5-fold increase in abundance in IPMNs relative to NDs were identified, 45% of which were also identified in cyst fluids. The over-expression of selected proteins was validated by immunolabeling. Proteins and glycoproteins overexpressed in IPMNs included those involved in glycan biosynthesis and the immune system. In addition, multiomics clustering identified two subtypes of IPMNs. This study provides a foundation for understanding tumor progression and targets for earlier detection and therapies. Significance: This multilevel characterization of intraductal papillary neoplasms of the pancreas provides a foundation for understanding the changes in protein and glycoprotein expression during the progression from normal duct to intraductal papillary neoplasm, and to invasive pancreatic carcinoma, providing a foundation for informed approaches to earlier detection and treatment.

Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

Multiple intraductal papillary neoplasms of bile duct diagnosed based on endoscopic ultrasonography and peroral cholangioscopy findings.

A man in his 30s was referred to our department for evaluation of bile duct stricture and removal of an intrahepatic bile duct stone. Five years before his presentation, he underwent left hepatectomy for a giant hepatic hemangioma. There were no abnormalities in blood biochemical tests. Magnetic resonance cholangiopancreatography showed one 5 mm oval defect in region B6 and two 8 mm semicircular defects in the hilar bile duct. Endoscopic ultrasound revealed a 3.5 mm hypoechoic focal raised lesion in the hilar bile duct. Oral cholangioscopy revealed his two lesions in the hilar bile duct as white papillary elevations with mucus production. The pathological diagnosis of intraductal papillary neoplasm was determined (low-grade dysplasia, type 1, gastric type). After 1 and a half years, no expansion of the bile duct lesion was observed. Initially, it was thought to be a benign stenosis after liver resection, but based on the results of endoscopic ultrasound, we suspected a tumorous lesion, and we were able to make an accurate diagnosis, including histological type, using transoral cholangioscopy.

Comprehensive Characterization of Intraductal Oncocytic Papillary Neoplasm of the Pancreas: A Systematic and Critical Review.

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine its most essential features with the systematic review tool. PubMed, Scopus, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathologic, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) The male-to-female ratio was 1.5:1. Pancreatic head was the most common site (131/237; 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1 out of 5 cases (49/237; 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1 or pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and molecular features were as follows. The most commonly expressed mucins were MUC5AC (110/112; 98.2%) and MUC6 (78/84; 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (P < .01). Moreover, fusions involving PRKACA or PRKACB gene were detected in all of the 68 cases examined, with PRKACB::ATP1B1 being the most common (27/68 cases; 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (P < .01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathologic and molecular features. Considering the clinical or prognostic implications, its recognition is essential for pathologists and, ultimately, patients' management.

Prognostic performance of microscopic size measurements in small invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas.

AIMS: Small invasive carcinomas arising in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can present as multiple, small foci. In such cases, there is no clear optimal measurement method for determining the invasive size for tumour staging and prognostication. METHODS: In all, 117 small invasive IPMNs (size of largest invasive component ≤2 cm) from seven institutions (2000-2016) were reviewed, and all individual foci of invasive carcinoma were measured. T stages (AJCC 8th edition) based on the largest single focus size (LS), average size of all foci (AS), and total sum of all foci (TS) were examined in association with clinicopathologic parameters and patient outcomes. RESULTS: The cohort comprised IPMNs with invasive tubular-type (n = 82, 70%) and colloid-type (n = 35, 30%) carcinomas. The mean LS, AS, and TS were 0.86, 0.71, and 1.32 cm, respectively. Based on the LS, AS, and TS, respectively, 48, 65, and 39 cases were classified as pT1a; 22, 18, and 11 cases as pT1b; and 47, 34, and 50 cases as pT1c. Higher pT stages based on all measurements were significantly associated with small vessel, large vessel, and perineural invasion (P < 0.05). LS-, AS-, and TS-based pT stages were not significantly associated with recurrence-free survival (RFS) or overall survival (OS) by univariate or multivariate analyses. However, among tubular-type carcinomas, higher LS-, AS-, and TS-based pT stages trended with lower RFS (based on 1-, 3-, and 5-year survival rates). All microscopic measurement methods were most predictive of RFS and OS using a 1.5-cm cutoff, with LS significantly associated with both RFS and OS by univariate and multivariate analysis. CONCLUSIONS: For invasive tubular-type carcinomas arising in IPMN, microscopic size-based AJCC pT stages were not significant predictors of patient outcomes. However, for LS, a size threshold of 1.5 cm was optimal for stratifying both RFS and OS. The AJCC 8th ed. may not be applicable for stratifying small invasive IPMNs with colloid-type histology that generally portend a more favourable prognosis.

Clonal analysis of metachronous double biliary tract cancers.

The molecular mechanisms underpinning the development of metachronous tumors in the remnant bile duct following surgical resection of primary biliary tract carcinomas (BTCs) are unknown. This study aimed to elucidate these mechanisms by evaluating the clinicopathologic features of BTCs, the alterations to 31 BTC-related genes on targeted sequencing, and the aberrant expression of p53, p16, SMAD4, ARID1A and ß-catenin on immunohistochemistry. Twelve consecutive patients who underwent resection of metachronous BTCs following primary BTC resection with negative bile duct margins were enrolled. Among the 12 metachronous tumors, six exhibited anterograde growth in the lower portion and six exhibited retrograde growth in the upper portion of the biliary tree. Surgical resection of metachronous BTCs resulted in recurrence-free survival in seven, local recurrence in five, and death in two patients. Nine achieved 5-year overall survival after primary surgery. Molecular analyses revealed that recurrently altered genes were: TP53, SMAD4, CDKN2A, ELF3, ARID1A, GNAS, NF1, STK11, RNF43, KMT2D and ERBB3. Each of these was altered in at least three cases. A comparison of the molecular features between 12 paired primary and metachronous BTCs indicated that 10 (83%) metachronous tumors developed in clonal association with corresponding primary tumors either successionally or phylogenically. The remaining two (17%) developed distinctly. The successional tumors consisted of direct or evolved primary tumor clones that spread along the bile duct. The phylogenic tumors consisted of genetically unstable clones and conferred a poor prognosis. Metachronous tumors distinct from their primaries harbored fewer mutations than successional and phylogenic tumors. In conclusion, over 80% of metachronous BTCs that develop following primary BTC resection are probably molecularly associated with their primaries in either a successional or a phylogenetic manner. Comparison between the molecular features of a metachronous tumor and those of a preceding tumor may provide effective therapeutic clues for the treatment of metachronous BTC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth.

Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.

International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas.

This study group aimed to revise the 2017 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and mainly focused on five topics; the revision of high-risk stigmata (HRS) and worrisome features (WF), surveillance of non-resected IPMN, surveillance after resection of IPMN, revision of pathological aspects, and investigation of molecular markers in cyst fluid. A new development from the prior guidelines is that systematic reviews were performed for each one of these topics, and published separately to provide evidence-based recommendations. One of the highlights of these new "evidence-based guidelines" is to propose a new management algorithm, and one major revision is to include into the assessment of HRS and WF the imaging findings from endoscopic ultrasound (EUS) and the results of cytological analysis from EUS-guided fine needle aspiration technique, when this is performed. Another key element of the current guidelines is to clarify whether lifetime surveillance for small IPMNs is required, and recommends two options, "stop surveillance" or "continue surveillance for possible development of concomitant pancreatic ductal adenocarcinoma", for small unchanged BD-IPMN after 5 years surveillance. Several other points are also discussed, including identifying high-risk features for recurrence in patients who underwent resection of non-invasive IPMN with negative surgical margin, summaries of the recent observations in the pathology of IPMN. In addition, the emerging role of cyst fluid markers that can aid in distinguishing IPMN from other pancreatic cysts and identify those IPMNs that harbor high-grade dysplasia or invasive carcinoma is discussed.

Gene Rearrangement and Expression of PRKACA and PRKACB Govern Morphobiology of Pancreatobiliary Oncocytic Neoplasms.

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 ß (PRKACB), phosphorylated cAMP response element-binding protein, and aberrations of p16, p53, SMAD4, STK11, and ß-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.

Machine Learning of Histopathological Images Predicts Recurrences of Resected Pancreatic Ductal Adenocarcinoma With Adjuvant Treatment.

OBJECTIVES: Pancreatic ductal adenocarcinoma is an intractable disease with frequent recurrence after resection and adjuvant therapy. The present study aimed to clarify whether artificial intelligence-assisted analysis of histopathological images can predict recurrence in patients with pancreatic ductal adenocarcinoma who underwent resection and adjuvant chemotherapy with tegafur/5-chloro-2,4-dihydroxypyridine/potassium oxonate. MATERIALS AND METHODS: Eighty-nine patients were enrolled in the study. Machine-learning algorithms were applied to 10-billion-scale pixel data of whole-slide histopathological images to generate key features using multiple deep autoencoders. Areas under the curve were calculated from receiver operating characteristic curves using a support vector machine with key features alone and by combining with clinical data (age and carbohydrate antigen 19-9 and carcinoembryonic antigen levels) for predicting recurrence. Supervised learning with pathological annotations was conducted to determine the significant features for predicting recurrence. RESULTS: Areas under the curves obtained were 0.73 (95% confidence interval, 0.59-0.87) by the histopathological data analysis and 0.84 (95% confidence interval, 0.73-0.94) by the combinatorial analysis of histopathological data and clinical data. Supervised learning model demonstrated that poor tumor differentiation was significantly associated with recurrence. CONCLUSIONS: Results indicate that machine learning with the integration of artificial intelligence-driven evaluation of histopathological images and conventional clinical data provides relevant prognostic information for patients with pancreatic ductal adenocarcinoma.

Interobserver agreement of pathologic classification and grading of tumoral intraductal pre-invasive neoplasms of the bile duct.

Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was "substantial" (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was "slight" (κ-value, 0.201), while that of modified types 1 and 2 subclassification was "moderate" (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN.

Ablation of Dual-Specificity Phosphatase 6 Protects against Nonalcoholic Fatty Liver Disease via Cytochrome P450 4A and Mitogen-Activated Protein Kinase.

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.

Reduced expression of phosphorylated ataxia-telangiectasia mutated gene is related to poor prognosis and gemcitabine chemoresistance in pancreatic cancer.

BACKGROUND: Loss of expression of the gene ataxia-telangiectasia mutated (ATM), occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. In this study, we investigated the detailed molecular mechanism through which ATM expression affects the prognosis of patients with pancreatic cancer. METHODS: The levels of expression of ATM and phosphorylated ATM in patients with pancreatic cancer who had undergone surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ATM-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the invlovement of ATM in pancreatic cancer. RESULTS: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ATM and phosphorylated ATM, respectively. Low expression of phosphorylated ATM substantially reduced overall and disease-free survival in patients with pancreatic cancer. In the pancreatic cancer cell lines with ATM low expression, resistance to gemcitabine was demonstrated. The RNA sequence demonstrated that ATM knockdown induced the expression of MET and NTN1. In ATM knockdown cells, it was also revealed that the protein expression levels of HIF-1α and antiapoptotic BCL-2/BAD were upregulated. CONCLUSIONS: These findings demonstrate that loss of ATM expression increases tumor development, suppresses apoptosis, and reduces gemcitabine sensitivity. Additionally, loss of phosphorylated ATM is associated with a poor prognosis in patients with pancreatic cancer. Thus, phosphorylated ATM could be a possible target for pancreatic cancer treatment as well as a molecular marker to track patient prognosis.

Small Intestinal Adenocarcinoma Arising at the Anastomotic Site after Kasai Operation for Biliary Atresia: A Case Report and Literature Review.

Biliary atresia is an obliterative cholangiopathy of unknown etiology. Hepatic portoenterostomy, in which obliterated extrahepatic bile ducts are resected and bile flow is restored, known as Kasai operation, is performed within 3 months after birth. While this operation enhances long-term survival of patients, the occurrence of primary malignant hepatic tumors has been increasing. We report a case of small intestinal adenocarcinoma arising at the anastomotic site after Kasai operation. A 49-year-old man, who underwent Kasai operation for biliary atresia when he was 2 months old, experienced rapidly progressive jaundice and liver dysfunction. Deceased-donor liver transplantation was performed for liver failure. Macroscopically, there was a white-yellow tumor located at the anastomotic site of hepatic portoenterostomy of the resected liver. Pathological examination revealed a well-differentiated adenocarcinoma with some Paneth cells in the neoplastic lesion. Immunohistochemically, the tumor cells were negative for cytokeratin 7 (CK7) but positive for cytokeratin 20 (CK20) and a homeobox domain-containing transcription factor (CDX2). Mucin expression in tumor cells was negative for mucin 1 (MUC1) and mucin 6 (MUC6) and positive for mucin 2 (MUC2) and mucin 5AC (MUC5AC). The pathological diagnosis was small intestinal adenocarcinoma originating from the jejunum. The patient was discharged 48 days after the operation. The patient had not experienced recurrence at 10 months after the operation. This is the first report of small intestinal adenocarcinoma arising at the anastomotic site after Kasai operation for biliary atresia. Special care should be taken for the patients after Kasai operation with acute progressive jaundice and liver dysfunction because there is a possibility of malignancy in their native liver.

Systematic review of challenging issues in pathology of intraductal papillary mucinous neoplasms.

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.

Co-occurring IPMN and pancreatic cancer: the same or different? An overview from histology to molecular pathology.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is one of the most well-established precursors of pancreatic cancer. Its progression to acquire invasiveness is a complex process, based on the accumulation of morphological and genetic alterations. Recent advances in DNA sequencing also showed that co-occurring IPMNs and pancreatic cancers could be totally independent, further complicating our understanding of this complex scenario. The distinction between IPMN and related pancreatic cancer vs IPMN and co-occurring-but not related-pancreatic cancer is a challenging task in routine diagnostic activity, but may have important implications for precision oncology. Of note, recent multiregional sequencing-based studies focused not only on IPMN multi-step tumourigenesis, but also on the divergent intratumoural heterogeneity of this neoplasm. Globally considered, there are three different situations in which co-occurring IPMNs and invasive carcinomas can be found in the same pancreata, indicated with different terminologies: (1) IPMN-associated carcinoma: this definition indicates a carcinoma arising from an IPMN and can be also defined as IPMN-derived carcinoma, sequential or likely related; (2) independent IPMN and invasive carcinoma: the two lesions are not related, and this situation is defined as concomitant, de novo or likely independent; (3) branch-off pathway, where an invasive carcinoma and an adjacent IPMN develop divergently in a forked fashion from a common ancestral clone. In this review, we aim at clarifying the most important nomenclature/definitions of these different situations, also providing an overview of the molecular state-of-the-art and of the clinical implications of this complex landscape.

Salivary gland cancer organoids are valid for preclinical genotype-oriented medical precision trials.

Salivary gland cancers (SGCs) are heterogeneous tumors, and precision oncology represents a promising therapeutic approach; however, its impact on SGCs remains obscure. This study aimed to establish a translational model for testing molecular-targeted therapies by combining patient-derived organoids and genomic analyses of SGCs. We enrolled 29 patients, including 24 with SGCs and 5 with benign tumors. Resected tumors were subjected to organoid and monolayer cultures, as well as whole-exome sequencing. Organoid and monolayer cultures of SGCs were successfully established in 70.8% and 62.5% of cases, respectively. Organoids retained most histopathological and genetic profiles of their original tumors. In contrast, 40% of the monolayer-cultured cells did not harbor somatic mutations of their original tumors. The efficacy of molecular-targeted drugs tested on organoids depended on their oncogenic features. Organoids recapitulated the primary tumors and were useful for testing genotype-oriented molecular targeted therapy, which is valuable for precision medicine in patients with SGCs.

Branch-duct Intraductal Papillary Mucinous Neoplasm with Rapidly Developing Intracystic Xanthogranulomatous Nodules.

We herein report a case of a branch-duct intraductal papillary mucinous neoplasm (IPMN) with rapidly developing intracystic xanthogranulomatous nodules. A unilocular cystic lesion without a mural nodule was found in the pancreatic tail of a 69-year-old man. Ten months later, multiple mural nodules emerged unexpectedly within the cyst, and the patient underwent distal pancreatectomy. Based on immunohistochemical studies and a molecular analysis, we diagnosed him with branch-duct IPMN of the gastric immunophenotype. Fragility of the pancreatic duct mucosa and consequent exposure of the wall to pancreatic juice might have caused marked granulation nodule formation in the cyst lumen.